Comment

Appendicitis: is surgery the best option?

The need to surgically remove the appendix in patients
with acute appendicitis is so entrenched in the minds
of surgeons, patients, and physicians alike that nonoperative management is almost never considered or
oered to patients. In The Lancet, Corinne Vons and
colleagues1 present data from a randomised noninferiority trial that compared antibiotics (amoxicillin
plus clavulanic acid) with emergency appendicectomy.
In their study, 243 patients were randomised in ve
French hospitals and the primary endpoint, 30-day
postintervention peritonitis, was more frequent in
the antibiotic group (8% vs 2%, treatment dierence
58, 95% CI 03121). However, 68% of patients with
uncomplicated appendicitis assigned to the antibiotic
group did not need an appendicectomy. This incidence of
unnecessary appendicectomy was similar to four earlier
randomised trials25 comparing antibiotic therapy with
appendicectomy for the treatment of uncomplicated
appendicitis (table). Yet Vons and colleagues could not
show non-inferiority of antibiotic treatment compared
with appendicectomy, owing perhaps to study design
and choice of antibiotic.
Vons and colleagues1 compared the 30-day posttherapeutic occurrence of an intra-abdominal infectious
complication between antibiotic and appendicectomy
groups with a non-inferiority margin of 10%. A 10%
margin is usual in comparisons of dierent drug treatments, but is probably too narrow when comparing a
surgical option with a non-surgical option, with very
dierent riskbenet ratios.6 There is no guidance in the
literature for the appropriate non-inferiority margin to
use when comparing a non-surgical with a surgical group.
If a 15% margin had been chosen, which in my view is not
unreasonable considering the risks associated with surgery,
non-inferiority would have been shown. Furthermore,
the overall rate of Escherichia coli non-susceptibility to

Number of patients in antibiotic group

amoxicillin-clavulanic acid is substantially greater than the

non-inferiority margin chosen.7 E coli is the most common
organism isolated from patients with appendicitis, and
resistance of E coli to aminopenicillins in Europe can
reach 66%.8 For this reason, amoxicillin-clavulanic acid
is not recommended in the non-operative treatment
of appendicitis.9 In fact, in the four other published
comparisons,25 amoxicillin-clavulanic acid was never used.
The most appropriate way to analyse missing data
continues to be a challenge for researchers. Vons
and colleagues rst imputed missing data points
as successes, and in a secondary analysis excluded
these data. However, in the webappendix when the
missing data were imputed as failures, the incidence
of a primary event in the antibiotic group was 108%
(13 of 120 patients) compared with 58% (seven of 119)
in the appendicectomy group, which is statistically
consistent with similarity between antibiotic therapy
and appendicectomy (Pearson =191, p=0167).
Localised thickness of the digestive tract walls with
free uid present at operation, subjectively determined
by the surgeon, was a primary endpoint in the antibiotic
group having surgery (see protocol section 7-1). A similar
determination of densication of soft tissue with or
without organised uid collection could not be assessed
in patients in the surgery group, because they did not
routinely have a CT scan at follow-up, and were assessed
1 week later than patients in the antibiotic group. In my
experience, intestinal thickening and postoperative uid
would have been detected in some surgical patients
after appendicectomy if they had been followed up at
day 8 and if all patients with symptoms had a CT scan,
as was done for patients in the antibiotic group. Use of
dierent follow-up procedures between groups biases
the data, and potentially changes the outcome. I would
suggest that patients in both groups should have had a

Eriksson (1995)2

Styrud (2006)5

Hansson (2009)3

Malik (2009)4

Vons (2011)1

20

128

202

40

120

Antibiotic failure needing appendicectomy

15

105

14

Normal appendix

Recurrence requiring appendicectomy

16

11

30

Normal appendix with recurrence

Did not need appendicectomy

0
13/20 (65%)

0
98/128 (77%)

0
89/202 (44%)

0
34/40 (85%)

See Articles page 1573

For the study protocol see

http://www.medecine.u-psud.fr/
modules/resources/download/
ufrmedecine/Recherche/
Publications/Appendop_
biomedical_resarch_protocol_C_
VONS_et_al.pdf

4
81/120 (68%)

Table: Summary of randomised trials comparing antibiotics with appendicectomy

www.thelancet.com Vol 377 May 7, 2011

1545

Comment

day 8 follow-up with mandatory abdominal imaging,

irrespective of symptoms, to eliminate bias.
The success of source control surgery or antibiotic
treatment of appendicitis is determined by resolution of
the condition strictly by means of the assigned treatment.
Patients who developed postoperative peritonitis in
the antibiotic group were correctly included as failed
treatments, even though this complication arose from
surgery. The same stringent criteria were not applied
in the surgery group, since 21 (18%) of these patients
had complicated appendicitis and received antibiotics
postoperatively, but were not considered treatment
failures. Some of the patients in the surgery group would
probably have developed postoperative peritonitis
without antibiotics.8 These patients should be classied
as treatment failures because appendicectomy alone did
not provide adequate source control. Equivalence might
have been shown if the patients undergoing surgery had
not received this preferential treatment.
The incidence of post-treatment peritonitis is
interesting and as yet unaccounted for. When the
management of appendicitis with antibiotics was
successful, the incidence of post-treatment peritonitis
was zero. However, if antibiotics failed, the organ
space surgical site infection rate was very high, at 14%
(two of 14 patients) compared with 17% (two of 120)
in the appendicectomy group.
Finally, an alternative to appendicectomy in patients
who did not respond to initial treatment with antibiotics
and those who had recurrent appendicitis could be
another course or dierent antibiotic, since the cause
of failure could be antibiotic resistance. This acceptable
alternative strategy3 is analogous to the present standard
of care for recurrent uncomplicated diverticulitis.10

I congratulate Vons and colleagues for tackling this

important, controversial, and relevant topic. Hopefully
their conclusion, once the biases have been considered,
will not overshadow major advances that have been made
in the past 15 years towards the conservative treatment of
appendicitis. The fact that two-thirds of patients can be
spared an operation deserves more attention.
Rodney J Mason
University of Southern California, Keck School of Medicine,
Division of General and Laparoscopic Surgery, Los Angeles,
CA 90033, USA
rjmason@med.usc.edu
I declare that I have no conicts of interest.
1

2
3

4
5

10

Vons C, Barry C, Maitre S, et al. Amoxicillin plus clavulanic acid versus

appendicectomy for treatment of acute uncomplicated appendicitis:
an open-label, non-inferiority, randomised controlled trial. Lancet 2011;
377: 157379.
Eriksson S, Granstrom L. Randomised controlled trial of appendicectomy
versus antibiotic therapy for acute appendicitis. Br J Surg 1995; 82: 16669.
Hansson J, Korner U, Khorram-Manesh A, Solberg A, Lundholm K.
Randomised clinical trial of antibiotic therapy versus appendicectomy as
primary treatment of acute appendicitis in unselected patients.
Br J Surg 2009; 96: 47381.
Malik AA, Bari SU. Conservative management of acute appendicitis.
J Gastrointest Surg 2009; 13: 96670.
Styrud J, Eriksson S, Nilsson I, et al. Appendectomy versus antibiotic
treatment in acute appendicitis. a prospective multicenter randomized
controlled trial. World J Surg 2006; 30: 103337.
Powers JH, Ross DB, Brittain E, Albrecht R, Goldberger MJ. The United
States Food and Drug Administration and noninferiority margins in clinical
trials of antimicrobial agents. Clin Infect Dis 2002; 34: 87981.
Oteo J, Campos J, Lazaro E, et al. Increased amoxicillin-clavulanic acid
resistance in Escherichia coli blood isolates, Spain. Emerg Infect Dis 2008;
14: 125962.
Andersen BR, Kallehave FL, Andersen HK. Antibiotics versus placebo for
prevention of postoperative infection after appendicectomy.
Cochrane Database Syst Rev 2005; 3: CD001439.
Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of
complicated intra-abdominal infection in adults and children: guidelines
by the Surgical Infection Society and the Infectious Diseases Society of
America. Surg Infect (Larchmt) 2010; 11: 79109.
Chautems RC, Ambrosetti P, Ludwig A, Mermillod B, Morel P, Soravia C.
Long-term follow-up after rst acute episode of sigmoid diverticulitis:
is surgery mandatory?: a prospective study of 118 patients.
Dis Colon Rectum 2002; 45: 96266.

Improving treatment outcome for children with HIV

Published Online
April 20, 2011
DOI:10.1016/S01406736(11)60363-2
See Articles page 1580

1546

Over 2 million children are infected with HIV, and around

700 children die of HIV/AIDS-related causes every
day. Almost all children with HIV infection have been
infected through perinatal transmission, and without
antiretroviral treatment over half will die before the age
of 2 years.1
Antiretrovirals have had a dramatic eect on the
course of HIV/AIDS in children. Trials show excellent
long-term outcomes with protease inhibitors and

non-nucleoside reverse-transcriptase inhibitors,2

and current guidelines recommend starting antiretroviral therapy in children as soon as possible
after diagnosis of HIV infection.3 Poor availability of
ecient antiretroviral regimens, unclear strategies for
optimum drug sequencing, and maintenance of high
adherence from infancy and throughout adolescence
to adulthood are important challenges to long-term
treatment success.4
www.thelancet.com Vol 377 May 7, 2011