key: cord-0810491-gj4vjldd authors: Asrar Khan, Waseem; Woodhead, Mark title: Major advances in managing community-acquired pneumonia date: 2013-10-01 journal: F1000Prime Rep DOI: 10.12703/p5-43 sha: 6803ffb755ca44defc371b10e0ad52ccdbb67108 doc_id: 810491 cord_uid: gj4vjldd This article is a non-systematic review of selected recent publications in community-acquired pneumonia, including a comparison of various guidelines. Risk stratification of patients has recently been advanced by the addition of several useful biomarkers. The issue of single versus dual antibiotic treatment remains controversial and awaits a conclusive randomized controlled trial. However, in the meantime, there is a working consensus that more severe patients should receive dual therapy. Aetiology worldwide Periodic studies of community-acquired pneumonia microbial aetiology are vital to confirm whether causal pathogen frequencies have, or have not, changed to guide empirical antibiotic therapy strategies. A prospective population-based study in Spain of both inpatients and outpatients 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%), Chlamydia species (10.6%) and Legionella pneumophila (4.4%) [4] . The microbiology of communityacquired 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. Patients infected with conventional bacteria such as S. pneumoniae had a higher hospitalization rate, higher CURB65 (disease severity) scores at admission and more adverse clinical outcomes, such as severe sepsis, septic shock, ICU admission and longer length of stay compared to those with atypical and viral causes of pneumonia. Limitations in the study included an absence of sputum cultures and possible population bias. Outpatient community-acquired pneumonia A total of 568 outpatient community-acquired pneumonia episodes in Barcelona were recently studied [5] . Aetiology was established in a third of these cases and S. pneumoniae was again the most common proven pathogen, followed by mycoplasma and then legionella. In another study, the data for 198 patients were analysed from a prospective cohort of community-acquired pneumonia or healthcare-associated pneumonia in a 28-bed medical intensive care unit (ICU) [6] . These were patients that were severe enough to be admitted to the intensive care unit. The breakdown was that 35% of patients had a bacterial infection and 36% had a viral infection. Of the latter, the following viruses were identifiedrhino virus (23.6%), para influenza virus (20.8%), human metapneumovirus (18.1%), influenza virus (16.7%), and respiratory syncytial virus (13.9%). Mortalities of patients with bacterial, viral, and bacterial-viral co-infections were similar. Limitations of the study included a reliance on upper respiratory specimens. Lack of pharmacological therapies for most viral causes limits the value of this information at the current time. A recent case report in Saudi Arabia has led to the discovery of a sixth new coronavirus. The patient had pneumonia and acute respiratory distress syndrome with multi-organ dysfunction syndrome and died 11 days after admission [7] . This has also been recently referred to as the Middle East respiratory syndrome coronavirus. Human Coronavirus-Erasmus Medical Center (HCoV-EMC) is the first human corona virus in lineage C of the betacoronavirus genus. Its closest relatives are coronaviruses HKU4 and HKU5 found in bats. Additional cases in the Middle East have raised concerns over the potential for more widespread dissemination. Bacterial co-infection was present in 33% of 128 consecutive adult patients hospitalized with a diagnosis of influenza A (H1N1) and community-acquired pneumonia. Predictors of bacterial co-infection included underlying chronic obstructive pulmonary disease (COPD) and a higher platelet count at admission. Bacterial co-infection was not related to increased mortality [8] . H5N1 continues to cause sporadic human infections in Egypt and South East Asia, but more alarming is the recent emergence of H7N9 as a cause of human illness [9] . Cases reported so far suggest a link with birds as the source with little or no human-to-human spread. Severe multi-organ failure with mortality of about one third is reported [10] . All guidelines recommend severity scoring tools in conjunction with clinical assessment in adult communityacquired pneumonia management, although controversy remains about which scoring system to use and when to use it. Recent systematic reviews showed that all of the standard scoring methods of the pneumonia severity index (PSI), CURB65, and CRB65 showed moderate to good accuracy 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 its negative likelihood ratio, therefore indicating its superior ability at identifying low risk patients. A higher positive predictive value than the PSI system suggests that CURB65/CRB65 may be superior for identifying high-risk patients in terms of mortality and decisions with regards to admission of high-risk patients (see Table 3 for more details). CURB65-guided antibiotic therapy was associated with a significant decrease in broad-spectrum antibiotic use. The intervention was safe with no impact on mortality, treatment failure or clinical response [12] . A recent study of the CRB65 score investigated whether it was useful in patients with lower respiratory tract infection in a primary care setting but showed that it had little correlation with severe symptom duration or hospitalisation [13] . In this study, however, respiratory rate and blood pressure were infrequently measured (22.7% and 31.9% respectively), suggesting that clinical practice would have to change if this score were to be used routinely. Another study of CRB65 score investigated whether the cut off age of 65 had any impact in terms of severity of patients presenting with pneumonia [14] . This study included nearly 700,000 patients hospitalised in Germany between 2008 and 2010. The age of 65 (resulting in CRB≥65) was a reasonable threshold for the assessment of the risk of death from community-acquired pneumonia in the total population, although age group 80 (CRB≥80) had the highest risk of death [14] . In patients aged less than 65 years, death prediction was best below age of 50, with excellent prediction of low-risk patients. In patients aged 65 or over with nursing home-acquired pneumonia, the optimal age group for death prediction continued to be 80 (CRB≥80). The American Thoracic Society-Infectious Diseases Society of America (ATS-IDSA) rule consists of two major (mechanical ventilation or shock) and nine minor criteria. The rule is considered positive in the presence of one major or three minor criteria. A meta-analysis found the ATS minor criteria, S-community-acquired pneumonia score, and SMART-COP to have good predictive characteristics for ICU admission [15] . A recent predictive cohort study [16] found that an increased serum glucose level at admission to hospital and no pre-existing diabetes was a predictor of death at 28 and 90 days in 6891 patients with communityacquired pneumonia. Whether this adds to the use of a scoring system and whether blood glucose management alters the outcome in community-acquired pneumonia is not known. Although the PSI scoring system includes serum glucose, this paper investigated serum glucose as an independent risk factor in predicting death in patients with community-acquired pneumonia. A systematic review of procalcitonin as a prognostic marker in community-acquired pneumonia found that complications during admission, severity of disease and death 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 the best predictor for bacterial aetiology and to select patients eligible for outpatient care in another study [17] . They suggested that levels of procalcitonin and C reactive protein positively correlate with increasing severity of community-acquired pneumonia and may have a role in disease prediction, perhaps in patients with low CURB65 scores [18] . Limitations of the study included study heterogeneity and risk of publication bias. Using a procalcitonin algorithm on antibiotic guidance reduced antibiotic use without increased complications. Good compliance with the procalcitonin algorithm was possible in real-life conditions but had to be reinforced by other measures to achieve an optimal benefit [19] . Limitations here included observational design and unclear diagnostic criteria. Another recent study showed that increased proadrenomedullin (proADM) levels closely correlated with increased severity scores and showed a predictive power in both long and short term complications in patients with community-acquired pneumonia, especially when used in conjunction with PSI and CURB65. An admission proADM level of 0.646 nmol correlated in such a fashion that 92% of the 139 patients in PSI classes 4 and 5 would have been correctly classified [20] . This was a single hospital study and serial biomarkers were not used throughout the study. Another study also reflected that proADM may be helpful in individual risk stratification of community-acquired pneumonia patients with a high PSI score in the Emergency Department, allowing better identification of patients at risk of death [21] . The highest levels of IL-6, IL-10 and lipopolysaccharidebinding protein (LBP) correlated best with a CURB65 score of 3 and 4 and the accuracy of CURB65 was greatly enhanced by the use of IL-6 levels [22] . These are best used as a predictor of severity of community-acquired pneumonia rather than prognosis. Serum cortisol level predicts mortality and critical disease independently of clinical scores and inflammatory biomarkers. A recent study showed that increased serum cortisol level was associated with the development of critical disease and increased 30-day-mortality in 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 was that controlling for the time point of blood sampling could not be done, so diurnal concentration changes may have influenced the results. Guidelines See Table 4 for a comparison of selected features in National and International community-acquired pneumonia Guidelines, drawn from [24] [25] [26] . Risk stratification and admission to ICU ATS/IDSA These guidelines make it quite clear that severity illness scores such as CURB65 and PSI should be used to identify patients for outpatient management. Physicians are advised to take into account factors such as availability of outpatient support resources. CURB65 scores ≥2 suggest hospital admission. Direct admission to ICU should be made upon factors such as septic shock requiring vasopressor support and /or respiratory failure requiring intubation and ventilation. The British Thoracic Society (BTS) guidelines are quite clear that the scoring system of CURB65 in conjunction with clinical assessment is the main requirement in deciding point of care admission of community-acquired pneumonia patients. Those with a score of CURB65 0 or 1 can be managed quite safely as outpatients. Patients with CURB65 score of 2 should be considered for hospital admission, as there is a significant increase in mortality with this group. Those with CURB65 scores of 3 and above should be reviewed by senior clinicians, and patients with CURB65 scores of 4 and above should be seriously considered for ICU admission. Persistent hypoxia, progressive hypercapnoea, shock or reduced consciousness are 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 to hospitalise community-acquired pneumonia patients is a clinical decision. A CRB score of 1 or more (except if age ≥65 is the only criterion met) suggests that hospitalisation should be considered. Factors such as acute respiratory failure, septic shock and decompensated comorbidities should be considered for early referral to intensive care. There has always been a debate with regards to the value of single (B-lactam or macrolide) versus dual (B-lactam plus macrolide) antibiotic therapya question that has never been addressed by a good-quality randomised controlled trial. Although there are some differences in the antibiotics recommended for first-line treatment in the Guidelines (Table 4) there is consensus that patients with more severe community-acquired pneumonia should be given dual therapy. A total of 23 studies with approximately 137,000 patients were included in a recent meta-analysis of the efficacy of macrolides in patients hospitalised with community-acquired pneumonia [27] . Macrolide-based regimens were associated with a significant 22% reduction in mortality compared to non-macrolides. However, this benefit did not extend to randomised controlled trials or patients that received guidelineconcordant antibiotics (also found in a study of community-acquired pneumonia patients with severe sepsis [26] ). Guideline-concordance may be more important than choice of antibiotic when treating community-acquired pneumonia [28] . Both studies point towards the need for good adherence to hospital prescribing guidelines. A very careful study conducted in 2007 came to a verdict that the benefit of dual therapy versus single therapy cannot be reliably assessed in observational studies, since the propensity to prescribe these regimens differs markedly [29] . Taking this into account may skew the results of previous studies comparing single and dual therapy. A total of 5240 patients were included in an audit of adult community-acquired pneumonia management in the UK [30] . The death rate was high at 24%. Patients treated with dual therapy had a significantly lower death rate in both moderate-and high-severity groups compared with b-lactam therapy alone. As in other studies, the propensity to prescribe could not be corrected for. The concordance of findings with other cohort studies may suggest a real result, but randomized controlled trial results are required to confirm this. These have often been an intervention of last resort in the failing patient. Studies in meningitis and pneumocystis pneumonia support their role in infection control but, until recently, studies in community-acquired pneumonia were absent. The conflicting results from studies in sepsis confirmed the need for community-acquired pneumoniaspecific studies, preferably randomised controlled trials. A recent double blind, placebo-controlled randomized controlled trial using 40 mg prednisolone for 7 days as the intervention found that there were no beneficial effects of adjunctive corticosteroids in patients hospitalized with community-acquired pneumonia. Other outcomes of the study showed that clinical cure was equal in both groups at Day 7 [31] . A similar study using dexamethasone for 3 days did find a reduced hospital stay of one day in the steroid-treated patients, but a large number of exclusions and lack of control for other factors limiting length of stay limited the usefulness of this study [32] . The only other randomised controlled trial evaluating patients with community-acquired pneumonia admitted to ICU found a reduction in mortality using hydrocortisone [33] . The small patient number and absence of any deaths in the intervention arm mean that these findings cannot be generalised unless reproduced in other studies. A role for steroids in patients with community-acquired pneumonia is yet to be proved. Pay for performance programs are being adopted internationally to try and improve patient outcomes with limited evidence of their effectiveness. One reason for this may be lack of robust evidence to support the quality indicators used [34] . Conversely, in a US study of 2076 patients, there was no association with either individual or combinations of quality indicator compliance and mortality [35] . In a study of 30-day inpatient mortality amongst 143,435 adults admitted with pneumonia, heart failure, or acute myocardial infarction to 24 UK hospitals covered by a pay-for-performance program [36] , an association between use of the program and significant mortality reduction was found when compared to other UK hospitals not using the pay-for-performance program. Of the three included conditions, however, only pneumonia was found to have an association with mortality reduction in the pay-for-performance group [36] . Not only are the quality measures controversial but so are the methods of implementation. A randomized controlled trial investigated the implementation of a three-step strategy of early mobilisation, objective criteria for switching to oral therapy and for deciding on hospital discharge, and showed interesting results [37] . The use of a three-step critical pathway was safe and effective in reducing the duration of intravenous antibiotic therapy and length of hospital stay for community-acquired pneumonia patients and this did not adversely affect patient outcomes [37] . The jury is still out with regards to performancerelated programmes but there is a need to develop further randomised controlled trials. The last few years have seen some major advances in the management of community-acquired pneumonia. Risk stratification of patients has recently been advanced by the addition of several useful biomarkers. The issue of single versus dual antibiotic treatment remains controversial and awaits a conclusive randomized controlled trial. However, in the meantime, there is a working consensus that more severe patients should receive dual therapy. Abbreviations ATS-IDSA, American Thoracic Society-Infectious Diseases Society of America; BTS, British Thoracic Society; COPD, chronic obstructive pulmonary disease; HCoV-EMC, Human Coronavirus-Erasmus Medical Center; ICU, intensive care unit; LBP, lipopolysaccharide-binding protein; proADM, pro-adrenomedullin; PSI, pneumonia severity index. 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