The condition of severe appendicitis still serves as one of the main reasons for performing emergency laparotomy and laparoscopy in patients of any age, and it is one of the most prevalent conditions causing severe abdominal pain, which requires urgent surgery [1]. It still presents with many diagnostic difficulties, since its presentation is often similar to many other causes of acute abdomen, including those originating from gynecology, urology, and gastroenterology, despite the current advances in imaging and laboratory testing [1,2].

Statistics of global epidemiology demonstrate the persisting problem of appendicitis among major diseases. The global age-standardized prevalence of 214 per 100,000 people or about 17 million cases each year, with the highest rates of incidence recorded in high-income Asia-Pacific regions [17]. Even though mortality and disability-adjusted life-years caused by appendicitis have been declining consistently since 1990, almost half of the regions included in the study have witnessed the increase in age-standardized rates of incidence [17,18]. Approximately 4.53 million new cases in children and teenagers have been diagnosed in 2021, with the number likely to rise more than 21% by 2040 [18].

The possibility of delayed diagnosis of appendicitis results in increased risks of perforation, peritonitis, and morbidity related to the surgery performed, but the problem of unnecessary surgery associated with overdiagnosis of appendicitis due to purely clinical suspicions results in negative appendectomies, which may even reach up to 15-20% of all procedures done [8,14]. Thus, balancing the risks mentioned above gave rise to the development of various prediction models that would facilitate decision making and reduce the impact of the subjective assessment.

The Alvarado Score created by Alfredo Alvarado in 1986 is the most extensively studied and widely applied clinical scoring system in the management of acute appendicitis [1]. The ten-point system is based on three symptoms (pain migrating into right iliac fossa, anorexia, nausea/vomiting), three signs (tenderness in the right iliac fossa, rebound tenderness, fever), and two laboratory data (leukocytosis and left shift/neutrophilia) [1]. The reasons for its wide acceptance are the simplicity of use, low costs, and application at the bedside without need for any imaging studies, which is particularly useful in cases of limited resources of many emergency rooms in Pakistan.

Nonetheless, several studies have found that the efficacy of using the Alvarado score in diagnosing appendicitis varies across populations. For instance, a systematic review involving data from 42 studies found that although the cut-off of 5 had good sensitivity in ruling out appendicitis, the cut-off of 7 (which is normally the cut-off value used to warrant an operation), had low specificity, with pooled specificity values of 57% in men and 73% in women, with the score having a propensity to over-diagnose appendicitis among women and children [2]. The differences have led to the development of other scoring systems, including the Raja Isteri Pengiran Anak Saleha Appendicitis (RIPASA) score [3] and Appendicitis Inflammatory Response (AIR) score [4], which have shown to be more sensitive and specific than the Alvarado score in Asian populations.

Recent comparative studies performed in Pakistan, especially in Peshawar, Lahore, Karachi, Rawalpindi and Bahawalpur, have revealed marked variability of the Alvarado score performance with sensitivities ranging between about 54% and 94% and specificities between 57% and 88% based on patient selection criteria, cut-offs and reference standards [5,7,8,11,13,15,16]. Variability highlights the need for local validation data instead of unjustified use of results obtained in other populations due to dietary differences, different health seeking behaviors, practice of self-medication with antibiotics and delays before presentation – all of which may affect clinical and laboratory signs and symptoms during the evaluation.

There are several big tertiary teaching hospitals in the federal capital city of Islamabad, which serve a heterogeneous population from urban, peri-urban and referred rural population from the twin cities and north Punjab/Khyber Pakhtunkhwa area. Despite high prevalence of appendicitis among patients attending their emergency rooms, there is no data available on validation of the Alvarado score in these tertiary centers in Islamabad. The study intends to fill this gap and perform prospective validation of the diagnostic accuracy of the Alvarado score with histopathology serving as a gold standard.

2. Literature Review

2.1 The Alvarado score and its diagnostic performance

The cut-off described by Alvarado in 1986 was that ≥7 indicated definite appendicitis, ≤4 ruled it out, and 5-6 was indeterminate, requiring monitoring [1]. In the past years, numerous validation studies done in various patient populations have examined this cut-off. The systematic review done by Ohle et al. that encompassed 42 such studies found that the score performed extremely well as a 'rule-out' test at the lower cut-off (with sensitivity of nearly 100 percent at a score of 5), but not as well as a 'rule-in' test at the higher cut-off, with decreasing specificity, particularly in females, where gynecological presentations of appendicitis are common [2].

This trend is also exhibited by more recent studies involving single centers. For instance, a retrospective study conducted in Yemen revealed that the sensitivity of the Alvarado score was 94.6%, and its specificity was 87.8% at a cut-off of 6, with an area under the curve of 0.985 and compared with histology and was equivalent to abdominal ultrasonography [6]. On the other hand, a previous prospective study in Jordan indicated that there was a significantly low sensitivity of 54% and specificity of 75%, and this means that the Alvarado score was not sensitive enough in their setting [8]. An Iraqi study conducted in 2025, focusing only on the ambiguous 5-7 score range, showed that the negative predictive value was low in this mid-range (45.7%).

2.2 Comparative studies against RIPASA and AIR scores

Several organizations have challenged the applicability of the original Alvarado group with respect to South and Southeast Asia since the former is a part of Western community. Thus, the RIPASA score was designed in Brunei considering additional features such as patient nationality/ethnicity and duration of symptoms [3]. Since then, several comparative research have been done in Pakistan where the two scales are used simultaneously. Though the Alvarado scale was slightly more accurate than the RIPASA one (89% vs 88%), the latter showed better specificity for that group of patients, according to the 2025 study done in Hayatabad Medical Complex, Peshawar [5]. On the other hand, a comparative study made in Lahore and published in the Journal of the College of Physicians and Surgeons Pakistan and a cross-sectional study from Karachi using histopathology as the gold standard confirmed the fact that RIPASA demonstrated better sensitivity for the diagnosis of appendicitis, though at the expense of specificity [7,13]. Comparable results on setting-related differences in diagnostic efficacy were found in the study conducted in Combined Military Hospital, Rawalpindi [16].

In Pakistani cohorts, there is also a direct comparison of the AIR score, where the laboratory signs of inflammation (neutrophils percentage and CRP) have more importance compared to the Alvarado score. None of the scores has demonstrated consistency regarding superiority over others, and local validation remains important, as concluded in a study from Hayatabad Medical Complex, comparing the Alvarado, AIR, and RIPASA scoring systems in 132 patients [11].

2.3 Modified and combined scoring approaches

Considering the well-known drawbacks of Alvarado score as a single diagnostic method, studies have been done on using this tool in combination with other tests. An Indian study published in 2025 used the Modified Alvarado Score in combination with ultrasound in a tertiary hospital and reported better results compared to any test used individually [12]. Likewise, a retrospective study conducted in Turkey came up with another score based on Alvarado score by incorporating imaging and laboratory tests to distinguish complicated cases of appendicitis from uncomplicated ones [10]. Another quasi-experimental study was done at Combined Military Hospital, Bahawalpur using both Modified Alvarado and RIPASA scores in a young adult group [15].

2.4 Emerging machine learning and artificial intelligence approaches

The application of machine learning (ML) and artificial intelligence (AI) to the diagnosis and estimation of appendicitis severity has gained momentum and quickly gone past the conventional scores. For example, in the study including over 1,800 individuals, Akbulut et al. proposed an explainable ML algorithm via CatBoost to differentiate between perforated and non-perforated appendicitis with acceptable prediction accuracy while being clinically interpretable [20]. The comparison of six machine learning algorithms to predict appendicitis severity in 2024 revealed that such systems work more effectively than grading approaches [21]. Even though the populations, input data, and outcome measures were different making any comparisons difficult and preventing generalizability to practical ED settings, systematic reviews provided some summaries of these findings noting that several ML models outperformed the Alvarado score in benchmarking [22–25]. Meanwhile, lowering the rates of negative appendectomies among the children who are at high risk of appendicitis according to pre-test likelihood has been studied in other recent papers [26, 27]. Though new methods are promising, their use in practical ED settings with limited resources remains impossible because they require computational means and external validation; therefore, Alvarado's score is still the best option [23, 24].

2.5 Rationale for the present study

Taken together, the literature indicates that (a) the Alvarado score's diagnostic accuracy differs greatly based on the population studied, its sex and age group, as well as the cut-off value used; (b) other scores, like the RIPASA or the AIR score, can perform better than the Alvarado score in certain South Asian populations, though they have not proven uniformly superior to it; and (c) there are only a few validation studies performed locally in the Islamabad's tertiary care emergency settings, even though there have been many studies conducted in Pakistan [5,7,11,13,15,16]. Validation research that takes place in a local setting and generates context-relevant estimates of diagnostic accuracy that could guide clinical decision-making is needed to understand the impact of such a score on triaging procedures and resource utilization in Islamabad's emergency departments.

3. Objectives

3.1 Primary objective

Using the cut-off point of ≥7, calculate the diagnostic efficiency of the Alvarado score in terms of sensitivity, specificity, PPV, NPV, and overall accuracy for diagnosing acute appendicitis in patients admitted to the ERs of tertiary care hospitals in Islamabad using the histopathology of the resected appendix as the gold standard.

3.2 Secondary objectives

● To identify the diagnostic efficiency of the Alvarado score in the low (1–4), intermediate (5–6), and high (7–10) probability categories.

● To estimate the diagnostic efficiency of the Alvarado score in children, adults, and the elderly, as well as in males and females.

● To identify the frequency of undiagnosed or late diagnoses of appendicitis and the rate of negative appendectomy for the Alvarado score.

● To construct the ROC curve and establish the locally optimal cut-off score maximizing the sum of sensitivity and specificity of the population.

●      To identify the frequency distribution of each item of the Alvarado score among cases of histologically proved and unproved appendicitis.

4. Research Hypothesis

4.1 Null hypothesis (H0)

In respect of acute appendicitis diagnosis in relation to histopathology in those who present themselves to the emergency departments of tertiary care centres in Islamabad, the Alvarado score is inaccurate in diagnosis even at the traditional cut-off point of ≥7 due to its inadequate sensitivity, specificity, and accuracy (which should be ≥80% in each case).

4.2 Alternative hypothesis (H1)

As compared to histopathological diagnosis, the Alvarado score, when applied with a cut-off point of ≥7, is relatively accurate in the diagnosis of appendicitis in patients presenting in the emergency departments of the tertiary care institutions in Islamabad (diagnostic sensitivity and specificity each ≥80% and overall accuracy ≥80%).

Based on previous studies, a secondary hypothesis is that there will be marked variation in diagnostic accuracy depending on sex and age group, with poor specificity amongst females in their reproductive years [2,5,7].

5.1 Study design Prospective, cross-sectional and analytical validation study based on STARD (Standards for Reporting of Diagnostic Accuracy Studies) Guidelines. 5.2 Study setting and duration The study will take place in the general surgery wards and emergency departments of two or three tertiary teaching hospitals in Islamabad. A period of twelve months for conducting research is recommended to allow enough time for recruitment of participants, variation due to seasons in presentation, and report of histopathology for each participant recruited. 5.3 Study population Eligible participants shall be all patients irrespective of gender visiting the emergency departments participating in the study period having clinical presentation of acute appendicitis. These patients shall be presenting with pain in right iliac fossa or migratory abdominal pain with or without associated gastrointestinal or systemic symptoms. 5.4 Sample size calculation The minimum sample size as per diagnostic accuracy sample size calculation formula is approximately 190-210 patients based on anticipated sensitivity of 85% (calculated from pooled estimates in the region [2,5,7,11]), anticipated proportion of confirmed appendicitis of 70% among clinically suspected cases, 95% confidence limit, and margin of error of 6%. A goal of at least 230 patients is recommended, considering an anticipated 10% dropout (incomplete histopathology, conservative treatment without surgery, or withdrawing consent). Consecutive sampling techniques will be employed to minimize selection bias. 5.5 Inclusion criteria ● Adult patients 12 years old and above come to the hospital ER with a clinical diagnosis of acute appendicitis. ● Individuals who are willing to give their written consent to participate (or minors who are willing to go along with parental consent). ● After the surgery, either open or laparoscopic appendectomy, the removed tissue will be subjected to histopathologic examination. 5.6 Exclusion criteria ● Individuals in whom, on initial assessment, a different clinical diagnosis was readily identifiable (verified ovarian pathology, ectopic pregnancy, perforated peptic ulcer). ● Individuals receiving non-surgical management of their periappendiceal mass or abscess (interval appendectomy cases as histology cannot be obtained immediately). ● Pregnant individuals owing to the recognized effects on laboratory and clinical parameters associated with pregnancy. ● Immunosuppressed individuals or those on long-term corticosteroid therapy may exhibit a poor leukocyte reaction or fever. ● Individuals decline an appendectomy or consent to one where there is no histological specimen available for examination. 5.7 Sampling technique All patients that qualify for participation during the research study period will undergo recruitment through screening of each eligible patient until the required sample size is attained.

5.8 Data collection procedure

Having been obtained informed consent, a structured proforma will be used for recording the clinical history, demographics (age, gender, and address), and eight component elements of the Alvarado score at the time of presentation to the emergency department. The physician making the assessment will be blind to the histopathology result. Routine laboratory workup (full blood count with differential) will be performed as part of the standard care. To ensure that the index test is independent of the reference test, results of any computer tomography or ultrasound performed as routine care will be documented but not used for any adjustment in reporting the Alvarado score. Histopathological assessment by a blinded consultant histopathologist will be done for all patients undergoing appendectomy. The histopathology report will form the gold standard for defining the final appendicitis status.

Table 1 provides details about the elements making up the Alvarado score, while Table 2 provides the pre-defined risk classification and the treatment recommendation.

Table 1. Components and point allocation of the Alvarado score [1]

Table 2. Alvarado score risk stratification and suggested clinical action

Table 3. Key study variables

5.9 Operational definitions

Evidence from histopathology will show presence of neutrophilic infiltration transmurally in the wall of the appendix to describe appendicitis (index disease). A resected appendix, which does not show any histopathological evidence of acute inflammatory changes, is known as a "negative appendectomy". A patient with an Alvarado score of ≥7 and who has proven appendicitis on histopathology is a "true positive", whereas a patient with an Alvarado score of ≥7 with negative histopathology is a "false positive". A patient with an Alvarado score of <7 and who has proven appendicitis on histopathology is a "false negative" (subsequently identified by deterioration and delayed appendectomy, or 2-week telephone/follow-up for those conservatively managed at presentation).

5.10 Blinding

About the guidelines on STARD for studies on diagnostic accuracy, the reporting histopathologist will be blinded with respect to the clinical Alvarado score while the clinician responsible for assessing the Alvarado score will be blinded with respect to the histopathology result.

6. Statistical Analysis Plan

All data obtained will be analyzed using SPSS (version 26 onwards) and/or R statistical software after the collection of all data in an electronically protected database. Normality of the continuous variables (age, total leukocytes, total Alvarado score) will be analyzed using Shapiro-Wilk test and histograms/Q-Q plots; the normally distributed variables will be expressed as mean ± SD while skewed variables will be expressed as median [interquartile range]. Categorical data (sex, score component, final histopathology) will be described using frequencies (%).

In the primary analysis, a 2X2 contingency table will be created comparing the histological diagnosis (positive for acute appendicitis vs. negative for acute appendicitis) with the result of Alvarado score (positive: ≥7, negative: <7). From the contingency table, sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio, diagnostic odds ratio, and accuracy will be calculated with 95% CI. The graph of sensitivity versus 1-specificity across the entire spectrum of possible Alvarado scores (from 0 to 10) will produce a receiver operating characteristic (ROC) curve, which area will then be calculated as an estimate of the overall discriminative power. The locally optimal cut-off point will be determined using the Youden index (sensitivity + specificity − 1).

The subgroup analysis will be performed in terms of sex (male/female) and age category (adolescent/young adult, adult, elderly) as determinants of diagnostic accuracy. Differences in proportions between groups will be evaluated using chi-square or Fisher's exact tests (in case where expected counts are less than five). Differences in the continuous variables (total Alvarado score) between groups with/without confirmed appendicitis will be evaluated using independent-samples t-test or Mann-Whitney U test, depending on the situation. Using age and sex adjustment, independent predictors of confirmed appendicitis among the Alvarado score elements will be assessed by multivariable logistic regression; results will be expressed as odds ratios and 95% confidence intervals. All statistical tests will be considered statistically significant at a two-sided p<0.05 level. Inter-observer agreement for the calculation of the Alvarado score (intraclass correlation coefficient for the overall score and weighted kappa for the categorical risk stratification).

7. Ethical Considerations

• Before recruiting the participants, approval will be sought from the IRB or ERC of each tertiary care hospital taking part in the study in Islamabad. The study will be conducted in accordance with the ethical standards outlined in the Declaration of Helsinki.
• Written informed permission will be obtained from all adult participants while informed assent will be obtained from the patients aged between 12 and 17 in addition to informed consent from the parent/guardian.
• The patients will be told that their decision not to participate will not have any effect on the quality of treatment they receive.
• Confidentiality of the patients will be ensured all through; only the core members of the research team will be allowed access to the information while all information will be de-identified at the time of entry into the research database through use of unique study codes instead of direct identifiers.
• This study will pose little additional risk to the subjects since the Alvarado score will be determined using information that has already been collected as part of the routine evaluation of patients with acute appendicitis (history, physical examination, and blood work done on admission); taking part in the study will not lead to any extra invasive procedure, experimental treatment, or departure from the standard of care.
• To ensure that there is no conflict between research and clinical practice, clinical decision-making will not be driven by the protocol but left to the clinical team’s judgment as to whether to operate.
• Any unexpected findings of clinical significance during data collection will be immediately communicated to the treating clinical team.
• Whenever appropriate, the study will be prospectively registered in a relevant clinical trial/study registry, and all the authors will disclose any conflict of interests.

Table 1. Comparison of categorical variables according to histopathological diagnosis (N = 300)

Table 1 depicts the comparison of distribution of categorical variables between histopathology positive cases of acute appendicitis (n=191) and histopathology negative cases (n=109). No significant difference in the distribution of gender was observed in the two groups with male gender accounting for 49.2% in the histopathology positive group and 49.5% in the histopathology negative group (P=1.000). Also, there was no significant difference in the place of residence (urban/rural) between the two groups (P=0.266).

Several clinical parameters showed significant associations with confirmed appendicitis. Migratory pain was significantly higher in the cases of positive histopathology when compared to the negative ones (56.0% vs. 40.4%; P = 0.013). Also, the incidence of anorexia was significantly higher in confirmed appendicitis (65.4% vs. 35.8%; P < 0.001) as well as nausea/vomiting (54.5% vs. 40.4%; P = 0.026). Rebound tenderness was strongly associated with confirmed appendicitis being seen in 60.2% patients in the histopathology positive group compared to 30.3% in the histopathology negative group (P < 0.001). All patients had tenderness in right iliac fossa (100%).

The distribution of Alvarado risk categories varied significantly based on histopathological diagnosis (P < 0.001). Most patients with appendicitis were high-risk (83.8%) while those without appendicitis were mostly in the category of equivocal risk (84.4%) and none had a high-risk score. This result indicates the ability of high scores of the test to distinguish patients with acute appendicitis. There was no significant difference between the groups with positive and negative histopathology results concerning ultrasound results (P = 0.690), CT scan results (P = 0.648), type of operation (P = 0.097), or intraoperative findings (P = 0.751). These variables had a similar distribution in both groups. Expectedly, the negative appendectomy rates were statistically different for the two groups (P < 0.001). While all the patients with positive histopathology findings had no negative appendectomy (100%), 63.3% of patients with negative histopathology findings had a negative appendectomy.

Table 2. Comparison of Age According to Histopathology

The following is the comparison of the age distribution of patients with histopathology-proven acute appendicitis and those without histopathology-proven acute appendicitis. According to the results of the independent samples t-test, there was no statistical difference between the mean ages of both groups (t = 0.041, P = 0.967). Also, according to the results of the non-parametric Mann–Whitney U test, there was no statistical difference between the medians of the age distribution of both groups (U = 10,461.0, P = 0.944). Since the results obtained from the above analyses are consistent, the age of patients was similar in both groups.

Table 3. Binary Logistic Regression

Outcome: Histopathology (Positive)

Predictor: Alvarado Score

Table 3 shows the findings from the binary logistic regression analysis performed to determine the relationship between the total Alvarado score and the confirmed acute appendicitis through histopathology. From the analysis, the total Alvarado score was found to be a significant predictor of confirmed acute appendicitis (β = 1.585, P < 0.001). The odds ratio (OR) of 4.88 (95% CI: 3.36–7.09) suggests that for every unit increase in the total Alvarado score, there is an increase in the odds of having histopathologically confirmed acute appendicitis by about 4.9 times.

The 95% confidence interval was not equal to 1.0, implying that there was statistical significance of the relationship. These findings indicate that a higher total Alvarado score is strongly related to an increased risk of developing acute appendicitis.

ROC Analysis

ROC analysis showed that the Alvarado Score had outstanding diagnostic properties in terms of diagnosis of histopathologically proven acute appendicitis. The area under the ROC curve (AUC) was 0.907, which is the indication of outstanding discrimination ability between cases of acute appendicitis and its absence. An AUC > 0.90 proves the accuracy of the Alvarado Score in the diagnosis of acute appendicitis.

Table 4. Diagnostic Accuracy (Cut-off: Alvarado Score ≥7)

Diagnostic performance of the Alvarado Score at cut-off point of ≥7 for diagnosis of histopathologically confirmed acute appendicitis is presented in Table 6. According to the data presented, sensitivity of the Alvarado score was found to be 83.77%, which means that approximately 84% of patients with histopathologically confirmed acute appendicitis were diagnosed correctly according to the score. Specificity was 100.00%, meaning that all patients without acute appendicitis were diagnosed as negative, with no false-positive outcomes found.

Positive predictive value (PPV) was 100.00%, meaning that all patients who received Alvarado scores of ≥7 had histopathological confirmation of acute appendicitis. Negative predictive value (NPV) was 77.86%, meaning that approximately 78% of patients with Alvarado score of less than 7 did not have acute appendicitis, with the remaining ones being false negatives.

Overall diagnostic accuracy was 89.67%, showing that Alvarado scoring system diagnosed almost nine out of every ten patients accurately. In conclusion, these results show that cut-off point of ≥7 gives extremely high sensitivity and specificity and PPV equal to 100%. Additionally, diagnostic accuracy is also quite high.

Table 5. Sex and age-group subgroup analyses of the diagnostic performance of the Alvarado score

The table below shows the diagnostic efficacy of the Alvarado score (cut-off ≥7) based on subgroups by sex and age group. The results showed that the diagnostic efficacy of the Alvarado score was consistent in all the subgroups, having a specificity of 100% for each of the subgroups. There were no cases of false-positive diagnosis in any of the groups.

In terms of sex subgroups, the diagnostic efficacy of the test was equal in both men and women. In men (n=148), the Alvarado score had a sensitivity of 83.0%, a specificity of 100.0%, and a diagnostic accuracy of 89.2% for true positive and negative cases totalling 78 and 54, respectively. Likewise, in women (n=152), the sensitivity of the test was 84.5%, specificity was 100.0%, and diagnostic accuracy was 90.1%.

Subgroup analysis by age also revealed very good diagnostic accuracy in all age strata. In adolescents (aged ≤19), sensitivity was 86.4%, specificity was 100.0%, and overall accuracy was 90.3%. Young adults (aged 20-39) had the highest diagnostic accuracy with sensitivity 87.7%, specificity 100.0%, and overall accuracy 92.5%. Adults aged 40-64 also had high diagnostic accuracy, sensitivity being 86.2%, specificity 100.0%, and overall accuracy 91.5%.

Conversely, elderly (aged ≥65) group had lower sensitivity (74.5%) and overall accuracy (82.9%), though the specificity was 100.0%. Lower sensitivity in elderly patients is explained by the fact that a higher number of histopathologically diagnosed cases of appendicitis had the Alvarado scores below the diagnostic cut-off, thus leading to false negatives. However, lack of false positives in the elderly group demonstrates excellent specificity of the scale.

All in all, these analyses of subgroups prove that the Alvarado score is characterized by excellent specificity and high diagnostic accuracy in both genders and in all age categories. Highest diagnostic performance was achieved in young adults, while lower sensitivity in the elderly patients suggests that further clinicalevaluation and diagnostic imaging is needed when diagnosing elderly patients with acute appendicitis.

The results obtained from the current study are in line with recent evidence indicating that the Alvarado score is still useful for the diagnosis of acute appendicitis. Applying the cut-off value of ≥7, the Alvarado score had sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy of 83.77%, 100.00%, 100.00%, 77.86%, and 89.67%, respectively. This means that the tool can identify those who have appendicitis with high accuracy without conducting unnecessary appendectomy procedures. These results are in line with the findings of a recent systematic review and meta-analysis performed in 2025, which examined 40 studies that compared different appendicitis scoring tools. Even though the systematic review found out that the RIPASA score was more accurate than the Alvarado score, it still concluded that the latter is among the most widely used scoring systems. Indeed, the specificity (100%) of the current study is more than the pooled specificity documented in many meta-analyses. According to a systematic review of Alvarado score items, high-risk individuals (score 7-10) were found to have a significantly high chance of acute appendicitis, and thus, it was concluded that the score is quite useful in confirming appendicitis in situations where there are limited resources. This may explain the higher specificity documented in the current study because of different factors such as the type of participants, disease prevalence, surgical decision making, and the use of histopathology as the gold standard. Binary logistic regression also indicated that the odd of having histopathologically confirmed appendicitis increases by almost five times with each increase in the score by one point (OR= 4.88; 95% CI: 3.36-7.09; P < 0.001). This positive correlation agrees with existing evidence showing an increasing trend of the probability of appendicitis with increasing Alvarado scores. Of all individual clinical predictors, migratory pain, anorexia, nausea and vomiting, rebound tenderness, and general Alvarado risk score proved to be significantly correlated with histopathological diagnosis. These results are consistent with the conclusions of recent meta-analyses, where anorexia, nausea, and tenderness of the right lower quadrant were found to be the most sensitive parameters, while rebound tenderness demonstrated high specificity in the diagnosis of acute appendicitis. The results of subgroup analyses of the current work demonstrated similar diagnostic capabilities of the score in males (sensitivity of 83.0%) and females (84.5%), as well as perfect specificity in both subgroups. The existing systematic reviews have shown different sensitivity of the Alvarado score in diverse populations, especially in female patients and in children; however, the results of this work indicated similar performance in both sexes of adults. Age stratified analysis showed that the most accurate diagnosis in terms of both sensitivity (96.1%) and specificity (100.0%) was found in young adults, while sensitivity in elderly patients was significantly decreased (74.5%), although the specificity remained perfect. These results are clinically relevant, as older patients may have atypical symptoms and a late diagnosis, resulting in poor sensitivity of the scoring system in them. The receiver operating characteristic curve from this study revealed an AUC of 0.907, demonstrating excellent discriminative ability. Such an impressive diagnostic performance is better than those of many previous studies assessing the Alvarado score but like those from many newer scores described in the literature. However, several recent meta-analyses of comparative characteristics of the scores revealed the presence of higher pooled sensitivity, diagnostic odds ratios, and AUCs in case of some alternatives, namely RIPASA, Tzanakis, and the Appendicitis Inflammatory Response (AIR) score, in certain populations. However, even though newer diagnostic tools appeared, the Alvarado score is still highly beneficial due to its simplicity, low cost, and exclusive use of only clinical and laboratory parameters. Therefore, the results obtained in this study confirm the continuing relevance of using the Alvarado score in clinical practice, especially in emergency departments and other places where imaging is not available or delayed. High specificity, high PPV, good diagnostic accuracy, and statistically significant correlation with histopathological verification all confirm its high efficiency as the primary clinical decision tool. However, given the low negative predictive value and sensitivity in older people, exclusion of acute appendicitis based on low scores of this test should be avoided. 8.1 Anticipated strengths Prospective design, blinding of the index test from the reference standard, histopathology serving as the objective gold standard, and an appropriately sized sample constitute the expected strengths of methodology that will reduce verification bias and ensure precision of diagnostic accuracy estimates for the Islamabad tertiary care setting. 8.2 Anticipated limitations ● Consecutive sampling without probability sampling from only a few tertiary care hospitals might pose a challenge in the generalizability of the results from primary or secondary care settings, or from hospitals in the private sector, where there could be differences in patient population. ● The patients that are treated conservatively without surgery would miss out on histological proof of perforation, resulting in partial verification bias even though the patients are to be followed up clinically. ● Inter-observer difference in assessing the subjective complaints of patients (e.g., anorexia, character of pain migration) may affect measurement even with standard proforma based data collection. ● Being a one-region (Islamabad-based) study, the results might not be generalizable to other regions in Pakistan.

In the current study, it was evident that the Alvarado scoring system is a reliable and accurate tool for diagnosis of acute appendicitis using clinical parameters. With the cut-off score being ≥7, it was found to have a very high diagnostic accuracy (89.67%), a very high sensitivity (83.77%), very good specificity (100.00%), a positive predictive value of 100.00% and a negative predictive value of 77.86%, when compared to histopathology.

Binary logistic regression analysis revealed that the Alvarado score was a significant predictor of histopathologically diagnosed appendicitis, with the odds of having acute appendicitis increasing by 4.9 times with one point increment in the score (OR = 4.88, 95% CI: 3.36 – 7.09; P < 0.001). Migratory pain, anorexia, nausea/vomiting, rebound tenderness and high Alvarado risk scores were significant predictors of acute appendicitis as per histopathology while gender, residency, imaging results, surgical technique, and intraoperative findings were not.

In subgroup analysis, no differences were found in terms of diagnostic efficiency between sexes, while in young people, diagnostic efficiency was higher than in elderly patients due to low sensitivity. However, specificity was always 100% in all age and sex subgroups.

In general, the results suggest that the Alvarado score can be effectively used in the preliminary assessment of patients suffering from acute appendicitis. In case of an Alvarado score equal to or greater than 7, the patient can be predicted to suffer from acute appendicitis histopathologically confirmed. Nevertheless, as there were cases of patients suffering from acute appendicitis with scores lower than 7, the use of the Alvarado score is advisable in combination with clinical diagnosis and, where necessary, radiologic studies.

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