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ORIGINAL ARTICLE
Multicenter Study of the Treatment of Appendicitis in America
Acute, Perforated, and Gangrenous (MUSTANG), an EAST Multicenter Study
Daniel Dante Yeh, MD MHPE,  Y Ahmed I. Eid, MD,y Katelyn A. Young, BS,z Jeffrey Wild, MD,z
Haytham M. A. Kaafarani, MD MPH,y Mohamed Ray-Zack, MD,§ Tala Kana’an, MBBS,§ Ryan Lawless, MD,ô
Alexis L. Cralley, MD,ô and Marie Crandall, MD MPHjj, for the EAST Appendicitis Study Group
Objective: We sought to describe contemporary presentation, treatment, and
outcomes of patients presenting with acute (A), perforated (P), and gangre-
nous (G) appendicitis in the United States.
Summary Background Data: Recent European trials have reported that
medical (antibiotics only) treatment of acute appendicitis is an acceptable
alternative to surgical appendectomy. However, the type of operation (open
appendectomy) and average duration of stay are not consistent with current
American practice and therefore their conclusions do not apply to modern
American surgeons.
Methods: This multicenter prospective observational study enrolled
adults with appendicitis from January 2017 to June 2018. Descriptive
statistics were performed. P and G were combined into a ‘‘complicated’’
outcome variable and risk factors were assessed using multivariable logistic
regression.
Results: A total 3597 subjects were enrolled across 28 sites: median age was
37 (27–52) years, 1918 (53%) were male, 90% underwent computed tomog-
raphy (CT) imaging, 91% were initially treated by appendectomy (98%
laparoscopic), and median hospital stay was 1 (1–2) day. The 30-day rates
From the Ryder Trauma Center, Miami, FL; yMassachusetts General Hospital,
Boston, MA; zGeisinger Medical Center, 100 N Academy Ave., Danville, PA;
§Mayo Clinic, Rochester, MN; ôDenver Health, Denver, CO; and jjUniversity
of Florida Jacksonville, Jacksonville, FL.
Y dxy154@miami.edu.
EAST Appendicitis Study Group (alphabetically by center): Baystate Medical
Center—Reginald Alouidor, MD, FACS (Reginald.alouidor@baystatehealth.-
org), Kailyn Kwong Hing, MD (kailyn,kwonghingmd@bhs.org); Beaumont
Hospital—Victoria Sharp, DO (vsharpdo@gmail.com), Kelly Dinnan DO,
FACOS (Kelly.dinnan@beaumont.org); Boston Medical Center—George
Kasotakis, MD, MPH, FACS(George.kasotakis@duke.edu), Sean Perez, BS
(seanpz@bu.edu); Carilion Clinic—Stacie L. Allmond, DO (slallmond@car-
ilionclinic.org), Bruce Long, MD, FACS (balong@carilionclinic.org); Cooper
University Hospital—Nadine Barth, MD, FACS (barth-nadine@cooper-
health.edu), Janika San Roman, MPH (sanroman-janika@cooperhealth.edu);
Denver Health—Ryan A. Lawless, MD FACS (ryan.lawless@dhha.org),
Alexis L. Cralley, MD (alexis.cralley@dhha.org); Emory University—Rondi
Gelbard, MD, FACS (rgelbard@hotmail.com), Crystal Szczepanski, MSN, NP-
C, ACNP-BC (cszczep@emory.edu); Essentia Health—Steven Eyer, MD,
FACS (steven.eyer@essentiahealth.org), Kaitlyn Proulx, PA (Kaitlyn.proul-
x@essentiahealth.org); Geisinger Medical Center—Jeffrey Wild, MD, FACS
(jwild80@yahoo.com), Katelyn A. Young, BS (kayoung1@geisinger.edu);
Inova Fairfax—Erik J. Teicher, MD, FACS (erik.teicher@inova.org), Elena
Lita, BS, (elena.lita@inova.org); Intermountain Medical Center—David
Morris, MD, FACS (dave.morris2@imail.org), Laura Juarez, PA-C (laurae-
juarez@outlook.com); Loma Linda University—Richard D. Catalano, MD,
FACS (rcatalano@llu.edu), David Turay, MD, PhD, FACS (dturay@llu.edu);
Marshfield Clinic—Daniel C. Cullinane, MD, FACS (cullinane.daniel@-
marshfieldclinic.org), Jennifer C. Roberts, MD (Roberts.jennifer@marshfield-
clinic.org); Massachusetts General Hospital—Haytham M.A. Kaafarani MD,
MPH, FACS (hkaafarani@partners.org), Ahmed I. Eid, MD (ahme-
deid1983@gmail.com); Mayo Clinic—Mohamed Ray-Zack, MD (ray-
zackmd@gmail.com), Tala Kana’an, MBBS (kanaan.tala@mayo.edu);
Medical City Plano—Victor Portillo, MD, FACS (victor.portillo@emcare.-
com), Morgan Collom, DO (morgancollom@gmail.com); Medical College of
Wisconsin—Chris Dodgion, MD, FACS (cdodgion@mcw.edu), Savo Bou
Zein Eddine, MD (savobouzeineddine@gmail.com); North Shore Medical
Annals of Surgery  Volume XX, Number XX, Month 2019
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
of Emergency Department (ED) visit and readmission were 10% and 6%. Of
219 initially treated with antibiotics, 35 (16%) required appendectomy during
index hospitalization and 12 (5%) underwent appendectomy within 30 days,
for a cumulative failure rate of 21%. Overall, 2403 (77%) patients had A,
whereas 487 (16%) and 218 (7%) patients had P and G, respectively. On
regression analysis, age, symptoms >48 hours, temperature, WBC, Alvarado
score, and appendicolith were predictive of ‘‘complicated’’ appendicitis,
whereas co-morbidities, smoking, and ED triage to appendectomy >6 hours
or >12 hours were not.
Conclusion: In the United States, the majority of patients presenting
with appendicitis receive CT imaging, undergo laparoscopic appendectomy,
and stay in the hospital for 1 day. One in five patients selected for initial
non-operative management required appendectomy within 30 days. In-hos-
pital delay to appendectomy is not a risk factor for ‘‘complicated’’ appendi-
citis.
Keywords: appendectomy, appendicitis, United States
(Ann Surg 2019;xx:xxx–xxx)
Center—Maryam B. Tabrizi, MD, FACS (mtabrizi@partners.org), Ahmed I.
Eid, MD (ahmedeid1983@gmail.com); Ryder Trauma Center—D. Dante
Yeh, MD, MHPE, FACS (dxy154@miami.edu), Georgia Vasileiou, MD (geor-
gia.vas@gmail.com); Ohio State University Wexner Medical Center—
David C. Evans, MD, FACS (davidevansMD@gmail.com), Daniel E. Vazquez,
MD, FACS (Daniel.vazquez@osumc.edu); St. Vincent Hospital Indianapo-
lis—Jonathan Saxe, MD, FACS (jonathan.saxe@stvincent.org), Lewis Jacob-
son, MD, FACS (lejacobs@ascension.org); Oregon Health Sciences
University—Brandon Behrens, MD (behrensb@ohsu.edu), Martin Schreiber,
MD, FACS (schreibm@ohsu.edu); University of Arizona, Tucson—Bellal
Joseph, MD, FACS (bjoseph@surgery.arizona.edu), Muhammad Zeeshan, MD
(mzeeshan@surgery.arizona.edu); University of California, Irvine—Jeffry
Nahmias, MD, MHPE, FACS (jnahmias@uci.edu), Beatrice Sun, BS
(sunbj@uci.edu); University of Florida, Jacksonville—Marie Crandall,
MD, MPH, FACS (marie.crandall@jax.ufl.edu), Jennifer Mull, MSN, RN,
CCRC (Jennifer.mull@jax.ufl.edu); University of Maryland—Jason D. Pas-
ley, DO, FACS (jpasley999@gmail.com), Lindsay O’Meara (lomeara@um-
m.edu); University of Southern California—Ali Fuat Kann Gok, MD
(ag_075@usc.edu), Jocelyn To, BS (jocelyntoe@gmail.com); Walter Reed
National Military Medical Center—Carlos Rodriguez, DO, FACS
(nycom99@hotmail.com), Matthew Bradley, MD, FACS (matthew.j.bra-
dley22.mil@mail.mil).
Participating investigators listed alphabetically by last name: Andrew Benson, BS;
Ashley Boyer, PA-C; Benjamin Dixson, BA; Cesar Figueroa, MD; Rebecca E.
Jackson, MS; Wilson D. Lo, BS; Anna B. Newcomb, PhD, MSW, LCSW; Liz
G. Penaloza, MD; Juan Quispe, MD; Kim Roadarmel; Caitlin K. Robinson, BS;
Kathy Rodkey, RCIS, CCRC; Jacqueline Schultz, BA; Erika Williams, BA.
The authors report no conflicts of interest.
This study was presented at the 32nd Annual Scientific Assembly of the Eastern
Association for the Surgery of Trauma (EAST) as an Oral Podium presentation
on January 18, 2019 in Austin, TX.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journal’s Web site (www.annalsofsurgery.com).
Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0003-4932/16/XXXX-0001
DOI: 10.1097/SLA.0000000000003661
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ANNSURG-D-19-00897
Yeh et al
T he designation of acute appendicitis as a ‘‘surgical emergency’’
dates back to the preantibiotic era when high mortality rates were
observed for perforated appendicitis. Since the seminal article by
Fitz1 in 1886, surgical appendectomy has been the standard of care
for the treatment of acute appendicitis in the United States. The
prevailing belief for over a century was that rapid excision of the
appendix was required to prevent perforation and the accompanying
worse clinical outcomes. So strong was this belief that relatively high
rates of negative appendectomies were tolerated and even encour-
aged to minimize the risk of disease progression to complicated
appendicitis through inaction.2 However, some have questioned this
progression and have proposed alternative models for the pathophys-
iologic development of complicated appendicitis.3,4
As early as 1946, it was recognized that medical therapy
(antibiotics) alone can also sometimes successfully treat appendici-
tis.5 Several recent randomized trials have challenged the supremacy
of surgical treatment for simple appendicitis.6–10 However, these
trials had strict inclusion criteria, were all performed outside the
United States, and employed methodologies not applicable to current
American practice (ex: open appendectomy), thereby limiting gen-
eralizability. Although there is a very large corpus of appendicitis
literature, most studies have methodological limitations. For exam-
ple, studies examining administrative databases utilize data that were
not collected specifically for research and lack granularity of detail
specific to the disease.11– 13 Single-center retrospective studies are
confounded by bias and small sample size,14 or limited to specific
types of appendicitis, while excluding others.15 High-profile Euro-
pean studies have limited their enrollment to only simple appendici-
tis10 or did not use imaging to confirm the diagnosis of appendicitis,
resulting in >10% negative appendectomy rate.16 We performed this
pragmatic multicenter prospective observational study to 1) explore
the hypothesis that perforated and gangrenous appendicitis result
from untreated acute appendicitis; and 2) document the modern
disease presentation, treatment, and clinical outcomes of acute,
perforated, and gangrenous appendicitis in the United States.
METHODS
This study was approved by the Eastern Association for the
Surgery of Trauma (EAST) and by the Institutional Review Board of
all participating sites. Between January 26, 2017 and June 30, 2018,
all adult (age 18 years) patients with confirmed or strong suspicion
for acute, perforated, or gangrenous appendicitis were eligible for
inclusion. Patients were excluded if they: were transferred from
another institution or if the patient encounter occurred outside of the
Emergency Department (ED) setting (ie, inpatient consultation).
Demographics, history and physical examination findings, radio-
graphic, intraoperative, pathologic findings, and clinical outcomes
were collected on all patients. The final study cohort comprised only
subjects who underwent initial treatment with appendectomy and had
acute, perforated, or gangrenous appendicitis as described on final
pathologic examination, which we considered the criterion standard
for this study.
Demographic data collected included: age, sex, pregnancy
status, weeks gestation, weight (kilograms), body mass index, date/
time of ED triage, co-morbid medical conditions, Charlson Comor-
bidity Index (CCI),17 previous abdominal operations, steroids/ che-
motherapy/other immunosuppressant, and tobacco use. History of
present illness data collected included duration of symptoms in 6-
hour intervals up to 96 hours, and the presence/absence of: nausea,
vomiting, anorexia, diarrhea, migration to the right lower quadrant
(RLQ), and previous episodes. Duration of symptoms was defined as
the time from the onset of symptoms to presentation to the ED.
Physical examination data collected included the first recorded ED
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Annals of Surgery  Volume XX, Number XX, Month 2019
temperature (Celsius), heart rate, systolic blood pressure (SBP),
Alvarado score, 18 and the presence/absence of: RLQ tenderness,
diffuse abdominal tenderness, RLQ rebound tenderness, diffuse
abdominal rebound tenderness, Rovsing sign, Obturator sign, and
Psoas sign, as documented by the surgeon or surgical trainee.
Laboratory data collected included the first recorded ED value for
WBC, % polymorphonuclear cells, % band cells, C-reactive protein
(CRP), and erythrocyte sedimentation rate (ESR). Radiographic data
collected included imaging type [none, ultrasound (US) only, com-
puted tomography (CT) only, US and CT, magnetic resonance
imaging (MRI) only, US and MRI, or other], and imaging findings.
Evidence of ‘‘complicated’’ appendicitis on imaging was considered
positive if any of the following were present: appendiceal wall
necrosis with contrast nonenhancement, air in appendiceal wall,
local periappendiceal fluid, contrast extravasation, regional soft
tissue inflammatory changes, diffuse abdominal/pelvic inflamma-
tory changes, perforated appendicitis, or phlegmon. The American
Association for the Surgery of Trauma (AAST) severity grading scale
for appendicitis was recorded for the clinical, imaging, operative, and
pathology dimensions.19 Pathology data included intraoperative
microbiological specimens and the final pathologic diagnosis: nor-
mal appendix, acute appendicitis, acute-on-chronic appendicitis,
chronic appendicitis, gangrenous appendicitis, perforated appendi-
citis, adenocarcinoma, neuroendocrine (carcinoid) tumor, or other.
Management data collected included initial treatment strategy
(antibiotics, percutaneous drainage, appendectomy, or other) and
antibiotics (class and duration). The time from symptom onset to
initial intervention and time from ED triage to initial intervention
were also recorded in 6-hour intervals up to 96 hours. Operative data
included initial operative approach, final operative approach,
intraoperative findings, intraoperative adverse events,20 operative
duration, surgical drains, and post-operative antibiotics (class
and duration).
Outcomes were assessed for index hospitalization and at 30
days, including the presence/absence of complications defined when
possible by the National Cancer Institute Common Terminology
Criteria for Adverse Events v.3: surgical site infection (SSI), intra-
abdominal abscess (IAA), wound complications, hospital acquired
pneumonia, blood stream infection, catheter-associated urinary tract
infection (UTI), Clostridium difficile infection (CDI), sepsis defined
according to Sepsis-3,21 ileus, supraventricular, and nodal arrhyth-
mia, ventricular arrhythmia, cardiac ischemia/infarction, radiograph-
ically confirmed deep vein thrombosis or pulmonary embolism,
hemorrhage/bleeding, urinary retention, acute kidney injury, acute
respiratory distress syndrome defined according to Berlin criteria,22
Clavien-Dindo complications,23 secondary interventions, intensive
care unit (ICU) length of stay (LOS), hospital LOS, ED visits,
appendicitis-related ED visits, hospital readmissions, and mortality.
A composite infectious complication endpoint was created to
include: SSI, IAA, pneumonia, bloodstream infection, UTI, CDI, and
sepsis. A composite complications endpoint for index hospitalization
was created to include the following events: any infectious compli-
cation, Clavien-Dindo complication, secondary intervention, and
mortality. Similar composite endpoints for infections and all com-
plications were created for 30-day outcomes and cumulative (index
and 30-day) occurrences.
Owing to the observational nature of the study, subjects were
not contacted after index hospitalization discharge and therefore
clinical outcomes were extracted from the electronic medical record.
If the subject was not encountered after index hospitalization dis-
charge, then the subject was considered ‘‘lost to follow-up.’’
Study data were collected and managed using Research
Electronic Data Capture (REDCap) electronic data capture tools
hosted at the University of Miami.17 All participating sites were
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Annals of Surgery  Volume XX, Number XX, Month 2019
instructed to record data elements on the case report form (CRF) only
as specifically documented in the medical record or examined for by
the clinician. If a data element was not recorded in the medical
record, then it was left blank in the CRF and recorded as ‘‘missing.’’
Missing items were excluded from data analysis.
Continuous data were reported as means  standard deviation
or median (interquartile range) for nonparametric distributions and
compared with Student t test or Mann-Whitney U test as appropriate.
Based on final pathologic diagnosis, subjects were categorized into
acute, perforated, and gangrenous groups. Comparisons between
groups were performed using analysis of variance, chi-squared test,
and Kruskal-Wallis test. Counts were reported as frequencies and
compared with chi-squared test. For the purposes of regression
analysis, the perforated and gangrenous groups were combined into
a single ‘‘complicated’’ appendicitis group. Multivariable logistic
regression analysis was performed for the dependent variable of
‘‘complicated’’ appendicitis, controlling for age, duration of symp-
toms >48 hours, temperature, WBC, Alvarado score, appendicolith,
CCI, tobacco use, and interval between ED triage to appendectomy >
6 hours. These independent variables were chosen on the basis of
biological plausibility. A P value of <0.05 was considered statisti-
cally significant. Owing to the hypothesis-generating nature of these
analyses, no adjustment for multiple testing was performed. Statisti-
cal analyses were performed using Stata v.14.2.
RESULTS
A total 3597 subjects were enrolled across 28 sites, with each
site contributing a median 82 (51–144) (range 11–659) subjects.
Median age was 37 (27–52) years, 1918 (53%) were male, and 3237
(90%) underwent CT imaging. Of these patients, 3262 (91%) were
initially treated with appendectomy, 219 (6%) with antibiotics alone,
and 110 (3%) with percutaneous drainage.
Nonoperative Management
Of the 329 subjects treated initially with nonoperative man-
agement (NOM) (ie, antibiotics alone or percutaneous drainage), the
majority (n ¼ 320, 97%) underwent CT imaging, with the majority
having evidence of ‘‘complicated’’ appendicitis: AAST Image Grade
1 ¼ 85 (26%); Grade 2 ¼ 1 (0.3%); Grade 3 ¼ 32 (10%);, Grade 4 ¼
183 (57%); and Grade 5 ¼ 21 (7%). A total 48 (15%) subjects
experienced failure of medical treatment and underwent appendec-
tomy (laparoscopic or open) during index hospitalization and another
18 (5%) experienced failure of medical treatment within 30 days of
hospital discharge for an overall 30-day failure rate of (20%). For
those experiencing failure of NOM, the final pathologic diagnosis
was acute (n ¼ 18), gangrenous (n ¼ 2), perforated (n ¼ 24), chronic
appendicitis (n ¼ 2), and adenocarcinoma (n ¼ 1). Only 2 subjects
underwent elective interval appendectomy within 30 days.
Neuroendocrine/Carcinoid Tumor and
Adenocarcinoma
Of the 3262 subjects treated initially with appendectomy, 58
(2%) had a normal appendix, 28 (1%) had adenocarcinoma, and 18
(1%) had a neuroendocrine (carcinoid) tumor. When comparing
those with a neoplastic diagnosis to those with a benign diagnosis,
cancer patients were older (51.8  18.5 vs 39.9  16.0 years, P <
0.001), had higher median Charlson Comorbidity Index scores [1 (0–
3) vs 0 (0–1), P < 0.001], had higher incidence of previous
abdominal operation (37% vs 22%, P ¼ 0.0305), and had significant
differences in Time from ED Triage to Initial Intervention (P ¼
0.0065) (eTable 1, http://links.lww.com/SLA/B807).
The ensuing study cohort included 3108 subjects with acute (n
¼ 2403), perforated (n ¼ 487), or gangrenous (n ¼ 218) appendicitis
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Appendicitis in the Contemporary United States
as categorized by final pathologic diagnosis after appendectomy.
Variation across enrollment sites was observed for the mean pro-
portions of patients with the diagnosis of acute (73%  10%, range
50%–90%), perforated (14%  8%, range 4%–36%), and gangre-
nous appendicitis (6%  5%, range 0%–23%). The surgeon’s intra-
operative diagnosis was concordant with the pathologist’s final
diagnosis for acute, perforated, and gangrenous appendicitis in
88%, 66%, and 53% of cases, respectively (eTable 2, http://link-
s.lww.com/SLA/B807). Similarly, the surgeon’s intraoperative diag-
nosis was concordant with the radiologist’s impression for normal
appendix, acute, perforated, and gangrenous appendicitis in 20%,
76%, 17%, and 60% of cases, respectively (eTable 3, http://link-
s.lww.com/SLA/B807).
Demographics and History of Present Illness
When compared to patients with acute appendicitis on uni-
variate analysis, those with perforated and gangrenous appendicitis
were significantly older [50 (36–60) and 45 (32–58) vs. 34 (26–47)
years, P < 0.001], had a higher CCI [0 (0–2) and 0 (0–2) vs 0 (0–1),
P < 0.001] and were more likely to have diabetes (12% and 8% vs
6%, P ¼ 0.001), coronary artery disease (6% and 6% vs 2%, P <
0.001), congestive heart failure (3% and 1% vs 1%, P ¼ 0.004),
hypercholesterolemia (17% and 13% vs 9%, P < 0.001), chronic
obstructive pulmonary disease (COPD) (6% and 4% vs 2%,
p < .001), and were less likely to have never used tobacco (59%
and 64% vs 70%, P < 0.001) (Table 1). The symptoms upon
presentation were mostly similar, with the exception that anorexia
and diarrhea were less common in acute appendicitis compared to
perforated appendicitis.
Duration of Symptoms
The distribution of duration of symptoms (time from symptom
onset to ED triage) is presented in Figure 1. The majority presented
within the first 30 hours after the onset of symptoms. Thereafter,
the incidence of acute appendicitis decreased sharply, with smaller
peaks at 48, 72, and >96 hours. In comparison, perforated and
gangrenous appendicitis had a relatively stable incidence across
all time intervals, with smaller, less pronounced peaks at 24, 48,
72, and >96 hours.
Laboratories and Physical Examination
There were significant differences between groups regarding
temperature, heart rate, diffuse abdominal tenderness, RLQ rebound
tenderness, diffuse abdominal rebound tenderness, Alvarado score,
Clinical AAST Appendicitis Severity Grade, WBC, % polymorpho-
nuclear cells, % band cells, and C-reactive protein (eTable 4, http://
links.lww.com/SLA/B807). Overall, the perforated and gangrenous
cohort had higher incidence rates of markers of systemic illness
(fever, tachycardia, leukocytosis, neutrophil predominance, and left
shift to immature granulocytes) and peritoneal signs (diffuse abdom-
inal tenderness, RLQ rebound tenderness, and diffuse abdominal
rebound tenderness).
Time from ED Triage to Initial Intervention
For acute, perforated, and gangrenous appendicitis, the vast
majority of interventions occurred within 30 hours after ED presen-
tation (Fig. 2) and there were no significant differences between
groups.
Time From Symptom Onset to Initial Intervention
Figure 3 presents the distribution of time from symptom onset
to initial intervention according to type of appendicitis. Similar to
‘‘duration of symptoms,’’ there was an early, pronounced peak for
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Yeh et al Annals of Surgery  Volume XX, Number XX, Month 2019

TABLE 1. Demographics, History of Present Illness, Physical Examination, and Laboratories, and Physical Examination
All Acute Perforated Gangrenous
(n ¼ 3108) (n ¼ 2403) (n ¼ 487) P (n ¼ 218) Py Pz
Demographics
Age, y 37 (27–52) 34 (26–47) 50 (36–60) <0.001 44.5 [32–58] < 0.001 < 0.001§
Male (%) 1668 (54) 1275 (53) 278 (57) 0.104 115 (53) 0.931 0.257
Weight, kg (missing ¼ 68) 83.4  22.0 82.8  21.5 85.6  24.2 0.0112 84.6  21.6 0.2407 0.0277
BMI (missing ¼ 98) 28.7  6.6 28.5  6.6 29.2  7.0 0.048 29.2  6.5 0.1505 0.0692
Diabetes mellitus (%) 221 (7) 146 (6) 57 (12) <0.001 18 (8) 0.196 < 0.001
Coronary artery disease (%) 97 (3) 55 (2) 28 (6) <0.001 14 (6) < 0.001 < 0.001
Congestive heart failure (%) 37 (1) 21 (1) 13 (3) 0.001 3 (1) 0.455 0.004
Hypercholesterolemia (%) 322 (10) 210 (9) 84 (17) <0.001 28 (13) 0.043 < 0.001
COPD (%) 80 (3) 45 (2) 27 (6) <0.001 8 (4) 0.069 < 0.001
CCI 0 (0–1) 0 (0–1) 0 [0–2] <0.001 0 [0–2] < 0.001 < 0.001§
Prior abdominal operations (%) 680 (22) 508 (21) 119 (24) 0.108 53 (24) 0.274 0.184
Steroids (%) 52 (2) 37 (2) 13 (3) 0.081 2 (1) 0.467 0.138
Chemotherapy (%) 16 (1) 11 (1) 3 (1) 0.646 2 (<1) 0.355 0.625
Other immunosuppressants (%) 51 (2) 43 (2) 3 (1) 0.060 5 (2) 0.598 0.132
Tobacco (%) <0.001 0.113 < 0.001
Never 2098 (68) 1670 (70) 288 (59) 140 (64)
Former 440 (14) 313 (13) 88 (18) 39 (18)
Current 564 (18) 416 (17) 109 (23) 39 (18)
Clinical AAST appendicitis (n ¼ 3089) (n ¼ 2384) (n ¼ 487) <0.001 (n ¼ 218) 0.004 < 0.001
severity (%)
Grade 1, 2, and 3 3025 (98) 2362 (99) 451 (93) 212 (97)
Grade 4 13 (<1) 6 (<1) 7 (1) 0 (0)
Grade 5 51 (2) 16 (1) 29 (6) 6 (3)
AAST, American Association for the Surgery of Trauma; BMI, body mass index.

Bivariate comparisons between acute vs perforated appendicitis.
yBivariate comparisons between acute vs gangrenous appendicitis.
zANOVA and Chi-square test for acute vs gangrenous vs perforated appendicitis.
§Kruskal-Wallis H test.

FIGURE 1. Duration of symptoms.

y-Axis represents absolute counts.

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Annals of Surgery  Volume XX, Number XX, Month 2019 Appendicitis in the Contemporary United States

FIGURE 2. Time from ED triage to

initial intervention. y-Axis repre-
sents absolute counts.

FIGURE 3. Total time from symp-

tom onset to initial intervention.
y-Axis represents absolute counts.

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Yeh et al Annals of Surgery  Volume XX, Number XX, Month 2019

TABLE 2. Imaging Studies and Operative Details

All Acute Perforated Gangrenous
(n ¼ 3108) (n ¼ 2403) (n ¼ 487) P (n ¼ 218) Py Pz
Imaging
Type (%) 0.001 0.070 0.001
None 28 (1) 21 (1) 3 (1) 4 (2)
US only 104 (3) 94 (4) 5 (1) 5 (2)
US and MRI 12 (<1) 9 (<1) 2 (<1) 1 (1)
US and CT 154 (5) 137 (6) 12 (3) 5 (2)
MRI 11 (<1) 7 (<1) 2 (<1) 2 (1)
CT only 2799 (90) 2135 (89) 463 (95) 201 (92)
Image AAST appendicitis severity (%) (n ¼ 2948) (n ¼ 2264) (n ¼ 475) <0.001 (n ¼ 209) <0.001 <0.001
Grade 1 2128 (721) 1825 (81) 182 (38) 121 (58)
Grade 2 91 (3) 61 (3) 16 (3) 14 (7)
Grade 3 467 (16) 293 (13) 128 (27) 46 (22)
Grade 4 206 (7) 66 (3) 119 (25) 21 (10)
Grade 5 56 (2) 19 (1) 30 (6) 7 (3)
Operative
Initial operative approach (%) 0.001 0.013 < 0.001
Laparoscopic (single-incision, 3055 (98) 2384 (99) 462 (95) 213 (98)
3-incision, or robotic)
Open 46 (2) 18 (1) 23 (5) 5 (2)
Other 5 (<1) 1 (<1) 3 (1) 1 (1)
Final operative approach (%) <0.001 <0.001 <0.001
Laparoscopic (single-incision, 2933 (94) 2337 (97) 401 (83) 195 (90)
3-incision, or robotic)
Open, RLQ incision 77 (3) 34 (1) 31 (6) 12 (6)
Open, midline incision 88 (3) 26 (1) 51 (11) 11 (5)
Open, other incision 7 (<1) 5 (<1) 2 (1) 0 (0)
Other 15 (1) 9 (<1) 5 (1) 1 (1)
Conversion from laparoscopic to open (%) 126 (4) 47 (2) 61 (13) <0.001 18 (9) <0.001 <0.001
Operative AAST appendicitis severity (%) (n ¼ 3078) (n ¼ 2373) (n ¼ 487) <0.001 (n ¼ 218) <0.001 <0.001
Grade 1 2275 (74) 2154 (91) 75 (15) 46 (21)
Grade 2 152 (5) 68 (3) 10 (2) 74 (34)
Grade 3 318 (10) 76 (3) 188 (39) 54 (25)
Grade 4 175 (6) 43 (2) 105 (22) 27 (12)
Grade 5 158 (5) 32 (1) 109 (22) 17 (8)
Intraoperative adverse events (%) 38 (1) 21 (1) 14 (3) <0.001 3 (1) 0.456 0.001
Operative duration, min 62.8  32.1 58.9  28.1 79.9  42.0 <0.001 67.6  63.0 <0.001 <0.001
Surgical drains (%) 209 (7) 51 (2) 130 (28) <0.001 28 (13) <0.001 <0.001
Postintervention antibiotics (%) 1315 (42) 734 (30) 433 (89) <0.001 148 (68) <0.001 <0.001
<24 h 466 (36) 332 (45) 395 (91) <0.001 120 (81) <0.001 <0.001
24 h 847 (65) 401 (55) 437 (9) 28 (19)
Duration of post-intervention 6 (4–9) 5 (3–7) 7 (4–9) <0.001 7 [4–9] 0.009 0.001§
antibiotics (days)

Bivariate comparisons between acute vs perforated appendicitis.
yBivariate comparisons between acute vs gangrenous appendicitis.
zANOVA and chi-square test for acute vs perforated vs gangrenous appendicitis.
§Kruskal-Wallis H test.

acute appendicitis and relatively stable incidence across all time
intervals for perforated and gangrenous appendicitis.
Imaging Findings
Only 28 (1%) of all 3108 patients undergoing appendectomy
had no preoperative imaging studies and the majority (90% overall)
underwent CT scanning alone (Table 2). Additional detailed imaging
findings are presented in (eTable 5, http://links.lww.com/SLA/
B807). Ultrasound was used infrequently and was commonly fol-
lowed by MRI or CT. There were significant differences between
groups for Image AAST Appendicitis Severity Grade.
infrequent, occurring in about 1% of cases. Compared to acute
appendicitis, perforated and gangrenous appendicitis cases had
significantly longer operative duration (79.9  42.0 and
67.6  63.0 vs 58.9  28.1 minutes, P < 0.001) and a higher rate
of postoperative surgical drain utilization (28% and 13% vs 2%, P <
0.001). Variation across enrollment sites was observed for the
proportion of patients receiving a postoperative surgical drain
[median 5% (2%–9%), range 0%–29%] (Supplemental Figure 1,
http://links.lww.com/SLA/B807). Postoperative antibiotic utilization
was 42% and more common in perforated and gangrenous appendi-
citis cases (89% and 68% vs 30%, P < 0.001).

Operative Findings Clinical Outcomes During Index Hospitalization and

The majority (>98%) of subjects underwent initial laparo- at 30 Days After Discharge
scopic operative approach and only 4% required conversion to open Infectious complications, wound complications, Clavien-
incision (Table 2). Intraoperative adverse events (iAE) were Dindo complications, ICU admission, and secondary

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Annals of Surgery  Volume XX, Number XX, Month 2019 Appendicitis in the Contemporary United States

TABLE 3. Clinical Outcomes During Index Hospitalization and at 30 Days After Discharge
Index Hospitalization Outcomes
All Acute Perforated Gangrenous
(n ¼ 3108) (n ¼ 2403) (n ¼ 487) P (n ¼ 218) Py Pz
SSI (%) (missing ¼ 1) 15 (1) 6 (<1) 8 (2) <0.001 1 (1) 0.567 <0.001
Intra-abdominal abscess (%) 54 (2) 15 (1) 33 (7) <0.001 6 (3) 0.001 <0.001
Wound complications (%) (missing ¼ 1) 9 (<1) 2 (<1) 6 (1) <0.001 1 (1) 0.116 <0.001
Composite Infectious (%) 95 (3) 30 (1) 53 (11) <0.001 12 (6) <0.001 <0.001
Clavien-Dindo Complication (%) 308 (10) 114 (5) 157 (32) <0.001 37 (17) <0.001 <0.001
Composite Complications (%) 310 (10) 114 (5) 158 (32) <0.001 38 (17) <0.001 <0.001
ICU admission (%) 62 (2) 22 (1) 28 (6) <0.001 12 (6) <0.001 <0.001
Secondary Intervention (%) 50 (2) 14 (1) 31 (6) <0.001 5 (2) 0.004 <0.001
Hospital LOS, days 1 [1–2] 1 [1–1] 3 [2–5] <0.001 2 [2–3] <0.001 <0.001§
Mortality during index hospitalization (%) 5 (<1) 2 (<1) 3 (1) 0.010 0 (0) 0.670 0.046

30-day Outcomes
Acute Perforated Gangrenous
All (n ¼ 1982) (n ¼ 433) P (n ¼ 190) Py Pz
Lost to follow-up (%) 484 (16) 405 (17) 51 (11) <0.001 28 (13) 0.118 0.001
Did the patient attend post-op 0.050 0.239 0.10
surgical clinic visit? (%)
No 292 237 39 16
(11.2) (12.0) (9.0) (8.4)
Yes 2306 1740 393 173
(88.5) (87.8) (90.3) (91.1)
Return to ED within 30 days (%) 225 (9) 158 (8) 48 (11) 0.035 19 (10) 0.328 0.088
Readmission to hospital within 113 (4) 56 (3) 44 (10) <0.001 13 (7) 0.003 <0.001
30 days (%)
SSI (%) 53 (2) 36 (2) 12 (3) 0.197 5 (3) 0.430 0.368
Intra-abdominal abscess (%) 65 (3) 22 (1) 31 (7) <0.001 12 (6) <0.001 <0.001
Clavien-Dindo complication (%) 180 (7) 101 (5) 54 (13) <0.001 25 (13) <0.001 <0.001
30-day hospitalization LOS, days 3 (2–5) 3 (1.25–5) 4 (2–7) 0.0387 3 [2–8.5] 0.1753 0.0860§
(excluding index hospitalization)
30-Day composite infections (%) 120 (5) 59 (3) 41 (9) <0.001 20 (11) <0.001 <0.001
30-Day composite complications (%) 205 (7) 102 (5) 55 (13) <0.001 25 (13) <0.001 <0.001
Secondary intervention (%) 51 (2) 19 (1) 20 (5) <0.001 12 (6) <0.001 <0.001
30-day mortality (%) 3 (<1) 1 (<1) 2 (<1) 0.024 0 (0) 0.761 0.057
Cumulative composite infections (%) 209 (8) 89 (5) 89 (20) <0.001 31 (16) <0.001 <0.001
Cumulative composite complications (%) 459 (17) 207 (10) 195 (43) <0.001 57 (30) <0.001 <0.001
Cumulative secondary interventions (%) 105 (4) 33 (2) 50 (11) <0.001 17 (9) <0.001 <0.001

Bivariate comparisons between acute vs perforated appendicitis.
yBivariate comparisons between acute vs gangrenous appendicitis.
zANOVA and chi-squared test for acute vs perforated vs gangrenous appendicitis.
§Kruskal-Wallis H test.

interventions were significantly more common for perforated/
gangrenous compared to acute appendicitis (Table 3). Mortality
was extremely uncommon at index hospitalization and within
30 days after hospital discharge. Approximately 15% of patients
were lost to follow-up after index hospitalization. Subjects who
were lost to follow-up had significantly different demographic
and pathologic diagnosis features compared to those who were
not lost to follow-up (Supplemental Table 6, http://links.
lww.com/SLA/B807).
Adverse clinical outcomes were significantly more common
in perforated/gangrenous compared to acute appendicitis, specifi-
cally hospital readmission (10% and 7% vs 3%, P < 0.001), IAA (7%
and 6% vs 1%, P < 0.001), any Clavien-Dindo complication (13%
and 13% vs 5%, P < 0.001), 30-day composite infectious compli-
cations (9% and 11% vs. 3%, P < 0.001), 30-day composite
complications (13% and 13% vs 5%, P < 0.001), secondary inter-
ventions (5% and 6% vs 1%, P < 0.001), cumulative composite
infections (20% and 16% vs 5%, P < 0.001), cumulative composite
complications (43% and 30% vs 10%, P < 0.001), and cumulative
secondary interventions (11% and 9% vs. 2%, P < 0.001).
Multivariable Regression Analysis Using
‘‘Complicated’’ Appendicitis as Dependent Variable
On regression analysis, age [odds ratio (OR) 1.05, 95%
confidence interval (CI) 1.04–1.06, P < 0.001], duration
of symptoms >48 hours (OR 2.72, 95% CI 2.23–3.33, P <
0.001), temperature (OR 1.79, 95% CI 1.53 –2.11, P < 0.001),
WBC (OR 1.08, 95% CI 1.05–1.10, P < 0.001), Alvarado score
(OR 1.11, 95% CI 1.04–1.21, P ¼ 0.004), and appendicolith (OR
1.82, 95% CI 1.50 –2.21, P < 0.001) were significantly positively
associated with ‘‘complicated’’ appendicitis, whereas Charlson
Comorbidity Index (OR 0.98, 95% CI 0.89–1.07, P ¼ 0.68)
and ED triage to appendectomy >6 hours (OR 1.22, 95% CI
0.91 –1.63, P ¼ 0.1889) or >12 hours (OR 1.12, 95% CI 0.86–
1.46, P ¼ 0.3933) were not. Tobacco never-use was negatively
associated with ‘‘complicated’’ appendicitis (OR 0.79, 95% CI

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Yeh et al
0.62 –1.0, P ¼ 0.049). The area under the curve for this model was
0.7739 (95% CI 0.7541–0.7938).
DISCUSSION
To our knowledge, this is the first large, multicenter, prospec-
tive observational study documenting highly granular detail about
modern American practice and outcomes of appendicitis. The novel
findings pertain to differences observed in the time course of
presentation and the demographics of patients presenting with acute,
perforated, and gangrenous appendicitis. Many believe that compli-
cated appendicitis represents the natural history of untreated simple
appendicitis based on the observation that the percentage of compli-
cated appendicitis cases (defined as complicated appendicitis cases/
total appendicitis cases) increases with increasing duration of symp-
toms. It is commonly assumed that this increase is due to an increase
in the numerator, assuming a constant overall number of total cases
over time. To the contrary, our data show that the number of cases of
complicated appendicitis remains relatively stable over time, but that
the relative percentage increases mainly because of a decrease in the
total number of simple appendicitis cases, affecting primarily the
denominator. This phenomenon was predicted by Andersson in a
proposed alternative model of appendicitis.3 Our observations sup-
port (but do not prove) this alternative model and challenge the
natural history paradigm by showing that complicated appendicitis
can occur very early after a very short duration of symptoms and
conversely; simple appendicitis can persist despite a very long
duration of untreated symptoms.
Another closely linked and commonly accepted paradigm is
that complicated appendicitis is simply a more severe manifestation of
simple appendicitis on a spectrum of illness for the same disease. If this
were true, one would expect similar cohorts of afflicted patients, that is,
the epidemiologic risk factors are the same, but the complicated cases
had a longer untreated duration of this short-lived disease. On the
contrary, our data demonstrate that simple (acute) and complicated
(perforated and gangrenous) appendicitis affect different populations,
with the latter disease affecting patients who are older and have more
co-morbid medical conditions such as diabetes, coronary artery dis-
ease, hypercholesterolemia, COPD, and tobacco use. Thus, rather than
one disease (acute) leading to different manifestations (perforated and
gangrenous) because of delayed treatment, it is plausible that compli-
cated appendicitis develops by 1) the effect of co-morbid illness
modulating the disease process or individual’s response to disease,
or 2) through a different pathophysiologic mechanism altogether.18 For
example, although the young and healthy nonsmoking patient may
develop simple appendicitis from abrupt luminal occlusion, perhaps
the older patient with diabetes and vasculopathy develops progressive
microvascular transmural ischemia (independent of luminal occlusion)
leading to gangrene, perforation, and abscess. This alternate pathway
could explain the atypical symptoms and expanded time course of
symptoms seen in the older complicated appendicitis patients. Taken
together, our observations suggest that treating acute appendicitis as a
surgical ‘‘emergency’’ may not lower the occurrence of complicated
appendicitis if the latter is neither temporally- nor mechanistically
related to the former. Indeed, the ideal treatment (appendectomy vs
antibiotics alone) may differ between these appendicitis disease types,
although this remains to be determined in prospective randomized
trials.
Arguably, the most influential recent publication is the Appen-
dicitis Acuta (APPAC) trial, a randomized clinical trial that enrolled
adults with CT scan-confirmed uncomplicated acute appendicitis.10
The authors highlight the fact that 73% of patients were successfully
treated with antibiotics and some have cited APPAC as proof that
antibiotics should be strongly considered,19 especially since the
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Annals of Surgery  Volume XX, Number XX, Month 2019
overall complication rate in the surgical arm was reported to be
significantly higher than in the antibiotic arm (21% vs 3%, respec-
tively). However, only 6% of subjects randomized to surgery under-
went laparoscopic appendectomy and surgical site infections
comprised a large proportion of the reported complications. We
cannot apply the APPAC findings to modern American practice
where open appendectomy is no longer favored.20 In the APPAC
trial, both treatment groups spent a median 3 days in the hospital, 3
times longer than our observed median hospital LOS (1 day) for acute
appendicitis. In actual clinical practice in the United States, we
observe that the majority of patients selected for NOM had high
AAST Image Grade appendicitis and the majority of those who failed
NOM had complicated forms of appendicitis. These observations are
helpful for establishing selection criteria and estimating event rates
for future randomized trials exploring the optimal treatment of
complicated appendicitis.
Much has been written about delay in presentation and delay
in treatment of appendicitis, with some arguing that it is safe to delay
appendectomy for up to 48 hours21,22 and others arguing that in-
hospital delays in appendectomy increase the risk of perforated
appendicitis.23,24 In a recent study of >9000 adults presenting with
appendicitis (16% perforated), Drake et al25 reported that there was
no difference in mean time from ED presentation to appendectomy
for those with perforated vs. non-perforated appendicitis. Our results
are concordant and add further evidence that perforation may not be
as preventable (by urgent appendectomy) as previously thought. Our
multiple regression analysis revealed that delays of up to 12 hours
after ED presentation were not associated with increased likelihood
of complicated appendicitis on pathologic examination.
Several additional findings are noteworthy. The majority (90%
overall) of our subjects underwent preoperative CT scanning and
only 1% underwent appendectomy without pre-operative imaging.
Although some may criticize this as overuse of ionizing radiation
imaging, we note that the rate of negative appendectomy was only
2%, far lower than the historically reported rates in the pre-CT era. It
is interesting to note that concordance between radiologist and
surgeon was low (eTable 3, http://links.lww.com/SLA/B807), a
finding which has been previously reported by others.26–28 Our data
(and others) suggest that CT is highly specific for distinguishing an
uninflamed appendix from an inflamed appendix (as shown by the
low rate of normal appendectomy specimens), but performs rather
poorly for discriminating between types of appendicitis. Thus, unless
the findings are highly specific (such as abscess or extraluminal gas),
clinicians should probably not use CT imaging to drive clinical
decision-making based upon severity grade. Second, we observed a
wide variance in practice in the use of surgical drains after appen-
dectomy (nearly 30% in cases of perforated appendicitis) and in the
use of postoperative antibiotics. Finally, we were surprised that
nearly one-third of subjects with simple, acute appendicitis received
postoperative antibiotics and more than half of those received anti-
biotics for >24 hours after operation. Clearly there is community
equipoise on these topics and thus they represent areas ripe for
future study.
Limitations
There are several limitations to this study. First, this was an
observational study and for the majority of enrollment sites, the
requirement to obtain informed consent was waived. Therefore, we
were unable to contact the subjects for research follow-up and were
dependent upon clinical encounters for our follow-up. This resulted
in a lost-to-follow-up rate of approximately 15%, which varied
significantly according to appendicitis type and demographic fea-
tures such as age and male sex. We acknowledge this selection bias in
comparing the 30-day outcomes between groups and those findings
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Annals of Surgery  Volume XX, Number XX, Month 2019
should be interpreted with caution. Second, because of resource
limitations, we could not strictly enforce that all consecutive patients
with confirmed or suspected appendicitis were screened for enroll-
ment; it is possible that we missed some patients during times when
research staff were unavailable. Third, the observational study design
precludes any conclusions about cause and effect and we can only
describe associations. Furthermore, we were unable to discern the
reasons for choosing nonoperative management and additionally the
exact reasons why some subjects failed nonoperative management.
The strengths of our study include the large sample size and diverse
population. Our 28 enrollment sites included both urban and rural,
academic and community, large and small hospitals located through-
out the United States. We had broad geographic representation,
which improves the generalizability of our findings. Additional
strengths include the prospective study design and the use of
standardized definitions for complications and outcomes. This study
contributes to the existing literature by documenting the modern
uniquely American approach to appendicitis, providing incident rates
for a variety of clinically important, patient-centered outcomes, and
providing strong supporting evidence for an alternative hypothesis
for the disease pathophysiology which had previously only
been theorized.
CONCLUSIONS
In American adults presenting to the Emergency Department
and undergoing same-admission appendectomy, acute, perforated,
and gangrenous appendicitis affect different epidemiologic popula-
tions and present with different constellations of signs and symp-
toms. In-hospital delay to appendectomy is not a risk factor for
‘‘complicated’’ appendicitis. In the United States, the majority of
patients presenting with suspected or confirmed appendicitis receiv-
ing CT imaging, undergo laparoscopic appendectomy, and stay in the
hospital for 1 day. By 30 days, 1 in 5 patients selected for initial
nonoperative management experienced failure of antibiotic therapy.
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