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Abstract
Background Diagnosing hospital-acquired pneumonia (HAP) (ventilator-associated pneumonia (VAP) and non-ventilator associated pneumonia (Non-VAP)) is still a hot issue. Soluble urokinase plasminogen activator receptor (suPAR) is prognostic in critically ill children with sepsis regarding mortality prediction. Our aim was to evaluate suPAR levels in children with HAP.
Methods An observational, prospective study was conducted on 45 children diagnosed HAP (VAP and Non-VAP) and 40 healthy controls. Paediatric Sequential Organ Failure assessment Score (pSOFA) was assessed for each patient. Plasma suPAR levels were measured with ELISA on the day of diagnosis.
Results On comparison levels of plasma suPAR for the children with HAP with the healthy control group, no statistically significant difference was observed (148 pg/mL (22.4–1939.7) and 184.4 pg/mL (31.6–1311.7), respectively, (p=0.32). suPAR was significantly increased in children with elevated pSOFA score on the day of diagnosis of pneumonia (p=0.034). suPAR was significantly increased in children with shock (p=0.005). suPAR levels was negatively correlated with oxygen saturation (rs=0.31,p=0.048). suPAR was not significantly correlated with C reactive protein.
Conclusions suPAR can be used as a predictor for severity of illness in children with HAP. We firmly know that plasma suPAR, a novel marker, could indicate the disease if carried out on larger patient groups.
- Infant
- Mortality
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Hospital-acquired pneumonia (HAP) is still a hot issue. Soluble urokinase plasminogen activator receptor (suPAR) is prognostic in critically ill children with sepsis.
WHAT THIS STUDY ADDS
suPAR is of limited value in diagnosing HAP in paediatric patients but it is useful for predicting HAP severity.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Highlights the potential need for early prediction of HAP to prevent the progression of the disease.
introduction
Definition of hospital-acquired pneumonia (HAP) is a pneumonia occurring 48 hours after admission of the hospital and not incubating at admission time. Ventilator-associated pneumonia (VAP) is a subtype of HAP defined as pneumonia acquiring in a patient who mechanically ventilated for 48 hours.1
The rate of HAP is 5–10 per 1000 of hospital admissions.2 VAP represents 20% of all hospital-acquired infection among children in paediatric intensive care unit (PICU) with a rate of (2.9–21.6)/1000 ventilator days.3
VAP may be early onset VAP (≤ 96 hours) or late onset (> 96 hours). Early onset VAP is caused by community acquired organisms such as Streptococcus pneumoniae, Chlamydia pneumoniae and Staphylococcus aureus. Late-onset VAP is resulted from hospital-acquired organisms like Pseudomonas aeruginosa, methicillin-resistant S. aureus, Acinetobacter species and Enterobacter species.4
Critically ill paediatrics who are in need of using antibiotics, more time of intubation and longer time of PICU admission are more risk of acquiring VAP, which has been related with further prolonged time of mechanical ventilation, PICU and hospital stay.5
Soluble urokinase plasminogen activator receptor (suPAR) is the soluble structure of the cell membrane-bound protein uPAR, which is released from cells of immunity, endothelium and smooth muscle. uPAR is expressed during inflammatory process or activation of immune system, so level of suPAR reflects the extent of immune system stimulation in the children.6
uPAR is a receptor of urokinase (uPA) which divides plasminogen into active form of plasmin. Furthermore, uPAR reacts with different proteins and has a vital role in many cell procedures as migratory process, cell adhesion, vascular angiogenesis, proliferation of cells and chemotaxis of organisms.6
suPAR levels are elevated in many conditions involving infectious diseases and inflammation process. Moreover, levels of plasma suPAR are high in the paediatric critical care unit.7 However, the role of suPAR in paediatric HAP is almost unknown. Consequently, the aim of this study was to investigate the relation of suPAR level to HAP severity and outcome.
Patients and materials
Study design and subjects
In this prospective observational research, 45 children with HAP (VAP and Non-VAP) were included. The studied groups were enrolled from Menoufia University Hospital, Egypt from May 2020 to April 2021. Additionally, a group of the control, comprising of 40 healthy children, was involved.
The child who aged 1 month to 18 years with HAP was included in the research after taking informed consent which written from his parents. A diagnosis of HAP was made when pneumonia occurred >48 hours after hospital admission.8 The exclusion criteria involved age less than 1 month or more than 18 years; the presence of another infection with HAP, for example, gastroenteritis; and failure to take a blood sample within 24 hours of HAP diagnosis.
For the included children, the vital parameters and saturation of oxygen (SPO2) were measured. The diagnostic investigations involved are chest X-ray, arterial blood gas, complete blood count, C reactive protein (CRP), hepatic function tests and kidney function tests. Paediatric Sequential Organ Failure assessment Score (pSOFA) was assessed for all included children.9
In addition, suPAR was measured for each patient within 24 hours of HAP diagnosis. For the healthy control group, history and clinical examination were performed besides serum suPAR measurement.
Laboratory methods
Serum suPAR was withdrawn from patients, within 24 hours of HAP diagnosis, as well as to controls. 3 mL of venous blood were taken from all studied groups into a plain tube and left to clot at temperature room then undergone to centrifugation at 3000 rpm for 15 min. Sera were separated and kept frozen at –20°C until analysis. Serum suPAR concentration was detected by using human soluble urokinase type plasminogen activator receptor or suPAR (ELISA) kit (changing Biospes Co., China) according to the manufacturer’s instructions.
Statistical analysis
Quantitative data are shown as mean±SD when are normally distributed or median and range when are non-normally distributed, while qualitative parameters were exhibited in form of numbers and percentages. Spearman’s correlation was done for correlations between non-normally distributed parameters. Logistic regression test was performed for prediction of mortality by suPAR and other parameters. The p value was significant when it was less than 0.05. Statistical analyses were done by Statistical Package of Social Science, V.20 (SPSS).
Results
Characteristics of the study population
The patient group consisted of 45 children with HAP. The control group consisted of 40 healthy children. Their main demographic and clinical characteristics are shown in table 1. Patients were classified; into 34 VAP and 11 Non-VAP subgroups. The mortality rate was significantly higher among patients with VAP.
Demographic, clinical and laboratory data of patients and controls
Association of suPAR with HAP
There was no significant difference in suPAR level between the patient and control groups (table 1 and figure 1), indicating that suPAR lacks a diagnostic value for HAP.
Boxplot showing soluble urokinase plasminogen activator receptor (suPAR) level in patients and controls.
suPAR level in different patient subgroup
suPAR level was significantly increased in children with shock than patients who did not have shock on admission. There was significant increase in suPAR level among patients with elevated pSOFA score on the day of pneumonia diagnosis. suPAR level was elevated in children who were mechanically ventilated and in children with prolonged hospital stay than those with short hospital stay but the difference was not significant. suPAR was also elevated in non-survivors but the difference was not significant (table 2).
suPAR level in different patient subgroups
Correlations of suPAR with clinical and laboratory parameters
A significant negative correlation was found between suPAR and oxygen saturation (rs= −0.31; p=0.048) but no significant correlation was found between suPAR and other variables, including CRP, WBC and platelet count (table 3).
Correlation between suPAR and other clinical and laboratory parameters
Predictors of HAP mortality
In logistic regression analysis, VAP diagnosis, lobar infiltrate, pSOFA score and PCO2 were positively associated with mortality while WBC and platelet count were negatively associated with mortality (table 4).
Logistic regression analysis for prediction of mortality by suPAR and other variables
Discussion
Many experimental studies have determined increased suPAR levels in tumours and in many infections and inflammatory illness. The infections and inflammatory illness include HIV, malaria, tuberculosis, infections of nervous system, urinary tract infections, arthritis, hepatic fibrosis and inflammatory bowel syndrome.7 10–14 Moreover, high suPAR levels detected in critically and dangerous illness as blood stream infection, systemic inflammatory response syndrome, or bacteraemia and has a prognostic value of the disease.15 16
In the present study, suPAR level was not significantly different between patients and controls, implying lack of diagnostic role of suPAR. The sample size might provide an explanation for this finding. However, it was also noted that assay type used to calculate suPAR could affect its results.17 Importantly, the present research is the first one to assess levels of suPAR in HAP. Previous studies evaluated the role of suPAR specifically in patients with VAP. Similarly, Alaa Refaat et al reported that no significant difference was found in BAL suPAR level in defined patients with VAP in comparison to absent VAP or undefined patient with VAP.18
Conversely, Van Oort et al reported that suPAR can diagnose VAP with a fair accuracy for diagnosis and a moderate accuracy for prognosis in critically ill patients.19Also, Sunnetcioglu et al showed that suPAR was elevated in patients with VAP than Non-VAP patients suggesting that suPAR is a valuable biomarker in diagnosis of patients with VAP.20
It is necessary to compare the value of suPAR in both community-acquired pneumonia (CAP) and HAP. Wrotek et al noticed that suPAR levels in children with CAP were significantly elevated than control.21 Similar studies were conducted in adult patients with CAP. For example, Ping Kun Tsai et al reported that suPAR levels were significantly increased in patients with CAP than the controls.22
In this research, there is no significant correlation between suPAR and age, a finding similar to previous adult studies.10 23
In addition to the diagnostic value, we studied suPAR for a potential association with mortality. We found that suPAR was higher among non-survivors but the difference was not significant. Conversely, Kotch et al reported that changes in levels of suPAR did not appear to be different between survivors and non-survivors.23
Conversely, we found that suPAR was significantly higher among patients with HAP with shock and among those with higher pSOFA score. Similarly, in patients with bacteraemia, elevated suPAR levels were associated with high SOFA scores.24 Moreover, suPAR was noted to have a significant negative correlation with oxygen saturation.
In this research, there is no significant correlation between suPAR and hospital LOS, a finding similar to previous adult studies.23
Conclusion
suPAR is of limited value in diagnosing HAP in paediatric patients but it is useful for predicting disease severity. Further researches with larger patient numbers is needed to uncover the real value of suPAR in paediatric HAP.
Limitation of the study
First, sample size was small; suPAR level was not measured serially before the diagnosis of the disease and after the diagnosis. Additionally, the absence of an available gold standard for the diagnosis of VAP is a critical limitation of this study. In addition, it is useful to assess the role of suPAR levels in another body fluids which can give good results.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This research was matched with the Menoufia University and Faculty of Medicine ethical standards. Approval number was 4/2020 PED1-2. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors express their gratitude to all cases participated in the research.
References
Footnotes
Contributors Conceptualisation, formal analysis, funding acquisition, writing – review and editing: NYS and MAA. Investigation: NYS, MIG and MAA. Methodology and resources: NYS, MAA and SES. Supervision: all authors. All authors have read and agreed to the published version of the manuscript. The guarantor accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish: NYS.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests There is no competing of the interests.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.