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Acem 13181
Acem 13181
ABSTRACT
Background: Acute appendicitis (AA) is the most common surgical emergency in children. Accurate and timely
diagnosis is crucial but challenging due to atypical presentations and the inherent difficulty of obtaining a reliable
history and physical examination in younger children.
Objectives: The aim of this study was to determine the utility of history, physical examination, laboratory tests,
Pediatric Appendicitis Score (PAS) and Emergency Department Point-of-Care Ultrasound (ED-POCUS) in the
diagnosis of AA in ED pediatric patients. We performed a systematic review and meta-analysis and used a test–
treatment threshold model to identify diagnostic findings that could rule in/out AA and obviate the need for further
imaging studies, specifically computed tomography (CT) scan, magnetic resonance imaging (MRI), and radiology
department ultrasound (RUS).
Methods: We searched PubMed, EMBASE, and SCOPUS up to October 2016 for studies on ED pediatric
patients with abdominal pain. Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) was used to
evaluate the quality and applicability of included studies. Positive and negative likelihood ratios (LR+ and LR–) for
diagnostic modalities were calculated and when appropriate data was pooled using Meta-DiSc. Based on the
available literature on the test characteristics of different imaging modalities and applying the Pauker-Kassirer
method we developed a test–treatment threshold model.
Results: Twenty-one studies were included encompassing 8,605 patients with weighted AA prevalence of
39.2%. Studies had variable quality using the QUADAS-2 tool with most studies at high risk of partial
verification bias. We divided studies based on their inclusion criteria into two groups of “undifferentiated
abdominal pain” and abdominal pain “suspected of AA.” In patients with undifferentiated abdominal pain,
history of “pain migration to right lower quadrant (RLQ)” (LR+ = 4.81, 95% confidence interval [CI] = 3.59–6.44)
and presence of “cough/hop pain” in the physical examination (LR+ = 7.64, 95% CI = 5.94–9.83) were most
strongly associated with AA. In patients suspected of AA none of the history or laboratory findings were
strongly associated with AA. Rovsing’s sign was the physical examination finding most strongly associated with
AA (LR+ = 3.52, 95% CI = 2.65–4.68). Among different PAS cutoff points, PAS ≥ 9 (LR+ = 5.26, 95% CI =
3.34–8.29) was most associated with AA. None of the history, physical examination, laboratory tests findings,
From the Department of Emergency Medicine (RB, RS) and the Department of Pediatrics (MH), State University of New York/SUNY Downstate
Medical Center, Brooklyn, NY; and the Department of Emergency Medicine (RB, JS, RS) and the Department of Pediatrics (MH), Kings County
Hospital Center, Brooklyn, NY.
Received November 13, 2016; revision received January 17, 2017; accepted February 6, 2017.
The authors have no relevant financial information or potential conflicts to disclose.Supervising Editor: Elizabeth Alpern, MD, MSCI.
Address for correspondence and reprints: Richard Sinert, DO; e-mail: nephron1@gmail.com.
ACADEMIC EMERGENCY MEDICINE 2017;24:523–551.
or PAS alone could rule in or rule out AA in patients with undifferentiated abdominal pain or those suspected
of AA. ED-POCUS had LR+ of 9.24 (95% CI = 6.24–13.28) and LR– of 0.17 (95% CI = 0.09–0.30). Using our
test–treatment threshold model, positive ED-POCUS could rule in AA without the use of CT and MRI, but
negative ED-POCUS could not rule out AA.
Conclusion: Presence of AA is more likely in patients with undifferentiated abdominal pain migrating to the RLQ
or when cough/hop pain is present in the physical examination. Once AA is suspected, no single history, physical
examination, laboratory finding, or score attained on PAS can eliminate the need for imaging studies. Operating
characteristics of ED-POCUS are similar to those reported for RUS in literature for diagnosis of AA. In ED patients
suspected of AA, a positive ED-POCUS is diagnostic and obviates the need for CT or MRI while negative ED-
POCUS is not enough to rule out AA.
patients with abdominal pain. The design of this sys- A meeting was held and any disagreements in study
tematic review and meta-analysis follows the recom- selection were resolved by consensus before a final list
mendations of the Preferred Reporting Items for of included studies was made. A reference list of
Systematic Review and Meta-analyses (PRISMA)27 included studies was reviewed to seek additional stud-
guideline and Meta-analysis of Observational Studies ies that could be included.
in Epidemiology (MOOSE) statement.28
Data Analysis
Search Strategy Sensitivities, specificities, and likelihood ratios (LRs)
In conjunction with a medical librarian, we searched were calculated based on construction of two-by-two
the medical literature in PubMed, EMBASE, and tables for findings of each included study. When more
SCOPUS from their inception up to October 2016 than one study reported a variable, we pooled the data
for search terms diagnosis and appendicitis. See Data using Meta-DiSc software with random-effects model.29
Supplement S1 [available as supporting information in Inter-study heterogeneity was assessed using the
the online version of record of this paper, which is DerSimonian-Laird random-effect model. We pooled
available at http://onlinelibrary.wiley.com/doi/10. data only when I-square was less than 50% and
1111/acem.13181/full] for search strategies and MeSH reported point estimates for variables demonstrating
terms used. The PubMed, EMBASE, and SCOPUS high heterogeneity.
searches were combined and limited to human sub-
jects and English language for three separate search Quality Assessment
topics: history and physical examination, laboratory Two authors (RB, MH) independently assessed the
tests, and ED-POCUS. Narrative reviews, case-control quality and applicability of each included study
studies, and case reports were excluded. using the Quality Assessment Tool for Diagnostic
Accuracy Studies (QUADAS-2).30 Agreement
Study Selection and Data Abstraction between the two reviewers was assessed by calculat-
Two authors (RB, MH) independently selected articles ing kappa using SPSS (IBM SPSS, Version 21,
for each index test category (history and physical exami- IBM Corp.)
nation, laboratory tests, and ED-POCUS) from the Four domains were assessed for biases: 1) patient
combined PubMed, EMBASE, and SCOPUS search selection, 2) index test, 3) reference test, and 4) flow
for the full-text review. Each reviewer independently and timing. Several considerations were established
selected potentially eligible studies. Studies eligible for prior to assessing the quality of individual studies, and
inclusion were those that described patients with the a set of signaling questions was developed for each sec-
maximum age of 21 years presenting to the ED with tion of the QUADAS-2.
either “undifferentiated abdominal pain” or abdominal The ideal study population would be patients who
pain “suspected of AA.” In studies with both adult presented to the ED with abdominal pain and subse-
and pediatric participants, we included only those that quently received both index test and reference test
either presented the data from their pediatric partici- with the interpreter of each test blinded to the results
pants separately or could provide us with that data of the other. An exclusion based on previous history
upon contacting the author. Studies on ED-POCUS of abdominal surgeries other than appendectomy,
were included only if performed and interpreted by an abdominal trauma, or previous workup such as surgi-
ED physician. Studies were included only if provided cal consultation, imaging studies, or laboratory tests
sufficient data to construct two-by-two tables either in were judged to be inappropriate.
the text or after contacting the author. Included studies If the execution of the index test was not clearly
were those which described positive and negative index defined or the index test was performed after knowing
test along with the final diagnosis using a criterion the result of the reference test, that portion of QUA-
standard, histopathologic diagnosis of AA. Among tri- DAS-2 would be at high risk for bias. For laboratory
als on clinical scores, we decided to include only those tests and ED-POCUS the criteria for a positive test
dedicated to PAS, as the most broadly studied clinical needed to be clearly specified for that study to be at
score for the diagnosis of AA in children. We decided low risk of bias. For physical examination, the deci-
not to review Alvarado score as it was originally devel- sion to qualify a finding as positive or negative was left
oped for identifying adult patients at high risk of AA. at physician’s discretion. We assessed the index-
526 Benabbas et al. • DIAGNOSING ACUTE APPENDICITIS IN CHILDREN IN THE ED
n= 2,171
(H&P: 713- Labs: 378-ED-POCUS: 1,080)
(n=86)
-Retrospecve Design (n=37)
Figure 1. Study selection process. H&P = history and physical examination; ED-POCUS: Emergency Department Point-of-Care Ultrasound.
[Color figure can be viewed at wileyonlinelibrary.com]
reference test interval as appropriate if patients tests were conducted in a manner that differed from
received the index test upon presentation to the ED routine clinical practice.
and were sent to the operating room in a timely man-
ner if indicated. If performance of the reference test Test–Treatment Threshold Estimates
was not clearly defined or the interpreter of the refer- We used the Pauker-Kassirer method31 to assess the
ence test was not blinded to the result of the index testing and treatment thresholds for CT scan and
test, that portion of QUADAS-2 would be at risk of MRI and investigated which element(s) of history and
bias. Concerns regarding the applicability of the physical examination, laboratory tests, PAS, or ED-
results of index or reference test were raised if these POCUS could have sufficient discriminatory power to
ACADEMIC EMERGENCY MEDICINE • May 2017, Vol. 24, No. 5 • www.aemj.org 527
Table 1
Description of Reviewed Studies: History, Physical Exam and Lab findings
(Continued)
ACADEMIC EMERGENCY MEDICINE • May 2017, Vol. 24, No. 5 • www.aemj.org 529
Table 1 (continued)
(Continued)
530 Benabbas et al. • DIAGNOSING ACUTE APPENDICITIS IN CHILDREN IN THE ED
Table 1 (continued)
*F/u = Follow-up in patients who were treated nonsurgically. Follow-up was done via telephone unless otherwise specified.
CRP = C-reactive protein; LLQ = left lower quadrant; M = male; NS = not specified; PAS = Pediatric Appendicitis Score; RLQ = right
lower quadrant, T = temperature; WBC = white blood cells.
ACADEMIC EMERGENCY MEDICINE • May 2017, Vol. 24, No. 5 • www.aemj.org 531
characteristics with “pain migration to RLQ” demon- Across studies on patients suspected of AA, most
strating the highest LR+ (1.75, 95% CI = 1.58–1.94) laboratory tests had poor test characteristics (Table 7).
and “anorexia” having the lowest LR– (0.58, 95% Of laboratory tests reported in more than one article,
CI = 0.52–0.65). In patients with undifferentiated CRP > 3 was most suggestive of AA (LR+ = 2.10,
abdominal pain (Table 4) and based on the results 95% CI = 1.61–2.76) while WBC count < 10,000
from a single study (O’Shea et al.109) fever was most was most associated with absence of AA (LR– = 0.21,
suggestive of AA, LR+ 3.4 (95% CI = 2.42–4.76) 95% CI = 0.19–0.25). A combination of WBC count
while absence of fever decreased the probability of AA ≥ 12,000 and CRP > 3 had the highest LR+ (4.36,
the most (LR– = 0.32, 95% CI = 0.16–0.64). 95% CI = 2.26–8.42); however, this combination was
Among studies on patients suspected of AA only described in one101 study (Table 7).
(Table 5), Rovsing’s sign was the physical examination One study, by Bachur et al.,114 on patients with “sus-
finding most suggestive of AA (LR+ = 3.52, 95% pected AA” investigating the effect of age on WBC
CI = 2.65–4.68) while its absence had a minimal count and ANC in AA patients found these variables
effect on probability of AA (LR– = 0.72, 95% CI = to have a better diagnostic performance in older chil-
0.66–0.78). Presence or absence of fever in physical dren. Across reported cutoff points of WBC count
examination (as measured in the ED) did not signifi- (≥5,000 to ≥15,000) LR+ was 1.05 to 1.91 in children
cantly alter the probability of AA (LR+ = 1.13 and younger than 5 years versus LR+ of 1.05 to 5.25 in chil-
LR– = 0.94). Grouping studies based on cutoff point dren older than 12 years. Similarly, across different cut-
used to define fever did not improve the test character- off points of ANC (≥5,000 to ≥15,000), LR+ was 1.25
istics of this variable (Table 6). Only one study (Gold- to 1.87 in children younger than 5 years versus 1.7 to
man et al.14) investigated physical examination 5.85 in children older than 12 years.
findings in patients with undifferentiated abdominal Only one study (Goldman et al.14) reported labora-
pain (Table 4). In Goldman et al.14 study “cough/hop tory tests in patients with undifferentiated abdominal
pain” (LR+ = 7.64, 95% CI = 5.94–9.83) and “right pain (Table 4). In the study by Goldman et al.,14
iliac fossa tenderness” (LR+ = 4.74, 95% CI = 3.94– ANC ≥ 7,500 was most associated with diagnosis of
5.70) were most suggestive of AA. AA (LR+ = 2.33, 95% CI = 1.89–2.88) while
absence of leukocytosis was most associated with
Laboratory Tests absence of AA (LR– 0.22, 95% CI = 0.13–0.36).
Eleven studies provided data on laboratory tests: Ten
studies15,23,94,101,103–105,111,112,114 were done on patients PAS
suspected of AA and one study14 on patients with undif- Seven studies evaluated PAS at different cutoff points.
ferentiated abdominal pain (Table 1). All except for Five studies included patients suspected of AA, Wu
two104,114 were single-center studies. White blood cell et al.108 only included patients with RLQ pain, and
(WBC) count was the most commonly reported labora- Goldman et al.14 included patients with undifferenti-
tory test (10 studies) followed by absolute neutrophil ated abdominal pain. Sample size ranged from 9916 to
count (ANC) or percentage of neutrophils (seven 1,395108.
studies). The cutoff point for WBC count was 10,000 Two studies, Mandeville et al.103 and Goldman
cells/mm3 in nine studies and 12,000 cells/mm3 in one et al.,14 reported data on every possible cutoff point
study (Kwan and Nager101). The cutoff point for ANC for PAS (0–10) while three studies (Schneider et al.,94
varied among studies: ≥7,500 cells/mm3 (Zuniga et al.,15 Khanafer et al.,113 and Escriba et al.16) described data
Goldman et al.14) and ≥6,750 cells/mm3 (Sivitz et al.25). on PAS cutoff points 1 to 10. Bachur et al.23 catego-
One study (Bachur et al.114) investigated various cutoff rized the results in the following groups: PAS < 4,
points of WBC count and ANC in three different age PAS = 4–6, and PAS ≥ 7 and Wu et al.108 described
groups (less than 5, 5–12, and older than 12 years). PAS ≥ 7 cutoff point on days 1 to 3 of presentation.
Several studies reported percentage of neutrophils. For the purpose of this review we only included data
Bachur et al.,23 Mandeville et al.,103 and Schneider collected on Day 1 (at presentation).
et al.94 reported neutrophils ≥ 75% and Santillanes We decided to exclude one study, Escriba et al.,16
et al.111 reported neutrophils ≥ 67%. Other variables from final analysis. Escriba et al.16 used “more than”
studied were D-dimer, C-reactive protein (CRP), urine (>) as the definition of cutoff point. It is unclear
ketones, and procalcitonin. what the authors mean by PAS > 10 as PAS = 10
532 Benabbas et al. • DIAGNOSING ACUTE APPENDICITIS IN CHILDREN IN THE ED
Table 2
Description of Reviewed Studies: ED-POCUS
CT = computed tomography; ED-POCUS = Emergency department point-of-care ultrasound; EM = emergency medicine; F/u = follow-up;
IBD = inflammatory bowel disease; M = male; PEM = pediatric emergency medicine; US = ultrasound.
is the maximum score a patient can get on PAS. of AA (Table 8), the highest LR+s were for PAS = 10
We unsuccessfully tried to contact the author to (LR+ = 5.80), PAS ≥ 9 (LR+ = 5.26), and PAS ≥ 8
clarify this point. In the article by Schneider et al.,94 (LR+ = 4.40) making only highest scores (PAS = 8, 9,
“1 – specificity” was incorrectly reported in place of and 10) good predictors of AA. The results were very
“specificity.” After contacting one of the authors and heterogeneous (I2 = 77.2%–85.6%) for the lowest cut-
confirming that this was in fact an error in print, off points of PAS (PAS = 1, 2, and 3) and therefore
we recalculated the reported specificities and used pooled data could not be calculated. In one study on
the data. patients with undifferentiated abdominal pain
Data from six studies were included in the (Table 9), moderate PAS cutoff points had the highest
meta-analysis, five on patients suspected of AA and LR+ (PAS ≥ 5 with LR+ = 4.56, and PAS ≥ 6 with
Goldman et al.14 on patients with undifferentiated LR+ = 4.07). In Goldman et al.,14 PAS ≥ 0 (LR– =
abdominal pain. Across studies on patients suspected 0.01) and PAS ≥ 1 (LR– = 0.24) had the lowest
Table 3
History Findings in Children Suspected of Appendicitis*
Bachur et al., 201523 728 71 (64–77) 47 (42–40) 1.31 (1.17–1.48) 0.63 (0.50–0.80)
Doniger and Kornblith, 2016110 40 75 (47–93) 54 (33–74) 1.64 (0.97–2.74) 0.46 (0.18–1.16)
Pooled data 3,003 75 (72–78) 44 (42–46) 1.33 (1.26–1.40) 0.58 (0.52–0.65)
Pain migration to RLQ Schneider et al., 200794 588 49 (42–56) 73 (69–78) 1.85 (1.49–2.30) 0.69 (0.60–0.80)
Mandeville et al., 2011103 287 45 (37–53) 64 (56–73) 1.27 (0.95–1.69) 0.85 (0.70–1.03)
Zuniga et al., 201215 101 46 (28–66) 77 (65–86) 1.99 (1.12–3.55) 0.70 (0.48–1.01)
Kentsis et al., 2012102 49 63 (41–81) 72 (51–88) 2.23 (1.11–4.50) 0.52 (0.29–0.92)
Huckins et al., 2013104 503 69 (61–77) 61 (56–66) 1.77 (1.49–2.09) 0.50 (0.39–0.65)
Sivitz et al., 201425 231 50 (38–62) 68 (60–75) 1.55 (1.13–2.14) 0.74 (0.58–0.95)
Bachur et al., 201523 728 50 (43–57) 75 (71–79) 1.99 (1.63–2.43) 0.67 (0.58–0.77)
Cayrol et al., 2016105 134 33 (20–47) 80 (70–88) 1.68 (0.93–3.02) 0.84 (0.67–1.04)
Pooled data 2,621 I2 = 77.6% I2 = 77% 1.75 (1.58–1.94) 0.70 (0.62–0.79)
Pain RLQ Santillanes et al., 2012111 475 91 (86–95) 36 (30–42) 1.42 (1.28–1.57) 0.25 (0.15–0.40)
Khan et al., 2012112 50 82 (60–95) 39 (22–59) 1.35 (0.94–1.92) 0.46 (0.17–1.25)
Cayrol et al., 2016105 134 75 (61–86) 38 (27–49) 1.21 (0.96–1.52) 0.66 (0.38–1.14)
Pooled data 703 I2 = 77.4 37 (32–42) 1.38 (1.26–1.51) I2 = 72.5
Periumbilical Santillanes et al., 2012111 475 50 (43–57) 50 (44–56) 1.0 (0.83–1.21) 0.99 (0.82–1.19)
LLQ Khan et al., 2012112 50 4 (0.1–22) 99 (82–100) 1.27 (0.08–19.22) 0.99 (0.88–1.11)
Epigastric Khan et al., 2012112 50 9 (1–29) 82 (62–93) 0.51 (0.10–2.38) 1.10 (0.95–1.28)
Diffuse Santillanes et al., 2012111 475 30 (24–37) 72 (67–78) 1.08 (0.81–1.45) 0.97 (0.86–1.09)
Khan et al., 2012112 50 4.5 (1–23) 96 (82–100) 1.27 (0.08–19) 0.99 (0.88–1.11)
Pooled data 525 I2 = 88.3% I2 = 90.6% 1.09 (0.81–1.45) 0.98 (0.90–1.06)
(Continued)
533
534
Table 3 (continued)
*Pooled data are reported only when I-square (I2) ≤ 50%. See Table 6 for test characteristics of “fever” based on temperature cutoff point used.
Benabbas et al. • DIAGNOSING ACUTE APPENDICITIS IN CHILDREN IN THE ED
ACADEMIC EMERGENCY MEDICINE • May 2017, Vol. 24, No. 5 • www.aemj.org 535
Table 4
History, Physical Examination and Laboratory Tests Findings in Children With Undifferentiated Abdominal Pain
LR– and therefore PAS = 0 and PAS = 1 were most Fox106 and Doniger and Kornblith110 excluded preg-
suggestive of absence of AA. nant patients. Doniger and Kornblith110 also excluded
those with recent abdominal imaging and Kim
et al.107 did not specify any exclusion criteria. The
ED-POCUS
duration of follow-up in patients who were managed
Five studies24,25,106,107,109 met our inclusion criteria. nonsurgically varied from 2 weeks110 to 6 months.25
All five studies included patients suspected of One study107 did not specify the duration of follow-
AA (Table 2). While four studies were done exclu- up. In four studies,24,25,106,110 the treating and the
sively on pediatric patients, Fox et al.106 included both enrolling physician could be the same. Kim et al.107
adult and pediatric patients; however, they presented did not provide details about their treating physicians.
data for their pediatric population (n = 42) separately. In all studies ED residents and attending physicians
Sivitz et al.25 reported number of positive and nega- or pediatric emergency medicine fellows and attending
tive ED-POCUS studies, which was slightly higher physicians obtained and interpreted the ED-POCUS.
than the sample size suggesting that some patients Fox et al.106 limited the duration of ED-POCUS to 5
received more than one ED-POCUS study. Since the minutes, whereas the rest of the studies did not use
number of scans was close to the sample size (264 such limitation.
ED-POCUS studies in 231 patients), we decided to Elikashvili et al.24 reported significantly higher per-
include this study in our review. In one study (Kim centage of equivocal results compared to all other stud-
et al.107), both EM residents and attending physicians ies in this group. A high number of equivocal results
(either on site or via teleultrasonography) performed in Elikashvili et al.24 can be attributed to the fact that
ED-POCUS on the same group of participants. To full visualization of a normal appendix was mandatory
avoid any overlapping data, we decided to include to consider an ED-POCUS scan negative whereas
only the ED-POCUS scans done on site by residents. other studies in this group did not mandate a full visu-
Sample size varied widely between studies ranging alization. Due to high prevalence of equivocal results
from 40 (Doniger and Kornblith110) to 264 (Sivitz in Elikashvili et al.,24 we decided to exclude this study
et al.25). Four studies24,25,106,110 excluded patients who from our final analysis. Across the remaining four
had unstable vital signs. Sivitiz et al.25 excluded studies,25,106,107,109 ED-POCUS had a sensitivity of
patients with history of abdominal surgery while 86% (95% CI = 79%–90%), specificity of 91% (95%
536 Benabbas et al. • DIAGNOSING ACUTE APPENDICITIS IN CHILDREN IN THE ED
Table 5
Physical Examination Findings in Children Suspected of Appendicitis
Table 6
Fever in Patients Suspected of Appendicitis
Table 7
Laboratory Tests in Patients Suspected of Appendicitis
CI = 87%–94%), LR+ = 9.24 (95% CI = 6.42– 0.82). A meeting was held between two reviewers (RB,
13.28), and LR– = 0.17 (95% CI = 0.09–0.30) mak- MH) and the third author (RS) to resolve any disagree-
ing positive ED-POCUS a good predictor of AA while ments by consensus and all authors agreed 100% on
negative ED-POCUS considerably decreases the proba- the final QUADAS-2 scoring (Figure 3).
bility of AA (Table 10, Figure 2). A sensitivity analysis
adding Elikashvili et al.24 results did not drastically Patient Selection. We found several studies at
change LR+ (9.56 vs 9.24) while significantly increased risk of bias due to inappropriate exclusion: Several
the heterogeneity. studies23,25,94,101,103 excluded patients with history of
any abdominal surgery (and not exclusively appendec-
QUADAS-2 Analysis of Included Studies tomy), abdominal trauma,104,109 or abdominal
Initial inter-rater reliability among the two QUADAS imaging.94,103 Inappropriate exclusion reduces the gen-
reviewers was substantial (j = 0.75, 95% CI = 0.61– eralizability of the results. Certain exclusions can result
538 Benabbas et al. • DIAGNOSING ACUTE APPENDICITIS IN CHILDREN IN THE ED
Table 8
PAS in Patients Suspected of AA
in missing milder cases of AA. For instance, exclusion Index Test. In all studies, the interpreter of the
of all patients without surgical consultation, imaging index test (history and physical examination, laboratory
studies, or laboratory tests.15,23,102,113,114 Several stud- tests, PAS, or ED-POCUS) was blinded to the refer-
ies15,16,23,94 excluded all patients in whom missing ence test (operative report and histopathology). In all
data prevented investigators from calculating PAS, of the studies on laboratory tests or ED-POCUS, crite-
which can introduce significant bias. It is unclear how ria for a positive test were prespecified. For physical
this bias skews the results; more severe cases of AA examination, whether to qualify a finding as positive
might have received less workup and were sent straight or negative was left at the discretion of the treating
to surgery and therefore miss data for calculating PAS. physician.
On the other hand, patients least suspected of having
AA might have been discharged without any labora- Reference Test. Surgery and histopathologic exam-
tory tests and therefore miss data for calculating PAS. ination of removed tissue was used as the reference test
ACADEMIC EMERGENCY MEDICINE • May 2017, Vol. 24, No. 5 • www.aemj.org 539
Table 9
PAS in Patients with Abdominal Pain
Table 10
ED-POCUS in Patients Suspected of Appendicitis
in all studies. With the exception of three studies (Kent- and PAS in patients suspected of AA are at a high
sis et al.,102 Khanafer et al.,113 Fox et al.106) all trials risk of partial verification bias. Partial verification bias,
failed to specify if the interpreter of the reference test as described by Kohn et al.,116 occurs when the result
(pathologist) was blinded to the results of the index of the index test determines who receives the reference
tests; this can introduce incorporation bias. Incorpora- test. In studies that included only patients suspected
tion bias is likely when the result of the index test can of AA, the index tests (history, physical examination,
determine whether the reference test classifies patients and labs) are already used to decide who enters the
as disease-positive or disease-negative. In several studies study and later receives the reference standard.
the pathologist was solely blinded to the main index Although PAS was not used independently as an
test. For instance, in Schneider et al.,94 Goldman inclusion criterion, the risk of partial verification bias
et al.,14 and Bachur et al.23 the interpreter of the refer- is still high given that PAS is calculated using a combi-
ence test (pathologist) was blinded to the final calculated nation of history, physical examination, and laboratory
PAS but not necessarily to the components of PAS findings. Partial verification bias could inflate estimates
(history, physical examination, and laboratory tests). of sensitivity while underestimating the specificity of
Similarly, in studies by Khan et al.,112 Cayrol et al.,105 index tests.
and Huckins et al.104 pathologist was blinded to the We found all studies at high risk of differential verifi-
main laboratory test studied but not to the history, cation bias. Differential verification bias, also called
physical examination findings, or other laboratory tests “double gold standard bias”, can occur when patients
and in Sivitz et al.,25 pathologist was only blinded to with a positive index test are more likely to receive an
ED-POCUS. immediate reference test whereas those with negative
index test receive only clinical follow-up.116 All trials
Flow and Timing. Studies that examine the accu- used follow-up as an alternate for histopathology in
racy of history, physical examination, laboratory tests, patients undergoing nonsurgical management. Although
540 Benabbas et al. • DIAGNOSING ACUTE APPENDICITIS IN CHILDREN IN THE ED
Figure 2. Forest plots—operating characteristics of ED-POCUS. LR = likelihood ratio. [Color figure can be viewed at wileyonlinelibrary.com]
no case of AA was reported in the follow-up group, cases searching electronic records101,113 or contacting patient’s
of self-resolving AA are reported in the literature.117,118 pediatrician,94 the risk of missing AA still exists. Loss to
Furthermore, most included studies did not specify if follow-up, even in small numbers, can introduce signifi-
they discharged any patient on antibiotics, which can cant bias.120,121
result in resolution of milder cases of AA.119 Differential In four studies24,25,106,110 on ED-POCUS, the treating
verification bias can falsely increase the calculated sensi- and the enrolling physician were the same in all or some
tivity and specificity of the index test.116 The risk of bias patients, which introduces differential verification bias
is higher in the study by Huckins et al.104 due to lack of since the results of ED-POCUS could influence further
follow-up or in those studies16,25,94,101,103,106–108,111,113 testing and determine who receives the reference test.
that lost patients to the standard follow-up. Although Sivitz et al.25 reduced this risk by blinding the treating
some of these studies tried alternative follow-up such as physician to the results of ED-POCUS when possible.
ACADEMIC EMERGENCY MEDICINE • May 2017, Vol. 24, No. 5 • www.aemj.org 541
Figure 3. QUADAS-2 assessment of included studies. QUADAS-2 = Quality Assessment Tool for Diagnostic Accuracy Studies. [Color figure
can be viewed at wileyonlinelibrary.com]
Doniger and Kornblith110 and Fox et al.106 decreased reviews. In a review of 26 articles with a total popula-
the risk of differential verification bias by ensuring that tion of 9,356 pediatric patients, Doria et al.122 reported
the treating physician made any decision regarding 94% sensitivity and 95% specificity for CT scan. Moore
diagnosis and treatment approach before performing the et al.123 reviewed 11 studies, encompassing 1,698 pedi-
ED-POCUS. Kim et al.107 did not specify whether their atric patients, and found MRI to be 96.5% sensitive
enrolling and treating physician were the same. and 96.1% specific in diagnosis of AA.
Several studies were at risk of bias due to exclusion We defined Rrx as the risk of mortality and morbid-
of subgroups of their enrolled patients from the final ity following appendectomy. Aziz et al.124 reviewed 23
analysis: Khanafer et al.,113 Bachur et al.,23 Schneider studies with a total population of 6,477 and found the
et al.,94 Wu et al.,108 Zuniga et al.,15 Khan et al.,112 risk of complications, including wound infection, to be
and Escriba et al.16 excluded patients due to incom- 1.5% to 4.9% depending on the technique used (open
plete data or missing data. Fox et al.,106 Mandeville and laparoscopic appendectomy, respectively). In a
et al.,103 Santillanes et al.,111 Wu et al.,108 Escriba review of nine studies with a total population of
et al.,16 and Kim et al.107 excluded patients who were 65,995, Healy et al.125 reported the overall risks of
lost to follow-up from the final analysis, and Kentsis intraabdominal collection formation, wound infection,
et al.102 excluded patients with perforated AA who and readmission to be 2.4, 1.8, and 1.5%, respectively.
underwent interval appendectomy. Based on the literature we estimated Rrx to be 0.05.
We judged the risk of the diagnostic test (Rt) as
Test–Treatment Threshold Estimates 0.00026 for CT scan and zero for MRI. The risk of
We used the method of Pauker and Kassirer31 to estimate CT scan is based on the lifetime risk of radiation-
thresholds for testing or treatment when caring for a pedi- induced cancer following a single abdominal CT scan
atric patient with abdominal pain in the ED. Operative in a 5-year-old (20/100,000 in males and 26/100,000
characteristics for ED-POCUS (Table 10; sensitivity = in females).126
86%, specificity = 91%) were very similar to those of Finally, the Brx of patients with AA has never been,
RUS (sensitivity = 88%, specificity = 94%) reported in nor ever will be, tested by a randomized double-
the literature122 and therefore we decided to remove blinded placebo-controlled methodology; it would be
RUS from our test–treatment threshold model. This unethical to study the spontaneous recovery rate of
model utilizes the unique operating characteristics of each AA without antibiotics or surgery. Without available
diagnostic modality (CT scan and MRI) while controlling evidence we used a conservative estimate for the bene-
for the risk of treatment (Rrx), risks associated with each fit of treating AA (Brx = 0.90).
diagnostic modality (Rt), and the benefit of treatment In the lower half of the Figure 4, the test thresholds
(Brx). Variables are presented as probabilities. are depicted as the left-most open arrow for each diag-
In Figure 4, we created two test–treatment threshold nostic modality (CT scan 0.3% and MRI 0.2%). The
models: 1.CT scan and 2.MRI. The top half of treatment thresholds are represented by the right-most
Figure 4 describes the variables and calculations used open arrow for each diagnostic modality (CT scan
to produce the test and treatment thresholds for CT 46.5% and MRI 60.4%).
and MRI. We used the operating characteristics of CT The vertical dashed lines represent the post-test
scan and MRI documented in recent systematic probabilities of AA in the presence of a negative or a
542 Benabbas et al. • DIAGNOSING ACUTE APPENDICITIS IN CHILDREN IN THE ED
positive ED-POCUS. Applying Bayes theorem and Across history and physical examination findings,
using the AA prevalence in patients suspected of AA only cough/hop pain (LR + 7.64) showed high
(42.8%) as the pretest probability, a negative ED- enough LR+ to obviate the need for CT scan (but not
POCUS (LR– = 0.17) would result in a decrease in MRI) in patients with “undifferentiated AA.” How-
the posttest probability from 42.8% to 11% repre- ever, this finding is from a single study and therefore
sented by the left-most vertical dashed line. In case of the results may not be generalizable. No history, physi-
a positive ED-POCUS (LR+ = 9.24), the posttest cal examination, laboratory test, or PAS cutoff point
probability of AA would increase from 42.8% to 87% had a low enough LR– to exclude AA without use of
represented by the right-most vertical dashed line. CT or MRI. In patients suspected of AA, it is inaccu-
As seen in Figure 4, the far right vertical dashed rate to estimate the posttest probability of AA based
line (the probability of AA in presence of a positive on the operating characteristics of history, physical
ED-POCUS, 87%) falls to the right of the treatment examination, laboratory tests, and PAS due to high
threshold for both diagnostic modalities (46.5% for risk of the biases mentioned earlier.
CT scan and 60.4% for MRI). Therefore, in a patient The test–treatment model presented here is an
suspected of AA, a positive ED-POCUS could obviate interactive tool and some variables can be modified in
the need to perform CT scan or MRI and treatment the Microsoft Excel calculator published online (Data
can be initiated. The far left vertical dashed line (the Supplement S2, available as supporting information
probability of AA after a negative ED-POCUS, 11%) in the online version of record of this paper, which is
falls to the right of the test threshold for both CT scan available at http://onlinelibrary.wiley.com/doi/10.1111/
(0.3%) and MRI (0.2%) and, therefore, negative ED- acem.13181/full). For instance, we judged the Rrx to
POCUS is not sufficient to rule out AA without the be 5%. Assigning a greater risk to appendectomy,
need for CT scan or MRI. based on the clinical judgment, will result in an
Based on this model, in patients with undifferenti- increased treatment threshold and therefore additional
ated abdominal pain (pretest probability of 13.4%) a testing may be needed.
test needs to have LR+ > 5.8 and LR+ > 11 to estab-
lish the diagnosis of AA without the need for CT and
DISCUSSION
MRI, respectively. In the same population, a test with
LR– < 0.03 can rule out AA obviating the need for Our systematic review examined the utility of history,
CT and MRI (posttest probability = 0%). physical examination, laboratory results, PAS, and ED-
and reported a sensitivity of 100% and specificity of Khanafer et al.113) for a total of eight studies
92%. However, numerous studies aiming to validate (N = 4,128). One criticism to the review by Ebell and
PAS have not found such favorable operating charac- Shinholser127 is inappropriately pooling of the data
teristics.94,103,113 Moreover, studies that aim to validate from studies with different inclusion criteria and
PAS in a cohort of patients suspected of AA are at heterogeneous results128 (I2 = 91%–96%). Although
considerable risk of partial verification bias. Patients we grouped studies with similar inclusion criteria
suspected of AA are more likely to be positive for together, we still observed heterogeneous results for
many variables of PAS (Table 11) and consequently most cutoff points of PAS (I2 = 75%–94%). Even
assigned a higher final score. The use of the operating studies with similar settings and AA prevalences had
characteristics of PAS, derived from a series of studies heterogeneous results. We unsuccessfully attempted to
with such bias and their reapplication on patients sus- contact the authors of the included studies to utilize
pected of AA, substantially increases the risk of bias. their raw data to calculate interval LRs instead of using
A similar logic applies to any other scoring arbitrary cutoff point and therefore decrease hetero-
system13,93,95,98 derived and validated on patients sus- geneity.
pected of AA. Studies on patients with undifferenti- One possible explanation for high heterogeneity
ated abdominal pain are at lower risk of such bias. observed across PAS studies is that six of eight vari-
We could only find one study that met our inclu- ables composing the PAS are history and physical
sion criteria and tested PAS in patients with undif- examination findings and therefore examiner-depen-
ferentiated abdominal pain and thus at lower risk of dent. In one recent study focusing solely on the
partial verification bias. Goldman et al.14 suggested interexaminer reliability of history and physical exami-
PAS ≥ 7 to be diagnostic of AA and PAS ≤ 2 to nation findings in pediatric abdominal pain patients
have high validity for ruling out AA. However, with and without AA,129 only vomiting showed high
using the data from Goldman et al.14 (pretest proba- interexaminer reliability (j = 0.82) with other findings
bility of 14.5%) and applying Bayes theorem, in failing to show acceptable interexaminer reliabilities
patients with undifferentiated abdominal pain and (j = 0.14–0.54). Yen et al.130 also found poor interex-
PAS ≥ 7, the posttest probability of AA would aminer reliability of physical examination findings in
increase to only 32%, which is lower than the treat- pediatric patients with abdominal pain (j = 0.13–
ment threshold for both CT scan (46.5%) and MRI 0.54). When most components of a clinical score are
(60.4%). In the same population but with PAS ≤ 2, inherently at risk of low reproducibility, it is only natu-
the posttest probability of AA would decrease to ral for the end results to be heterogeneous as well.
7%, which is above the test threshold for both CT Observing the high heterogeneity and poor opera-
scan (0.3%) and MRI (0.2%). Therefore, neither ting characteristics of history, physical examination,
PAS ≥ 7 nor PAS ≤ 2 can eliminate the need for laboratory tests, and PAS, we decided to investigate
CT scan or MRI. According to our test–treatment the operating characteristics of ED-POCUS. Test char-
model, only PAS = 0 decreases the posttest probabil- acteristics of ED-POCUS were similar to those of
ity of AA low enough to obviate the need for CT RUS as reported by Doria et al.122 (sensitivity = 86%
or MRI. In other words, if a patient with undiffer- vs. 88% and specificity = 91% vs. 94%). Therefore,
entiated abdominal pain is negative for all
variables of PAS, the probability of AA is nearly
0% and the patient can be discharged without fur- Table 11
ther investigation. Variable of Pediatric Appendicitis Score (PAS)
we decided not to include RUS in our test–treatment In one RCT in children, Svensson et al.131 treated
threshold model. 24 pediatric patients suspected of AA with antibiotics
Using our test–treatment threshold model (Fig- alone while 26 were sent to surgery. During the
ure 4) in patients suspected of AA (pretest probabil- follow-up period of 1 year, two patients (8%)
ity of 42.8%) and a positive ED-POCUS, the had appendectomy with pathologically proven AA.
physician can assume the diagnosis of AA (posttest This is similar to the recurrence rate in antibiotic ther-
probability of 87%) without the need for CT scan apy in pediatric patients with complicated AA with or
or MRI. A negative ED-POCUS decreases the postt- without interval appendectomy.135 Based on the litera-
est probability of AA from 42.8% to 11% exceeding ture,131–133,136–138 we hypothesized the risk of antibio-
the testing threshold for CT (0.3%) and MRI tic treatment failure to be 10 to 20 percent. Therefore,
(0.2%), and further investigation is recommended. the risk of recurrence in ED-POCUS–negative patients
The low testing threshold of CT scan and MRI can discharged on antibiotics will be 1% to 2%. This is a
be attributed to a combination of high benefit of rough estimate considering that most trials on treating
treatment, low risk associated with these diagnostic AA patients with antibiotics are not RCTs and, there-
modalities, and the low complication rate of appen- fore, at substantial risk of selection bias. Whether or
dectomy. In fact, to obviate the need for CT and not to accept the risk of treatment failure depends on
MRI using ED-POCUS, the pretest probability must physician’s clinical judgment and the setting in which
be lower than 2.8%, which is extremely unlikely in patient is being treated. If patient can be followed and
a patient evaluated for abdominal pain “suspected of transferred to a hospital in case of a recurrence, 1% to
AA”. Factors such as availability of radiology modali- 2% may be a reasonable risk to accept. However, if
ties, cost of treatment, and length of stay undeniably the treating physician has high clinical suspicion for
play important roles in a real-life setting. However, AA despite negative ED-POCUS or anticipates poor
such factors are beyond the scope of this review medication compliance or loss to follow-up, using CT
and are not accounted for within the aforemen- scan or MRI to make the final diagnosis may be a
tioned calculations. better approach.
In a patient with negative ED-POCUS, the decision
to use further imaging studies, observe in the ED,
obtain surgical consultation, or discharge to home is LIMITATIONS
based on treating physician’s clinical judgment. An We excluded all studies in languages other than Eng-
alternative management approach to performing CT lish, which can decrease the generalizability of the
or MRI in patients with negative ED-POCUS could findings. We did not have access to patient-level data;
be antibiotic therapy. While nonoperative manage- therefore, it was impossible to evaluate the effect of
ment of AA is not the main focus of this review, we factors such as severity of the disease, ethnicity, or
briefly address it here given the increasing evidence socioeconomics. All studies on ED-POCUS included
supporting this approach. Antibiotic therapy is a com- in this review were performed in academic settings
mon practice in pediatric patients with complicated decreasing the generalizability of the results to other
AA but less studied in uncomplicated AA. Few stud- settings.
ies on this subject131–133 demonstrated no difference
in the rate of postoperative complications between
children who underwent appendectomy after failure of CONCLUSIONS
antibiotic therapy and those who were treated surgi-
While the aim of this review is not to provide a prac-
cally upon first presentation of AA. This is similar to
tice guideline, the results can be used by physicians to
the findings from the adult population. In a system-
make decisions in the ED when caring for a child
atic review of five randomized controlled trials (RCTs)
with abdominal pain. The following is the summary
in adult patients with uncomplicated AA, Rollins
of our findings:
et al.134 showed that risk of complications was lower
in those who had appendectomy following “failure” of • In patients presenting to the ED with undifferenti-
antibiotic therapy compared to those who underwent ated abdominal pain, migration of pain to the right
appendectomy upon their first presentation (10.9% vs lower quadrant or presence of cough/hop pain in
17.9%). physical examination increases the probability of
546 Benabbas et al. • DIAGNOSING ACUTE APPENDICITIS IN CHILDREN IN THE ED
acute appendicitis. Once acute appendicitis is sus- 3. Becker T, Kharbanda A, Bachur R. Atypical clinical features
pected, no single history, physical examination, lab- of pediatric appendicitis. Acad Emerg Med 2007;14:124–9.
oratory finding, or Pediatric Appendicitis Score 4. Nance ML, Adamson WT, Hedrick HL. Appendicitis in
result can confirm the diagnosis without the need the young child: a continuing diagnostic challenge. Pedi-
atr Emerg Care 2000;16:160–2.
for imaging studies.
• The pooled operating characteristics for ED point-
5. Davenport M. Acute abdominal pain in children. BMJ
1996;312:498–501.
of-care ultrasound in this review are similar to
6. Marzuillo P, Germani C, Krauss BS, Barbi E. Appendici-
those reported for radiology department ultrasound tis in children less than five years old: a challenge for the
in the literature. If the operator of ED point-of-care general practitioner. World J Clin Pediatr 2015;4:19–24.
ultrasound has similar expertise and training as 7. Bundy DG, Byerley JS, Liles EA, Perrin EM, Katznelson
operators in our included studies, ED point-of-care J, Rice HE. Does this child have appendicitis? JAMA
ultrasound can replace radiology department ultra- 2007;298:438–51.
sound for the diagnosis of acute appendicitis. 8. Bratton SL, Haberkern CM, Waldhausen JH. Acute
• In a pediatric patient suspected of acute appen- appendicitis risks of complications: age and Medicaid
dicitis, a positive ED point-of-care ultrasound is insurance. Pediatrics 2000;106:75–8.
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pediatric patients. Pediatr Emerg Care 2006;22:475–9.
dicitis without the use of computed tomography
10. Narsule CK, Kahle EJ, Kim DS, Anderson AC, Luks FI.
scan or magnetic resonance imaging.
Effect of delay in presentation on rate of perforation in
children with appendicitis. Am J Emerg Med
Areas of Future Research 2011;29:890–3.
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Pediatric Appendicitis Score on the emergency depart-
observed without surgery undergo a complete follow-
ment of a secondary level hospital. Pediatr Emerg Care
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The authors thank Christopher Stewart, senior assistant librarian Emerg Care 2011;27:165–9.
at SUNY Downstate Medical Center, for his help in formulating 17. Bhatt M, Joseph L, Ducharme FM, Dougherty G, McGil-
the literature searches. livray D. Prospective validation of the Pediatric Appen-
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