Rodríguez-Fanjul et al. Respiratory Research (2020) 21:255 https://doi.org/10.1186/s12931-020-01476-z STUDY PROTOCOL Open Access Procalcitonin and lung ultrasound algorithm to diagnose severe pneumonia in critical paediatric patients (PROLUSP study). A randomised clinical trial Javier Rodríguez-Fanjul1, Carmina Guitart2,3, Sara Bobillo-Perez2,3, Mònica Balaguer2* and Iolanda Jordan2,3,4 Abstract Background: Lung ultrasound (LUS) in combination with a biomarker has not yet been studied. We propose a clinical trial where the primary aims are: 1. To assess whether an algorithm with LUS and procalcitonin (PCT) may be useful for diagnosing bacterial pneumonia; 2. To analyse the sensitivity and specificity of LUS vs chest X-ray (CXR). Methods/design: A 3-year clinical trial. Inclusion criteria: children younger than 18 years old with suspected pneumonia in a Paediatric Intensive Care Unit. Patients will be randomised into two groups: Experimental Group: LUS will be performed as first lung image. Control Group: CXR will be performed as first pulmonary image. Patients will be classified according to the image and the PCT: a) PCT < 1 ng/mL and LUS/CXR are not suggestive of bacterial pneumonia (BN), no antibiotic will be prescribed; b) LUS/CXR are suggestive of BN, regardless of the PCT, antibiotic therapy is recommended; c) LUS/CXR is not suggestive of BN and PCT > 1 ng/mL, antibiotic therapy is recommended. Conclusion: This algorithm will help us to diagnose bacterial pneumonia and to prescribe the correct antibiotic treatment. A reduction of antibiotics per patient, of the treatment length, and of the exposure to ionizing radiation and in costs is expected. Trial registration: NCT04217980. Background therapeutic approach (whether antibiotics are indicated Pneumonia is responsible for more than 2 million child and the treatment duration), a different prognosis in the deaths around the world; it is the leading cause of child- short and long term, and requires a different hospital hood morbidity and mortality [1]. Moreover, severe isolation policy [4, 5]. It is challenging to rule whether a lower respiratory infection is the most common cause of case of pneumonia is viral or bacterial in origin [6–8]. admission to paediatric intensive care units (PICUs) [2]. Clinical symptoms are similar and although conventional Around 60–70% of these have a viral etiology [3]. For chest radiographs (CXR) have traditionally been consid- physicians, it is important to differentiate between viral ered the best diagnostic option [9], the specificity of and bacterial infection because each entails a different CXR for determining bacterial etology remains low. Chest computed tomography may detect smaller pul- * Correspondence: mbalaguer@sjdhospitalbarcelona.org monary consolidations not visible via CXR, but it cannot 2 Paediatric Intensive Care Unit, Hospital Sant Joan de Déu, University of Barcelona, P° Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain be routinely performed on critically ill patients due to Full list of author information is available at the end of the article cost, exposure to radiation, and transportation risk [9]. © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Respiratory Research (2020) 21:255 Page 2 of 6 Therefore, there is a need to have an examination tool Study aim that can be used at the patient’s bedside and which is Our primary goal is to improve the quality of care in easily reproducible to help detect lung consolidations. children with suspected community or nosocomial LUS has recently emerged as a radiation-free technique; pneumonia in a PICU. it is non-invasive, with a high interobserver [10] agree- The main objectives are: ment for lung pathologies such as consolidation [11], pleural effusion [12], interstitial syndrome [13], and 1. To assess whether a diagnostic algorithm for pneumothorax [14]. To determine the etiology, conven- pneumonia that combines LUS and PCT may be tional microbiology tests such as blood culture, pleural useful in indicating and determining the duration of aspiration, and bronchoalveolar lavage are usual prac- antibiotic treatment. tices, but some of these are invasive, may not detect all 2. To analyse the sensitivity and specificity of LUS, etiologies [15], and the results may not be immediate. compared to CXR, for severe community or Besides this, the use of biomarkers such as procalcito- nosocomial pneumonia. nin (PCT) has become more widespread during the past 10 years, helping clinicians diagnose bacterial etiology, The secondary aims are: especially in patients who have only had a fever for a few hours or those admitted to intensive care units [16–20]. 1. To quantify the irradiation dose avoided using LUS The use of PCT has allowed for a decrease in antibiotic to replace CXR, and to determine if there is an prescription [21, 22], even in nosocomial and commu- associated decrease in costs. nity pneumonia [23, 24]. Despite its role in the diagnosis 2. To analyse interobserver agreement in LUS of pneumonia, PCT values without any other tests may not be a complete diagnostic biomarker for pneumonia. Quality of care is defined by the World Health Inclusion and exclusion criteria Organization as medical care in which the patient is Inclusion: Children under 18 years old with suspected diagnosed and treated correctly, according to current community pneumonia who require admission to the medical knowledge (scientific and technical quality), PICU or patients with suspected nosocomial pneumonia and to their biological factors (optimal state of during their PICU stay. health to attain), with a minimum cost (efficiency), Exclusion: Patients with underlying pathologies such minimum possible exposure to risk for more harm, as cystic fibrosis or who are immunocompromised. Pa- and maximum patient satisfaction [25]. At the hos- tients who develop nosocomial pneumonia after being pital level, a quality assurance plan should include included in the study due to community pneumonia. Pa- different levels of action. The first step is level 1 of tients who have a CXR taken before being admitted to quality promotion, which requires institutional sup- the PICU. port and the availability of clinical and quality proto- Withdrawal and abandonment criteria: Violation of cols. The second step is the research level: study protocol, withdrawal of parental consent, death. descriptive studies for detecting and quantifying a Patients withdrawing or with loss of protocol adher- specific situation or health issue, and the use of da- ence will be excluded from the study. tabases or specific studies to evaluate health services, among others. Therefore, we propose this clinical trial, based on Definitions combining LUS and PCT in an algorithm with the aim to improve quality of care in children with pneumonia – Community pneumonia: Patients with compatible in a PICU. We hypothesize that the diagnostic perform- clinical suspicion (fever, cough, tachypnoea, ance of LUS and PCT will be better than conventional shortness of breath, abnormal respiratory CXR. auscultation sounds, hypoventilation, tubular breath sounds, thoracic or abdominal pain), compatible CXR (lobar consolidation, airspace opacity, pleural Methods and design effusion, bullae, etc.) or LUS, changes in blood with The study is designed as a randomized, blinded clinical a C-reactive protein higher than 50 mg/L and/or trial of children with severe community or nosocomial PCT higher than 1 ng/mL. pneumonia. It will be conducted at a single PICU at Sant – Nosocomial pneumonia: Based on the Clinical Joan de Déu Hospital, a tertiary children’s hospital in Pulmonary Infection Score (CPIS) (Table 1). Barcelona. Period of recruitment and follow-up was – Ventilator-associated pneumonia: defined according from September 2017 to December 2019. to the Center for Disease Control criteria (CDC). Rodríguez-Fanjul et al. Respiratory Research (2020) 21:255 Page 3 of 6 LUS procedure first lung image test. If the paediatrician assistant LUS will be performed by any of the 8 intensive care (PA) requires a CXR, it can be performed, but the physicians who have received standard training in LUS PR will not see the CXR. Patients will be subdivided (Winfocus PNCUS BL1P) and who have at least 3 years into 3 groups: of experience using it. Team sessions focusing on the a. If PCT is < 1 ng/mL and LUS is not suggestive of diagnosis of pneumonia with LUS will be repeated every bacterial pneumonia (normal or viral), the 3 months to ensure quality and consistency in the LUS patient will not receive an antibiotic. exam. The supplemental data included in the Shah et al. b. If LUS is suggestive of bacterial pneumonia, article will be used [26]. regardless of PCT value, an antibiotic will be Subjects will be examined while they are in supine recommended. position. Imaging will be performed using a portable c. If LUS is not suggestive of bacterial pneumonia, ultrasound device (Toshiba® Xario 200). A 12-MHz lin- but PCT values are > 1 ng/mL, an antibiotic will ear or a 5-MHz convex probe will be used, depending be recommended to cover other infectious on the weight or size of the patient. A scan will be taken etiologies. systematically in 3 areas for each hemithorax (anterior, – Control Group 2: CXR will be performed as a first lateral, and posterior), according to international recom- lung image test. Criteria to start an antibiotic will mendations [27]. Each area will be examined longitudin- depend on the current unit protocol. ally and transversally. a. If PCT is < 1 ng/mL and CXR is not suggestive In each area the following will be evaluated [27]: A- of bacterial pneumonia (normal or viral), the lines, B-lines (number and distance between them), lung patient will not receive an antibiotic. sliding (M-mode), pleural space, lung consolidations, b. If CXR is suggestive of bacterial pneumonia, small subpleural consolidations, dynamic air broncho- regardless of PCT value, an antibiotic will be gram, vascular pattern, presence of lung point, and lung recommended. pulse. c. If CXR is not suggestive of bacterial pneumonia, The determination of a bacterial pneumonia ultra- but PCT value is > 1 ng/mL, an antibiotic will be sound pattern will be based on the presence of lung con- recommended to cover other infectious solidation with air bronchograms, which in initial stages etiologies. are detected as small subpleural hypoechoic zones of less than 1 cm with bronchogram (not seen using conven- Radiological and ultrasound patterns will be classified tional CXR) [28–31]. The determination of a viral pneu- as: pneumonia (viral or bacterial), atelectasis, or para- monia ultrasound pattern will be based on the presence pneumonic pleural effusion (Table 2). of B-lines or coalescent B-lines with small subpleural LUS will be performed every day following admission consolidations of less than 1 cm, without bronchogram and recorded and stored. LUS images will be later ana- [32, 33]. lysed by a paediatric radiologist who is an expert in LUS and who has not seen the initial assessment and CXR, in Methodology order to evaluate interobserver agreement. CXR will be The first thing to do will be to obtain consent from the also be reported on by a paediatric radiologist consultant parent(s) or legal guardian(s). who has not seen the other results. Patients who meet the inclusion criteria and sign the inform consent were randomly assigned to two groups Outcomes using the “random” function in MS-Excel XP® program. The antibiotics protocol guided by LUS and PCT will be A binary series of random numbers were generated ac- considered an improvement in the quality of care if a re- cording to the procedure described by Friedman. To duction in the prescription of antibiotics is observed, procure a similar number of patients in both groups, the and also if there is a reduction in the number of days on procedure created the sequence through a balanced antibiotics. Another primary outcome will be the in- block sampling. The series of numbers were held by the crease in the sensitivity and specificity when diagnosing principal investigator and depending on the number of bacterial pneumonia using LUS. Secondary outcomes the patient tit was be assigned to on or another group. A will be the reduction of the irradiation dose using the total of 8 physicians enrolled participants, and the prin- new protocol (with a reduction in economic costs as cipal investigator assigned participants to interventions, well), and a high LUS interobserver agreement. depending on the randomized list. (Fig. 1) Data collection – Experimental Group 1: The paediatrician-researcher The study coordinator will register patients, verifying (PR) performs the LUS at admission/suspicion as the compliance with all the inclusion criteria. An external Rodríguez-Fanjul et al. Respiratory Research (2020) 21:255 Page 4 of 6 company will be appointed to monitor the study and en- factor or not, in terms of quality. The analysis of the in- sure compliance with correct clinical practice principles terobserver agreement will be performed using Cron- (ICHE6). Once the notebooks are audited, they will be bach’s alpha. A p < 0.05 will be considered significant. entered into a validated database, one with restricted ac- The statistical program SPPS® 20.0 will be used. cess by user level, which is equipped with inconsistency detection filters, and which affords data traceability until Discussion the database is no longer needed. Nowadays, care standards are focused on the quality of Data access: All the physicians and clinical researchers care. As the World Health Organization stipulates, the involved in the study, the Ethics Committee, and the patient must be diagnosed and treated correctly. This relevant health authorities will have access to the data. clinical trial is focused on improving the quality of care for paediatric patients with suspected bacterial pneumo- Sample size nia. LUS has good diagnostic accuracy for pneumonia in Sample size calculations will be performed using the stat- children, even if the exam is performed by a nonexpert istical program Ene 2.0®. The main variable will be the ex- physician [35]. Our algorithm will help us to diagnose istence of differences between CXR and LUS in patients bacterial pneumonia accurately, and to prescribe the with community pneumonia and nosocomial pneumonia. correct antibiotic treatment. A reduction in patients on H1 will be considered as the existence of differences be- antibiotics and in the number of days on antibiotics is tween LUS and CXR. An 80% power will be required to expected. Secondarily, a reduction in exposure to ioniz- detect differences in the contrast of the null hypothesis ing radiation and in costs is expected. H0: p1 = p2, using a bilateral X2 test for two independent For many years, LUS has been integrated into the samples. If we consider a significance level of 5%, it will be management of critically ill paediatric and neonatal pa- necessary to include 63 units in the control group and 63 tients at our hospital. Some articles have been published units in the experimental group. A total of 126 patients by our group regarding the use of LUS in different path- will be included for community pneumonia. Twenty-eight ologies, such as prematurity, pulmonary arterial hyper- patients per group will be included for nosocomial pneu- tension, during the postoperative period after monia; therefore, there will be 56 patients in total for this cardiopulmonary bypass, etc. [36–38]. For the applica- kind of pneumonia. After 12 months of recruitment, a tion of this clinical trial, all the researchers will be inten- preliminary analysis will be carried out to guarantee the sivists who are experts in LUS, and regular internal safety of the patients. Respiratory infection represents training will be essential to guarantee objective results. around 30–70% of the PICU admissions, depending on In addition, our group has extensive experience in the the season. There will be an estimated 200–300 recruit- use of PCT for the diagnosis of bacterial infection in able patients per year, so it is expected that the calculated other medical situations, such as after cardiopulmonary sample size will be attainable. bypass in children and new-borns [19, 39]. Furthermore, we have experience in PCT-guided antibiotic policy, with Statistical analysis a reduction in the number of days on antibiotics without Using the “Random” function of the MS-Excel XP® pro- adverse events in children with nosocomial infections gram, a binary series of random numbers will be gener- [40] and in children after cardiopulmonary bypass [22]. ated, according to the procedure described by Friedman [34]. This procedure creates the sequence by means of Conclusion balanced block sampling to ensure a similar number of The use procalcitonin and lung ultrasound algorithm patients in each group. The series of numbers will be in will help us diagnose bacterial pneumonia accurately the possession of the PICU’s head researcher. Depending and prescribe the correct antibiotic treatment. A reduc- on that number, each patient will be assigned to one tion in patients on antibiotics and in a reduction in ex- group or the other. If a patient is randomized but does posure to ionizing radiation and in costs is expected. not complete the treatment, their data will not be ana- This clinical trial is focused on improving the quality of lysed, and their random number will not be reused. care for paediatric patients with suspected bacterial The categorical variables will be compared using the pneumonia. Chi-square test. The quantitative analysis will be com- pared using Student’s t-test or the Mann-Whitney U Supplementary information test, depending on whether the sample follows a normal Supplementary information accompanies this paper at https://doi.org/10. distribution or not. A multivariate logistic regression 1186/s12931-020-01476-z. analysis will be performed on those variables with statis- tical significance or a clear tendency in the univariate Additional file 1 Supplemental Table 1. Clinical Pulmonary Infection Score. analysis to detect which factors represent a protective Rodríguez-Fanjul et al. Respiratory Research (2020) 21:255 Page 5 of 6 Additional file 2 Supplemental Table 2. Summary of the main Ethics approval and consent to participate findings using chest X-rays and lung ultrasound for diagnosing The study will be conducted in accordance with the ICH CP (ICH E6 and ICH pneumonia. E11) and the Declaration of Helsinki. The protocol study was approved by the local Health Care Ethics Committee and the institutional review board of Additional file 3 Supplemental Figure 1. Study protocol diagram. the Sant Joan de Déu Hospital. The identities of the patients will be kept confidential throughout the entire study. Complete filiation data and written consent will be kept in the researcher’s file. The data obtained will be Abbreviations treated according to the Organic Law 3/2018 on Protection of Personal Data. LUS: Lung ultrasound; PCT: Procalcitonin; CXR: Chest X-ray; BN: Bacterial According to this law, the personal data collected from the subjects will be pneumonia; PICU: Pediatric intensive care unit; CPIS: Clinical Pulmonary only those necessary to fulfil the study’s objectives. Study participants will Infection Score; CDC: Center for Disease Control Criteria have the right to access their personal data and to request its rectification or cancellation. Given that the patients included in the study will be minors or Acknowledgments will be in critical condition, in all cases informed consent will be requested Not applicable. from the legal representatives of these patients. Study limitations Consent for publication We expect that with the estimated number of patients, relatively high for a Not applicable. paediatric study, and the homogeneity of the patients suffering from this pathology, we will have sufficient statistical power to obtain reliable data. Another limitation could be that since ultrasound-based assessments are Competing interests user-dependent, there could be interobserver variability. Thanks to the in- The authors declare that they have no competing interests. ternal training program, we believe that this limitation will be minimized. Author details 1 Study status Neonatal Intensive Care Unit, Department of Paediatrics, Hospital Germans This protocol is for a study that it is ongoing, authors are still analysing data. Trias i Pujol, Autonomous University of Barcelona, Badalona, Spain. 2 Paediatric Intensive Care Unit, Hospital Sant Joan de Déu, University of Barcelona, P° Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. Related articles 3 Immunological and Respiratory Disorders in the Paediatric Critical Patient No publications containing the results of this study have been already Research Group, Institut de Recerca Sant Joan de Déu, University of published neither submitted to any journal. Barcelona, Barcelona, Spain. 4Paediatric Infectious Diseases Research Group. Institut de Recerca Sant Joan de Déu, CIBERESP, Barcelona, Spain. Disclosure statement Authors disclose any potential financial or ethical conflicts of interest Received: 3 April 2020 Accepted: 29 July 2020 regarding the contents. Category of study References Clinical trial, Trial Registration: NCT04217980. 1. United Nations Children’s Fund (UNICEF). Commiting to child survival: a What is the key message of your article? promise renewed; 2014. We propose an algorithm to use in the diagnosis of pneumonia to improve 2. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign; 2017. the quality of care in paediatric critical care. 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