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Community-acquired pneumonia

Summary Community-acquired pneumonia causes great mortality and morbidity and high costs worldwide. Empirical selection of antibiotic treatment is the cornerstone of management of patients with pneumonia. To reduce the misuse of antibiotics, antibiotic resistance, and side-effects, an empirical, effective, and individualised antibiotic treatment is needed. Follow-up after the start of antibiotic treatment is also important, and management should include early shifts to oral antibiotics, stewardship according to the microbiological results, and short-duration antibiotic treatment that accounts for the clinical stability criteria. New approaches for fast clinical (lung ultrasound) and microbiological (molecular biology) diagnoses are promising. Community-acquired pneumonia is associated with early and late mortality and increased rates of cardiovascular events. Studies are needed that focus on the long-term management of pneumonia.

absence of fever, and extrapulmonary manifestations are frequent. For example, patients with pneumonia due to Legionella spp can present with headache, confusion, diarrhoea, and clinical manifestations of hyponatraemia. 8 Mycoplasma pneumoniae can be associated with upper respiratory involvement (otitis, pharyngitis), skin changes (Stevens-Johnson-like syndrome), and haemolytic anaemia. 9 Investigators have clearly shown that differentiation between typical and atypical pneumonia on the basis of patient history and chest radiograph is not reliable in guidance of antibiotic treatment. 3,10 By contrast, the use of validated scores for antibiotic decisions is promising. A 2014 study 11 proposed a score that can rule out Legionella spp pneumonia with a negative predictive value of 99%.

Diff erential diagnosis
Many diseases and syndromes have clinical signs and symptoms that can mimic pneumonia (appendix). When the probability of a diff erential diagnosis is high, careful assessment is needed because delays in correct diagnoses increase the risks of poor outcomes. 12 In patients with not-severe community-acquired pneumonia, the main diff erential diagnosis is upper respiratory infection. In these cases, clinicians should rely on clinical evaluations (including manifestations of LRTI, focal chest sounds, exclusion of other possible diagnosis) and point-of-care tests (eg, C-reactive protein [CRP]). 6 Patients with severe community-acquired pneumonia should be monitored for other life-threatening disorders. Because diff erentiation of pneumonia from noninfectious disorders such as acute heart failure is occasionally diffi cult, prompt start of antibiotic treatment is recommended. Biomarkers (eg, procalcitonin [PCT]) can help in the early diff erentiation from heart failure decompensation, avoiding antibiotic misuse. 13 When the diagnosis of pneumonia is excluded, antibiotic treatment must be stopped. Dynamic evaluation of the patient also helps the clinician in terms of management (eg, pulmonary infi ltrates that resolve completely after positive pressure ventilation are probably due to heart failure or atelectasis). In patients with recurrent pneumonia, underlying diseases should be suspected such as lung cancer, metastasis, tuberculosis, foreign bodies, hypersensitivity pneumonitis, and unknown immunosuppressed status.

Worldwide incidence
The Global Burden of Disease Study 14 reported that LRTI remains the second biggest cause of deaths and years of life lost in 2013. The age-standardised death rate was 41·7 (95% CI 37·1-44·1) per 100 000 population for LRTI. 14 The incidence of pneumonia is estimated to be between 1·5 and 14·0 cases per 1000 person-years. [15][16][17] This rate varies according to the region, season, and population characteristics. In terms of age, incidence of community-acquired pneumonia is U-shaped-it is common in children younger than 5 years and adults older than 65 years. The incidence is also higher in men and boys than in women and girls. Patients who do not need admission into hospital have a mortality rate of lower than 1%. 18,19 Short-term mortality (in-hospital and 30 day mortality) for hospitalised patients ranges from 4·0% to 18·0%; 17,20,21 however, for patients in intensive care, this rate can reach 50%. 22 Costs related to community-acquired pneumonia are high, 23 and few approaches (such as reducing the length-of-stay, adequate use of antibiotics, and the introduction of vaccines) have reduced these costs so far. 24,25

Causative pathogens
Streptococcus pneumoniae is the main pathogen that causes community-acquired pneumonia worldwide, independent of age. 23,26,27 In Europe, nearly 35% (12-68%) 23 of cases are caused by pneumococcal disease; worldwide it is about 27·3% (95% CI 23·9-31·1). 28 Other frequent causes include Haemophilus infl uenzae, which accounts for 12% (2·4-44·9%) of cases 23 and the so-called atypical bacteria (including Mycoplasma, Chlamydia, and Legionella spp), which caused 22% of cases in a large worldwide cohort. 29 In recent years, the availability of molecular microbiological tests and clinical suspicion has increased isolation of respiratory viruses in community-acquired pneumonia. 30 In adults, viruses, particularly infl uenza, rhinovirus, and coronaviruses, cause a third of cases of pneumonia. 30 However, the attribution of the aetiology to respiratory viruses is debatable because it is diffi cult to defi ne the virus as the causative agent of pneumonia.
Resistance of S pneumoniae to penicillin and macrolides has been nearly stable in recent years. 2-4 The introduction of the conjugated pneumococcal vaccine in children has decreased the incidence of the invasive penicillin-resistant cases; however, infections with serotypes not aff ected by the vaccine have increased. 31 The incidence of Mycoplasma pneumoniae resistant to macrolides varies greatly with geography (eg, with peak of about 69% in China). 32,33 Although the proportion of patients infected with pathogens not covered by standard empirical treatment is low, these pathogens are associated with high mortality and costs. In immunocompetent patients with communityacquired pneumonia, these pathogens are more frequently Pseudomonas aeruginosa, Enterobacteriaceae extendedspectrum β-lactamase (ESBL+), and meticillin-resistant Staphylococcus aureus (MRSA). 34,35 Pathophysiology In healthy individuals, many microorganisms colonise the nasopharynx and oropharynx. Microaspiration of contaminated secretions can cause infections in the lower airways. The glottal refl exes, the presence of complement proteins and immunoglobulins, the secretion of peptides with antimicrobial activities, and the inhibition of bacteria binding all protect the lower airways. 36 The healthy microbiota of the upper airway also exert protection eff ects by competing with pathogens for nutritional resources and interacting with cellular receptors. The use of broad-spectrum antibiotics can modify the microbiota and predispose to infection. 37 The interactions between the virulence of the pathogens, the amount of inoculum, and the innate and adaptive immune responses determine the development of pneumonia. 36

Risk factors and genetics
All individuals are at risk for development of pneumonia. However, some individuals are more prone to pneumonia than are others due to intrinsic and extrinsic factors (appendix). 38 New fi ndings have revealed individual genetic variability in the predisposition to the development of pneumonia and its clinical presentation. 39 For example, specifi c variants of the FER gene are associated with a reduced risk of death in patients with sepsis due to pneumonia. Thereby, the FER gene might be a potential target for new therapies. 40 Misch and colleagues 41 showed that TLR6 polymorphism is associated with increased risk of Legionnaires' disease (odds ratio [OR] 5·83, 95% CI 2·21-16·39).

Diagnostic investigations Laboratory evaluation
In patients who clinicians suspect to have communityacquired pneumonia, blood tests can provide information about the infl ammatory state (ie, leucocyte cell number and characteristics [neutrophilia] and CRP), the associated organ damage (ie, acute renal failure), and the severity of the disease. Biomarkers can support clinicians in the diff erentiation of bacterial pneumonia from other disorders (eg, upper respiratory tract disorders). A meta-analysis suggested that antibiotic exposure can be reduced in suspected LRTI via the use of CRP measurements in primary care (risk ratio [RR] 0·78 [95% CI 0·66-0·92]). 42 The 2014 NICE guidelines 6 recommend not to off er antibiotics when CRP is lower than 20 mg/L in primary care for patients without a convincing clinical diagnosis of community-acquired pneumonia.
PCT had high sensitivity but moderate specifi city to diff erentiate bacterial and viral infections. For outpatients, patients in emergency departments, and inpatients, an antibiotic is encouraged when PCT concentrations are higher than 0·25 μg/L and is strongly encouraged when PCT concentrations are higher than 0·5 μg/L; whereas they are discouraged when concentrations are lower than 0·10 μg/L. 43 In patients admitted to intensive care, antibiotic treatment is always strongly encouraged with PCT concentrations higher than 0·25 μg/L. A meta-analysis reported that the use of PCT to guide antibiotic treatment in pneumonia resulted in a reduction in the exposure to antibiotics from median 8 days [IQR 5-12] to 4 days [0-8], with an adjusted diff erence of −3·34 days (95% CI −3·79 to −2·88) without increases in mortality or treatment failure. 44 Moreover the use of PCT to guide antibiotic treatment reduced costs of treatment. 45

Microbiological evaluation
Despite many improvements, the pathogen is not detected in nearly half of pneumonia episodes. 3 Microbiological tests are recommended in patients in whom the probability of changing the empirical antibiotic is high: reducing treatment failure and preventing antibiotic overuse. Microbiological evaluations (fi gure 1) are recommended for higher-risk patients such as those with severe community-acquired pneumonia, special disorders (eg, asplenia, immunosuppression, HIV infection, and alcohol abuse), severe sepsis or septic shock, a risk of resistant pathogens, and failure of the initial empirical treatment. 3-5 By contrast, recommendations for micro biological testing remain controversial in less severe pneumonia because such tests are expected to have little eff ect on antibiotic management due to good responses to empirical treatment. [46][47][48] However, microbiological evaluations could be valuable for surveillance.
Although a positive blood (or pleural fl uid) culture test defi nitively identifi es the pathogen responsible for pneumonia, a positive respiratory tract sample needs clinical interpretation because the microorganism can be present due to colonisation or be part of the healthy fl ora. The main diffi culties are related to the need for a high-quality sample. 3 Furthermore, the collection of any sample after the administration of antibiotics increases the rate of false-negative results. Despite these limitations, in patients in hospital with purulent sputum, a sample collection for Gram stain and culture is recommended. 5,6 Urinary antigens are useful for the detection of all serotypes of S pneumoniae and for serogroup 1 of Legionella pneumophila (responsible for about 90% of legionella cases of community-acquired pneumonia). Advantages of these tests are promptness (<15 min), reasonable accuracy, and the ability to detect the infection while the patient is receiving antibiotic therapy. 6 The main drawback is the absence of information about resistance. The urinary antigen for S pneumoniae has a sensitivity of 74·0% (95% CI 66·6-82·3) and a specifi city of 97·2% (92·7-99·8). 49 For L pneumophila, sensitivity is 74·0% (68·0-81·0) and specifi city is 99·1% (98·4-99·7). 50 Two randomised controlled trials have tested empirical versus pathogen-directed antibiotic treatment through urinary antigen tests in patients in hospital with stable pneumonia 51,52 and shown no diff erences in major outcomes, although their conclusions were hampered by methodological issues.
For atypical pathogens, blood serology tests are available for Chlamydia pneumoniae, M pneumoniae, and Legionella spp; however, their clinical usefulness is limited by the delay in the results and diffi culty in interpretation. PCR tests are available for bacterial causes related to Mycoplasma, Chlamydia, Streptococcus, and Legionella spp, which have to be done on bronchoalveolar lavage fl uid or nasopharyngeal swabs. Real-time and multiplex-panel PCR aim to provide results in a few hours and are promising methods for fast bacterial aetiological diagnoses of communityacquired pneumonia. 53 However, their cost-eff ectiveness is unclear, and there are no data about resistance. PCR tests are available for several respiratory viruses. 30 In view of the controversies about the use of antiviral therapy, diffi culties related to the diagnosis of viral pneumonia, and cost-eff ectiveness, clinicians should reserve testing for viruses for special groups of patients and within infl uenza season.

Imaging
Thoracic images are essential for several aspects of pneumonia management. Chest radiograph has diagnostic accuracies of 75% for alveolar consolidation and 47% for pleural eff usion, considering CT as the gold standard technique. 54 Performing both posteroanterior and laterolateral projections increases its accuracy. By contrast, chest radiograph has less accuracy in bedridden, obese, and severely immunosuppressed patients and in patients with previous alterations on chest radiograph.    54 and provides detailed information about the lung parenchyma and media stinum and can also reveal alternative diagnoses. However, CT has limitations that include increased cost, radiation exposure, and the impossibility of doing CT at the bedside. 54,55 For these reasons, CT is reserved for specifi c situations such as excluding the presence of other diagnoses (eg, pulmonary embolism), when the suspicion of a fungal lung infection is present, in patients with unclear chest radiograph (eg, occult pneumonia in chronic obstructive pulmonary disease), and in non-responding pneumonia for the detection of complications (eg, lung abscesses).
Lung ultrasound is a useful method for evaluating respiratory diseases including pneumonia. 56 A recent meta-analysis showed a sensitivity of 94·0% (95% CI 92·0-96·0) and a specifi city of 96·0% (94·0-97·0) in the diagnosis of pneumonia in adults. 57 Compared with previous methods, lung ultrasound has some advantages; it is radiation-free, can be done at the bedside and on pregnant woman, allows for dynamic evaluations, has increased accuracy in the detection of consolidation and pleural eff usion compared with chest radiograph, and takes less time. [56][57][58] Lung ultrasound is limited by its learning curve, repeatability, and operator dependency. 59

Site of care
Early in the evaluation of patients with communityacquired pneumonia, two questions need to be answered: does the patient need to be admitted in the hospital and should they be treated in intensive care? These decisions need to be made early because it has been widely shown that late admission into intensive care is associated with increased mortality. 60 By contrast, the admission of patients who can be treated outside the hospital is associated with increased costs and risk of the development of nosocomial infections. 61 Clinical judgment is the main determinant of the site-ofcare decision. 6 Oxygen saturation (SpO₂) and arterial gas analysis can give important information about severity (eg, SpO₂ <92% can be considered a safer cutoff than can SpO₂ <90% for hospital admission). 62 Furthermore, scores and biomarkers can assist the clinical judgment. The Pneumonia Severity Index (PSI) 18 and CURB-65 63 are the most frequently used scores. PSI is composed of 20 items and classifi es patients into fi ve categories of severity that are associated with the risk of mortality. Age and comorbidities are highly weighted in the PSI, and for these reasons, PSI can underestimate the severity of pneumonia in young patients and in those without previous diseases. CURB-65 uses fi ve items and is practical for calculations, although it does not account for comorbidities. Important considerations not included in either score are socioeconomic status and social support, both of which can aff ect outcomes. 64 Both PSI and CURB-65 were not developed to predict complications associated with community-acquired pneumonia; clinical research is needed to develop specifi c scores to predict these events.
Patients should be admitted to intensive care when they require mechanical ventilation or vasopressors (both of which are major criteria for severe pneumonia in the American Thoracic Society and Infectious Diseases Society of America guidelines). 3 In addition to the major criteria, nine minor criteria are included to predict admission into intensive care. 3 A meta-analysis proposed a simplifi cation of the American Thoracic Society and Infectious Diseases Society of America minor criteria through removal of three variables (thrombocytopenia, hypothermia, and leucopenia), which had a similar accuracy. 65 Other useful scores that are used to predict admission into intensive care are the SMART-COP 66 and the REA-ICU for late admission. 67 Some biomarkers can increase the performance of some scores to predict ICU admission (eg, proadrenomedullin) 68 and can identify severe community-acquired pneumonia (eg, CRP). 69 Biomarkers can also identify patients who are fi rst admitted to the ward who might need an admission into intensive care later. 70

Selection of antibiotics
Antibiotic treatment is typically chosen empirically because of the absence of microbiological results upon diagnosis. The choice of the empirical antibiotic depends on the most likely pathogen, individual risk factors, comorbidities, allergies, and cost-eff ectiveness (appendix). Figure 2 and the table describe the management and antibiotic treatment proposed by community-acquired  Several studies have shown reductions in mortality when these guidelines are followed. 71,72 Guidelines suggest the coverage of S pneumoniae and atypical pathogens (eg, combination of a β-lactam plus macrolide or respiratory fl ouroquinolone). 3,6 However, dual coverage is still debated, 6,73 and three metaanalyses reported diff erent results about mortality. [74][75][76] Furthermore, concerns exist about side-eff ects (such as an increased risk of cardiovascular events in patients who receive macrolides) 77,78 and selective pressure for resistance to macrolides and fl uoroquinolone. Two recent randomised controlled trials provided important results about antibiotic treatment for people admitted into hospital with non-severe communityacquired pneumonia. A cluster-crossover trial assessed the non-inferiority of β-lactam versus β-lactam plus macrolide versus fl uoroquinolone regimens with 90 day mortality as the primary outcome. Including 2283 patients with clinically suspected pneumonia treated in non-intensivecare-unit wards, monotherapy with β-lactam was not inferior to the other antibiotic regimens. 79 Another noninferiority, open-label trial randomly assigned 580 patients with moderately severe community-acquired pneumonia to receive β-lactam or β-lactam plus macrolide. 80 The study was unable to show non-inferiority for clinical stability after 7 days of treatment. Nevertheless, a non-signifi cant trend for superiority was shown in favour of dual therapy (between-group diff erence 7·6%, two-sided 95% CI −0·8% to 16·0%). For severe community-acquired pneumonia, coverage of typical and atypical pathogens seems to be protective of mortality and is recommended by major guidelines. 3-5 Macrolides seem to have additional benefi ts due to their immuno modulatory eff ects in severe community-acquired pneumonia. 81,82 A small proportion of patients with specifi c pathogens require a diff erent treatment because they do not respond to the standard empirical treatment. 34 For this reason, the 2005 American Thoracic Society and Infectious Diseases Society of America nosocomial pneumonia guidelines introduced a new category of pneumonia called health-care-associated pneumonia to help clinicians to select patients who need an extendedspectrum antibiotic due to a high probability of resistant pathogens. 83 This defi nition has been widely criticised because it has many limitations, and studies have shown it not to be accurate in the detection of at-risk patients. 84,85 Other scores have been developed and have better accuracies; however, they also have some limitations and still need strong external validation. 34,[86][87][88] A summary of risk factors for resistant pathogens is contained in the appendix. Because resistant pathogens have diff erent treatments, scores based on specifi c risk factors for each pathogen might be more useful methods compared with general defi nitions. 34,35,89 Another concern is related to the treatment of patients who are at risk for resistant pneumococcus, such as elderly patients (age >65 years), those who have received recent therapy with β-lactams, macrolides, or fl uoroquinolones; alcohol consumption; and immunosuppression (appendix). 3, 90 New antibiotics are urgently needed for infections because of the spread of resistance in some settings. A recent phase 3 trial showed promising results for ceftaroline fosamil, a fi fth-generation cephalosporin with activity against MRSA, in the treatment of community-acquired pneumonia with PSI III-IV in Asian patients. 91 Among macrolides, solithro mycin is a potential new antibiotic with activity against macrolideresistant bacteria. 92 The effi cacy of neuraminidase inhibitors to prevent and treat infl uenza pneumonia is still controversial. 93 For patients with infl uenza A H1N1, a recent meta-analysis †Respiratory fl uoroquinolone limited to situations in which other options cannot be prescribed or are ineff ective (eg, hepatotoxicity, skin reactions, cardiac arrhythmias, and tendon rupture). ‡Preferred β-lactam drugs include cefotaxime, ceftriaxone, or ampicillin-sulbactam. ¶β-lactamase-stable β-lactams include co-amoxiclav, cefotaxime, ceftaroline fosamil, ceftriaxone, cefuroxime, and piperacillin-tazobactam. §Third-generation cephalosporin (eg, cefotaxime, ceftriaxone).

Timing of antibiotic treatment
The fi rst dose of antibiotics should be given as soon as possible after diagnosis of community-acquired pneumonia. The antibiotics should be started preferably within the fi rst 4-8 h of hospital arrival and a shorter time to the fi rst dose of antibiotic can be a marker of quality of care. 95 However, a meta-analysis of stable patients with community-acquired pneumonia revealed that administration within 4 h was not associated with lower mortality (OR 0·95, 95% CI 0·73-1·23) 96 and the pressure for rapid antibiotic administration was associated with an increased risk of misdiagnosis and an increased risk of adverse eff ects. 97 In unstable patients with severe sepsis or septic shock, the time to the fi rst dose is strongly associated with a reduction in mortality, and administration in the fi rst hour after diagnosis is recommended. 82,98

Care of pneumonia-related sepsis
Pneumonia is the main cause of sepsis worldwide, and for severe sepsis or septic shock, the previous aspects of care are the priority (ie, assessment of pathogens, antibiotics, and whether early intensive care unit admission is needed). 82,98 The Surviving Sepsis Campaign also advocates the measure of lactate concentration at diagnosis and prompt initial expansion with 30 mL/kg of crystalloid for hypotension or lactate concentrations of 4 mmol/L or higher. 82 Results related to recommendation of early goal-directed therapy are controversial mainly because of insuffi cient benefi ts reported in well designed multicentre randomised controlled trials. [99][100][101] A major concern about patients with sepsis due to pneumonia are the risks associated with cumulative fl uid balance and blood transfusion because of worsening in respiratory function. 102,103

Respiratory support
Patients with acute respiratory failure due to pneumonia must be assessed early for a need for respiratory support, and oxygen saturation is an important marker for outcome. 62 Patients with severe pneumonia are candidates for invasive mechanical ventilation, and a delay can lead to an increased mortality. 104 Patients with moderately severe disease can be cautiously managed with the use of non-invasive ventilation by trained staff . 105 A meta-analysis suggested that the appropriate use of non-invasive ventilation in pneumonia can reduce the need for endotracheal intubation (OR 0·28, 95% CI 0·09-0·88), intensive care unit mortality (0·26, 0·11-0·61), and the lengthof-stay in intensive care units (mean −1·00, 95% CI −2·05 to −0·05). However, this meta-analysis included only 151 patients in three randomised trials, and benefi ts were particularly evident in patients with chronic obstructive pulmonary disease or immunosuppression. 106 Non-invasive ventilation can also be considered a palliative treatment in patients with terminal illness. 107 For mechanically ventilated patients, protective ventilation is strongly recommended on diagnosis of acute respiratory distress syndrome. For less severe pneumonia, protective ventilation also seems to prevent the progression of lung injury. 3,108

Adjunctive therapy
The use of corticosteroids for community-acquired pneumonia is debated, especially how it aff ects mortality. 109 Meta-analyses 110,111 have reported reduced hospital length-of-stay (mean −1·21 days, 95% CI −2·12 to −0·29) with use of corticosteroids. A multicentre randomised controlled trial 112 showed a shorter time to reach clinical stability in patients with pneumonia receiving oral prednisone (50 mg a day for 7 days) in relation to the placebo group (3·0 days vs 4·4 days, hazard ratio 1·33 95% CI 1·15-1·50). Another multicentre randomised controlled trial 113 showed that methylprednisolone (0·5 mg/kg per 12 h for 5 days) reduced risk for treatment failure compared with placebo (OR 0·34, 95% CI 0·14-0·87) in patients with severe communityacquired pneumonia with high baseline concentrations of CRP. For mortality, updated meta-analyses 110,111,[114][115][116] report no conclusive results for hospitalised patients, although corticosteroids were associated with better survival in the subgroup with severe community-acquired pneumonia. [114][115][116][117] However, trials included in the metaanalyses were small, have high heterogeneity, and insuffi cient power to assess mortality. No defi nitive data are available for the best type and dose of corticosteroids for patients with community-acquired pneumonia, nor those for whether they should be given continuously or to intermittent and tapering schemes. 6 The clinician should be aware of possible steroid-induced side-eff ects in patients. In controlled settings (eg, randomised controlled trials), only hyperglycaemia was more frequently reported for patients with community-acquired pneumonia receiving a corticosteroid. However, large trials including patients with severe sepsis or septic shock with community-acquired pneumonia as the main source of infection, showed other steroid side-eff ects such as superinfection. 6,118 Investigators have proposed statins as an adjunctive therapy in pneumonia due to their anti-infl ammatory activities and ability to reduce cardiovascular events, but their eff ects are controversial. 119

Long-term management Evaluation of clinical stability
After the initial management of community-acquired pneumonia, the subsequent days are fundamental for good outcomes and high-quality management needs a multidimensional approach (fi gure 3). The evaluation of clinical stability (appendix) is a fundamental aspect of community-acquired pneumonia care. 120,121 Stability criteria off er information about antibiotic treatment (eg, the appropriateness of such treatment, switching to oral medication, and short antibiotic treatment durations) and indications for hospital discharge that reduce hospital length-of-stay. [122][123][124] Stewardship When microbiological tests become available, it is important to re-evaluate antibiotic treatment. Antibiotics should be adapted according to antibiogram results, narrowed according to the identifi ed pathogen, and discontinued when a diagnosis of pneumonia is unlikely. 25 Stewardship is fundamental to avoid the continuation of unnecessary treatment, increasing the selective pressure for resistance, and reducing the risks of unnecessary complications (eg, Clostridium diffi cile infection). 125

Switch to oral therapy
Most patients in hospital with community-acquired pneumonia began treatment with an intravenous antibiotic. A switch to oral therapy should be considered for patients who reach clinical stability. Two randomised controlled trials 25,126 have shown no diff erence in mortality, but important reductions in the length-of-stay and adverse drug reactions, in patients who switch to oral therapy early.

Duration of therapy
5 days of treatment should be given for low-severity pneumonia with clinical stability after 3 days of treatment, and 7 days should be given for severe pneumonia, which should be adapted depending on the improvements in symptoms and stability. 3,4,6,122,127 Indeed, two meta-analyses reported similar effi cacies for short-course (≤7 days) and long-course (>7 days) treatments when patients with severe pneumonia were excluded. 127,128 Additionally, an observational study with robust analyses reported similar outcomes for short-course and long-course antibiotic treatments for patients with severe community-acquired pneumonia. 123 Patients with extra pulmonary complications or empyema and pneu monia due to specifi c pathogens (eg, Legionella spp and MRSA) seem to have benefi ts from prolonged treatments.
Biomarkers can be used to guide antibiotic duration. One-time PCT values lower than 0·25 μg/mL or a decrease from the peak by 80-90% are a strong indication that antibiotics should be discontinued. [43][44][45] A randomised controlled trial 129 to compare PCT and CRP for antibiotic guidance in patients with severe sepsis and septic shock showed similar outcomes; however, more studies are needed to compare cost-eff ectiveness among biomarkers. 6

Clinical failure
Patients with community-acquired pneumonia can present with deterioration, known as clinical failure, which predicts mortality. 130 Therefore, defi nition of the causes of failure is essential. Early failure (<72 h) seems to be related to the severity of the primary infection (eg, the development of septic shock), whereas the late failures (>72 h) tend to be due to secondary events (eg, nosocomial superinfection, exacerbation of comorbidities). The development of severe sepsis is the primary reason for failure. 131 Outpatients also need an early follow-up (after 72 h) to detect development of failure. 132 Non-responding pneumonia is a diff erent disorder that comprises the persistence of pulmonary infi ltrates 1 month after symptom onset and can be due to many causes, such as the presence of lung cancer or an underlying lung disease. 3

Early rehabilitation
Patients in hospital seem to benefi t from early mobilisation and rehabilitation. 133,134 Follow-up and outcomes

Readmission rate
Between 7% and 12% of patients who are admitted into hospital for community-acquired pneumonia are readmitted within 30 days. 135,136 In more than half of cases, comorbidities are the cause of readmission (mainly cardiovascular, pulmonary, or neurological diseases), whereas in other patients, a new episode of pneumonia is the cause of readmission. The main risk factors for readmission are initial treatment failure, clinical instability at hospital discharge, older age, comorbidities, and impaired functional status. 135,136 Long-term mortality Pneumonia causes much short-term and long-term mortality. Mortality for patients with community-acquired pneumonia is higher than for those with other infections

Cardiovascular events
Community-acquired pneumonia is associated with an increased risk of cardiovascular complications. 138 Some explanatory reasons for this include hypoxaemia, infl ammation, prothrombotic status, pathogen-specifi c factors, and host characteristics. 137,139 A meta-analysis for the incidence of cardiac events within 30 days of hospital admission for community-acquired pneumonia reported a cumulative rate of heart failure of 14% (range 7-33%), an arrhythmia rate of 5% (range 1-11%), and an acute coronary syndrome rate of 5% (range 1-11%). 140

Prevention and vaccines
Clinicians should pay attention regarding modifying factors available to decrease the risk of a new episode of community-acquired pneumonia (appendix). Infl uenza vaccines are robustly associated with a reduced rate of pneumonia and better outcomes. 3,4 A study of 286 000 individuals older than 65 years reported a 30% reduction in the rate of pneumonia and infl uenza infection that was followed by a reduction in all-cause mortality. 141 Two vaccines are available for S pneumoniae: the pneumococcal polysaccharide vaccine and the pneumococcal conjugate vaccine. The pneumococcal polysaccharide vaccine contains polysaccharides for 23 pneumococcal serotypes and the most recent version of pneumococcal conjugate vaccine contains 13 serotypes. By comparison with pneumococcal polysaccharide vaccine, the pneumococcal conjugate vaccine seems to induce a stronger and longer-lasting secondary immune response with booster eff ect. 142 Results from a recent meta-analysis showed strong evidence for the recommendation for pneumococcal polysaccharide vaccine-23 vaccination to prevent invasive pneumococcal disease in adults. 143 Nevertheless, there is less clear evidence for its effi cacy in the prevention of non-bacteraemic pneumonia, 143 in patients with chronic illnesses, and for the reduction of all-cause pneumonia and mortality. 143 The pneumococcal conjugate vaccine-13 was approved for clinical use in adults by the US and European agencies. The CAPiTA study 144 (a double-blind, randomised, placebo-controlled clinical trial involving nearly 85 000 adults older than 65 years) showed clinical effi cacy of pneumococcal conjugate vaccine-13 in the prevention of the fi rst episode of vaccine-serotype pneumococcal community-acquired pneumonia (including non-bacteraemic pneumonia and invasive pneumococcal disease); 144 however, the trial excluded immunosuppressed patients and previously vaccinated person. Because a substantial number of cases of pneumonia is caused by serotypes not included in the Panel 1: Controversies and uncertainties 1 The implementation of rapid diagnostic testing using PCR techniques for viruses and bacteria might increase the number of microbiological diagnoses and consequently the number of initial appropriate treatments; although some devices are able to provide rapid diagnoses, well designed studies are needed to investigate major outcomes and cost-eff ectiveness 4,53 2 The real rates of diff erent to treat pathogens in community-acquired pneumonia, such as Pseudomonas aeruginosa, Enterobacteriaceae extended-spectrum β-lactamase, and meticillin-resistant Staphylococcus aureus, diff er between continents and countries (eg, the USA and Japan vs Europe); the concept of health-care-associated pneumonia is not accurate and has resulted in the excessive administration of broad-spectrum antibiotics; 84 risk factors for these microorganisms have been described recently, but implementation in clinical practice is still lacking 34,35 3 Combination antibacterial therapy is a matter of debate; such therapy is recommended for patients with community-acquired pneumonia who are admitted to the intensive care unit, 3,4 and in patients with bacteraemic Streptococcus pneumoniae; 82 furthermore, patients with high mortality admitted to the ward might benefi t from this treatment strategy 80 4 Recent data from randomised controlled trials 112,113 showed a reduction of time to clinical stability and of treatment failure in patients with community-acquired pneumonia receiving corticosteroids; however, data are controversial for eff ect on mortality; a prematurely halted trial of severe community-acquired pneumonia revealed an important decrease in mortality (39% vs 0%) 117 5 The long-term cardiovascular complications of patients with community-acquired pneumonia are not completely understood; but it seems that residual infl ammation might have an important role in triggering procoagulation pathways and leading to cardiovascular complications 37,138 Panel 2: Outstanding research questions 1 Interventional studies are needed of microbiological testing techniques to increase the rate of initial appropriate treatments, which would result in improved outcomes and reduced overuse of antibiotics 2 Validation studies that use risk factors for diff erent-to-treat microorganisms to confi rm the accuracies of these risk factors for their implementation in clinical practice are also needed 3 Interventional studies should be done to assess cost-eff ectiveness for C-reactive protein and procalcitonin in low-income and middle-income countries and specifi c settings 4 A randomised controlled trial is needed in patients with severe communityacquired pneumonia who are not admitted to the intensive care unit that compares monotherapy with respiratory quinolones and combination therapy (β-lactam plus macrolide) 5 Investigators should do a large randomised controlled trial in patients with community-acquired pneumonia who are admitted to intensive care units that assesses the administration of corticosteroids versus placebo powered to address mortality and quality-of-life outcomes 6 Studies of severe community-acquired pneumonia are needed, both in animal models and in human beings, to test new coadjutant treatments, such as enriched immunoglobulin M, monoclonal antibodies, and molecules that can block the endotoxins and exotoxins of the microbes 7 Prospective observational follow-up studies in patients with community-acquired pneumonia are needed to better describe the clinical and biological risk factors for cardiovascular complications to design a pharmacological randomised controlled trial pneumococcal conjugate vaccine-13 (38% of invasive pneumococcal disease in the US in 2013), the US Centers for Disease Control and Prevention recommended the administration of both pneumococcal conjugate vaccine-13 and pneumococcal polysaccharide vaccine-23 in series to all adults aged 65 years and older (panel 1). 142 Outstanding research questions remain, which should be addressed in future large trials (panel 2).