1
Acute appendicitis: modern understanding of pathogenesis,
2
diagnosis and management
3
4
Aneel Bhangu PhDa, b, Professor Kjetil Søreide MDc, d , Salomone Di Saverio MDe,
5
Jeanette Hansson Assarsson MDf, Frederick Thurston Drake MDg
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8
9
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a. Academic Department of Surgery, Queen Elizabeth Hospital, Edgbaston,
Birmingham B15 2TH, UK. aneelbhangu@doctors.org.uk
b. University of Birmingham, College of Medical and Dental Sciences, Birmingham,
B15 2TH, UK
c. Department of Gastrointestinal Surgery, Stavanger University Hospital, P.O.
Box 8100, N-4068 Stavanger, Norway. ksoreide@mac.com
13
d. Department of Clinical Medicine, University of Bergen, Bergen, Norway
14
e. Emergency and General Surgery Department, CA Pizzardi Maggiore Hospital,
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Largo B Nigrisoli 2, 40133 Bologna, Italy. salo75@inwind.it
f. Department of Surgery, Kalmar County Hospital, 391 85 Kalmar, Sweden.
jeanette.assarsson@ltkalmar.se
g. Department of Surgery, University of Washington, 1959 NE Pacific Street, Box
356410, Seattle, WA 98195, USA. ftdrake@u.washington.edu
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Word count: 3993
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Summary word count: 150
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Article type: Review
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Correspondence to: Professor Kjetil Søreide, Department of Gastrointestinal
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Surgery, Stavanger University Hospital, P.O. Box 8100, N-4068 Stavanger, Norway.
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ksoreide@mac.com
27
Acknowledgements: Dr S Di Saverio provided the images and videos, for which
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patient consent is held.
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Summary
31
32
Acute appendicitis is one of the most common abdominal emergencies globally.
33
Etiology remains poorly understood with few advances over the past decades.
34
Obtaining a confident pre-operative diagnosis remains a challenge, as appendicitis
35
must be entertained in any patient presenting with an acute abdomen. While
36
biomarkers and imaging may be valuable adjuncts to clinical evaluation, none have
37
superior accuracy. A clinical classification is used to stratify management based on
38
simple (non-perforated) and complex (gangrenous or perforated) inflammation,
39
although many patients remain with an equivocal diagnosis, which remains one of
40
the most challenging dilemmas. An observed divide in disease course suggests some
41
simple appendicitis may be self-limiting or responding to antibiotics alone; another
42
appears to frequently perforate before reaching hospital. Although mortality is
43
low, post-operative complications are frequent in complex disease. We discuss
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current knowledge in pathogenesis, modern diagnosis and evolving strategies in
45
management that are leading to stratified care for patients.
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47
48
Introduction
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50
Acute appendicitis is one of the most common general surgical emergencies
51
worldwide,1 with an estimated lifetime risk reported at 7-8 %._ENREF_2
52
Accordingly, appendectomy is one of the most commonly performed surgical
53
procedures and represents an important burden on modern health systems. Despite
54
being so common, limited understanding of etiology and absence of reliable
55
discriminators for disease severity still exist. Limited clinical research has produced
56
uncertainty about best practice with subsequent international variation in delivery
57
and, as a possible consequence, variation in outcome. The aim of this review is to
58
provide a state of the art update into the current controversies in pathogenesis,
59
diagnosis and clinical management of acute appendicitis.
60
61
62
63
64
Search strategy and selection criteria
65
66
We searched the Cochrane Library, MEDLINE, and EMBASE, limited to the final
67
search date (01/02/2015). We used the search terms “appendicitis” or “acute” in
68
combination with the terms “diagnosis” or “treatment”. We largely selected
69
publications in the past five years, but did not exclude commonly referenced and
70
highly regarded older publications. We also searched the reference lists of articles
71
identified by this search strategy and selected those we judged relevant. We
72
searched ClinicalTrials.gov (01/01/2000-01/02/2015) for current trials in acute
73
appendicitis.
74
75
76
Evolving understanding of acute appendicitis
77
78
Epidemiology
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Acute appendicitis occurs at about 90-100 cases per 100,000 inhabitants per year in
80
the Western world. Peak incidence usually occurs in the 2nd or 3rd decade of life,
81
and the disease is less common at both extremes of age. Most studies show a slight
82
male predominance. Geographical differences are reported, with lifetime risks for
83
appendicitis of 16% in South Korea,_ENREF_3 9.0% in the USA_ENREF_4 and 1.8% in
84
Africa.2, 3_ENREF_2_ENREF_2
85
86
Etiology
87
Direct luminal obstruction may cause appendicitis (commonly by a faecolith,
88
lymphoid hyperplasia or impacted stool; rarely by an appendiceal or caecal
89
tumour) but may be exceptions rather than regular occurrences. While several
90
infectious agents are known to cause or be associated with appendicitis,4, 5 etiology
91
is still largely unknown. 6 Recent theories evolve around genetic factors,
92
environment and infections.
93
Although no defined gene has been identified, there is an almost three times
94
increased risk of appendicitis in members of families with a positive history for
95
appendicitis,7 and a twin study suggests genetic effects account for about 30%
96
variance in risk for developing appendicitis.8
97
Environmental factors may play a role, as studies note a predominate seasonal
98
presentation during the summer, which has been statistically associated with
99
higher level of ambient ground-level ozone, used as a marker of air pollution.9
100
Time-space clusters of disease presentation may further indicate an infectious
101
etiology._ENREF_6 Pregnant women appear to have a lower risk for appendicitis,
102
with lowest risk in third trimester, although being a diagnostic challenge when
103
present.10
104
Population level data on ethnicity from the UK and USA shows that appendicitis
105
is less common in non-white groups, albeit with little understanding of why. 11
106
Ethnic minority groups are conversely at higher risk of perforation, although this
107
might be due to unequal access to care rather than predisposition; definitive
108
evidence is lacking.12
109
Neurogenic appendicitis has also been suggested as a causative mechanism of
110
pain. Characterised by excess proliferation of nerve fibres into the appendix with
111
over-activation of neuropeptides, this poorly understood condition may be
112
relatively common, especially in children. From a case series of 29 patients,
113
neurogenicity was present in both inflamed and normal app_ENREF_11endix
114
specimens.13 It may theoretically provide an explanation for improvement after
115
normal appendectomy, although evidence for this and for its general importance is
116
limited.
117
118
The microbiome in appendicitis
119
The appendix may serve as a microbial reservoir for repopulating the
120
gastrointestinal tract in times of necessity, but data is limited. The bacterial
121
growth in removed inflamed appendices consists of a mix of aerobic and anaerobic
122
bacteria, most frequently dominated by E.coli and Bacteroides spp. A small yet
123
novel study using next-generation sequencing found a larger number and greater
124
variation of (up to 15) bacterial phylae than expected in patients with acute
125
appendicitis.14 Notably, the presence of Fusobacterium appeared to correspond to
126
disease severity (including risk of perforation), corroborating findings from archival
127
material in two other studies.15
128
Evidence of a role in immune balance comes from epidemiological studies
129
demonstrating a reduced risk of developing ulcerative colitis after appendectomy,16
130
with a slightly increased risk of Crohn’s disease.17 Further, appendectomy has been
131
associated with increased risk of future severe Clostridium difficile colitis requiring
132
colectomy.18 Whether these findings point to alterations of the human gut
133
microbiome or to the removal of a lymphoid organ with a role in human immune
134
function is currently unknown._ENREF_31
135
136
Classification
137
Irrespective of etiology, clinical stratification of severity at presentation, which
138
relies on pre-operative assessment rather than post-operative histopathology, is
139
advantageous for surgeons and patients as it allows stratified peri-operative
140
planning. However many patients can only be classified with an equivocal
141
diagnosis, which remains one of the most challenging dilemmas in the management
142
of acute abdominal pain. The pathological basis of each strata are shown in table 1
143
and figure 1.
144
A debated theory divides acute appendicitis into separate forms of acute
145
inflammation processes with different fates. One is the simple inflamed
146
appendicitis without gangrene or necrosis that does not proceed to perforation.
147
This “reversible” form may present as phlegmonous (pus-producing), or advanced
148
inflammation (but without gangrene or perforation) that may require surgery, or
149
alternatively a mild inflammation who may settle spontaneously or with antibiotic
150
therapy. In contrast, the more severe inflammatory type rapidly proceeds to
151
gangrene and/or perforation. Data to support separate types of inflammation arises
152
from clinical registries19 and laboratory studies.20 In population-based studies, the
153
rate of non-perforated appendicitis declined in males, with even greater declines
154
in females.21 However a similar decline in rate of perforated appendicitis was not
155
seen. Although this points to disconnect between perforated and non-perforated
156
disease, it may also represent improved diagnosis with increased used of imaging
157
over the period, reclassifying some previous labelled early appendicitis into other
158
diagnoses.
159
160
161
Modern diagnostic strategies
162
Modern diagnosis aim to firstly confirm or eliminate a diagnosis of appendicitis, and
163
secondly to stratify simple and complex disease when appendicitis is suspected.
164
The optimum strategy that limits harm (e.g. radiation from imaging) whilst
165
maintaining a high degree of accuracy has still not achieved consensus,
166
representing the difficulty faced by patients and surgeons.
167
168
Biomarkers
169
Biomarkers are used to supplement history and clinical exam, especially in
170
children, women of fertile age and the elderly where diagnosis is difficult. No
171
inflammatory marker alone, including white blood cell (WBC) count, c-reactive
172
protein (CRP) or other novel tests including procalcitonin, can identify appendicitis
173
with high specificity and sensitivity.22_ENREF_24_ENREF_25 However, WBC count is
174
obtained in virtually all patients being assessed for appendicitis, where available. A
175
range of novel biomarkers has been suggested over the last decade, including
176
bilirubin_ENREF_28, but these lack external validity and repeatedly suffer from low
177
sensitivity, meaning they are unlikely to come into clinical practice. 23
178
179
Clinical decision rules/risk scores
180
Each and every clinical sign for appendicitis alone has a poor predictive value.
181
However, in combination the predictive ability is much stronger, although not with
182
perfect accuracy. Consequently, a number of clinical risk scores have been
183
developed, the purpose of the clinical scores are to identify low, intermediate or
184
high-risk patients for appendicitis (figure 2), allowing further investigations to be
185
stratified according to risk (figure 3).24
186
The most widely used to date is the Alvarado score. _ENREF_26A systematic
187
review and pooled diagnostic accuracy study showed that the score has good
188
sensitivity (especially in men) but low specificity, limiting its clinical impact and
189
meaning few surgeons rely on it to guide management above and beyond their own
190
clinical opinion. The predictive ability of each component of the recently derived
191
modified Alvarado score in children is shown in supplemental table 1. 25 Recently
192
the appendicitis inflammatory response score has been developed, and appears to
193
outperform the Alvarado score in accuracy.26
194
195
Transabdominal ultrasonography
196
Initial reliance on ultrasound has been more recently guarded due to moderate
197
sensitivity (86%, 95% confidence interval 0.83-0.88) and specificity (81%, 78%-84%%)
198
shown through pooled diagnostic accuracy of 14 studies27,_ENREF_35 limiting its
199
diagnostic ability. Due to the need for a specialist operator, it is frequently
200
unavailable out of hours and at weekends, further limiting its usefulness. Its first
201
line investigative role is greater in paediatric populations, who typically have
202
thinner musculature, less abdominal fat than adults and a greater need for
203
radiation avoidance_ENREF_68.
204
205
Computed tomography
206
In adolescent and adult patients, computed tomography has become the most
207
accepted imaging strategy. In the USA, it is used in 86% of patients, with a
208
sensitivity of 92.3%.28 This has led to a normal appendectomy rate of 6%. Uptake
209
outside of North America is lower due to concerns over risk of radiation exposure in
210
children and young adults, differing hospitals remuneration systems, unavailability
211
outside of normal hours and absence of scanners in low resource hospitals.
212
In one RCT comapring low-dose versus standard-dose CT in 891 patients, the
213
normal appendectomy rate was 3.5% versus 3.1% respectively, although these
214
advanced technology scanners are not in widescale use. 29 For older patients at
215
higher risk of malignancy, pre-operative CT is recommended to identify malignancy
216
masquerading as (or, causing) appendicitis. Selective CT based on clinical risk
217
scores is likely to target its use and justify radiation exposure (figure 3)._ENREF_36
218
219
Magnetic resonance imaging (MRI)
220
MRI for patients with an acute abdomen may eliminate the risks associated with
221
radiation use in young patients._ENREF_31 However, little is know about the exact
222
utility and accuracy in acute abdomen. For one, there are few units worldwide able
223
to provide immediate access MRI at present. Second, MRI currently has no better
224
accuracy than ultrasound in discriminating perforated appendicitis. 30
225
226
Diagnostic strategies in young female patients
227
In fertile female patients, the initial approach includes urinary pregnancy test to
228
identify possible ectopic pregnancy and transvaginal ultrasound to identify ovarian
229
pathology. In equivocal cases, a thorough clinical assessment (including pelvic
230
examination) by on-call gynaecologists can differentiate alternative pathology and
231
direct further investigations. Early laparoscopy has been suggested as a method to
232
improve diagnosis in female patients with an equivocal diagnosis, having so far
233
been assessed in single centre randomised trials. When compared to clinical
234
observation and selective escalation, routine early laparoscopy increases the rate
235
of diagnosis and may facilitate earlier discharge.31, 32
236
237
Differentiating simple from complex disease
238
At present, both CT and emergency MRI lack ability to discriminate between non-
239
perforated and perforated appendicitis30._ENREF_31 This limits clinicians’ ability to
240
objectively stratify patients for short in-hospital delays prior to surgery or for
241
selection to trials of non-operative treatment with antibiotics. Presence of an
242
appendicolith in radiological imaging is associated with both a higher risk of
243
antibiotic failure and recurrence,33 whereas the triad of CRP <60g/L, WCC<12x109
244
and age <60 years has been reported to predict antibiotic success. 34
245
246
Treatment strategies
247
248
Non-operative management
249
Primary antibiotic treatment of simple inflamed appendicitis
250
Antibiotics have more recently been proposed as single treatment for
251
uncomplicated appendicitis, but not without controversy. Meta-analysis of RCTs
252
c_ENREF_41omparing antibiotics with appendectomy has shown that although
253
antibiotic treatment alone can be successful, _ENREF_45_ENREF_45patients should
254
be made aware of a failure rate at one year of around 25-30% with need for
255
readmission or surgery (table 2).35 Pilot RCT suggests this strategy may also be
256
effective in children36, although similarly to adults, 38% require subsequent
257
appendectomy during follow-up.
258
The RCTs have methodological limitations including different criteria for
259
diagnosis, low inclusion rate, inadequate outcome measures and different follow-
260
up between groups.37-40 Importantly, some studies did not confirm diagnosis with
261
imaging, which in combination with substantial crossover between study arms, has
262
led some surgeons to question the validity. Within the most recent meta-analysis,
263
three studies originated from Sweden_ENREF_41 and one from France,_ENREF_44
264
meaning that these findings may not be automatically generalizable worldwide due
265
to potential ethnicity and health care access issues.
266
Until more accurate selection criteria emerge (based on combinations of
267
clinical risk scores and imaging) for patients or subgroups who are likely to succeed
268
in the long term from primary antibiotic treatment, suitable patients with mild
269
symptoms (representing mild to moderate appendicitis) should ideally be entered
270
into randomised clinical trials, or at minimum be counselled about a 25-30% one
271
year failure rate.
272
273
Choice of antibiotic regimen
274
Antibiotics with aerobic and anaerobic coverage for ordinary bowel bacteria should
275
be given, taking into account local resistance patterns and the potential for
276
heterogeneous etiology. Antibiotics have been given intravenously for one to three
277
days in all the referred trials; total oral therapy has not been tested. Therefore, it
278
is reasonable to recommend at least one day of intravenous treatment and also
279
hospital surveillance considering that rescue appendectomy has been judged
280
necessary for 5-23% of patients (table 2). Oral antibiotics have subsequently been
281
given for 7-10 days as part of this regimen, illustrating the potential for slower
282
recovery in some patients, albeit whilst avoiding early surgery. The length and
283
nature of treatment should be subject for future research.
284
285
_ENREF_47_ENREF_40Spontaneous resolution
286
Periods of active observation resulting in resolution suggest that spontaneous
287
resolution of simple appendicitis is possible. RCTs comparing active observation
288
with antibiotic treatment have not been made and therefore it is impossible to
289
know whether the reported recovery rates (77-95%; table 2) after primary
290
antibiotics represents a true treatment effect or just the natural course of simple,
291
acute appendicitis. Safe selection criteria for active observation alone to treat
292
confirmed appendicitis do not exist and so it is not recommended as a current
293
treatment strategy outside trials.
294
295
Appendiceal abscess
296
Pre-surgery intra-abdominal or pelvic abscess is found in 3.8% (95% CI 2.6-4.9) of
297
patients presenting with appendicitis and should be suspected in those presenting
298
with a palpable mass. Whilst pre-hospital delay was considered a traditional risk
299
factor, evidence of disconnect between the strata of disease severity means that
300
some patients may be at risk of abscess formation despite prompt treatment. 21
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Meta-analyses on mainly retrospective studies recommend conservative treatment
302
consisting of antibiotics with percutaneous drainage of abscess if needed.
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Immediate surgery is associated with higher morbidity (pooled odds ratio 3.3, 95%
304
CI 1.9-5.6) and risk of unnecessary ileoceacal resection; the recurrence rate is 7.4%
305
(95% CI 3.7-11.1).41
306
307
Follow-up after non-operative management
308
Following conservatively treated abscess, 1.2% of patients will be found to have
309
malignancy.41 Follow-up with colonoscopy and/or CT after conservatively treated
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appendiceal abscess is recommended in patients aged ≥40 years, or those with
311
symptoms or laboratory/radiologic signs that are suspicious of colonic malignancy.
312
The rate of occult appendiceal malignancy after initial successful antibiotic
313
treatment for simple (non-perforated) appendicitis is unknown. Long-term (beyond
314
one year) evidence of outcome and optimum follow-up of is lacking; only one study
315
reports a recurrence rate of 14% after two years.42 Extrapolating from abscess,
316
patients ≥40 or those with other suspicious symptoms should be considered for
317
further investigation to identify malignancy, which may include interval
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appendectomy in selected cases based on age, on-going symptoms and/or
319
radiological findings.
320
_ENREF_23
321
Operative treatment
322
Timing of surgery
323
Outcomes in relation to timing of surgery have been controversial, especially since
324
disease presentation may vary with time of day. Meta-analysis of 11 non-
325
randomised studies (8858 patients) showed that short in-hospital delays of 12-24
326
hours in selected, stable patients were not associated with increased risk of
327
perforation (odds ratio 0.97, 95% CI 0.78-1.19, p=0.750).43 Notably, allowing a
328
delay or, rather, an increased observation time in patients with equivocal signs,
329
with renewed interval clinical assessment increases diagnostic accuracy without
330
increased risk of perforation in acute appendicitis. Delays can aid service provision,
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avoiding night-time operating and increasing access to daytime technological
332
resources where available.44
333
Emergency surgery models can structurally separate elective from
334
emergency care, reduce night-time surgery and improve emergency theatre
335
efficiency.45 Planned early laparoscopy in patients with an equivocal diagnosis can
336
improve the diagnostic rate and facilitate early discharge (without increasing the
337
risk of complications).31, 32 Ambulatory appendectomy, leading to day of surgery
338
discharge, has been reported from single centres and is potentially attractive to
339
improve patient satisfaction and reduce costs in patients with simple
340
inflammation.46
341
342
Surgical approach
343
_ENREF_53Use of laparoscopic appendectomy depends on availability and
344
expertise, with equivalent results achievable from urban centres in India and Africa
345
compared to the UK and USA47. The concept of low-cost laparoscopy, using simple,
346
inexpensive, reusable devices can lead to equivalent costs and outcomes even in
347
complex appendicitis.48
348
349
Role of laparoscopic appendectomy in specific populations
350
Laparoscopy is safely performed in children and the obese with favourable
351
outcomes and low risk profile.
352
and access to specialist equipment and so does not need to be mandated.
353
Appendicitis in pregnancy remains challenging due to displacement of the caecum
354
by the growing uterus. Meta-analysis of low-grade observational evidence suggests
355
that laparoscopic appendectomy in this group is associated with a higher rate of
356
foetal loss compared to an open approach (3415 women, 127 events, relative risk
357
1.91, 95% CI 1.31-2.77).51 However, selection bias and confounders might have
358
influenced these observational results; open appendectomy remains as standard. A
359
selection of best available evidence for surgeons guiding intra-operative decision-
360
making is shown in supplemental table 2.
49 50
Its availability and use depends on expertise
361
362
Novel surgical technologies
363
Single incision laparoscopic surgery (SILS) and low-cost SILS techniques (e.g.
364
“surgical glove port”, supplemental videos 1 and 2) have been recently described
365
and may be performed with inexpensive equipment and routine instruments,
366
leading to satisfactory functional and cosmetic results52. Meta-analysis of 7 RCTs
367
comparing SILS to conventional laparoscopy demonstrate no real differences for
368
SILS, and considerable heterogeneity exist between studies. 53
369
Natural orifice transluminal endoscopic surgery (NOTES) is a technological
370
adaptation of laparoscopy that is available in well-funded centres. Its role and
371
application (transvaginal approach in women; transgastric approach in both
372
genders) is controversial and debated.54
373
Since the role of these technologies seems to be in providing marginal gains
374
to selected patients (which may only be neutral or at best improved cosmetic
375
outcome at the cost of longer operative times and higher post-operative pain53, 55),
376
widespread adoption seems unlikely in light of raised cost and increased procedural
377
complexity.
378
379
Administration of pre-operative and duration of post-operative antibiotics
380
Pre-operative prophylactic antibiotics should be started well before skin incision
381
commences (>60 minutes) and may be initiated as soon as the patient is scheduled
382
for surgery. Broad coverage of gram-negatives is warranted based on studies on
383
microbiology cultures. Metronidazole given intravenously is usually well tolerated,
384
and given alone or in combinations in most studies.56 Piperacillin/tazobactam is
385
also adequate, in particular if perforation or complex disease is suspected on pre-
386
operative diagnosis. Meta-analysis of randomised trials comparing prophylactic pre-
387
operative antibiotics to placebo showed significant reduction of wound infection
388
with either single agent (11 studies, 2191 patients, OR 0.34, 95% CI 0.25-0.45) or
389
multiple agents (2 studies, 215 patients, OR 0.14, 95% CI 0.05-0.39).57
390
_ENREF_57_ENREF_61
391
Administration of post-operative antibiotics is stratified by disease severity.
392
Routine post-operative antibiotics following surgery for simple inflamed
393
appendicitis are not recommended.58 Currently, 3-5 days of post-operative
394
intravenous antibiotics are recommended for complex, perforated appendicitis.
395
Adjusted observational data suggests that three days post-operative antibiotic
396
duration is as effective as 5 days.59 Shorter duration of antibiotics based on
397
cessation following resolution of bedside clinical parameters (core temperature <
398
38 degrees C for 24 hours, tolerated two consecutive meals, mobilizing
399
independently, requiring only oral analgesia) may be equally as efficacious, as
400
proven in paediatric populations.60 Patients should be informed about a continued
401
risk of post-operative abscess formation in perforated appendicitis.
402
403
404
Outcomes
405
Histopathological assessment and risk of neoplasm
406
Routine histopathological assessment of all appendectomy specimens has been
407
debated (as a means to save costs), but remains as a best practice
408
recommendation, primarily due to the ability to identify malignancy in 1%. This is
409
most often in the form of a neuroendocrine tumour of the appendix (so-called
410
carcinoid), an adenocarcinoma or mucinous cystadenoma.61 Specific definitions of
411
appendiceal inflammation lack consensus agreement through a lack of multicentre
412
research, thus meaning some patients labelled with a normal appendix and
413
subsequently being subject to further investigation may in fact have had subtle
414
inflammation.62
415
416
Mortality
417
Although the most severe of all adverse events, mortality in developed health
418
systems is low (between 0.09%63 and 0.24%64) and lacks sensitivity to detect
419
differences in care processes which lead to variation in other outcomes. In LMIC
420
countries, mortality is reported as 1-4%, and so it may represent a useful marker
421
for worldwide care.65, 66
422
423
Perforation rate
424
Low perforation rates were previously used as a marker of better performing units
425
with more prompt access to surgical intervention. However, patients presenting
426
from rural versus urban locations in both developed and developing nations have
427
longer duration of symptoms with higher rates of perforation, although this could
428
also be the result of ethnic predisposition to perforation.67 Additionally, since
429
perforation may result from a separate clinical process than the one at work in
430
non-perforated disease21, it is increasingly recognised that, as a marker of hospital
431
quality, it is a poor measure.
432
433
Normal appendectomy rate
434
In countries with rapid access to CT and diagnostic laparoscopy, the normal
435
appendectomy rate has fallen over the last decade. Rates vary from 6% in the USA
436
(high use of pre-operative CT),28 6.1% in Switzerland (routine use of laparoscopy),68
437
20.6% in the UK (selective use of CT and laparoscopy),69 with variable rates from 9%
438
to 27.3% across India, China, Sub-Saharan Africa, North Africa and the Middle
439
East.61, 65 This rate is also dependent on inter-observer variability of
440
histopathological examination and definitions used. 62 Although normal
441
appendectomy rate can act as a marker of individual hospital pathways, it is one-
442
dimensional in approach, since it does not take into account patients treated non-
443
operatively and is thus a relatively poor universal marker of quality.
444
445
Short-term morbidity
446
Post-operative adverse event profiles vary depending on disease severity, the
447
specific complication, method of detection and the geographical location. Overall
448
complication rates of 8.2%-31.4%, wound infection rates of 3.3%-10.3% and pelvic
449
abscess rates up to 9.4% have been reported.69, 70
450
451
Long-term morbidity
452
Population level data comparing laparoscopic and open surgery shows small long-
453
term outcome differences of little clinical relevance.71 This data also showed that
454
negative appendectomy was associated with higher mortality at 30 days and five
455
years compared to perforated appendicitis.72 Although this could be due to
456
association with underlying undetected morbidity, it could also reflect morbidity of
457
surgical exploration, potentially justifying greater use of pre-operative cross-
458
sectional imaging. Trials with outcome measures related to medium and long-term
459
patient reported satisfaction are severely lacking.
460
461
462
Future research directions
463
A range of research for each step of the patient pathway is required to modernise
464
and standardise the treatment of acute appendicitis internationally; on-going
465
research is shown in supplemental table 3. Research relevant to both low-middle
466
income and high-income countries should be promoted. Both randomised and non-
467
randomised research can promote equality of access to care and reduce variation
468
in outcome. Correct application of technology, for both diagnosis and treatment,
469
needs to be rationalised, justified and optimised through formalised research
470
programmes. Population level data currently being collected should be used to
471
better define variation, plan relevant research questions and develop networks for
472
delivery of trials.
473
474
475
Panel: Key messages
476
477
 An accurate pre-operative diagnosis of acute appendicitis is challenging, as
478
the diagnosis must be entertained in patients of all ages presenting with an
479
acute abdomen.
480
481
 Worldwide variation in care is indicated by variance in use of computed
tomography, administration of antibiotics and removal of a normal appendix.
482
 A clinical classification system based on simple (non-perforated) and
483
complex (gangrenous or perforated) inflammation allows a stratified
484
approach to management. This stratification includes timing of surgery,
485
trials of non-operative management and use of post-operative antibiotics.
486
 Independent of diagnostic and management approach, the perforation rate
487
has remained stable. The non-perforated appendicitis rate has changed,
488
suggesting possible independent disease processes.
489
 Increased use of pre-operative computed tomography results in lower normal
490
appendectomy rates, at the cost of higher radiation exposure for patients.
491
 Some simple appendicitis may be treated with antibiotics alone, although
492
more accurate selection criteria to support this approach are required. At
493
present, patients should be counselled about a high rate of failure (25-30%)
494
at one year.
495
496
497
 Appendectomy is related to inflammatory bowel disease, pointing to
immunological mechanisms and potential role of the gut microbiome.
 Laparoscopy is the surgical approach of choice where local resources allow,
498
with slightly improved short-term outcomes (including less post-operative
499
pain and shorter length of stay) but no difference in long-term outcomes
500
compared to open surgery.
501
502
503
Conflict of interest statement
504
AB – no conflicts of interest
505
KS – no conflicts of interest
506
SDS – no conflicts of interest
507
JA – no conflicts of interest
508
FTD – no conflicts of interest
509
510
Contribution by authors: AB and KS planned the review. Each author drafted a
511
topic section outline. AB collated the sections and drafted the first version. AB, KS,
512
SDS, JA, FTD performed rounds of revisions, edited the draft and approved the
513
final manuscript.
514
515
516
517
Table 1: Stratified disease approach to acute appendicitis.
Disease
state
Normal
(figure 1A)
Underlying
pathology
Normal
Macroscopic
appearances
No visible changes
Acute intraluminal
inflammation
No visible changes
Acute mucosal/
submucosal
inflammation
No visible changes
Simple, nonperforated
(figure 1B)
Suppurative/
phlegmonous
Congestion, colour
changes, increased
diameter, exudate,
pus.
Complex
(figure 1C)
Gangrenous
Friable appendix
with purple, green
or black colour
changes
Perforated
Visible perforation
Abscess (pelvic/
abdominal)
Mass found during
examination or
abscess seen on
pre-op imaging;
abscess or found at
surgery
Microscopic
appearances
Absence of any
abnormality
Luminal neutrophils
only with no
mucosal
abnormality
Mucosal/
submucosal
neutrophils and/or
ulceration
Transmural
inflammation/
ulceration/
thrombosis, +/extramural pus
Transmural
inflammation with
necrosis
Clinical relevance
Perforation;
not always visible in
microscope
Transmural
inflammation with
pus +/- perforation
Higher risk of
post-operative
complications
Higher risk of
post-operative
complications
Consider other
causes
May be cause of
symptoms;
consider other
causes.
May be cause of
symptoms;
consider other
causes
Likely cause of
symptoms
Impending
perforation
518
519
520
521
Legend: modified from the classification system by Carr6. Photographic examples of macroscopic
pathology are shown in figure 1.
522
523
Table 2: Clinical trials comparing primary antibiotic treatment vs. surgery for acute
524
appendicitis.
525
Study design
Patients
(n)
Antibiotic
treated
patients
(n)
Age
(years)/
gender
Diagnosis
Antibiotic
regimen
(days)
Recovery
rate (%)
1-year
failure
(%)
1-year
efficacy**
(%)
RCT
40
20
≥18
US
iv 2
oral 8
95
37
60
Styrud
200638
RCT
multicentre
252
128
18-50
male
clinical
iv 2
oral 10
88
14
76
Hansson
200939
RCT
multicentre
369
119
≥18
clinical
(+US/CT)*
iv 1
oral 9
91
14
78
Vons
201140
Svensson
201436
RCT
multicentre
239
120
≥18
CT
88
25
68
RCT
50
24
5-15
US (+CT)*
92
5
62
Turhan
200973
Prospective
interventional
290
107
≥16
US or CT
iv 3
oral 7
82
10
74
Hansson
201274
Prospective
interventional
558
442
≥16
clinical
(+US/CT)*
iv 1
oral 9
77
11
69
Di Saverio
201442
Prospective
159
interventional
RCT multicentre
(Estimated
600
completion
2025)
159
≥14
clinical
(+US/CT)*
total 5-7
88
13
77
-
-
-
-
-
-
-
Eriksson 199537
APPAC study
(on-going;
NCT01022567)
526
527
528
529
530
531
CT = computer tomography
US = ultrasound
Iv = intravenous
* if judged clinically necessary
** overall efficacy at one year including recurrence
iv 2
oral 8
Iv 2
oral 8
532
533
Figure 1: Panel title: Macroscopic pathological features of appendicitis
534
535
Figure 1A: Macroscopically normal appendix.
536
537
Figure 1B: Simple inflamed appendicitis.
538
539
540
Figure 1C: Complex appendicitis showing perforation with pus formation.
541
542
543
Figure 2: Clinical risk scoring for suspected acute appendicitis
544
545
Figure 3: Flowchart illustrating guidance for a stratified approach to pre-operative
546
management of suspected appendicitis
Presentation
Guidance for a stratified
approach to pre-operative
management of suspected
appendicitis
Acute right iliac fossa pain
>History and examination, urine dipstick (including pregnancy test), blood tests
Clinical risk score
Imaging
Initial clinical
impression
Low risk
Intermediate
risk
Consider ultrasound
Consider CT
Normal
appendix
High risk
Consider CT confirmation
(dependent on local practice)
Equivocal
Clinically appendicitis
Simple
>non-perforated
Mild clinical
signs
Initial management
Failure of initial
management
Non-operative
>Discharge
Non-operative
>Active observation
Further investigations
>consider CT
Operative:
Diagnostic laparoscopy
547
548
Trial non-operative:
>Primary antibiotic
therapy
Operative:
>appendicectomy
Complex
>likely or impending
perforation
Advanced
>unlikely to settle
without surgery
Operative:
>appendicectomy
Established abscess
>mass, may be painless
>extended history
Non-operative:
>Antibiotics
>Radiological drainage
Operative:
>Surgical drainage
549
550
551
552
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