|Ahead of print
|A prospective study to determine the incidence, clinical profile, and outcomes of patients with ventilator-associated pneumonia
Sagnik Bhattacharjee1, Annie B Khyriem2, Clarissa Jane Lyngdoh2, Abhijit Kumar Prasad3
1 Department of Microbiology, Tripura Medical College and Dr. Bram Teaching Hospital, Agartala, Tripura, India
2 Department of Microbiology, NEIGRIHMS, Shillong, Meghalaya, India
3 Department of Microbiology, Bethany Hospital, Shillong, Meghalaya, India
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|Date of Submission||09-Jul-2022|
|Date of Decision||30-Sep-2022|
|Date of Acceptance||01-Oct-2022|
|Date of Web Publication||12-Nov-2022|
Objective: The objective was to determine the incidence, etiological agents, and antibiotic susceptibility pattern of isolates causing ventilator-associated pneumonia (VAP). Methods: The prospective observational study was carried out on 146 adults admitted to the hospital, who were put on mechanical ventilation for a minimum period of 48 h at NEIGRIHMS, Shillong. The study was conducted for 1 year from December 2019 to December 2020. VAP was diagnosed as per the Clinical Pulmonary Infection Score. Demographic, clinical characteristics, culture reports, and antibiotic susceptibility of the patients were noted. Patients were followed up till discharge or death. Outcome measures were risk factors for VAP and mortality. Results: We report an incidence of VAP as 10.6/1000 ventilator days. The predominant organisms seen were Acinetobacter baumannii (62.33%), Klebsiella pneumoniae (47.26%), and Pseudomonas aeruginosa (19.18%). 33/146 (22.6%) patients expired, among which 17 patients had VAP (40.48% vs. 15.38%, P = 0.001). VAP patients had significantly higher odds of smoking (odds ratio [OR] = 2.412, P = 0.016), more polybacterial infections (OR = 2.271, P = 0.024), and more mortality (OR = 3.681, P = 0.001). Among the organisms, P. aeruginosa (OR = 0.115, P = 0.013) and K. pneumoniae (OR = 6.818, P = 0.003) were significantly associated with mortality in patients with VAP. Conclusion: We report an incidence of VAP as 10.6/1000 ventilator days among intensive care unit patients. Smoking was a significant risk factor for VAP. VAP patients had a significantly higher risk of mortality with K. pneumoniae and P. aeruginosa being significant organisms responsible for it.
Keywords: Mortality, risk factors, ventilator-associated pneumonia
|How to cite this URL:|
Bhattacharjee S, Khyriem AB, Lyngdoh CJ, Prasad AK. A prospective study to determine the incidence, clinical profile, and outcomes of patients with ventilator-associated pneumonia. APIK J Int Med [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.ajim.in/preprintarticle.asp?id=361014
| Introduction|| |
Ventilator-associated pneumonia (VAP) is a morbid complication for prolonged intubated patients in the intensive care unit (ICU). The incidence varies from 13 to 51 cases/1000 ventilator days.
VAP is defined by the occurrence of pneumonia after a minimum period of 48 h of mechanical ventilation. It is categorized into early VAP, i.e., within 2 days, and late VAP, i.e., within 3–5 days after an initial 48 h of mechanical ventilation. If the mechanical ventilation continues for a longer time, late VAP is diagnosed up to 3 days after discontinuation of mechanical ventilation.
VAP holds importance in the current times because of more cases of late-onset VAP – which is more severe and caused by multidrug-resistant organisms (MDRO). One of the primary reasons for this is the use of empirical antibiotics without a proper culture sensitivity report.,
In the background of lack of regional Indian data, western treatment guidelines are being followed, which promotes pathogen-drug mismatch., Moreover, this increases the morbidity and mortality related to VAP and the emergence of MDRO.,
Thus, the study was conducted to provide an insight into the incidence, etiological agents, and antibiotic susceptibility pattern of isolates causing VAP in our country, so as to determine the risk factors for the occurrence of VAP, associated organisms, and mortality.
The data of the present study may provide an insight into the current incidence of VAP and various factors associated with VAP, based on which practical changes may be applied to the empirical antibiotics for bringing down the associated morbidity and mortality.
| Methods|| |
The prospective observational study was carried out in the Department of Microbiology, NEIGRIHMS, Shillong, for one year from December 2019 to December 2020 (after institutional ethical clearance).
Inclusion and exclusion criteria
The inclusion criteria were adult patients >18 years, who were on mechanical ventilation for at least 48 h in ICU. Any patient who was withdrawn from mechanical ventilation before 48 h, pregnant females, patients with age <18 years, patients whose culture reports could not be retrieved, reverse transcription–polymerase chain reaction-confirmed COVID-19 patients, and any patient with culture growth for pneumonia before mechanical ventilation were excluded.
The sample size calculation for the study was based on the previous reported incidence of VAP as 57.14% in the study by Ranjan et al. Taking this value as a reference, the minimum required sample size with 8.5% margin of error and 5% level of significance is 131 patients. To reduce the further margin of error, the total sample size taken was 146.
The formula used:
n ≥ (p (1-p))/(ME/zα) 2
Where Zα is the value of Z at two-sided alpha error of 5%
ME is the margin of error
p is the proportion of patients with VAP
n ≥ ([0.5714] × [1-0.5714])/(0.085/1.96)2 = 130.22 = 131 (approximately).
| Methodology|| |
The study included 146 adults admitted to the hospital ICU, who underwent a minimum of 48 h of mechanical ventilation. The consent was obtained from the patients or the guardians. Patient details were noted regarding age, gender, comorbidities, smokers, primary diagnosis, treatment, culture, and antibiotic susceptibility on a predesigned proforma. Parameters of the patients such as temperature, white blood cell count, FiO2, and PaO2, were recorded, and their tracheal secretions (whether purulent or not) were documented. Chest X-rays and tracheal aspirate culture results were also noted. Sample collection for culture was done within 5 days after the initial 48 h of mechanical ventilation. Any positive culture found after 5 days of discontinuation of mechanical ventilation was not considered VAP, but rather considered hospital-acquired infection. The diagnosis of VAP was made if the patient's Clinical Pulmonary Infection Score (CPIS) was >6 or else the patient was labeled non-VAP.
Follow-up and outcomes
The patients were monitored until their discharge or death. The primary outcomes were mortality and risk factors associated with VAP.
The data presentation was done in the form of number and percentage (%), mean ± standard deviation, and median with 25th and 75th percentiles (interquartile range). The data normality was analyzed by the Kolmogorov–Smirnov test. The comparison of the variables, i.e., sample collection day, which were quantitative and not normally distributed in nature was analyzed using Mann–Whitney test (for two groups), and the independent t-test was used for comparison of age between two groups. The comparison of the variables, i.e., gender, hypertension, diabetes, smoking, previous respiratory infection, duration of antibiotics (days), organisms, and mortality between VAP and non-VAP, was analyzed using Fisher's exact test. The odds ratio with 95% confidence interval for VAP and mortality was calculated using univariate logistic regression.
Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, version 21.0, was used for analysis. For statistical significance, P < 0.05 was considered statistically significant.
| Results|| |
Demographics of the study population
The mean age of the study patients was 49.08 ± 17.8 years with 60.27% of males and 39.73% of females. The comorbidities noted among the patients were hypertension (113 [77.4%]), diabetes (71 [49.32%]), and COPD (33 [22.6%]). Seventy-one (48.63%) patients were smokers.
Characteristics of VAP
In our study, 42 (28.77%) patients had VAP and non-VAP was seen in 104 (71.23%) patients with a VAP incidence as 10.6/1000 ventilator days.
Among the cases of VAP, early VAP was seen in 22 cases (52.4%) and late VAP was seen in 20 cases (47.6%). The clinical conditions among the VAP patients, for which they were put on mechanical ventilation, were cerebrovascular accident infarct (22 [52.4%]), head injury (10 [23.8%]), encephalitis (5 [11.9%]), pleural effusion (1 [2.38%]), seizures (1 [2.38%]), space-occupying lesion (1 [2.38%]), hepatic encephalopathy (1 [2.38%]), and spinocerebellar ataxia (1 [2.38%]).
The predominant organisms seen among the VAP patients were Acinetobacter baumannii (71.43%), Klebsiella pneumoniae (42.86%), and Pseudomonas aeruginosa (28.57%) with lesser common organisms being Escherichia coli (16.67%) and Enterobacter species (2.38%). Polybacterial infections were seen in 26 (61.9%) cases of VAP.
In our study, 33/146 (22.6%) patients expired, among which 17 patients had VAP. The presence of VAP was significantly associated with mortality (40.48% vs. 15.38%, P = 0.001). Among the organisms, P. aeruginosa (odds ratio [OR] = 0.115, P = 0.013) and K. pneumoniae (OR = 6.818, P = 0.003) were significantly associated with mortality [Table 1].
Risk factors: VAP versus non-VAP
Compared to patients of non-VAP, VAP patients had significantly higher odds of smoking (OR = 2.412, P = 0.016), more polybacterial infections (OR = 2.271, P = 0.024), and more mortality (OR = 3.681, P = 0.001). There was no significant association of age, gender, and comorbidities with VAP [Table 1] and [Table 2].
|Table 2: Comparison of baseline demographic characteristics between nonventilator-associated pneumonia and ventilator-associated pneumonia|
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MDR was seen in 28 cases (66.67%), extended-spectrum beta-lactamases (ESBL) was seen in 13 (30.95%) cases, carbapenem resistance was seen in nine (21.42%) cases, and metallo-β-lactamases was seen in 6 (14.28%) cases.
A. baumannii showed 88.64% resistance to piperacillin, 88% to cotrimoxazole, 87.04% to ciprofloxacin, 92% to cefotaxime, 91.67% to ceftriaxone, 83.33% to ceftazidime, 83.87% to cefepime, 82.81% to piperacillin + tazobactam, 62.75% to imipenem, 73.44% to meropenem, 30.77% to amikacin, and 70.31% to gentamicin, whereas it showed 100% sensitivity to minocycline and 96.9% sensitivity to colistin.
Escherichia coli showed 33.33% resistance to piperacillin, 77.78% to cotrimoxazole, 20% to amikacin, 30% to gentamicin, 60% to ciprofloxacin, 20% to cefotaxime, 75% to ceftriaxone, 50% to ceftazidime, 30% to cefepime, 33.33% to meropenem, and 10% to piperacillin-tazobactam, while it showed 100% sensitivity to colistin and imipenem.
Enterobacter spp. showed 100% resistance to ciprofloxacin, cefotaxime, cefoperazone, imipenem, meropenem, and piperacillin + tazobactam, while it showed 100% sensitivity to cotrimoxazole, amikacin, and gentamicin.
K. pneumoniae showed 78.57% resistance to ciprofloxacin, 50% to levofloxacin, 92.31% to cefotaxime, 77.27% to ceftriaxone, 83.33% to cefoperazone, 96.67% to ceftazidime, 82.35% to cefepime, 44.44% to imipenem, 43.10% to meropenem, 57.63% to piperacillin-tazobactam, 100% resistance to cotrimoxazole, 45.45% resistance to amikacin, 56.52% resistance to gentamicin, and 92.16% resistance to amoxicillin-clavulanate, while it showed 100% sensitivity to ampicillin-sulbactam and colistin.
P. aeruginosa showed 33.33% resistance to piperacillin, 30.43% resistance to amikacin, 53.33% resistance to gentamicin, 83.33% resistance to ciprofloxacin, 60% resistance to ceftazidime, 33.33% resistance to cefepime, 26.67% resistance to imipenem, 65.22% resistance to meropenem, and 20% resistance to piperacillin-tazobactam, while it showed 93.33% sensitivity to colistin and 60% sensitivity to piperacillin.
| Discussion|| |
The present study was a prospective observational study on 146 adult patients for determining the incidence of VAP and its microbiological profile. In our study, there were 42 cases of VAP (28.77%) with an incidence rate of VAP as 10.6/1000 ventilator days. In other studies, this incidence was 57.14% in the study by Ranjan et al., 20% by Rit et al., and 27.71% by Patil and Patil. In the study by Joseph et al., the incidence of VAP was 30.67 and 15.87/1,000 ventilator days in the two different ICUs. The incidence of VAP may vary in different studies according to the condition of the patient, diagnosis, and the number of ventilator days.
We found 22 cases of early VAP and 20 cases of late VAP. In previous studies, as done by Joseph et al., 58.3% of the cases were late-onset VAP, whereas 41.7% were early-onset VAP similar to this study. Most of the patients had late-onset VAP (60.7%) in the study by Rit et al. Similarly, the majority of patients (82.43%) had late-onset VAP and 17.56% patients had early-onset VAP in the study by Patil and Patil. The classification of VAP into early and late types holds importance because late-onset VAP needs an appropriate diagnosis since it carries high morbidity and mortality, as it may go undiagnosed due to repeated cultures needed for those patients on prolonged mechanical ventilation.
Various diagnostic criteria have been established to diagnose VAP by including different clinical, imaging, and investigative parameters, though none is claimed to be the gold standard. We used the CPIS score (cutoff >6) which showed 73.8% sensitivity and 66.4% specificity for diagnosing VAP as per a systematic review and meta-analysis.
Other diagnostic methods include physical examination such as fever, chest radiography, and purulent secretions, which carry a further lower sensitivity and specificity. A recent publication in 2020 showed the use of pentraxin-3 (PTX-3), whereby Lung Ultrasound and Pentraxin-3 Pulmonary Infection Score (cutoff >7) entails a higher sensitivity of 84% and specificity of 87.7%, thereby superseding CPIS score. However, this score requires the investigation by PTX-3, making it a costly scoring system compared to the CPIS score which is more basic to apply.
VAP can be affected by the patient characteristics. Hence, we assessed and compared various patient characteristics and the risk associated with them for the development of VAP.
Advancing age (especially more than 60 years) remains a significant risk factor for VAP. It is due to decreasing physiological functions, lung capacity, and immunity, with advancing age. However, the present study found that the mean age in VAP and non-VAP was statistically comparable (51.12 ± 16.8 vs. 48.26 ± 18.18, P = 0.381) without any significant risk association of age with VAP. This might be because the mean age of the study participants was <60 years, and below that age, it may not account significantly for higher occurrence of VAP. This was in line with other studies done by Joseph et al. (41.4 ± 14.7 vs. 36.8 ± 16.3 years, P = 0.1770), John et al. (57.07 ± 19.6 vs. 51.84 ± 17.4, P = 0.361), and Rello et al. (62.3 ± 19.1 vs. 63.0 ± 17.7, P = 0.389), which showed that age had no significant association with the occurrence of VAP.
Among genders, males are prone to VAP, on account of different sex hormones, genes, type of pathogens affecting them, and drug immune responses.
However, in our study, the number of males/females in VAP versus non-VAP was comparable (61.90%/38.10% vs. 59.62%/40.38%, P = 0.798). This is in accordance with the study by Joseph et al., where the number of males/females was comparable in VAP and non-VAP groups (57.9%/42.1% vs.(66.7%/33.3%, P = 0.4354). Even, in the study by John et al.,1 male/female of the study was similar (P = 0.907). However, in the study by Rello et al., patients with VAP in the population were significantly more likely to be male.
As for comorbidities, no significant association was seen in the distribution of hypertension, diabetes, and COPD with VAP (p >.05). Similarly, in the study by John et al., comorbidities such as diabetes, hypertension, and chronic kidney disease were comparable in patients with VAP and non-VAP.
However, in the study by Rit et al., comorbid conditions such as hypertension and diabetes mellitus were significant risk factors associated with VAP. This suggests the importance of assessment of the comorbid conditions as the presence of diabetes may make an individual more prone to getting infection; however, the duration and severity of the comorbidity hold importance in this regard. However, the effect of comorbidities is more pronounced in the elderly population (>60 years), which was not the case in the present study.
Among the other factors, smoking was found to be a significant risk factor with a 2–3 fold higher risk of VAP. This was supported by Liu et al. where smokers had 4.37 higher odds of incidence of VAP than non-smokers. The reason was ascribed to impairment of functions of pulmonary alveolar macrophages, leading to decreased bacterial clearance and increased lung infections.
In our study, only gram-negative organisms were seen in the culture growth of the study patients that included A. baumannii (71.43%), K. pneumoniae (42.86%), and P. aeruginosa (28.57%) with lesser common organisms being Escherichia coli (16.67%) and a single isolate of Enterobacter spp. Our findings were in line with the study by John et al.,15 where gram-negative organisms were the most common pathogens associated with VAP.
In another retrospective, matched cohort study by Rello et al., P. aeruginosa was isolated most frequently in patients with VAP occurring >4 days after the start of mechanical ventilation (19.7%), while Staphylococcus aureus was isolated most frequently in patients whose episode of VAP was diagnosed during the first 4 days of mechanical ventilation (23.7%).
Joseph et al. reported that most of the cases of VAP were caused by gram-negative bacteria, which accounted for 80.9% of causative organisms. P. aeruginosa (21.3%) and A. baumannii (21.3%) were the most common gram-negative bacteria associated with VAP, and Staphylococcus aureus (14.9%) was the most common gram-positive bacteria in patients with VAP.
Among the outcomes, we assessed the mortality and found that 22.60% of the patients died. The number of patients who died was 40.48% in VAP group, which was significantly higher compared to non-VAP (15.38%). The patients with VAP showed 3–4 times increased risk of death than ventilated patients without VAP. Similar to our study, the overall mortality in patients with VAP in the study by Ranjan et al. was 48.33%, which was significantly higher than in the non-VAP group (20%, P < 0.05).
In contrast, in the study by Rello et al., 30.5% of the patients in the VAP group died and 30.4% patients in the non-VAP group died, with no significant difference between them. However, the morbidity and other hospital outcomes were dismal in the patients with VAP. In their study, the patients with VAP had a significantly longer duration of mechanical ventilation (14.3 ± 15.5 days vs. 4.7 ± 7.0 days, P < 0.001), ICU stay (11.7 ± 11.0 days vs. 5.6 ± 6.1 days, P < 0.001), and hospital stay (25.5 ± 22.8 days vs. 14.0 ± 14.6 days, P < 0.001) compared to healthy individuals who did not have VAP. Even in the study by Joseph et al., there was no statistically significant difference in mortality between VAP and non-VAP groups (16.2% vs. 20.5%; relative risk, 0.89; 95% CI, 0.40 to 1.95; P = 0.9486). The actual reason for this nonassociation has not been explained, but it may be linked with the pathogenic profile of the organisms. This can be said because, in our study, there was a significant association of the type of organisms with mortality as the proportion of patients with P. aeruginosa and K. pneumoniae was significantly higher in died patients compared to those who survived (P < 0.05).
In terms of the association of K. pneumoniae for higher mortality, it needs to be mentioned here regarding the emerging hypervirulent strains of K. pneumoniae (HvKp) against the older classical strains (cKp). HvKp is defined by a positive string test (hypermucoviscous phenotype) and is more virulent than cKp. It has become antibiotic resistant in terms of MDR hvKp, ESBL-producing hvKp, polymyxin-resistant hvKp, and carbapenem-resistant hvKp – thereby resulting in a higher mortality, especially in elderly, comorbid population acquiring VAP.
Overall, VAP occurs at a higher rate in developing countries as ours, compared to developed countries. This may be due to a lack of a good preventive strategies adopted by developing countries for VAP. The identification of the risk factors for VAP (in the present study) allows to develop a change in the clinical practice for the prevention of VAP. Certain preventive measures that we would like to suggest through the results of this study are the use of noninvasive positive pressure ventilation, maintenance of oral hygiene (to reduce infections), management and stabilization of comorbid conditions, cessation of smoking, and use of antibiotics such as piperacillin + tazobactam, amikacin, colistin, tetracycline, and piperacillin.
The study results must be interpreted in view of certain limitations. First, the culture growth showed no gram-positive organisms, and thus, their profile and associated outcomes could not be explored. Second, it was a single-center study, which lacked the power to recognize all vital VAP risk factors. Third, in terms of outcome, hospital and ICU stay were not recorded.
| Conclusion|| |
We report an incidence of VAP as 10.6/1000 ventilator days among ICU patients, with the most common organism being A. baumannii. Smoking and polybacterial infections were significant risk factors for the occurrence of VAP. K. pneumoniae and P. aeruginosa were significantly associated with a higher mortality in VAP patients.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Papazian L, Klompas M, Luyt CE. Ventilator-associated pneumonia in adults: A narrative review. Intensive Care Med 2020;46:888-906.
Wu D, Wu C, Zhang S, Zhong Y. Risk factors of ventilator-associated pneumonia in critically III patients. Front Pharmacol 2019;10:482.
Luyt CE, Hékimian G, Koulenti D, Chastre J. Microbial cause of ICU-acquired pneumonia: Hospital-acquired pneumonia versus ventilator-associated pneumonia. Curr Opin Crit Care 2018;24:332-8.
Jain S, Khety Z. Changing antimicrobial resistance pattern of isolates from an ICU over a 2 year period. J Assoc Physicians India 2012;60:27-8, 33.
Martin-Loeches I, Rodriguez AH, Torres A. New guidelines for hospital-acquired pneumonia/ventilator-associated pneumonia: USA vs. Europe. Curr Opin Crit Care 2018;24:347-52.
Gadani H, Vyas A, Kar AK. A study of ventilator-associated pneumonia: Incidence, outcome, risk factors and measures to be taken for prevention. Indian J Anaesth 2010;54:535-40.
] [Full text]
Ranjan N, Chaudhary U, Chaudhry D, Ranjan KP. Ventilator-associated pneumonia in a tertiary care intensive care unit: Analysis of incidence, risk factors and mortality. Indian J Crit Care Med 2014;18:200-4.
] [Full text]
Zilberberg MD, Shorr AF. Ventilator-associated pneumonia: The clinical pulmonary infection score as a surrogate for diagnostics and outcome. Clin Infect Dis 2010;51 Suppl 1:S131-5.
Rit K, Chakraborty B, Saha R, Majumder U. Ventilator associated pneumonia in a tertiary care hospital in India: Incidence, etiology, risk factors, role of multidrug resistant pathogens. Int J Med Public Health 2014;4:51-6. [Full text]
Patil HV, Patil VC. Incidence, bacteriology, and clinical outcome of ventilator-associated pneumonia at tertiary care hospital. J Nat Sci Biol Med 2017;8:46-55.
Joseph NM, Sistla S, Dutta TK, Badhe AS, Parija SC. Ventilator-associated pneumonia: A review. Eur J Intern Med 2010;21:360-8.
Fernando SM, Tran A, Cheng W, Klompas M, Kyeremanteng K, Mehta S, et al.
Diagnosis of ventilator-associated pneumonia in critically ill adult patients-a systematic review and meta-analysis. Intensive Care Med 2020;46:1170-9.
Haliloglu M, Bilgili B, Bilginer H, Kasapoglu US, Sayan I, Aslan MS, et al.
A new scoring system for early diagnosis of ventilator-associated pneumonia: LUPPIS. Arch Med Sci 2020;16:1040-8.
Chang L, Dong Y, Zhou P. Investigation on risk factors of ventilator-associated pneumonia in acute cerebral hemorrhage patients in intensive care unit. Can Respir J 2017;2017:7272080.
John J, Thomas SM, Mathai AS, Rajkumar A. A prospective study on incidence and microbiological profile of ventilator associated pneumonia in the intensive care unit of a tertiary care centre. Int J Contemporary Med Res 2017;4:1840-3.
Rello J, Ollendorf DA, Oster G, Vera-Llonch M, Bellm L, Redman R, et al.
Epidemiology and outcomes of ventilator-associated pneumonia in a large US database. Chest 2002;122:2115-21.
Forel JM, Voillet F, Pulina D, Gacouin A, Perrin G, Barrau K, et al.
Ventilator-associated pneumonia and ICU mortality in severe ARDS patients ventilated according to a lung-protective strategy. Crit Care 2012;16:R65.
Liu Y, Di Y, Fu S. Risk factors for ventilator-associated pneumonia among patients undergoing major oncological surgery for head and neck cancer. Front Med 2017;11:239-46.
Liu C, Guo J. Characteristics of ventilator-associated pneumonia due to hypervirulent Klebsiella pneumoniae
genotype in genetic background for the elderly in two tertiary hospitals in China. Antimicrob Resist Infect Control 2018;7:95.
Xie J, Yang Y, Huang Y, Kang Y, Xu Y, Ma X, et al.
The current epidemiological landscape of ventilator-associated pneumonia in the intensive care unit: A multicenter prospective observational study in China. Clin Infect Dis 2018;67:S153-61.
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Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]
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