key: cord-009667-8r8j0h08
authors: Cao, Bin; Huang, Yi; She, Dan‐Yang; Cheng, Qi‐Jian; Fan, Hong; Tian, Xin‐Lun; Xu, Jin‐Fu; Zhang, Jing; Chen, Yu; Shen, Ning; Wang, Hui; Jiang, Mei; Zhang, Xiang‐Yan; Shi, Yi; He, Bei; He, Li‐Xian; Liu, You‐Ning; Qu, Jie‐Ming
title: Diagnosis and treatment of community‐acquired pneumonia in adults: 2016 clinical practice guidelines by the Chinese Thoracic Society, Chinese Medical Association
date: 2017-09-26
journal: Clin Respir J
DOI: 10.1111/crj.12674
sha: 
doc_id: 9667
cord_uid: 8r8j0h08

Community‐acquired pneumonia (CAP) in adults is an infectious disease with high morbidity in China and the rest of the world. With the changing pattern in the etiological profile of CAP and advances in medical techniques in diagnosis and treatment over time, Chinese Thoracic Society of Chinese Medical Association updated its CAP guideline in 2016 to address the standard management of CAP in Chinese adults. Extensive and comprehensive literature search was made to collect the data and evidence for experts to review and evaluate the level of evidence. Corresponding recommendations are provided appropriately based on the level of evidence. This updated guideline covers comprehensive topics on CAP, including aetiology, antimicrobial resistance profile, diagnosis, empirical and targeted treatments, adjunctive and supportive therapies, as well as prophylaxis. The recommendations may help clinicians manage CAP patients more effectively and efficiently. CAP in pediatric patients and immunocompromised adults is beyond the scope of this guideline. This guideline is only applicable for the immunocompetent CAP patients aged 18 years and older. The recommendations on selection of antimicrobial agents and the dosing regimens are not mandatory. The clinicians are recommended to prescribe and adjust antimicrobial therapies primarily based on their local etiological profile and results of susceptibility testing, with reference to this guideline.

The revision of the guideline was initiated by Chinese Thoracic Society (CTS) and Chinese Medical Association (CMA). The overall framework and main content of the updated guideline were finalized following 3 face-to-face work meetings and 2 online video conferences. The experts specialized in methodology provided training on standardized literature search and grading of evidence to all the specialists contributing to the guideline. Level of evidence and grading of recommendation were based on the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines for CAP (2007) . 1 The level of evidence represents the assessment on the quality of study evidence, and the grading of recommendation refers to the assessment on the degree to which the benefits of an intervention outweighs the risks. Generally speaking, the higher the evidence level, the stronger the grade of recommendation, but they do not fully correspond to each other. The willingness and values of patients, as well as resource consumption should also be considered when making a recommendation (Table 1) .

This guideline document is composed of 8 sections. The core panel members are responsible for 8 separate groups to prepare the first draft by searching and reviewing the relevant domestic and international literature, evaluating evidence level with the unified standard. The grading of recommendations is decided by vote of all members participating in the preparation of the guidelines.

The principal writer was responsible for summarization and modification of the first draft. In the process, 6 face-toface work meetings were held to discuss revision of the draft. Three rounds of consultation were conducted to solicit advice and opinions from the specialists of the specialty groups within CTS, CMA, specialists in relevant disciplines

The distribution and antimicrobial resistance profile of CAP pathogens are significantly different across different countries and regions, and change over time. Currently, the results of several epidemiological surveys of CAP conducted in Level I (high) Evidence from well-designed, randomized, controlled trials (RCTs), authoritative guidelines and high quality systematic reviews and meta-analyses Level II (moderate)

Evidence from RCTs with some limitations (eg, trials without allocation concealment, nonblinded, or loss to follow-up not reported), cohort studies, case series and case-control studies Level III (low)

Evidence from case reports, expert opinions and in vitro antimicrobial susceptibility studies without clinical data

Grade of recommendation A (strong) Most patients, physicians and policy makers will adopt the recommended action.

The recommendation will be adopted by the majority, but not by some individuals. Decisions should be made with consideration of the specific condition of the patient to reflect his/her values and willingness. C (weak) Insufficient evidence; decisions must be made via mutual discussions involving the patients, physicians and policy makers.

Chinese adults have shown that Mycoplasma pneumoniae and Streptococcus pneumoniae are important pathogens of CAP in adults in China. [13] [14] [15] [16] [17] Other common pathogens include Haemophilus influenzae, Chlamydia pneumoniae, Klebsiella pneumoniae and Staphylococcus aureus; but Pseudomonas aeruginosa and Acinetobacter baumannii are infrequently isolated. 13, [16] [17] [18] In China, only a small number of cases of community-acquired methicillin-resistant S. aureus (CA-MRSA) pneumonia are reported in children and teenagers. [19] [20] [21] [22] CA-MRSA was not identified in the antimicrobial resistance surveillance of community-acquired respiratory tract pathogens in adults conducted in 2009-2010. 23 For special populations such as elderly patients or patients with underlying diseases (eg, congestive heart failure, cardiovascular or cerebrovascular diseases, chronic respiratory system diseases, kidney failure and diabetes mellitus), gramnegative bacteria such as K. pneumoniae and Escherichia coli are more common. 18, 24, 25 With the development and application of virus detection technology, the role of respiratory tract viruses is gradually gaining attention in the aetiology of CAP in Chinese adults. The results of several recently published multicenter studies showed that the detection rate of viruses was 15%-34.9% in Chinese adult CAP patients, of which influenza virus accounted for the largest proportion. Other contributing viruses included parainfluenza virus, rhinovirus, adenovirus, human metapneumovirus (hMPV) and respiratory syncytial virus (RSV). Among the patients with positive test results for viruses, 5.8%-65.7% could have concomitant infection caused by bacteria or atypical pathogens. 15, 18, 26, 27 Considering the resistance profile of major pathogens, the high percentage of S. pneumoniae resistant to macrolides found in Chinese adult CAP patients is an important characteristic that differs from that in European and American countries. Two nation-wide multicenter surveys on adult CAP conducted in [2003] [2004] [2005] showed that 63.2%-75.4% of S. pneumoniae isolates were resistant to macrolides. 13, 17 Recently, the results of 2 multicenter Community-Acquired Respiratory Tract Infection Pathogen Surveillance (CAR-TIPS) studies in adults conducted in urban tertiary hospitals in China showed that 88.1%-91.3% of S. pneumoniae isolates were resistant to azithromycin, the minimum inhibitory concentration of which required to inhibit the growth of 90% of organisms (MIC 90 ) was 32-256 mg/L and 88.2% of the isolates were resistant to clarithromycin. 23, 28 While in European and American countries, 12.9%-39% and 4.3%-33.3% of S. pneumoniae isolates were resistant to erythromycin and azithromycin, respectively. [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] Moreover, 24.5%-36.5% of S. pneumoniae isolates were resistant to oral penicillins, and 39.9%-50.7% resistant to second-generation cephalosporins in China. However, relatively low percentage of S. pneumoniae isolates were resistant to injectable penicillins and third-generation cephalosporins (1.9% and 13.4%, respectively). 23, 28 The high percentage of Mycoplasma pneumoniae strains resistant to macrolides is another important characteristic in the aetiology of CAP in China, which is different from that in most other countries. Study results showed that 58.9%-71.7% of the mycoplasma strains isolated from Chinese adult CAP patients were resistant to erythromycin, and 54.9%-60.4% resistant to azithromycin. [35] [36] [37] The infections caused by antibiotic-resistant mycoplasma may prolong the duration of fever and anti-infective treatment. 36 In addition to China, 25%-46% of the mycoplasma strains isolated from Japanese adult and teenage CAP patients were resistant to macrolides. Macrolides-resistant M. pneumoniae was also reported in France, Canada, the United States, Spain and Germany. [38] [39] [40] [41] [42] [43] M. pneumoniae is highly resistant to macrolides in China, but it remains susceptible to doxycycline, minocycline and quinolones. 35, 44 

A. Onset in community.

B. Relevant clinical manifestations of pneumonia: (1) New onset of cough or expectoration, or aggravation of existing symptoms of respiratory tract diseases, with or without purulent sputum, chest pain, dyspnea, or hemoptysis; (2) Fever; (3) Signs of pulmonary consolidation and/or moist rales; (4) Peripheral white blood cell count (WBC) > 10 3 10 9 /L or < 4 3 10 9 /L, with or without a left shift.

C. Chest radiograph showing new patchy infiltrates, lobar or segmental consolidation, ground-glass opacities, or interstitial changes, with or without pleural effusion.

Clinical diagnosis can be established if a patient satisfies Criterion A, Criterion C and any one condition of Criterion B and meanwhile, tuberculosis, pulmonary tumour, noninfectious interstitial lung disease, pulmonary edema, atelectasis, pulmonary embolism, pulmonary eosinophilia and pulmonary vasculitis are all excluded.

Step 1: Determine whether a diagnosis of CAP is valid or not. For patients with clinically suspected CAP, the possibility of unusual infections such as tuberculosis and noninfectious causes must be considered.

Step 2: Evaluate the severity of CAP and select the location for treatment.

Step 3: Predict the potential pathogens of CAP and risks of antibiotic resistance ( Table 2) : considering patient age, season of onset, underlying diseases and risk factors, symptoms or signs, characteristics of chest imaging (X-ray film or CT), laboratory tests, severity of CAP, prior antibacterial therapies and so on.

Step 4: Arrange for reasonable etiological tests, and initiate empirical anti-infective treatment in a timely manner.

Step 5: Evaluate the effectiveness of empirical antiinfective treatment on CAP in a dynamic manner; investigate the cause if initial treatment fails, and adjust treatment protocol promptly.

Step 6: Follow up after treatment; and provide education on health maintenance. CAP S EV ERI TY, C RI TER IA F OR  HOS P I TA L ADM I S S IO N AND  DI AGNO S TI C CR IT ERI A F OR  S 

The evaluation of CAP severity is crucial for selection of appropriate location of treatment, initial empirical antimicrobial agents, as well as adjunctive and supportive treatments.

The scoring systems of CAP severity differ from each other ( Table 3) . They can be used as an aid for evaluation and provide support for clinical diagnosis and treatment, but physicians should take clinical experience into consideration when making judgments, and monitor disease progression in a dynamic manner 56 (II A). CURB-65, CRB-65 (C: disturbance of consciousness, U: urea nitrogen, R: respiratory rate, B: blood pressure, 65: age), and pneumonia severity index (PSI) scoring systems underestimate the risk of death and severity of influenza pneumonia, 57-60 while oxygenation index combined with absolute reduction of peripheral blood lymphocyte is superior to CURB-65 and PSI in predicting the risk of death due to influenza pneumonia 61 (II B).

CURB-65 score is recommended as a standard for deciding whether a patient should be hospitalized or not. A score of 0-1 point: theoretically, patients should receive outpatient treatment; a score of 2 points: patients are recommended to receive inpatient treatment or extramural treatment with close follow-up; a score of 3-5 points: patients should be hospitalized (I A) .

However, other factors such as patient age, underlying diseases, socioeconomic status, gastrointestinal functions and treatment compliance should also be taken into account for comprehensive evaluation 62 (II B).

Criteria for diagnosis of severe CAP 63 : patients who meet any of the major criteria or 3 minor criteria could be diagnosed as severe pneumonia and need close monitoring and active treatment; it is also recommended that the patients should be hospitalized in ICU if applicable (II A). Acute onset, high fever with potential shivers, purulent sputum, brown bloody sputum, chest pain, significant increase in peripheral WBC, increased C-reactive protein (CRP), signs of pulmonary consolidation or moist rales; radiograph shows alveolar infiltrates or lobar or segmental distribution of consolidation. [45] [46] [47] [48] [49] Mycoplasma or Chlamydia Under 60 years of age, with few underlying diseases; continuous cough, no sputum or no bacteria discovered in sputum smear test, few pulmonary signs, peripheral WBC <10 3 10 9 /L; radiograph may show lesions in the upper lung field of both lungs, centrilobular nodules, tree-in-bud sign, ground-glass opacities, or thickening of bronchial wall and may show signs of consolidation with disease progression. 15, 46, [50] [51] [52] Virus Mostly seasonal, may have history of exposure to an epidemic or clustered outbreak, acute upper respiratory tract symptoms, myalgia, normal or decreased peripheral WBC, procalcitonin (PCT) < 0.1 ng/mL, unresponsive to treatment with antibacterial agents; radiograph shows bilateral, interstitial exudates in multiple lobes and/or ground-glass opacities, which may be accompanied by consolidation. 46, [53] [54] [55] iv. Patients without improvement after active anti-infective therapies, who require differential diagnosis with non-infectious pulmonary lesions (such as tumour, vasculitis and interstitial lung disease) (III B).

See Table 5 for the primary testing methods for CAP pathogens and their corresponding diagnostic criteria.

6 | S ECTI ON 4 . ANTI -I NF ECT I VE THER AP I ES F OR C AP

After clinical diagnosis of CAP is established, and etiological test and sampling arranged appropriately, the most potential pathogens should be assessed in terms of patient age, underlying disease, clinical characteristics, results of laboratory and radiography tests, severity of disease, hepatic and renal functions, and history of medication and antimicrobial susceptibility profile, then evaluate the risk for antibiotic resistance, select the appropriate anti-infective agent (s) and dosing regimen ( Table 6 ). The initial empirical antibacterial therapy should be administered promptly. It is important to note that the epidemiological distribution and antimicrobial resistance profile of pathogens may be different in different regions of China. The anti-infective drugs listed in Table 6 are optional for initial empirical therapy. The treatment recommendations are only theoretical. The selection of therapies for specific patients must be based on the actual situation in local healthcare facilities. Additionally, the pharmacokinetic and pharmacodynamic properties of antibacterial agents must be taken into consideration. For time-dependent antibacterial agents (such as penicillins, cephalosporins, monobactams and carbapenems), their bactericidal ability is almost saturated at 4-5 times of MIC, 115 and T > MIC (time above MIC) is an important determinant of efficacy. 116 Better clinical efficacy can be achieved by multiple doses per day based on half-lives. Meanwhile, the bactericidal ability of concentrationdependent antibacterial agents, such as aminoglycosides and quinolones, increases with drug concentration. The effect improves with higher peak drug concentration. 116 Therefore, these drugs are usually administered once daily in order to increase drug activity and decrease the risk of drug resistance and kidney injury caused by aminoglycosides.

Recommendations of this guideline for empirical antiinfective treatment of CAP are provided in the following.

1. The first dose of anti-infective agent should be used as early as possible after diagnosis of CAP is established in 1. Fluorescent smear microscopy is more sensitive than Ziehl-Neelsen staining 85, 86 2. The sensitivity of mycobacteria culture is superior to that of smear microscopy; in vitro susceptibility testing can be performed, but it is more timeconsuming and complex, and has a higher biological safety requirement for laboratories 85 order to improve efficacy and decrease mortality and hospital stay. However, it is important to note that a correct diagnosis is a prerequisite. Physicians should not ignore necessary differential diagnosis for the purpose of early diagnosis [117] [118] [119] [120] 8. Anti-infective therapy can usually be terminated 2-3 days after fever is relieved and the primary respiratory tract symptoms are improved significantly. However, the duration of therapy should differ based on the severity of disease, treatment response, complications and pathogens. It is not necessary to use chest X-ray or CT as an indication of termination of anti-bacterial agents. Generally, the duration of therapy should be 5-7 days for patients with mild or moderate CAP, which could be reasonably prolonged for patients with severe CAP or with extra-pulmonary complications. The duration of therapy can be prolonged to 10-14 days for patients with atypical pathogens and/or slow response to treatment. S. aureus, P. aeruginosa, Klebsiella and anaerobic bacteria may cause necrosis of lung tissues, therefore, the duration of therapy may be prolonged to 14-21 days 1,2,122,156-159 (I B).

Once aetiology of CAP is determined, targeted therapies can be delivered according to the results of in vitro susceptibility testing. See Table 7 for common pathogens of CAP, common anti-infective agents, as well as dosage and administration.

CAP is the primary cause of death among infectious diseases. In addition to anti-infective treatment targeting the pathogens, it is also necessary for patients with moderate or severe CAP to receive adjunctive therapies such as rehydration, maintenance of fluid and electrolyte balance, nutrition support and physical therapy 2 (II B). For patients with concomitant low blood pressure, early fluid resuscitation is an important measure to decrease the mortality of serious CAP 1,168 (II B). For patients with hypoxemia, oxygen (2) repeated doses of antibacterial drugs or glucocorticoids due to chronic airway disease. Combination therapy is recommended for patients with severe CAP or proven antimicrobial resistance I generation cephalosporins: cefazolin, cefradine, cephalexin, cefathiamidine and so on. II generation cephalosporins: cefuroxime, cefamandole, cefotiam, cefaclor, cefprozil, and so on. III generation cephalosporins: intravenous: ceftriaxone, cefotaxime, ceftizoxime and so on; oral: cefdinir, cefixime, cefpodoxime proxetil, cefditoren pivoxil and so on. Respiratory quinolones: levofloxacin, moxifloxacin, gemifloxacin. Aminopenicillins: amoxicillin, ampicillin. Penicillins-b-lactamase-inhibitor combinations (not including penicillins with antipseudomonal activity, such as piperacillin, ticarcillin): amoxicillin-clavulanic acid, amoxicillin-sulbactam, ampicillinsulbactam and so on. Macrolides: azithromycin, clarithromycin, erythromycin. Quinolones with antipseudomonal activity: ciprofloxacin, levofloxacin. Beta-lactams with antipseudomonal activity: ceftazidime, cefepime, aztreonam, piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanic acid, cefoperazone, cefoperazone-sulbactam, imipenem-cilastatin, meropenem, panipenem-betamipron, biapenem. weeks; followed by TMP-SMX for 3-4 months The duration of therapy is 3-4 months for primary pulmonary nocardiosis.

Ampicillin 2 g IV q8h, for 4-6 weeks, followed by penicillin V potassium 2-4 g/kg per day, oral, for

Piperacillin; amoxicillin-clavulanic acid; ampicillin-sulbactam; piperacillin-tazobactam; doxycycline; minocycline; ceftriaxone; clindamycin; chloramphenicol; azithromycin; erythromycin; moxifloxacin; imipenem; ertapenem Penicillin G is an alternative to ampicillin: 10-20 million U/d, IV, divided into 4-6 separate doses, for 4-6 weeks.

Gentamicin 5 mg/kg IV once daily Doxycycline; minocycline TMP-SMX can be used to prevent Yersinia pestis pneumonia.

Chloramphenicol is effective but with high toxicity. Cephalosporins and quinolones are effective in animal models.

Ciprofloxacin 400 mg IV q12h or levofloxacin 500 mg IV once daily or doxycycline 100 mg IV q12h 1 clindamycin 900 mg IV q8h 6 rifampin 300 mg IV q12h;

Switch to oral therapy and reduce dosage after improvement: ciprofloxacin 500 mg oral, twice daily; clindamycin 450 mg oral, q8h, and rifampin 300 mg oral, twice daily. Duration of therapy is 60 d.

Penicillin G Clindamycin can inhibit the production of toxins. Rifampin can enter cerebrospinal fluid and into cells. If the isolated pathogen is susceptible to penicillin, penicillin 4 million U IV q4h should be given. If structural or inductive b-lactamase is produced, penicillin or ampicillin should not be used alone.

Cephalosporins or TMP-SMX should not be used. Erythromycin and azithromycin have borderline activity. Clarithromycin is effective. Moxifloxacin is effective, but without clinical data. 

Cidofovir 1 mg/kg IV once daily 3 2 weeks, and oral probenecid 2 g should be given every time before injection. And 1 g oral probenecid should

The drug is contraindicated when serum creatinine >1.5 mg/dL, CrCl 55 mL/min, or urine protein 100 mg/L. 

No specific drug so far Ribavirin 0.5-1 g/d IV q12h (not recommended for regular use) Therapies are mainly symptomatic treatments, including fluid replacement and oxygen therapy.

No specific drug so far therapy and assisted ventilation are also important to improve the outcomes of patients. Additionally, nebulization, postural drainage and chest physical therapy are also used in CAP treatment [169] [170] [171] (II B) . Adjunctive drugs for severe CAP also include glucocorticoids, intravenous immune globulin and statins, although currently there is no conclusive evidence for their effectiveness 172 (II B).

7.1 | Oxygen therapy and assisted respiration 1. The blood oxygen level of hospitalized CAP patients should be evaluated in a timely manner. Oxygen therapy via nasal catheter or face mask is recommended for patients with hypoxemia in order to maintain blood oxygen saturation at above 90%. Additionally, for patients with risk of hypercapnia, oxygen saturation should be maintained at 88%-92% before obtaining the results of blood gas analysis 173, 174 (III A). The results of recent studies showed that heated and humidified high-flow oxygen therapy via nasal catheter (40-60 L/min) could also be used in clinical practice 175, 176 (II B).

2. Compared with high-concentration oxygen therapy, noninvasive ventilation (NIV, including bilevel positive airway pressure or continuous positive pressure ventilation) can decrease the endotracheal intubation rate and mortality of CAP patients with acute respiratory failure, [177] [178] [179] [180] [181] improve oxygenation index faster and more significantly, 177, 178, 182, 183 and decrease the incidence of multiple organ failure, 179 and septic shock. 177 These benefits are more significant for patients with concomitant chronic obstructive pulmonary disease 180 (II B). However, for CAP patients with acute respiratory distress syndrome (ARDS), NIV has shown high failure rate 184 and it cannot improve prognosis. 177 NIV is also not appropriate for CAP patients with severe hypoxemia (oxygenation index < 150 mm Hg) 184 (II A) . Additionally, the failure of NIV must be recognized timely. NIV failure is indicated if NIV cannot improve respiratory rate or oxygenation state within the initial 1-2 h, 180, 184, 185 or the therapy cannot decrease the blood carbon dioxide level in a patient with initial hypercapnia. 180 The oxygen therapy should be switched to tracheal intubation and ventilator-assisted ventilation immediately (II A).

3. Mechanical ventilation with low tidal volume (6 mL/kg ideal body weight) should be used for CAP patients with ARDS after tracheal intubation 186, 187 (I A) .

4. For patients with severe CAP and concomitant ARDS, extracorporeal membrane oxygenation (ECMO) can be used if regular mechanical ventilation cannot lead to improvement [188] [189] [190] [191] (II B). Indications of ECMO include:

(1) reversible respiratory failure associated with severe The selection of antimicrobial agents should ultimately depend on susceptibility testing results and the opinions of local microbiological specialists. The appropriate dosage of antimicrobial agents should be based on local data. CrCl, creatinine clearance; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus;

TMP-SMX, trimethoprim-sulfamethoxazole.

a Cefoxitin 1-2 g IV q8h-q6h; cefmetazole 1-2 g q8h-q12h; cefotetan 1-3 g IV q12h (maximum dose 6 g once daily); cefminox 1 g IV q8h.

b Levofloxacin, moxifloxacin, gemifloxacin (not as first-line therapy for penicillin-susceptible strains); ciprofloxacin is mainly used in treatment of gram-negative bacteria (including H. influenzae).

c Ticarcillin 3 g IV q4h-q6h; piperacillin 2-4 g IV q4h-q6h; piperacillin-tazobactam 4.5 g IV q6h-q8h; aztreonam 1-2 g IV q8h-q12h; ceftazidime 1-2 g IV q8h-q12h; cefepime 1-2 g IV q8h-q12h; cefoperazone 1-2 g IV q8h; cefoperazone-sulbactam (2:1) 3 g q8h-q12h; imipenem-cilastatin (for P. aeruginosa) 500 mg (based on imipenem) IV q6h-q8h; meropenem 1-2 g IV q8h; panipenem-betamipron 1-2 g IV q8h-q12h; biapenem 0. Piperacillin-tazobactam 4.5 g IV q6h-q8h; ticarcillin-clavulanic acid 3.2 g IV q6h-q8h; ampicillin-sulbactam 1.5-3 g IV q6h or amoxicillin-clavulanic acid 1.2 g IV q8h-q12h.

f Imipenem-cilastatin 500 mg (based on imipenem) IV q6h-q8h; meropenem 1-2 g IV q8h; ertapenem 1-2 g IV q24h; panipenem-betamipron 1-2 g IV q8h-q12h; biapenem 0.3 g IV q12h. 

Glucocorticoids can decrease the mortality of CAP patients complicated with septic shock. [193] [194] [195] Hydrocortisone succinate 200 mg/day is suggested based on the treatment of septic shock. 196 The drug should be stopped promptly after septic shock is corrected. The duration of therapy is normally no more than 7 days (II C 

The initial therapy is assessed as effective or failure based on the patient's response to treatment, and subsequent management is provided accordingly. Assessment after initial therapy should include the following 5 aspects:

1. Clinical manifestations: including respiratory and systemic symptoms and signs (III A).

2. Vital signs: general condition, consciousness, body temperature, respiratory rate, heart rate, blood pressure and so on. 2 (I A).

3. General laboratory tests: including routine blood test, blood biochemistry, blood gas analysis, C-reactive protein, procalcitonin and so on. It is recommended to repeat C-reactive protein, procalcitonin and routine blood tests after 72 h for hospitalized patients in order to differentiate between treatment failure and slow response to therapy. Patients with severe conditions should be monitored closely 2,206-209 (II B).

Microbiological tests: it is appropriate to repeat regular microbiological tests. Molecular biological and serological assays can be used when necessary. Efforts should be made to obtain etiological evidence [210] [211] [212] [213] [214] [215] [216] [217] [218] [219] [220] (II B).

Chest radiography: it is not recommended to repeat chest radiography regularly for patients with significant improvement in clinical symptoms. When symptoms and signs persist or exacerbate, chest X-ray or chest CT should be repeated to identify the changes of lung lesions 2 (I A).

1. An effective initial therapy is defined as the situation that the clinical condition of a patient is stabilized after therapy. All the 5 criteria below must be met for clinical stability: (1) 2. Subsequent management is recommended after an effective initial therapy: (1) For patients with significant improvement in symptoms after initial therapy, it is appropriate to continue the same anti-infective treatment (I A).

(2) For patients who have achieved clinical stability and are able to receive oral therapy, sequential therapy should be administered with pathogen-susceptible oral preparations of the same types of antimicrobial agents or another agent with similar antibacterial spectrum 1,222 (I A).

1. A failed initial therapy is defined as either of the following situations in a patient: the symptoms are not improved after initial therapy, and requiring alternative antibiotics; exacerbation and disease progression after initial improvement during initial therapy (II A). 

The epidemic season is from February to May. The virus is commonly seen in adults without underlying disease. 26 The incubation period is 3-8 d.

HAdV-55, HAdV-11 and HAdV-7 are relatively common serotypes 259, 260 Similar to pneumonia caused by influenza virus; more common in immunocompetent adults [259] [260] [261] [262] Patients with severe conditions primarily show pulmonary consolidation, which may be associated with ground-glass opacities or patchy nodule infiltrates in unilateral or bilateral lungs or multiple lobes 259 [273] [274] [275] and use of tumour necrosis factor-a antagonists. 277 The relevant epidemiological history includes contact with contaminated air conditioners, air conditioner cooling tower, or contaminated potable water, hot recreational spa, gardening activities or plumbing repairs and the history of traveling to an area with Legionella outbreak. 2, 275, 276, 278 The possibility of Legionella pneumonia should be suspected when an adult CAP patient develops the following conditions: fever but relative bradycardia, acute onset of headache, non-drug-induced disturbance of consciousness or sleepiness, non-drug-induced diarrhoea, acute renal and/or hepatic impairment, hyponatremia, hypophosphatemia and unresponsiveness to b-lactams. 164, 276, [278] [279] [280] [281] [282] [283] The relatively specific manifestations of Legionella pneumonia in chest radiograph is sharply demarcated consolidation intermingled with ground-glass opacities. Another characteristic of Legionella pneumonia is radiographic progression within a short period of time (1 week) even though improvement in clinical symptoms. Or it may take several weeks or even months for pulmonary infiltrates to be completely absorbed. [284] [285] [286] Macrolides, respiratory quinolones or doxycycline monotherapy are appropriate for immunocompetent patients with mild or moderate Legionella pneumonia. Quinolones combined with rifampin or macrolides are recommended for patients with severe conditions, or when monotherapy fails and those immunocompromised patient 1, 2, [287] [288] [289] [290] (I A) . When quinolones are combined with macrolides, physicians should pay close attention to the potential risk of abnormalities in cardiac electrophysiology 2 (I A).

Currently, CA-MRSA pneumonia is relatively rare in Mainland China. Only a small number of cases are reported in children and teenagers. [19] [20] [21] [22] Similarly, among the skin and soft tissue infections caused by S. aureus, MRSA only accounts for a small proportion (5/164). 291 Among the pathogens of hospitalized CAP patients, the proportion of MRSA is 4.3% in Taiwan, 292 3.3% in Japan 293 and 6.2%-8.9% in the United States according to a survey. 294 The estimated incidence of CA-MRSA pneumonia is 0.51-0.64/100 000 268, 269 Mainly pulmonary involvement in subpleural and basal segments of lungs; broad appearance of ground-glass opacities, which may be associated with consolidation. Pleural effusion, interlobular septal thickening may also appear 269, 270 Ribavirin combined with interferon 168, 271 (II C)

people. 295 CA-MRSA pneumonia is a severe disease associated with mortality up to 41.1%. 296 Vulnerable populations include patients or individuals with close contact with a MRSA carrier or patient, individuals affected by influenza virus, prisoners, professional athletes, individuals who serve in the army recently, men who have sex with men, intravenous drug users, regular sauna users and those using antibacterial agents before infection. 295 CA-MRSA pneumonia progresses rapidly. The clinical symptoms include influenza-like symptoms, 296,297 fever, cough, chest pain, gastrointestinal symptoms and skin rashes. For patients with serious conditions, severe pneumonia symptoms such as hemoptysis, confusion, ARDS, multiple organ failure and shock may appear, as well as complications such as acidosis, disseminated intravascular coagulation, deep vein thrombosis, pneumothorax or empyema, pneumatocele, pulmonary abscess and acute necrotic pneumonia. 295 Radiographic characteristics of CA-MRSA pneumonia include extensive pulmonary consolidation and multiple cavities in bilateral lungs. 298 CA-MRSA pneumonia should be suspected after influenza or in previously healthy young patients in case of cavitation, necrotic pneumonia associated with rapid increase of pleural effusion, massive hemoptysis, neutropenia and/or erythematous rashes. 299 Glycopeptides or linezolid are the primary choice for CA-MRSA pneumonia 1,299 (III B).

Currently, the consensus definition of CAP in the elderly (elderly CAP) is pneumonia occurring in the population aged 65 years. 2, 300, 301 The incidence of elderly CAP increases with age.

The clinical manifestations of elderly CAP can be atypical. 302, 303 The manifestations may only include poor appetite, urinary incontinence, tiredness and altered mental state and so on. 2, 301 Typical manifestations of pneumonia such as fever, cough and increased WBC/neutrophil count may not be so evident. 303 Therefore, missed diagnosis and misdiagnosis may occur. Tachypnea is a sensitive index for diagnosis of elderly CAP. 304 When fever or any of the abovementioned atypical symptoms appear, chest radiography should be done as early as possible to confirm the diagnosis. 304 S. pneumoniae is still the main pathogen for elderly CAP, but the possibility of Enterobacteriaceae infection should be considered for elderly patients with underlying diseases (congestive heart failure, cardiovascular and cerebrovascular diseases, chronic respiratory system diseases, renal failure, diabetes mellitus, etc.). 24,300,305 These patients should be further evaluated for risk factors of ESBLs-producing Enterobacteriaceae. Empirical treatment with cephamycins, piperacillin-tazobactam, cefoperazone-sulbactam, ertapenem or other carbapenems is recommended for patients with high risk of infections with ESBLs-producing Enterobacteriaceae [145] [146] [147] 306 (III B) . Relevant risk factors include history of ESBLs-producing bacterial colonization or infection, prior use of third generation cephalosporins, history of repeated or long-term hospitalization, indwelling medical devices, renal replacement therapies. [142] [143] [144] Elderly patients are associated with reduced organ functions, which must be monitored during treatment to avoid side effects. Reduced renal excretion may cause prolonged half-lives of drugs, so the dosage should be reasonably adjusted in terms of CrCl when treating such patients 304 (II B). If no contraindication exists, hospitalized elderly CAP patients should be evaluated for risk of deep vein thrombosis and prophylaxis with low molecular weight heparin should be administered when necessary 307 (II B).

The treatment failure rate is 6%-15% for elderly CAP. 308 Common reasons are concomitant severe sepsis, myocardial infarction, or progression of pneumonia. 309 Cardiovascular event is common in elderly CAP, which is one of the reasons for increased mortality. 308,309

Aspiration pneumonia is pulmonary infectious lesions caused by aspiration of food, oropharyngeal secretion, or gastric content into the throat or lower respiratory tract, not including chemical inflammation in the lung due to aspiration of sterile gastric fluid. [310] [311] [312] The majority cases of aspiration pneumonia are caused by silent aspiration, accounting for around 71% of elderly CAP. 312 The following points should be noted when making diagnosis of aspiration pneumonia: (1) whether there are risk factors for aspiration (eg, disturbance of consciousness due to cerebrovascular diseases or other reasons, dysphagia, periodontal diseases, or poor oral hygiene) 122,308,313-316 ; (2) whether chest radiograph shows primary lesions in the posterior segment of upper lobe and dorsal or basal segment of the lower lobe, just as in hypostatic pneumonia. 312, [317] [318] [319] Aspiration pneumonia is mostly caused by infections with anaerobic bacteria, gram-negative bacteria or S. aureus. The treatment should cover the above pathogens and based on the severity of disease using antimicrobial agents with antianaerobic activity, such as amoxicillin-clavulanic acid, ampicillin-sulbactam, moxifloxacin, carbapenems or in combination with metronidazole or clindamycin 136, [139] [140] [141] 316, 320, 321 (II A). Targeted treatment can be administered after the results of sputum culture and antimicrobial susceptibility testing are available.

Intensive care is required for the elderly patients with risk factors of aspiration in order to reduce the incidence of aspiration pneumonia, specifically: (1) the head of bed should be elevated to 35-408 for long-term bedridden patients if there is no contraindication, and the patient should be in appropriate position when feeding the patient; (2) oral hygiene should be maintained to reduce bacterial colonization in the oropharyngeal area; (3) for elderly patients with severe dysphagia who have already experienced aspiration, physicians should evaluate the risks and benefits of nasal feeding via indwelling gastric tube; (4) antipsychotic drugs, antihistamines and anticholinergic agents should be avoided or decreased 135, 322, 323 (II B).

Smoking cessation, 1 avoid excessive alcohol drinking, adequate nutrition and good oral health 324 are all helpful in preventing pneumonia (III B). Good hand hygiene habits should be maintained. During an episode of respiratory tract symptoms such as coughing or sneezing, wearing a mask or using tissues or elbow clothes to cover the nose and mouth can reduce the dissemination of respiratory tract pathogens 325 (III A).

Vaccination against S. pneumoniae can reduce the risk of pneumonia in specific populations. The S. pneumoniae vaccines currently in use include pneumococcal polysaccharide vaccine (PPV) and pneumococcal conjugate vaccine (PCV).

In China, 23-valent pneumococcal polysaccharide vaccine (PPV23) has been on the market. It can effectively prevent invasive S. pneumoniae infections. 326 PPV23 is recommended for the following populations (I B): (1) age 65 years; (2) age < 65 years, but with chronic pulmonary disease, chronic cardiovascular disease, diabetes mellitus, chronic renal failure, nephrotic syndrome, chronic hepatic disease (including hepatic cirrhosis), alcoholism, cochlear implant, cerebrospinal fluid leakage, immunodeficiency or functional or organic asplenia; (3) long-term residents in nursing homes or other medical institutions; (4) smokers. 327 For the above patients, one dose of vaccine by intramuscular or subcutaneous injection is recommended. Usually, repeat vaccination is not advised for immunocompetent individuals, although it is appropriate for individuals under 65 years of age, but with chronic renal failure, nephrotic syndrome, functional or organic asplenia or immunodeficiency. There should be at least a 5-year interval between two doses of PPV23. Repeat vaccination is not necessary for the individuals who are at least 65 years of age at the time of first vaccination (I B).

The 13-valent pneumococcal conjugate vaccine (PCV13) can cover 70%-80% of S. pneumoniae serotypes in China, 328,329 associated with excellent immunogenicity, 330 but it has not been available in China market. PCV13 vaccination strategy: adults aged 65 years who have not received S. pneumoniae vaccination should receive 1 dose of PCV13, and 1 dose of PPV23 within 6-12 months afterward; adults aged 65 years who have received one or more doses of PPV23 should receive 1 dose of PCV13 at least one year after the latest dose of PPV23; adults who have received PPV23 before the age of 65 should receive PCV13 after 65 years old (at least one year after the last vaccination), and can repeat PPV23 vaccination at least 6-12 months later, but there should be at least a 5-year interval between the two doses of PPV23 331 (I B).

Influenza vaccines can prevent influenza or reduce influenza-associated symptoms. 332, 333 They also have some protective effects against influenza pneumonia and bacterial pneumonia secondary to influenza. 334 The target population of influenza vaccines is broader than that of S. pneumoniae vaccines. See the Chinese Guidelines for Diagnosis and Treatment of Influenza 101 and visit the website for National Influenza Center 335 for details. One dose of influenza vaccine is recommended per annual influenza season 1 (I A). Combination of pneumococcal vaccines with influenza vaccines can decrease mortality in elderly patients 336 (II B).

Bin Cao, Yi Huang Drafting of Section 2: Qi-Jian Cheng Drafting of Section 3: Dan-Yang She

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SMART-COP: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia

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Nonvalue of the initial microbiological studies in the management of nonsevere community-acquired pneumonia

Applying sputum as a diagnostic tool in pneumonia: limited yield, minimal impact on treatment decisions

Radiology of community-acquired pneumonia

Radiological imaging in pneumonia: recent innovations

Pneumonia in the immunocompetent patient

Imaging of community-acquired pneumonia: roles of imaging examinations, imaging diagnosis of specific pathogens and discrimination from noninfectious diseases

Diagnostic work-up of pleural effusions. Respiration

Clinical relevance and characteristics of pleural effusion in patients with Mycoplasma pneumoniae pneumonia

Risk factors and outcome of community-acquired pneumonia due to Gramnegative bacilli

Pneumonia in the immunocompromised host

Infection in solid-organ transplant recipients

Respiratory tract infections in the immunocompromised

A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the

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Sensitivity and specificity of the Streptococcus pneumoniae urinary antigen test for unconcentrated urine from adult patients with pneumonia: a meta-analysis

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Systematic review and metaanalysis: urinary antigen tests for Legionellosis

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Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study

CT correlation with outcomes in 15 patients with acute Middle East respiratory syndrome coronavirus

IFN-alpha2a or IFN-beta1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study

Diagnostic, therapeutic and economic consequences of a positive urinary antigen test for Legionella spp. in patients admitted with community-acquired pneumonia: a 7-year retrospective evaluation

Update on Legionnaires' disease: pathogenesis, epidemiology, detection and control

Surveillance for Legionnaires' disease. Risk factors for morbidity and mortality

Epidemiology and clinical management of Legionnaires' disease

Legionella spp. and Legionnaires' disease

Incidence and risk factors of Legionella pneumophila pneumonia during antitumor necrosis factor therapy: a prospective French study

Current clinical management of Legionnaires' disease

Brainstem involvement in Legionnaires' disease

Clinical predictors for Legionella in patients presenting with communityacquired pneumonia to the emergency department

Severe Legionella pneumonia: rapid presumptive clinical diagnosis with Winthrop-University Hospital's weighted point score system (modified)

Acute tubulointerstitial nephritis complicating Legionnaires' disease: a case report

Clinical diagnosis of Legionella pneumonia revisited: evaluation of the community-based pneumonia Incidence Study Group scoring system

Chest CT findings and clinical features in mild Legionella pneumonia

Computed tomographic features of Legionella pneumophila pneumonia in 38 cases

The radiologic manifestations of Legionnaire's disease. The Ohio Community-Based Pneumonia Incidence Study Group

Guidelines for the management of adult lower respiratory tract infections

Treatment of Legionnaires' disease

Legionella pneumonia in cancer patients

The clinical efficacy of fluoroquinolone and macrolide combination therapy compared with single-agent therapy against communityacquired pneumonia caused by Legionella pneumophila

Characterization of community acquired Staphylococcus aureus associated with skin and soft tissue infection in Beijing: high prevalence of PVL1 ST398

Antimicrobial drug-resistant microbes associated with hospitalized community-acquired and healthcare-associated pneumonia: a multi-center study in Taiwan

Clinical features of healthcare-associated pneumonia (HCAP) in a Japanese community hospital: comparisons among nursing home-acquired pneumonia (NHAP), HCAP other than NHAP, and communityacquired pneumonia

Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia

Incidence, characteristics and outcomes of patients with severe community acquired-MRSA pneumonia

Analysis of risk factors related to mortality of patients with community-acquired pneumonia due to methicillin-resistant Staphylococcus aureus

Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients

Community-acquired methicillin-resistant Staphylococcus aureus pneumonia: radiographic and computed tomography findings

How important is methicillin-resistant Staphylococcus aureus as a cause of community-acquired pneumonia and what is best antimicrobial therapy?

Communityacquired pneumonia in elderly patients

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The following experts provided valuable opinions in the revision of these guidelines. Their efforts are highly appreciated: Writing group members: Yusheng Chen, Xiangqun Fang, Zhancheng Gao 

Bin Cao has been a speaker invited by Pfizer, GSK and Bayer. Jie-Ming Qu has been a speaker on behalf of MSD China, Pfizer, Bayer, Daiichi Sankyo and Sanofi-Aventis. All other authors declare no conflict of interests.

Li-Xian He and You-Ning Liu contributed to be advisors; all authors contributed to critical revision and final approval of the manuscript.

No ethics approval required.

Jing Zhang http://orcid.org/0000-0001-5305-6233