The burden of appendicitis and surgical site infection of appendectomy worldwide

Introduction: Appendicitis is a global abdominal disease and is often treated by appendectomy. Surgical site infection (SSI) is a common complication after an appendectomy that causes a significant burden on health systems. This study aimed to evaluate the trends and variations in the burden of appendicitis by year, region, socioeconomic status, and health expenditure and to assess associated SSI by appendicitis burden, surgical approach, and type of appendicitis. Methodology: Data on Disability-Adjusted Life Years (DALYs) and the human development index were collected from the Global Burden of Disease (GBD) Study and the United Nations Development Programme, respectively. Studies on SSI after appendectomy using the uniform definition and published in 1990-2021 were retrieved. Results: Between 1990 and 2019, the global age-standardized DALY rate of appendicitis decreased by 53.14%, with the highest burdens in Latin America and Africa. The burden of appendicitis was significantly negatively correlated with HDI (r = -0.743, p< 0.001) and health expenditure (r = -0.287, p< 0.001). Among 320 published studies on SSI after an appendectomy, 78.44% of studies did not report criteria for SSI diagnosis or adopt a uniform definition. In total, 69 studies with uniform SSI definitions were included. Studies with uniform SSI definitions were recorded poorly in regions with a heavy burden of appendicitis. The SSI of appendectomy was positively correlated with open appendectomy and complicated appendicitis. Conclusions: Uniform SSI definition, promotion of laparoscopic technology, and establishment of SSI special management are needed to decrease the burden of SSI after an appendectomy


Introduction
Appendicitis is a global and common abdominal disease associated with relevant morbidity, mortality and significant health care costs [1].A systematic review of population-based studies documented the pooled incidence of appendicitis to range from 100 to 151 cases per 100,000 person-years in Western countries, with a rising incidence trend in newly industrialized countries [2].Appendectomy is the common treatment of choice for appendicitis and constitutes one of the most common surgical procedures globally, resulting in a significant burden on health systems [3].
Surgical site infection (SSI) is a common complication after an appendectomy, especially in complicated appendicitis.However, the WHO provided a comprehensive range of evidence-based recommendations for interventions to be applied during the pre, intra, and postoperative periods for the prevention of SSI, such as preoperative bathing and maintaining normal body temperature [4], SSIs are the most frequent health-care-associated infections in developing countries [5].A recent meta-analysis showed an overall incidence of SSI of 7.0 per 100 appendectomies, varying from 0 to 37.4 per 100 appendectomies.This finding indicated that there is a heavy burden of SSI in some countries and regions after appendectomy [6].
This study set out to assess the trends and variations in the burden of appendicitis by year, region, socioeconomic status, and health expenditure, to investigate the status of research on SSI after appendectomy in regions with different appendicitis burdens, and to verify the correlation between surgical modalities/type of appendicitis and SSI of appendectomy among studies with standardized SSI definitions.Thereby discovering the weak regions and deficiencies in SSI surveillance and providing suggestions for SSI prevention and control strategies, except for routine SSI prevention measures.

Data extraction
Data for this study were based on the Global Burden of Disease (GBD) 2019 study providing burden of appendicitis, the United Nations Development Programme (UNDP) providing the corresponding HDI and health expenditure data, and literature retrieval analysis for SSI after appendectomies.
The GBD study by the Institute for Health Metrics and Evaluation (IHME) aimed to quantify health burden due to diseases, risk factors, impairments, and injuries after stratification by age, sex, and location.The GBD study of 2019 provided insights into the health burden of 369 diseases and injuries in 204 regions and countries [7].The burden of appendicitis was measured by DALYs in the GBD study of 2019.The following data regarding appendicitis burden were collected [8]: global and national DALY numbers, crude DALY rates, and age-standardized DALY rates of appendicitis from 1990 to 2019.
The human development index (HDI) of the UNDP is a comprehensive indicator of health, education, and living standards, ranging from 0.0 to 1.0 with a higher value indicating more advanced socioeconomic development.We obtained the HDI data and the health expenditure data of the corresponding year from the UNDP database [9].Health expenditure is the spending on health care goods and services, expressed as a percentage of GDP.It excludes capital health expenditures, such as buildings, machinery, information technology, and stocks of vaccines for emergencies or outbreaks.Countries were grouped into four categories according to HDI values ≥ 0.80, 0.70-0.79,0.55-0.69,and < 0.55, classified as very high, high, moderate, and low, respectively.
PubMed, Web of Science, and EMBASE were searched for studies published between 1 January 1990 and 31 December 2021 documenting the incidence of SSI after appendectomy using standardized definitions.Standardized definitions of SSI were issued by the USA National Nosocomial Infections Surveillance (NNIS) system and revised by the National Health care Safety Network (NHSN) [10].A standardized data collection form was used by two investigators (Lin Yang and Rongshou Zheng) to extract data from the included studies independently.First author, year of publication, country, population, sample size, surgical procedure (laparoscopy or open), type of appendicitis (simple or complicated) and SSI rates were extracted.

Statistical analysis
Disparity of age-standardized DALY rates across six continents was assessed by the Kruskal-Wallis test, followed by Dunn's multiple comparison test [11].Differences in SSI rates between open and laparoscopic appendectomy as well as simple and complicated appendicitis were assessed by the Wilcoxon test.Associations between two parameters were calculated using Spearman's rank correlation and expressed by Spearman's coefficient.Linear regression was applied to explore the associations of the age-standardized DALY rate with HDI and health expenditure and the associations of SSI with surgical modalities/type of appendicitis/HDI.A p value <0.05 indicated a statistically significant difference.Statistical analyses were conducted using SAS 9.4.There were no ethical issues involved in this study, as the data shown here were all extracted from online websites.

Appendicitis burden by year
DALY numbers due to appendicitis declined 31.82% globally, from 2.2 million in 1990 to 1.5 million in 2015, and remained relatively constant from 2015 to 2019 (Figure 1a).Similarly, DALY rates decreased by 52.92% from 41.23 per 100,000 people in 1990 to 19.41 per 100,000 people in 2019 after adjusting for population size (Figure 1b).We further controlled for age structure, gender composition, and growth of population size, which also showed a marked decrease in the age-standardized DALY rates (53.14%) from 41.29 to 19.35 per 100,000 people (Figure 1c).

Appendicitis burden by region and country in 2019
In total, 204 countries were included in the GBD 2019 study, including 54 African countries, 47 Asian countries, 44 European countries, 35 Latin American countries, 20 Oceania countries, and 4 North American countries.A significant difference in age-standardized DALY rates was found among the six continents (H = 100.386,p < 0.001).Figure 2 maps the global distribution of age-standardized DALY rates of appendicitis in 2019.The burden of appendicitis was highest in Latin America and Africa, followed by Asia, Oceania, North America, and Europe.The age-standardized DALY rates are also distributed disproportionately among countries, with the highest in Honduras and Haiti and the lowest in the Maldives (Figure 2).

Appendicitis burden by socioeconomic development and health expenditure
The age-standardized DALY rates of appendicitis in 2019 were significantly negatively correlated with the HDI (Figure 3，r = -0.743,p <0.001).The burden of appendicitis became higher with lower levels of socioeconomic development.Moreover, health expenditure was negatively correlated with appendicitis burden (Figure 4, r = -0.287,p <0.001).

Characteristics of studies on SSI after appendectomy
Among published studies on SSI after an appendectomy, 78.44% of the studies (251/320) did not report diagnostic criteria for SSI or did not adopt uniform criteria for SSI diagnosis (Supplementary Figure 1).Finally, 69 studies using unified diagnostic criteria for SSI were included, of which 4 were in Africa, 16 in Asia, 21 in Europe, 2 in Latin America, 24 in North America, 1 in Oceania, and 1 in multiple regions (Supplementary Table 1).The studies with consistently applied SSI definitions were recorded poorly in some regions that had a heavy burden of appendicitis, particularly in Africa and Latin American regions (Figure 2).

SSI after appendectomy by surgical modalities
Of the 69 included studies, 26 and 36 studies reported SSI after open and laparoscopic appendectomy, respectively.The remaining studies did not provide surgical modality information.SSI after open appendectomy was significantly higher than that after laparoscopic procedures (W = 679.000,p < 0.001; Supplementary Figure 2a).The linear regression analysis showed that surgical modalities had an effect on SSI after appendectomy (adjusted R 2 = 0.058; p = 0.045).SSI was positively associated with the proportion of open appendectomy (standardized β = 0.048, p = 0.045), Supplementary Figure 3.

SSI after appendectomy by type of appendicitis
Of the 69 included studies, 21 and 25 studies provided data on SSI of simple and complicated appendicitis, respectively.As expected, complicated appendicitis had significantly higher SSI than simple appendicitis (W = 154.000,p <0.001; Supplementary Figure 2b).
The linear regression analysis showed that the proportion of complicated appendicitis also had a positive effect on SSI after appendectomy (adjusted R 2 = 0.352, p < 0.001; standardized β = 0.608, p < 0.001; Supplementary Figure 4).

Multiple linear regression analysis
Based upon the above findings, we included surgical modalities, type of appendicitis, and HDI as independent factors to construct a multiple linear regression model of SSI rates after appendectomy.A significant association was found between surgical modalities (p < 0.001) and type of appendicitis (p = 0.015), and the model could explain 45.1% of the SSI variance (Table 1).

Discussion
In this study, we documented the tendencies and variations in the global appendicitis burden and showed that relatively few studies with uniform SSI definitions   after appendectomy have been reported from regions with a heavy burden of appendicitis.The analysis also clearly showed that higher SSI rates were associated with open appendectomy and complicated appendicitis, which could explain over 45.1% of the variation across studies.
To our knowledge, this is the first study to evaluate both the burden of appendicitis and SSI of appendectomy worldwide on the basis of considering the SSI standard definition; such data are necessary for planning health care resource utilization.A metaanalysis of 226 studies also revealed a high incidence of SSI after appendectomy (7 per 100 appendectomies) [6].However, uniform diagnostic criteria for SSI were not considered, and studies using a variety of different diagnostic criteria for SSI were included in that metaanalysis.Without a consistently applied definition, meaningful measurement and comparison of SSI rates are difficult to guarantee.
After accounting for the impact of population size and structure, the burden due to appendicitis has clearly decreased over the last 30 years in terms of agestandardized DALY rates.With advances in clinical diagnosis and treatment, appendicitis can be rapidly diagnosed, and its emergency can be treated promptly.As minimally invasive or laparoscopic surgery became a reality in 1983 [12], the morbidity and mortality related to appendectomy have been drastically reduced [13,14].Rates of diagnosis and cure and life expectancy therefore may increase, which could contribute to the descending trend of appendicitis burden.
Although the overall burden of appendicitis showed a decreasing trend, it remains a matter if concern in developing countries.This study showed that the burden of appendicitis was negatively correlated with HDI and health expenditures, thus suggesting that the burdens of appendicitis are heavy in countries with low levels of socioeconomic development and fewer health expenditures.Moreover, SSI rates after appendectomy in low and middle-HDI countries are dramatically higher than rates in high-HDI countries [15].Once surgical site infection occurs, it places a substantial burden on health care systems in terms of patient morbidity and mortality, a longer duration of hospital stay, and additional costs [4].All the above points suggest that we should focus on reducing the disease burden and associated SSI in developing countries.In addition to routine SSI prevention measures, the following aspects should also be noted.

Uniform monitoring definition for SSI
We found that nearly 78.44% of the studies on SSI after appendectomy did not report criteria for SSI diagnosis or adopt a uniform definition.Indeed, mapping the global distribution of appendicitis in terms of DALY and the number of studies reporting SSI after appendectomy, we found a paucity of studies with consistently applied SSI definitions in regions with a heavy burden of appendicitis.In addition, we found that the burden of appendicitis is negatively correlated with HDI and health expenditures.Therefore, it is suggested that developing countries lack a uniform monitoring definition for SSI.More than 30 definitions of SSI have been used in research publications [16].The application of a uniform definition is vital to the dependability of SSI surveillance and constitutes one of the minimal requirements for horizontal comparisons at international levels [17].The definition of SSI from the US Centers for Disease Control (CDC) and the National Healthcare Safety Network (NHSN) is most widely used and comprehensive and can be considered a candidate for uniform definition worldwide.Standardized surveillance is an effective intervention process itself, which may effectively reduce SSI rates [18].Surveillance using uniform SSI definitions is an effective measure for capturing a panoramic view of the global postoperative SSI of appendectomy and improving the prevention and control of surgical site infection.

Development and promotion of laparoscopic technology
However, several single, multicentre studies and meta-analyses have established correlations between open appendectomy [19][20][21][22], complex appendicitis [23][24], and increased SSI.We focused on studies with standardized SSI definitions and verified the correlation between surgical modalities/type of appendicitis and SSI of appendectomy, further suggesting that the development and promotion of laparoscopic procedures are conducive to reducing the SSI of appendicitis, especially in developing countries.

Establishment of SSI special management
Although appendicitis is a common local and global health concern, its geographical distribution in terms of disease burden is quite uneven globally.Aside from populational and genetic factors, differences at the medical level, including diagnostic modalities, medical management, and surgical practice, may partially explain the disparity in appendicitis burden observed among regions.Socioeconomic development is also associated with geographic disparity in appendicitis because more developed countries are supposed to have better health care systems and higher medical technology levels [17].Considering area variations and resource availability, the establishment of SSI special management (including evaluation, monitoring, feedback, funding, etc.) at the national or regional level may be more effective in reducing SSI.
In addition to appendectomy, medical treatment has become a popular treatment method in recent years, especially in cases of uncomplicated acute appendicitis.The analysis of the burden of medical treatment is also an issue worth exploring.Studies have shown that the total cost of medical treatment for appendicitis ranges from $2.7 to $3.9 (US $1000) [25][26][27].The mean difference between medical treatment and appendectomy in total cost in US $1000 was -$1.31.The length of stay in medical treatment for appendicitis ranged from 37 to 156 (in Hours) [26][27][28], and it was longer than in appendectomy, with a mean difference of 14.32 hours [29].
The advantage of our study lies in the evaluation of both the appendicitis burden and SSI of appendectomy on a global level, discovery of possible weak regions and deficiencies in SSI surveillance, and recommendations for reducing SSI, except for routine SSI prevention measures.
However, there are some limitations regarding statistical assumptions and data sources inherent in the GBD 2019 study [7] that might have impacted the study findings.Nevertheless, the GBD 2019 study is the most standard and scientific system available for disease burden assessment.Likewise, the confounders may be inadequately controlled because SSI data are derived from published literature, and specific demographic information at the individual level is unavailable, such as age, gender, educational level, and lifestyle.Therefore, it is impossible to adjust or stratify the SSI rate according to these variables.Further research at the individual level is warranted to acquire more accurate estimations.

Conclusions
In summary, the global burden of appendicitis has continued to decrease over the past 30 years, distributed unequally, and correlated negatively with socioeconomic development and health expenditure.The burden of appendicitis in developing countries remains heavy, and there is a lack of a uniform monitoring definition for SSI.We should focus on reducing SSI and the disease burden in developing countries, including uniform monitoring definition for SSI, promotion of laparoscopic technology, and establishment of SSI special management.

Figure 2 .
Figure 2. Global distribution of age-standardized DALY rates of appendicitis in 2019 and the number of studies reporting SSI after appendectomy using uniform diagnosis criteria, 1990-2021.(The size of dots indicates the number of studies).

Figure 3 .
Figure 3. Global burden of appendicitis in terms of DALY rates by national socioeconomic development in 2019.

Figure 4 .
Figure 4. Global burden of appendicitis in terms of DALY rates by health expenditure in 2019 (Health expenditure is spending on healthcare goods and services, expressed as a percentage of GDP).

Table 1 .
Multivariate linear regression model of SSI after appendectomy.

Table 1 .
Individual characteristics of the included studies.