https://orcid.org/0000-0002-7278-2289
Figures
Abstract
Objective
This study aimed to assess and determine the presentation, risk factors, and outcomes of pediatric patients who were admitted for cardiac-related chest pain.
Background
Although chest pain is common in children, most cases are due to non-cardiac etiology. The risk of misdiagnosis and the pressure of potentially adverse outcomes can lead to unnecessary diagnostic testing and overall poorer patient experiences. Additionally, this can lead to a depletion of resources that could be better allocated towards patients who are truly suffering from cardiac-related pathology.
Methods
This review was conducted per PRISMA guidelines. This systematic review used several databases including MEDLINE, Embase, Scopus, and Web of Science to obtain its articles for review.
Results
A total of 6,520 articles were identified, and 11 articles were included in the study. 2.5% of our study population was found to have cardiac-related chest pain (prevalence = 0.025, 95% CI [0.013, 0.038]). The most commonly reported location of pain was retrosternal chest pain. 97.5% of the study population had a non-cardiac cause of chest pain, with musculoskeletal pain being identified as the most common cause (prevalence = 0.357, 95% CI [0.202, 0.512]), followed by idiopathic (prevalence = 0.352, 95% CI [0.258, 0.446]) and then gastrointestinal causes (prevalence = 0.053, 95% CI [0.039, 0.067]).
Conclusions
The overwhelming majority of pediatric chest pain cases stem from benign origins. This comprehensive analysis found musculoskeletal pain as the predominant culprit behind chest discomfort in children. Scrutinizing our study cohort revealed that retrosternal chest pain stands as the unequivocal epicenter of this affliction. Thorough evaluation of pediatric patients manifesting with chest pain is paramount for the delivery of unparalleled care, especially in the context of potential cardiac risks in the emergency department.
Citation: Alsabri M, Elshanbary AA, Nourelden AZ, Fathallah AH, Zaazouee MS, Pincay J, et al. (2024) Chest pain in pediatric patients in the emergency department- Presentation, risk factors and outcomes-A systematic review and meta-analysis. PLoS ONE 19(4): e0294461. https://doi.org/10.1371/journal.pone.0294461
Editor: Antoine Fakhry AbdelMassih, Cairo University Kasr Alainy Faculty of Medicine, EGYPT
Received: July 26, 2023; Accepted: October 31, 2023; Published: April 16, 2024
Copyright: © 2024 Alsabri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: CP, Chest Pain; NOS, Newcastle Ottawa Scale; ED, Emergency Department; ICU, Intensive Care Unit
Background
Chest pain stands as one of the most frequently encountered complaints in emergency departments worldwide. While its etiology can span a spectrum from benign to life-threatening, it is crucial to distinguish between these categories for effective patient management. Serious causes of chest pain encompass aortic dissection, pulmonary embolism, and pneumothorax, demanding immediate attention.
On the other hand, non-emergent cardiac factors contributing to chest pain encompass valvular, infectious, or inflammatory conditions. Interestingly, a Study by Chen L et al. aimed to investigate the causes of chest pain in Chinese children and found that causes of chest pain in 7,251 children who visited the hospital during a 15-year period; 53.0% of the cases were idiopathic, 29.1% were related to Musculoskeletal diseases, 9.1% were related to respiratory diseases, 8.0% were cardiac, 0.6% were related to gastrointestinal diseases, 0.16% were related to mental diseases, and 0.04% were related to other conditions [1]. Nevertheless, according to this study, idiopathic chest pain was the most common cause of chest pain [1]. Muscloskeletal chest pain, strains, psychiatric conditions (including panic attacks), and systemic inflammatory and rheumatologic disorders round out the spectrum of potential causes in children, requiring thorough evaluation [1]. According to Januzzi et al., the cost of chest pain totals over 5 billion USD, with over 7 million presentations in emergency departments annually. Cardiovascular causes may be in up to 20% of patients presenting with chest discomfort; only 5.5% of these patients have an acute life-threatening condition, whereas more than 50% of patients presenting with chest discomfort receive a diagnosis of noncardiac pain [2]. On one hand, proper evaluation of chest pain must be done to rule out any significant issues, such as a myocardial infarction. Pope et al. discussed the complications of missed interventions, as missed myocardial infarctions can lead to a doubled risk of mortality after discharge [3]. On the other hand, prolonged assessment of all patients who present to the emergency department with chest pain is burdensome to all facets of the healthcare system. According to McCullough et al., the valuation per quality-adjusted life year (QALY) is over USD100,000 and would still be considered highly cost-ineffective compared with many other strategies and treatments for cardiovascular patients [4]. The goal of care should be to have a criterion that allows for efficient evaluation without unnecessary expenditures and waste of resources.
Chest pain in children without a prior history of cardiac abnormalities or significant family histories is unlikely to be related to a cardiac cause. According to a research article published in the Journal of Pediatric Health Care, a study of 50 children presenting to cardiology with chest pain had the following breakdown: 38 children (76%) had musculoskeletal/costochondral chest pain, 6 children (12%) had exercise-induced asthma, 4 children (8%) had chest pain resulting from gastrointestinal causes, and 2 children (4%) had chest pain resulting from psychogenic causes [5]. In an article written by Dr. Selbst in the Pediatric Clinics of North America journal, the approach to a child with chest pain should be taken seriously because the symptom of chest pain can cause great anguish to the child, disturbing their daily life, and can also create strain on the caretakers due to worry about a more malicious or dangerous pathology [6].
While chest pain in the pediatric population is even more rarely associated with a true cardiac etiology, some important information must be taken into consideration when reviewing past medical records or taking a history [7, 8]. The first would be a history of congenital heart disease. These conditions are often evaluated at birth and are noted for further management or observation in benign cases. Post-congenital causes of pediatric cardiac issues can include infections that can lead to cardiac inflammation, along with more systemic syndromes such as Rheumatic Fever and Kawasaki disease [6–8]. Genetic abnormalities and gene mutations can also lead to specific cardiac issues, such as dilated or hypertrophic cardiomyopathy and even a more systemic condition such as Marfan syndrome [6–8]. These conditions can all lead to chest pain being due to a cardiac etiology and can be effectively deduced through chart review, good history taking, and thorough physical examinations [7, 8]. The main objective of our study is to systematically review the literature that assesses the presentation, risk factors, and outcomes of pediatric patients who were admitted for cardiac chest pain.
Methods
This review was conducted per PRISMA guidelines [9]. All steps were done per the Cochrane Handbook of Systematic Reviews and Meta-analysis of Interventions [10]. Our research question was developed following the key elements of the PICO framework: Participants, Interventions, Comparison, and Outcomes [11]. The protocol was registered in PROSPERO), under number CRD42023397158
Inclusion and exclusion criteria
Both qualitative and quantitative studies were sought. Primary articles that focused on assessing the presentation, risk factors, and outcomes of pediatric (less than 21 years) patients who present to the ED with cardiac chest pain. In particular, articles that mentioned the incidence of cardiac-related chest pain were included in order to compare statistically to the general population of pediatric non-cardiac chest pain in the ED. Time limits were set from 2000 to the present and were included. Secondary or tertiary articles were excluded. Articles published before 2000 and non-English literature were excluded. Studies on the CP adult population (>21 years old), animals, or case series were also excluded. The list of excluded studies is included in the supplementary information. We also excluded studies performed only in urgent care, primary care, emergent medical services, or the ICU. There were no other restrictions regarding the type of ED, and studies performed in urban and community hospitals, public and private ED, academic and non-academic ED, trauma-center level I, II, and III will be included. Any patients aged 21 years or above who present to the ED with complaints of chest pain were excluded.
Data sources and study selection
The literature search strategies were developed using medical subject headings (MeSH) and text words related to chest pain in pediatrics. The following databases were queried for identifying peer-reviewed literature: MEDLINE, EMBASE, SCOPUS, and Web of Science. To ensure literature saturation, we scanned the reference lists of included studies and relevant reviews identified through the screening. Finally, we provided a bibliography of the included articles to the systematic review team. The most recent search was conducted in July 2023. The keywords used for the search are included in the attached supplement (S1 Appendix).
Screening was completed in two stages using the systematic review management program. Articles were screened for relevance based on the title and abstract and then evaluated for inclusion based on the full text. Two reviewers (M.S.Z and A.A.E) independently screened the titles and abstracts. The selection was focused only on peer-reviewed published studies. The reviewers read the full-text articles obtained and selected those that met all inclusion criteria. A third author (M.A) assisted in resolving any disagreements through consensus agreement. We used the input of two researchers at all stages of the analysis. A graphic of the screening and selection process can be seen in Fig 1.
PRISMA flow diagram illustrating the process of study selection for the systematic review and meta-analysis.
Quality assessment of studies
Two assessors independently rated the quality of the studies using the Cochrane Collaboration’s tool. In addition, if discrepancies were presented, these were resolved through discussion and consensus between the analysts. The certainty of evidence was assessed using GRADE methodology [12].
Data extraction
Data were collected on the study characteristics: design, setting, population, sample size, and main objective. Data on prognostic factors and outcomes were also extracted: demographics, clinical presentation, associated symptoms, and risk factors. Missing information on prognostic factors or outcome was requested from the authors.
Data analysis
We extracted and analyzed the data regarding the prevalence of cardiac and non-cardiac emergency causes, which were pooled to calculate overall prevalence estimates with a 95% confidence interval (CI). The random effect model using the DerSimonian-Laird method was applied. We investigated the statistical heterogeneity between studies using the I2 statistics and chi-squared test, with p < 0.1 considered heterogeneous and I2 ≥ 50% suggestive of high heterogeneity. We conducted statistical analyses using Comprehensive Meta-Analysis Software (CMA).
Results
Results of the literature search
A total of 6520 records were identified through searching the four included databases, resulting in 19819 records after discarding the duplicates. Seventy-one records resulted from the title and abstract screening, and after the full-text screening, 11 records were finally included in our systematic review; of them, 10 studies were included in the meta-analysis [13–23]. The selection process is described in the PRISMA flow chart in Fig 1.
Characteristics of the included studies
Our search retrieved 11 studies with 3,052,540 children suffering from chest pain. The reported mean age for studied patients ranged from 10.1 in Massin et al. to 13 years in Pissarra et al. and Lin et al. [18, 19, 23]. All our included studies were retrospective cohorts in design except for Massin et al., which was prospective, and Mohan et al., whose study was quasi-experimental [19, 20]. Only three of our studies reported the location or radiation of pain; Pissarra et al. revealed that the commonest chest pain location among their patients was retrosternal, and Massin et al. reported that two locations were left-sided and diffuse chest pain [19, 23]. However, Ocampo-Vázquez et al. reported that 58% of their patients showed no pain radiation [22]. Throughout the studies, ECG, chest radiography, and Echocardiography were the most demanded investigations. Characteristics and a summary of our included research are displayed in Tables 1 and 2, respectively.
Summary of studies on myocarditis and chest pain presentations, detailing study design, patient demographics, inclusion criteria, and observed symptoms. Beside the study ID the reference number of the study can be found.
Overview of studies examining cardiac and non-cardiac chest pain presentations, including methodologies, findings, and conclusions. Beside the study ID the reference number of the study can be found.
Risk of bias assessment
Most of our included studies demonstrated good quality on NOS assessment. However, most of them did not have an adequate follow-up period. S1 Table shows the detailed assessment of each study and their score in the individual items of the three major domains of NOS (selection, comparability, and outcome).
Quality of studies
The quality of the studies can be viewed in S1 Table. The quality of each study was assessed according to the Newcastle Ottawa Scale. The scores obtained during the analysis ranged from 6 to 8, categorizing all our studies as intermediate to high quality. The overall average NOS score for our studies was 6.7. Given full consideration of our studies, we would categorize the overall quality as intermediate.
Cardiac versus non-cardiac chest pain causes and presentation
Although the cardiac causes of chest pain in our studied population were less common (2.5%), they should be considered in the evaluation of chest pain in order to be excluded. Thus, ECGs and echocardiograms were commonly obtained in patients presenting with chest pain. Pissarra et al. reported that obtained ECG results were abnormal in 77.7% of their patients with cardiac etiologies of chest pain, and Lin et al. reported that 84.5% of the patients had ECG abnormalities [18, 23]. Additionally, Brancato et al. reported that 23.2% of their patients’ ECGs were abnormal [14]. Cardiac causes of chest pain included myocarditis, pericarditis, myopericarditis, myocardial infarction, pulmonary embolism, pneumopericardium, and rhythm disturbances (supraventricular tachycardia, long QT syndrome, premature ventricular contraction). Reporting of previous causes varied among studies: Drossner et al. revealed that six patients had pericarditis, four had myocarditis, three had myocardial infarction, and seven had supraventricular tachycardia [15]; Gesuete et al. showed that 87% of cardiac causes were due to pericardial diseases and 13% were due to dysrhythmia [16]; Massin et al. reported that cardiac problems were identified in only 9 out of 130 patients: three patients had supraventricular reentry tachycardia, two had mitral valve prolapse, and four had sick sinus syndrome, myocarditis with extrasystole, Still disease with pericarditis and cardiac hemochromatosis with left heart failure, respectively [19].
On the other hand, non-cardiac chest pain causes were more commonly identified than cardiac causes (97.5% vs 2.5%). The non-cardiac causes reported in our included studies were as follows: respiratory, gastrointestinal, psychogenic, musculoskeletal, and idiopathic. Of these causes, Lin et al. reported that respiratory problems in their patients were bronchitis in 11 patients, pneumonia in five, asthma in one, pneumothorax in three, and hyperventilation in five, while gastrointestinal causes were due to gastritis in three patients and gastroesophageal reflux in three patients also [18]. Ocampo-Vázquez et al. reported that 29% of patients suffered from gastroesophageal reflux disease, while 14.5% of patients had anxiety crises and 12.4% of patients had idiopathic psychological causes for non-cardiac chest pain [22].
Meta-analysis findings
The prevalence of chest pain causes among the studied population visiting the emergency department was ranked as follows, from most to least common: non-cardiac, musculoskeletal, idiopathic, respiratory, psychogenic, gastrointestinal, and cardiac. Presented are a few specific findings of our analysis for each of these outcomes:
Cardiac causes
Ten studies reported cardiac causes of chest pain among our studied population [15–20, 22, 23]. The pooled prevalence was (0.025, 95% CI [0.013, 0.038]). The pooled studies were heterogeneous with I2 and p-value = (98.7% and > 0.001, respectively). The forest plot for cardiac chest pain outcome is illustrated in Fig 2.
Forest plot illustrating the prevalence of cardiac chest pain across different studies, showing point estimates with 95% confidence intervals and associated statistical parameters. Test for overall effect; p-value = 0.00004, Z-value = 4.0946. Heterogeneity; p-value> 0.001, I2 = 98.7%.
Non-cardiac causes
Non-Cardiac chest pain was reported in 10 studies with pooled prevalence = (0.975, 95% CI [0.962, 0.987]) [13–20, 22, 23]. I2 and p values were (98.7%, and > 0.001, respectively) showing that pooled studies were heterogeneous. The forest plot for non-cardiac chest pain outcome is shown in Fig 3.
Forest plot illustrating the prevalence of non-cardiac chest pain across different studies, showing point estimates with 95% confidence intervals and associated statistical parameters. Test for overall effect; p-value> 0.001, Z-value = 156.7. Heterogeneity; p-value> 0.001, I2 = 98.7%.
Respiratory causes
The overall prevalence of respiratory chest pain outcome pooled from eight studies was (0.13, 95% CI [0.092, 0.168]) [14–20, 22, 23]. The pooled studies were heterogeneous (I2 = 98.6%, p > 0.001). The forest plot for this outcome is illustrated in Fig 4.
Forest plot illustrating the prevalence of respiratory chest pain across different studies, showing point estimates with 95% confidence intervals and associated statistical parameters. Test for overall effect; p-value = 2.698, Z-value = 6.66. Heterogeneity; p-value> 0.001, I2 = 98.6%.
Gastrointestinal causes
Nine studies reported gastrointestinal chest pain outcome in the studied population [14–20, 22, 23]. The pooled prevalence was (0.053, 95% CI [0.039, 0.067]). The pooled studies were heterogeneous with I2 and p-value = (98.4% and > 0.001, respectively). The forest plot for gastrointestinal chest pain outcome is illustrated in Fig 5.
Forest plot illustrating the prevalence of gastrointestinal chest pain across different studies, showing point estimates with 95% confidence intervals and associated statistical parameters. Test for overall effect; p-value = 1.243, Z-value = 7.412. Heterogeneity; p-value> 0.001, I2 = 98.4%.
Musculoskeletal causes
Musculoskeletal chest pain was reported in nine studies with pooled prevalence = (0.357, 95% CI [0.202, 0.512]) [14–20, 22, 23]. I2 and p values were (99.8%, and p > 0.001, respectively) showing that pooled studies were heterogeneous. The forest plot for this outcome is shown in Fig 6.
Forest plot illustrating the prevalence of musculoskeletal chest pain across different studies, showing point estimates with 95% confidence intervals and associated statistical parameters. Test for overall effect; p-value = 6.198, Z-value = 4.52. Heterogeneity; p-value> 0.001, I2 = 99.8%.
Psychogenic causes
The overall prevalence of psychogenic chest pain outcome pooled from six studies was (0.11, 95% CI [0.043, 0.177]) [14, 16, 17, 19, 22, 23]. The pooled studies were heterogeneous (I2 = 98%, p > 0.001). The forest plot for psychogenic chest pain outcome is illustrated in Fig 7.
Forest plot illustrating the prevalence of psychogenic chest pain across different studies, showing point estimates with 95% confidence intervals and associated statistical parameters. Test for overall effect; p-value = 0.0012, Z-value = 3.22. Heterogeneity; p-value> 0.001, I2 = 98%.
Idiopathic causes
Five studies reported idiopathic chest pain outcome among our studied population [14, 17, 18, 22, 23]. The pooled prevalence was (0.352, 95% CI [0.258, 0.446]). The pooled studies were heterogeneous with I2 and p-value = (96.6% and > 0.001, respectively). The forest plot for idiopathic chest pain outcome is illustrated in Fig 8.
Forest plot illustrating the prevalence of idiopathic chest pain across different studies, showing point estimates with 95% confidence intervals and associated statistical parameters. Test for overall effect; p-value = 1.97, Z-value = 7.35. Heterogeneity; p-value> 0.001, I2 = 96.6%.
GRADE assessment
The certainty of evidence assessed in our systematic review is detailed in (S2 Table). According to GRADE, all outcomes were at a very low level of certainty. The causes of their downgrading were the heterogeneity of pooled studies in each assessed outcome and the publication bias as the observational studies are more attributable to it.
Discussion
This systematic review showed important information regarding the etiology of chest pain in children. This is perhaps the first metanalysis that explores the causes of pediatric chest pain. The estimated incidence of sudden cardiac death in children ranges from 0.6 to 6.2 deaths per 100,000, with hypertrophic cardiomyopathy, coronary artery anomalies, and malignant arrhythmias being responsible for many cases, while coinciding with athletic activities [24]. The risk and fear of misdiagnosing can create stressful scenarios for healthcare providers. This can lead to excessive diagnostic testing, which can create poor patient experiences as well as place a great financial burden on the healthcare system. Additionally, determining which children are at risk for sudden cardiac death is challenging due to the frequent lack of alarming symptoms.
Chest pain is common in children and accounts for 0.6% of pediatric emergency department visits [25]. Chest pain always raises concern of cardiac abnormalities, but it is rarely cardiac in origin. When it is, the consequences of misdiagnosis are quite serious. Accurate diagnosis is required to prevent unnecessary emergency department evaluation and cardiology referral. In most cases, after obtaining a thorough history and focused physical examination, no immediate intervention is needed. However, some children may have serious and life-threatening conditions, and a careful evaluation is required in every child presenting with chest pain to determine whether a cardiac condition may exist and guide the evaluation strategy [26]. In general, chest pain associated with exercise, syncope, or palpitations requires further evaluation and workup.
This study showed that cardiac causes of chest pain are rare in children. More specifically, our study shows that only 2.5% of our study population had chest pain that was secondary to a cardiac cause. This supports the previous findings that cardiac-related causes for chest pain in children are very rare [7, 25, 27]. It is worth noting that our review found variation in the specific cardiac pathologies among the included studies. This could have been due to several different factors such as patient location, demographics, institution of care, etc. Pericardial disease was found to be a cause in all three of the studies that mentioned pathological cardiac etiologies, however it was not the most prevalent in all three studies[27, 28].
Regarding specific pediatric cardiac causes, arrhythmias are implicated in many cardiac-related presentations [29]. Supraventricular tachycardia is the most common rhythm disturbance, and ventricular tachycardia or bradycardias are the most ominous rhythms [29]. These presentations are serious and require urgent evaluation and pediatric cardiology consultation.
Our review found 97.5% of our study population have a non-cardiac induced presentation of chest pain. The alternative causes of chest pain reported were respiratory, gastrointestinal, psychogenic, musculoskeletal, and idiopathic. The most prevalent non-cardiac cause of chest pain was musculoskeletal followed by idiopathic and then gastrointestinal. This is consistent with previous studies which have found these causes to be among the most common non-cardiac causes of pediatric chest pain [7, 8, 27]. Despite that there was still variation in the prevalence of these non-cardiac causes in the included studies. The cause of chest pain in many children remains unknown and warrants further investigation for a clearer understanding of pediatric chest pain etiology.
Our review also analyzed reports of chest pain location and radiation of pain to determine common presentations of children with cardiac pathologies. Among the studies that reported this information, the most common presentation of chest pain was retrosternal chest pain. Diffuse chest pain was the second most common reported type of pain. To our knowledge this is the first review to report chest pain location and radiation amongst a study population.
Our findings have clinical relevance and implications as algorithm-based policies are expanding nationally to limit reimbursement for visits for non-emergent causes. These algorithms derive emergent need for ED visits from billing codes rather than the presenting symptoms. It is therefore important to limit the diagnostic workup and reserve it for patients with positive findings on initial assessment. A set of red-flag criteria have been determined to help in the assessment of patients with chest pain [30]. Some red-flag criteria include, but are not limited to, exertional chest pain, exertional syncope, chest pain radiation, and past medical history of sudden cardiac death and hypercoagulable state. If a patient does not exhibit any red-flag criteria at all, then it is likely that the etiology of their chest pain is non-cardiac.
Limitations
This systematic review has several limitations. First, there was significant heterogeneity among the included studies. Second, many studies were retrospective, which did not allow the authors to determine the precise cause of chest pain due to the clinicians not being present at the time of presentation. These studies also have a small patient population with limited follow-up. Furthermore, these results should be interpreted cautiously because only eleven studies could be included in this review. This may be related to our reliance on a relatively limited number of databases for the identification of potentially eligible research studies. Also, it is susceptible to selection bias. There is always a potential for misclassification. For example, a patient may have a significant diagnosis but may be coded with that specific diagnosis rather than the more general chest pain.
Future considerations
In our systematic review, it was noted that the prevalence of cardiac pathologies differed among the included studies. The studies that reported on this all differed in location, demographics, and institution of care. A similar observation was made for the prevalence of non-cardiac causes of chest pain as well. These observations warrant more research to further understand the causes of such variations among study populations.
None of the studies that we reviewed categorized the chest pain location by the specific cause of chest pain. Further investigation is needed in this area of study as it could prove to be an essential tool in the practice of ED physicians who encounter pediatric patients with a chief complaint of chest pain. We also noticed heterogeneity of studies.
Conclusions
Chest pain in children, an infrequent occurrence, typically presents as benign in the realm of pediatric emergency departments and cardiologist’s offices. Within this context, the approach to evaluation is marked by its simplicity and efficacy. A comprehensive history-taking, meticulous physical examination, and a judicious screening electrocardiogram (ECG) often prove to be the sole requisites for excluding the exceedingly rare, yet potentially life-threatening, causes of chest pain in the pediatric population.
The use of laboratory tests remains a selective strategy, triggered only when warranted by the clinical presentation and the findings of the physical assessment. This approach prioritizes precision and resource optimization in the diagnostic process.
Through this study, we aim to enrich available resources at the disposal of physicians, empowering them to navigate the intricacies of assessing pediatric patients with chest pain presentations. By embracing this innovative approach, we hope to enhance the quality of care delivered while concurrently curbing the utilization of unnecessary investigations, thereby advancing pediatric medicine.
Practice points
Most children present with chest pain do not have an underlying cardiac cause. Although evaluation of chest pain is extensive, it rarely yields cardiac etiology. Extensive workup may not be needed in patients for whom a clear etiology, other than cardiac disease, can be determined.
Declarations
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfy the criteria for authorship but are not listed.
We further confirm that the order of authors listed in the manuscript has been approved by all of us.
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In doing so, we confirm that we have followed the regulations of our institutions concerning intellectual property.
Supporting information
S1 Table. Assessing the quality of studies and evaluating the risk of bias using the Newcastle-Ottawa Quality Assessment Scale.
https://doi.org/10.1371/journal.pone.0294461.s003
(PDF)
S2 Table. Assessment of certainty for the etiologies of chest pain.
This table shows the certainty for the etiologies of chest pain.
https://doi.org/10.1371/journal.pone.0294461.s004
(PDF)
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