Introduction

Pertussis (whooping cough), caused by the gram-negative bacterium Bordetella pertussis, presents with paroxysmal severe coughing lasting weeks or even months, often accompanied by hallmark symptoms like whooping sounds during coughing and post-coughing vomiting1.Recent years have seen a rise in global pertussis cases rather than a decline, indicating a resurgence of pertussis2. Since the 1980 s, in countries with high vaccine coverage rates such as the United States3, Canada4, Australia5, the incidence of pertussis has once again shown an upward trend after maintaining low levels for many years. This phenomenon is known internationally as pertussis re-emergence6.Since China included the DTwP(Diphtheria,Tetanus toxoids and whole cell) vaccine in the national immunization program for children in 1978, the reported incidence of pertussis has significantly decreased. From 2006 to 2010, the average annual reported incidence of pertussis decreased from 100 to 200 cases per 100,000 to 0.2 cases per 100,0007. However, in recent years, even though the reported coverage rate of the three-dose DTaP (Diphtheria, Tetanus, and Acellular Pertussis Vaccine)vaccine in China has remained above 99%8, the reported incidence of pertussis has shown an upward trend9. In 2022, the number of reported cases in China was 38,295, which is a 17.5-fold increase compared to the 2,183 cases reported in 201210. In Zhejiang Province, there were 3,760 reported cases in 2022, which is a 35.5-fold increase compared to the 106 cases reported in 2012 (data source: Zhejiang CDC). The resurgence of pertussis has begun to emerge across China.

At the same time, the disease burden caused by pertussis cannot be overlooked. A study on the disease burden of pertussis in the United States showed that the average medical expenses for infants, children, and adolescents were $2822, $308 and $254,respectively,and the average parents missed 6work days (range: 1–35 days)11.A study in Canada showed that the average cost of pertussis in infants was $22,768 (95% CI:21,144 − 23,406). In terms of economic costs estimated in terms of per capita GDP, the cost of pertussis in the OHIP (Ontario Health Insurance Plan) medical system was 1/5 to 1/3 of the total annual economic cost in Canada, which was between $21.7million and $66 million per year12. The economic burden caused by pertussis in our province is currently unknown, and there may be a certain degree of underestimation.

Traditional approaches in disease economic burden studies, which primarily focus on direct medical costs and indirect expenses, often neglect the hidden socioeconomic losses caused by reduced health-related quality of life (HRQoL), leading to systematic underestimation of true disease burden. To enable a multidimensional and comprehensive assessment, our study incorporates the EQ-5D-3L utility measure and Visual Analogue Scale (VAS) into the questionnaire. The EQ-5D-3L quantifies health utility values by evaluating three severity levels across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The VAS utilizes a 0–100 patient-reported scale to reflect overall health perception. These tools provide critical parameters for cost-utility analysis (CUA), ensuring a balanced evaluation that avoids oversimplified conclusions.

The objective of this study is to examine the economic burden of pertussis in Zhejiang Province, which will provide valuable insights in our province within the global resurgence of the disease. The study aims to assess the economic burden of pertussis on individual families accurately, assist health administrators in developing sound health policies and strategies, and allocate resources effectively to maximize economic and social benefits.

Materials and methods

Subjects

The survey took the confirmed pertussis cases reported in the China Information System for Disease Control and Prevention in 2022 as the population, and calculated the cross-sectional survey sample size13 (α = 0.05, δ = 15%, σ = 1.56 (calculated from pre-survey data), considering a 10% loss to follow-up). A total of 458 cases were included in the survey. A phased stratified sampling method was used. First, four hospitals with a high number of reported pertussis cases in Zhejiang Province were selected (the Second Affiliated Hospital of Wenzhou Medical University, the Fourth Affiliated Hospital of the Medical College of Zhejiang University, Yiwu Central Hospital, and Yiwu Maternal and Child Health Hospital); then, based on the proportion of cases reported by provincial and city/county hospitals in the China Information System for Disease Control and Prevention (79% and 21% respectively), 360 cases and 98 cases of pertussis were selected as the survey subjects from provincial and city/county hospitals, respectively.We recruited our study participants from July to December 2022, and the data processing took place from January to June 2023.

This study has been approved by the ethics committee of the Zhejiang Provincial Center for Disease Control and Prevention. Prior to enrollment, written informed consent was obtained from adult participants or child guardians. Authors had access to such information during data collection.

Economic burden

The survey was conducted using a combination of methods including filling out questionnaires, conducting hospital medical record inquiries (with informed consent), and interviews with guardians of cases meeting the inclusion criteria. After receiving unified training, the investigators interviewed the guardians of the eligible cases and filled out the questionnaire. With informed consent, they obtained the basic information and medical costs of the children’s outpatient/inpatient treatment through the hospital information system.

The content of the survey questionnaire includes: (1) Demographic information, such as gender, age, household registration; (2) The respondents’ illness and treatment situation in the past month (hospital visited, number of visits, time of visit, etc.); (3) Transportation costs, accompanying time costs, etc. The economic burden of pertussis includes: (1) Direct economic burden investigation: Investigate the relevant outpatient fees, hospitalization fees, treatment and examination fees, medical fees (including self-purchased drugs), and transportation costs incurred due to pertussis treatment obtained through the hospital medical record system and fee collection system; (2) Indirect economic burden investigation: Investigate the indirect costs (accompanying costs, loss of working hours) and productivity loss costs caused by patients’ illness and death through interviews or questionnaires.The number of missed work days was determined based on the hospital system’s records of hospitalization days, outpatient visits, and interviews. The average daily cost of missed work was calculated using the per capita disposable income in the county or district where the case occurred. The indirect economic burden was calculated as the number of missed work days multiplied by the average daily cost of missed work.

The EuroQol five-dimensions three-levels(EQ-5D-3L) questionnaire has been confirmed by numerous studies and applied for evaluating the health-related quality of life across various populations14. It includes five dimensions: mobility (MO), self-care (SC), usual activities (UA), pain/discomfort (PD), and anxiety/depression (AD). Each dimension comprises three levels: no problems, some problems, extreme problems (coded as 1–3). Respondents are required to select the options that best match their health status within each dimension according to the questionnaire,the outcome reflects the health status from a societal perspective.The formula for calculating health utility value is U = 1-C-(MO + SC + UA + PD + AD)-N3. If all five dimensions are at the no problems level, then U = 1.The EQ-VAS (Visual Analogue Scale) records the self-assessed health status of respondents on a vertical visual scale, with the ends of the scale marked as “best imaginable health state” and “worst imaginable health state.”The self-assessment information from respondents can serve as a quantitative indicator of health outcomes to assessing health status from an individual perspective.

Surveyors receive professional training before conducting surveys, enabling them to accurately understand the questionnaire content and assess it appropriately.

Statistical analysis

The survey questionnaire was entered into a database using Epidata 3.1, and analyzed using SPSS 25.0. The comparison of constituent ratios was performed using the chi-square test or Fisher’s exact probability method. The differences in costs were tested using the rank sum test (Wilcoxon test or Kruskal–Wallis test).The analysis of cost factors was performed using logistic regression.Before constructing the regression model, we assessed the collinearity among the independent variables using the Variance Inflation Factor (VIF).The significance level was set at α = 0.05 (two-sided).

Results

Base case analysis

The surveyed subjects’ onset time was from 2022, and a total of 458 cases of pertussis economic burden were surveyed. Among all the cases, there were 175 outpatient cases (38.21%) and 283 inpatient cases (61.79%), The average number of hospitalization was 7.2 days; 237 were male (51.75%) and 221 were female (48.25%); there were 64 cases < 3 months old (13.97%), 97 cases 3 months to 18 months old (21.18%), 94 cases 18 months to 5 years old (20.52%), 136 cases 5 to 9 years old (29.69%), 45 cases 9 to 14 years old (9.83%), 17 cases 14 to 45 years old (3.72%), and 5 cases > 45 years old (1.09%); there were 109 outpatient cases in provincial hospitals (62.29%) and 251 inpatient cases (88.69%); there were 66 outpatient cases in county-level hospitals (37.71%) and 32 inpatient cases (11.31%); there were 310 cases from urban areas (67.69%) and 148 cases from rural areas (32.31%), a total of 438 cases (95.63%) had other complications besides pertussis, and 401 cases (87.55%) had 1–3 kinds of complications, of which 255 cases (90.11%) were inpatient cases. The differences in age distribution, medical institutions, and accompanying complications between outpatient and inpatient cases were statistically significant (c2 = 64.308, P < 0.001) (c2 = 44.833, P < 0.001) (c2 = 7.028, P = 0.030). Detailed patient characteristics are shown in Table 1.

Table 1 Basic information of the surveyed subjects.
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Economic burden

Among the 458 cases of pertussis patients surveyed, the total cost of 175 outpatient cases was 331,138.48 CNY. Of these, the direct cost totaled 127,462.78 CNY (38.49%) with an average cost of 728.36 CNY per case; the indirect cost totaled 203,675.69 CNY(61.51%) with an average cost of 1,163.86 CNY per case. The total cost of 283 inpatient cases was 2,914,291.84 CNY with an average cost of 10,297.85 CNY per case; the direct cost was 2,494,451.57CNY (85.59%) with an average cost of 8,814.32 CNY per case; and the indirect cost totaled 419,840.27 CNY (14.41%). The indirect cost of outpatients accounted for a larger proportion, and the main economic burden for inpatients was mainly due to direct treatment costs (Table 2).

Table 2 The economic burden of pertussis across healthcare-seeking pathways in zhejiang province.
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Influencing factors of pertussis economic burden

The economic burden of pertussis was analyzed using Kruskal–Wallis H test and Mann–Whitney U test (Table 3).The results showed that the gender distribution did not have statistical significance in the economic burden of outpatient and inpatient cases. Age distribution differences had statistical significance in the direct cost of outpatient cases (H = 12.894, P = 0.045), and had significant statistical significance in the cost differences of inpatients (direct cost: H = 45.298, P < 0.001; indirect cost: H = 27.487, P < 0.001; total cost: H = 51.563, P < 0.001). The distribution differences of patients’ household registration had statistical significance in the indirect costs of outpatient and inpatient cases, with Z = 3.500, P < 0.001 for outpatient cases and Z = 8.281, P < 0.001 for inpatient cases. The distribution differences of medical institutions had significant statistical significance in the cost composition. The number of accompanying complications had no significant difference in the cost of outpatient cases, but for inpatient cases, the number of accompanying complications had statistical significance in the direct cost and total cost(H = 8.209,P = 0.017、H = 6.868,P = 0.032).

Table 3 Single variable analysis of factors related to economic burden of pertussis cases in some regions of Zhejiang Province.
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In a total of 458 cases,consider age restrictions when using the scales we excluded cases of infants under 18 months old15, distributed 297 questionnaires, excluded incomplete questionnaire responses, and obtained a total of 196 valid questionnaires with complete EQ-5D scale information. The mean EQ-5D-3L utility value was higher than the mean EQ-VAS score (0.96 ± 0.10 vs 81.28 ± 12.90);Both the utility values and visual analog scale (VAS) scores were higher in cases treated at provincial hospitals compared to those at city or county hospitals (0.97 ± 0.07 vs 0.93 ± 0.20; 81.62 ± 12.17 vs 78.55 ± 18.16);Cases of individuals under 5 years old and those above 45 years old had slightly lower EQ-5D-3L utility values compared to other age groups; Cases with more than 3 complications had lower utility values and EQ-VAS scores compared to cases with 3 or fewer complications (0.93 ± 0.13; 61.67 ± 30.14). (Table4).

Table 4 EQ-5D utility and VAS scores by demographics and facility type.
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We use ordered logistic regression model to incorporate the variables that have been formulated into the cost of hospitalization. The cost is converted into a binary variable (< 10,297.85CNY = 1; ≥ 10,297.85CNY = 2). The results indicate that the number of hospitalization days, the type of medical unit visited, Number of complications and age have significant impacts on the total cost of hospitalization cases (Table 5).

Table 5 Analysis of the orderly logistic regression model for the total cost of pertussis hospitalized cases in Zhejiang Province.
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Discussion

In the context of the re-emergence of pertussis, even in countries with a high coverage of the diphtheria-tetanus-pertussis vaccine, pertussis remains a concerning public health problem16. In China, the number of reported cases of pertussis in 2022 was 38,295, with 3760 cases reported in Zhejiang Province, and the incidence rate was as high as 5.74/100,000, ranking in the top position among the 31 provinces in China. As the antibody level of the vaccine in the human body decreases17, it is of great significance to timely evaluate the current challenges and adjust the immune strategy for the prevention of pertussis. This study aims to accurately evaluate the economic burden caused by pertussis cases and explore the influencing factors of their cost, providing reliable reference for subsequent health economic evaluation and strategic research, and playing a positive role in the rational allocation of health resources.

We surveyed a total of 458 cases of pertussis in Zhejiang Province and identified the direct economic burden, indirect economic burden, and total burden of 175 outpatient pertussis cases at 127,462.78 CNY, 203,675.69 CNY, and 331,138.48 CNY, respectively. The average cost per case was 1,892.22 CNY, slightly higher than the outpatient survey costs in Yantai, Shandong17(1,253 CNY) and Tianjin18(1,450 CNY). For the 283 hospitalized pertussis cases, the direct economic burden, indirect economic burden, and total burden were 24,944,51.57 CNY, 4,198,40.27 CNY, and 29,142,91.84 CNY, respectively. The average total cost per case was 10,297.85 CNY, which was slightly lower than the average hospitalization costs for 106 patients in Yantai, Shandong17in 2019 and 78 patients in Chongqing19in 2019 (10,580 CNY and 15,784.09 CNY), but higher than the average costs for 114 hospitalized cases in Tianjin18 and 121 hospitalized cases in Jiangsu20 (7,105 CNY and 5,823 CNY).The former may be related to the average age of the included cases, as most of the surveyed subjects were infants under 4 years old, resulting in higher medical and accompanying costs. The latter may be related to the average length of hospital stay and monitoring mode; earlier treatment based on active monitoring leads to a relatively shorter treatment course and lower hospitalization costs21.Additionally, when comparing the economic burden of outpatient visits and inpatient hospitalizations, the choice of healthcare-seeking behavior and diagnostic decision-making at the institutional level (such as primary care versus tertiary care) can significantly impact both direct and indirect medical costs22. In 2022, the number of pertussis cases reported through the Chinese Disease Prevention and Control Information System was 3,760. Based on the results of this study, it is estimated that the direct economic burden, indirect economic burden, and total economic burden caused by pertussis are as high as 21.5259 million, 5.1191 million, and 26.6450 million, respectively. Domestic studies on the medical costs of pertussis are all lower than those abroad. A study of 11,378 cases of pertussis in the United States from 2006 to 201521 showed that compared with members of the healthcare plan without pertussis, the average medical cost after an attack of pertussis was 3.17 times higher ($5,195vs$1,637). The total economic cost of pertussis in Canada23 is estimated to range from$7.96billion to$241.3 million per year. High wages and high nursing labor costs in developed countries may be the reasons for this difference.

Our results showed that the age distribution of hospitalized cases had a statistically significant impact on the direct costs, indirect costs, and total burden of the disease. Among them, infants < 3 months of age without a history of vaccination had the highest costs. This age group has immature respiratory and immune systems, resulting in a weaker ability to resist pathogenic bacteria24. After contracting pertussis, they have a longer hospital stay, poorer prognosis, and a higher incidence of severe cases25.Especially in younger infants, treatment is more likely to incur a higher economic burden.Referring to the economic burden of pertussis in Canada, the average cost per case for infants is the highest, at $22,768 (95% CI: $21,144–$23,406). A study in the United States estimated that the direct cost for infants (0–23 months) with pertussis is $2,822 (€2,302)26. Among patients with a history of vaccination, children under 5 years of age still have a higher proportion of costs, consistent with a study conducted in the United States from 2006 to 201527. Adolescents and adults > 14 years old have higher outpatient costs than other age groups, which may be related to their active choice of outpatient services. The economic burden results of both outpatient and hospitalized cases of pertussis indicate that the costs of treatment at municipal and county-level medical institutions are higher than those at provincial-level medical institutions. This is consistent with previous studies and is mainly due to the impact of direct medical costs associated with pertussis28. It may also be related to the distribution of medical resources, different medical insurance payment methods, and other factors. Hospitalized cases with complications have higher costs than those without complications. According to estimates published in Germany, the direct cost for a case of uncomplicated pertussis is €210 (approximately $257), while cases requiring hospitalization are much more expensive, with an average direct cost of €1,700 (approximately $2,084)26. The direct economic burden increases with the number of complication types, consistent with previous research on the economic burden of other diseases29.

This study utilized an ordered logistic regression model to identify significant predictors of the economic burden of pertussis hospitalization costs. Patients with a hospital stay of ≥ 7 days were 7.64 times more likely to incur a high cost burden compared to those with a stay of < 7 days (95% CI: 4.06–14.36, p < 0.001), highlighting the crucial role of reducing hospitalization duration in controlling economic burden. Additionally, having ≥ 3 complications significantly increased cost risk (OR = 2.62, 95% CI: 1.54–4.47), while patients aged 5–18 years had an 82% lower cost risk than infants (< 18 months) (OR = 0.18, 95% CI: 0.09–0.34), indicating that infants are a high-risk group for disease burden. The cost risk at provincial medical institutions was 2.15 times higher than that at city or county hospitals (95% CI: 1.02–4.54), likely due to the referral of complex cases and the use of advanced technologies. However, neither household registration (urban vs. rural) nor gender had a statistically significant impact (p > 0.05), suggesting that cost differences primarily stem from clinical factors rather than sociodemographic characteristics.These findings are consistent with previous studies. For instance, a study on the economic burden of measles in Zhejiang Province showed that age, disease duration, hospitalization, and complications significantly impacted total costs30. Similarly, studies on influenza and hepatitis B (HBV) have emphasized the impact of the number of complications and hospitalization days on costs. Moreover, international research on pertussis in children ≤ 16 years old has identified age (< 16 weeks), premature birth, and encephalopathy as independent risk factors for ICU admission for pertussis31,32,33. These studies further support our findings that hospitalization duration, number of complications, and age are key factors influencing the cost of pertussis hospitalization.

Based on the findings from the EQ-5D-3L scale and EQ-VAS score, it appears that the health status following pertussis, as assessed from an individual standpoint, is more severe compared to a population-level perspective,the true indirect disease burden of pertussis may be significantly underestimated.In the present study, the number of complications did not show a statistically significant association with hospitalization costs, which may be related to the type of complications and cross-infection. There are certain differences in the treatment costs and methods for different accompanying complications.

This article has certain limitations.This study did not analyze the clinical characteristics of pertussis cases and the impact of specific comorbidities on the economic burden,the mental burden of patients accompanying family members were not fully considered, Future research should incorporate relevant methods from more fields (such as health literacy) to conduct assessments34,35. The economic burden of severe pertussis cases in the intensive care unit was not included,, which may have led to an underestimation of the economic burden. Therefore, further research on the economic burden of pertussis cases is needed nationwide, including larger sample sizes and consideration of comprehensive factors in different provinces.

Conclusion

This study clarifies the economic burden of pertussis cases, with results indicating that younger infants, patients with complications, and those with longer hospital stays bear a heavier economic burden. Understanding and implementing maternal vaccination strategies during pregnancy to provide passive immunity for newborns is crucial. Early screening to detect cases promptly and reduce the occurrence of severe disease and complications is also essential. Additionally, ensuring high pertussis vaccination coverage and booster doses for high-risk populations can significantly alleviate the economic burden on families and society.