Adolescent girls are frequently seen in the emergency department with symptoms of abdominal pain 1,2 and are more often diagnosed with nonspecific abdominal pain, constipation and urinary tract infections when compared with similarly aged boys 2. Furthermore, adolescent girls have more differential diagnoses for abdominal pain owing to gynaecological conditions like dysmenorrhoea, ovarian cyst rupture and torsion, Mittelschmerz, endometriosis, ectopic pregnancy and pelvic inflammatory disease. It is, therefore, not surprising that a few studies have observed a higher incidence of a nonincidental removal of a normal appendix [negative appendicectomy (NA)] in girls and women of childbearing age who present to hospital with abdominal pain 3–8.
Furthermore, in a recent meta-analysis, ultrasonography (USS) had a sensitivity of 88% and specificity of 94% for diagnosing appendicitis in children 9. Similarly, in another meta-analysis, C-reactive protein (CRP) had a sensitivity of 57% and specificity of 87% and white cell count (WCC) a sensitivity of 62% and specificity of 75% in detecting appendicitis 10. However, it remains to be shown that the use of these diagnostic tools translates to lower NA rates.
NAs are associated with unnecessary costs and morbidity 5. We aim to determine if young adolescent girls, aged 12–16 years, are more likely to undergo a NA when compared with similarly aged boys, and evaluate the usefulness of ultrasonography (USS) and inflammatory markers (WCC and CRP) in reducing NA rates in these young girls and boys.
Participants and methods
This study was carried out at the Children’s University Hospital in Dublin, Ireland. Over a 17-year period from January 1995 to December 2012, we retrospectively reviewed the electronically stored data on appendectomies performed in boys and girls, aged 12–16 years, who presented to the emergency department with abdominal pain. The mean age at onset of menarche in Ireland is 12 years 11 and upper age limit for assessing children at our institution is 16 years. Our adolescent age group was thus defined as children between ages 12 and 16 years. The documented histological findings of the appendix specimens and the preoperative data on WCC, CRP and USS were analyzed.
If the diagnosis was clinically obvious at the time of presentation, children were scheduled for appendicectomy. When the diagnosis was equivocal, children were admitted and prescribed intravenous fluids and analgesia. Twice daily clinical reassessment was performed for a period of 24–48 h, and additional investigations such as abdominal USS and serum inflammatory markers were requested. Frequently, serum inflammatory markers had been requested routinely by the emergency department before referral to the surgical team. WCC count and CRP levels greater than 13×109/l and 10 mg/l, respectively, were considered abnormally elevated based on our institutional laboratory criteria. Table 1 shows the findings on graded compression abdominal ultrasonography that were used to group patients into four categories: positive, suggestive, inconclusive and negative for appendicitis. Six radiologists performed these ultrasound examinations over the study period, and there were three primary consultant surgeons and up to five senior surgical trainees involved in making the decision to perform an appendicectomy in these children. The appendix specimens, removed nonincidentally, with normal histology were grouped as NAs. In symptomatic children, the following histological features, alone or in combination, of the excised appendices were considered positive: intramural infiltration by acute inflammatory cells, reactive lymphoid hyperplasia, Enterobius vermicularis colonization, presence of an obstructing appendicolith, submucosal fibrosis, and a few specimens with chronic inflammatory cell infiltration labelled granulomatous appendicitis.
The exclusion criteria included all interval and incidental appendicectomies and children who had a computed tomography (CT) scan or MRI performed before appendicectomy. Analysis of categorical data and continuous dependent variables utilized Fisher’s exact test and Student’s t test, respectively. The sensitivity and specificity of inflammatory markers and the positive predictive value and negative predictive value of ultrasonography were calculated. Odds ratios (OR) were calculated to analyze the influence of sex and the use of USS and inflammatory markers on NA rates. Significance was set at P less than 0.05.
Over the 17-year study period, 430 boys and 273 girls met the inclusion criteria. The mean age was 13.46 years (boys: 13.48 years and girls: 13.46 years; P=0.234). Table 2 shows the NA rates, the positive and negative predictive values [positive predictive value (PPV) and negative predictive value (NPV)] and diagnostic accuracy of USS. Moreover, shown in Table 2 is the sensitivity and specificity of the inflammatory markers, WCC and CRP, when evaluated alone and in combination. Not all children were investigated with USS and inflammatory markers. Table 3 shows how the use of USS and inflammatory markers differed between the adolescent boys’ and girls’ cohorts. More girls had USS performed (P<0.0001). There was no difference between groups in the use of inflammatory markers; however, more girls underwent appendicectomy with a normal WCC (P=0.0001), normal CRP (P=0.0001) and normal WCC and CRP combined (P=0.001).
The role of sex in negative appendicectomy rates
The overall NA rate was 9.1%, with 7.2% in boys and 12.1% in girls (Table 2). This finding translates to a statistically significant increased odds of a NA in adolescent girls compared with boys (OR: 1.77, 95% confidence interval (95% CI): 1.06–2.96; P=0.030; Table 4). However, as both groups differed in the use of USS and in the proportion of adolescents in each group that underwent appendicectomy with normal inflammatory markers (Table 3), the effects of these confounding variables were evaluated. First, we observed nonsignificant reduced odds of a NA in boys and girls individually, and combined, when USS was positive, suggestive or inconclusive for appendicitis, compared with no USS performed (Table 5). Second, we observed in each cohort individually, and combined, that when the inflammatory markers were normal there were increased odds of a NA. As shown in Table 6, these odds were significant in most scenarios (OR: 15.84, 95% CI: 2.12–118.50; P=0.007 for normal WCC and CRP compared with elevated WCC and CRP in both cohorts combined). Adjusting for this variance in USS use and the variance between cohorts in the proportion of children with normal and elevated inflammatory markers, the new odds of a NA in girls compared with boys were now not statistically significantly increased (OR: 2.27, 95% CI: 0.09–60.64; P=0.624; Table 4). In summary, when both groups had similar USS findings and elevated inflammatory markers, the increased odds of a NA in the girls compared with the boys were not statistically significant.
Role of inflammatory markers
As shown in Table 2, the specificity of WCC, CRP and both tests combined was much higher than the sensitivity in both cohorts individually and overall. A specificity of 96% was observed in boys and girls when both tests were combined. As shown in Table 6, this high specificity was evident as significantly increased odds of a NA when WCC and CRP combined were normal in boys and girls (OR: 15.84, 95% CI: 2.12–118.50; P=0.007).
Role of ultrasonography
Children who had USS performed, irrespective of the findings (positive, suggestive, inconclusive and negative), had higher NA rates compared with children with no USS performed. Overall rates were 13% in USS group versus 7.7% in no USS group (OR: 1.80, 95% CI: 1.05–3.07; P=0.033) (Table 5). This observation was significant in boys (USS vs. no USS: 13.4 vs. 6%; P=0.040), but nonsignificant in girls (USS vs. no USS: 12.8 vs. 11.5%; P=0.851). However, as shown in Table 5, when USS was positive, suggestive or inconclusive for appendicitis (negative USS excluded), the odds of a NA were still not significantly reduced. This was evident in both cohorts individually, and overall, when compared with not having an USS performed: (OR: 0.98, 95% CI: 0.48–2.02; P=0.960; boys and girls combined; Table 5). Furthermore, if appendicectomies had been performed with only a positive and suggestive USS (which has a PPV of 93.5% in both cohorts combined), the odds of a NA were still not significantly reduced when compared with not having USS performed (OR: 0.70, 95% CI: 0.29–1.68; P=0.419; Table 5). The group with no USS performed likely had more clinically obvious appendicitis compared with the equivocal cases in the USS group. USS was found to be more useful in diagnosing an inflamed appendix than a normal appendix in both cohorts, as shown by the PPV and NPV (Table 2). Finally, USS had a lower PPV and NPV and thus lower overall accuracy in girls compared with boys (Table 2).
NA rates in the literature vary widely from 1.1 to more than 36% 2,3. The rates depend on the definition of a NA 12, presence of obesity 13, age group 3,5,7, and the use of imaging 14 and laparoscopy 8. Interestingly, sex differences have been shown to be an important variable when reporting NA rates 2–8,13. Women of child-bearing age (15–45 years) have NA rates higher than men 5,8,15 and even other females 16, and this can be as high as 44% in some published studies 17. This finding has been largely attributed to gynaecological conditions like pelvic inflammatory disease and ovarian cysts that can masquerade as appendicitis 15,16. Similarly, young girls from the age of 10 years, and particularly teenage girls, have also been observed to have higher NA rates than boys 2,5–7 and gynaecological conditions are not entirely responsible for this 2. Nonspecific abdominal pain, constipation and urinary tract infections are more frequently diagnosed in adolescent girls 2. Some studies have even suggested that female sex is associated with slower colonic transit times that predispose them to constipation 18. Furthermore, adolescent girls may be more susceptible to stress 1 and have poorer eating habits which may be responsible for their higher incidence of irritable bowel syndrome 19,20. The findings of these aforementioned studies may partly explain why adolescent girls present to emergency departments more frequently with abdominal pain 1,2. Furthermore, girls have a lower incidence of appendicitis than boys 21. Therefore, the more frequent emergency department presentations, lower incidence of appendicitis and more common gynaecological and nongynaecological causes of abdominal pain 2 predisposes girls to being misdiagnosed with appendicitis. Our results initially corroborated this hypothesis. Over the 17-year study period, girls aged 12–16 years had higher NA rates and increased odds of a NA compared with boys. Several variables in the boys and girls cohorts can influence the NA rates and these include their sex, use of USS 3, differences in the serum levels of WCC and CRP 22, the variable severity of appendicitis (suppurative, gangrenous and perforated; the latter being more obvious clinically 23), presence of obesity 13 and fever 23, period of observation before appendicectomy, and the clinical expertise of the attending surgeon. When the variability of USS use and serum inflammatory markers was accounted for, we did not observe significantly increased odds of a NA in the girls compared with boys.
Ultrasonography has arguably been shown to be a useful aid when evaluating children and adults for appendicitis 3,16,24–27. It avoids the cost and the risk from radiation exposure associated with CT 28. However, the specificity and sensitivity is not quite on par with CT scanning 9,24,26,27. USS is operator dependent and is affected by body habitus and overlying bowel gas particularly when the appendix is retrocecal 29. The PPV range from 81.3 to 94%, NPV 23.9 to 98% and accuracy 43.4 to 92% depending on the study design and studied age groups 24–27. In our series, the overall PPV, NPV and diagnostic accuracy were 93.5, 26.9 and 69.4%, respectively; these values were slightly higher in boys, and significantly more girls had USS performed. These findings suggest that USS is more useful in confirming the presence of appendicitis rather than its absence. The low NPV (high false negative) of USS in our series may be owing to comments often used in USS reports such as ‘no sonographic evidence of appendicitis’, which was more commonly used than the more definitive comment of ‘normal appendix visualized’. Several reports have highlighted the difficulty in visualizing a normal appendix with USS 29. As shown in Table 1, diagnosing another pathology such as enlarged mesenteric lymph nodes or ovarian pathology along with the comment ‘no sonographic evidence of appendicitis’ was more confidently categorized as a negative USS, whereas the comment ‘cannot exclude appendicitis’ was categorized as inconclusive USS. Furthermore, we postulate that appendiceal pathology such as E. vermicularis colonization, submucosal fibrosis and lymphoid hyperplasia (all of which can cause appendix-mediated symptoms without gross appendiceal inflammation 30–33) may not always have met the USS diagnostic criteria required for appendicitis 29 thus also responsible for the high false negative (low NPV) of USS. These children who proceeded to appendicectomy despite having a negative USS were owing to their clinical signs becoming more suggestive for appendicitis while under observation. The USS group overall had a higher NA rate and so increased odds of a NA compared with the no USS group. This was owing to USS being performed in patients (mostly girls) who presented a diagnostic challenge clinically. When negative and inconclusive USS reports were excluded, the odds of a NA when USS was positive or suggestive were still not significantly reduced compared with not having an USS performed in boys and girls. The clinical expertise of the attending surgeons in the no-USS group was most of the time sufficient to accurately diagnose appendicitis without the use of USS. These limitations of USS present a role for CT and MRI to further reduce NA rates in equivocal cases. CT with a sensitivity of 94% and specificity of 95% 14 has been shown to reduce NA rates in girls older than 10 years but is not as valuable in boys older than 5 years who already have low NA rates independent of cross-sectional imaging 3. CT presents a risk from radiation exposure 28, thus the use of MRI, reported to have a 100% sensitivity and 98% specificity, has been evaluated for reducing NA rates particularly in the obese. Because of the higher costs and limited availability, its routine use in suspected appendicitis is not yet recommended by many researchers 14.
Many studies have evaluated the role of CRP and WCC in diagnosing appendicitis. They have been shown useful in scoring systems for appendicitis, 22 and the role of other inflammatory markers such as procalcitonin 10 and granulocyte colony stimulating factor 34 in diagnosing appendicitis has been evaluated. The published sensitivities and specificities of CRP and WCC vary widely, and a meta-analysis on the subject has shown higher specificities than sensitivities for both markers 10. Furthermore, in a meta-analysis by Andersson 35, the combination of elevated WCC and CRP had a higher predictive power for appendicitis than either marker alone. In our cohort of young adolescent boys and girls, we observed significantly increased odds of a NA when CRP and WCC were normal, when evaluated alone or in combination. This finding was more marked in boys particularly, as CRP alone and when combined with WCC had a higher sensitivity and specificity in boys compared with girls (Table 2). More studies are necessary to evaluate if the rise in serum levels of inflammatory markers in appendicitis are sex related, just as obesity in children may cause CRP to be a less reliable marker of appendiceal inflammation 36; for instance, the females may have a delayed rise in these inflammatory markers making appendicitis more likely with initially normal markers. Similar to other published findings, the specificities of these markers (alone or combined) were consistently higher than the sensitivities in both groups 10 and appendicitis was less likely when both inflammatory markers were normal 23,25,35. Therefore, when appendicitis is confirmed, these markers may not always have been raised (lower sensitivity owing to higher false negative rate); however, when these markers are raised in suspected appendicitis, the likelihood of appendicitis is much higher (higher specificity due to lower false positive rate). Finally, inflammatory markers, particularly CRP, are also useful in predicting the pathological severity of appendicitis 37.
Apart from retrospective nature of this study and the modest numbers, particularly in the USS group, the other limitations include the unaccounted aforementioned variables like obesity, period of observation before surgery, the surgeon’s clinical expertise and the stage of appendicitis (perforated or not) that may have differed in the boys and girls cohorts. Similarly, the numerous radiologists who performed these USS scans in equivocal cases were a limiting factor. This study did not evaluate the well-published role of scoring systems, CT scanning and MRI 14.
Adolescent girls aged 12–16 are more likely to have an unnecessary surgery for appendicitis when compared to their counterpart boys. When the inflammatory markers, WBC count and CRP, are utilized and found to be elevated, this increased likelihood of a NA is not observed in girls but rather reduced odds of a NA are seen in both girls and boys. Ultrasonography in equivocal cases is a helpful assessment tool, but it does not significantly reduce the odds of a NA and is thus not superior to clinical assessment alone. Therefore, in difficult cases, a period of observation and re-examination is warranted prior to early appendicectomy or premature discharge which predisposes to appendiceal perforation and subsequent litigation 38.
Conflicts of interest
There are no conflicts of interest.
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