Economic burden of pertussis in children: A single-center analysis in Hangzhou, China

ABSTRACT

The “reemergence of pertussis” has elicited international concerns, occurring paradoxically amidst the expansion of immunization programs. This study was aimed to evaluate quantitatively the economic burden and identify the determinants that influence the cost associated with treating pertussis in Chinese children. We evaluated the economic burden by Chinese children diagnosed with pertussis at the Children’s Hospital, Zhejiang University School of Medicine in 2022. Direct medical expenses and the utilization of medical resources attributed to pertussis were calculated. A generalized linear regression model was applied to analyze the determinants that were associated with the direct medical expenses among patients. Among the 1110 pertussis patients included in the study, 1060 were outpatients and 50 were inpatients. The average direct medical cost was ¥1878.70(i.e. $279.33). Living in urban areas (OR:1.27, p = .04), complications (OR:1.40, p < .001), hospitalization (OR:10.04, p < .001), and ≥ 3 medical visits (OR:3.71, p < .001) were associated with increased direct medical expenses. Having received four doses of the pertussis vaccine was associated with reduced direct medical expenses (OR:0.81, p = .04). This study underscores a substantial economic burden of pertussis in Hangzhou, with pronounced implications for patients residing in urban areas, experiencing complications, requiring hospitalization, having multiple medical consultations, or lacking comprehensive pertussis vaccination.

KEYWORDS:

• pertussis
• pertussis vaccination
• factors
• direct medical costs

Introduction

Pertussis, caused by the bacterium Bordetella pertussis, is a highly contagious acute respiratory infection and is a prominent contributor to infant mortality and morbidity globally.^1,2 Pertussis has a long course and can lead to a series of complications, such as pertussis encephalopathy, respiratory failure, severe pneumonia, etc., which seriously impairs the quality of life of patients.³ Based on estimates, the implementation of pertussis vaccination has reduced 80% pertussis cases and decreased the fatality by 95%.⁴ After the initiation of the national immunization program in 1978, China experienced a significant reduction in pertussis incidence. Cases plummeted from 100–200 per 100,000 individuals during the 1960s and 1970s to fewer than 0.2 per 100,000 between 2006 and 2010.⁵

However, a concerning trend termed the “resurgence of pertussis” denotes a progressive escalation in pertussis incidence observed over the past decade in developed countries boasting a high vaccination coverage. For instance, annual pertussis cases in the United States have surged to between 20,000 and 40,000.^6,7 Echoing this trend, the Chinese Center for Disease Control and Prevention has documented a significant augmentation in pertussis cases since 2014, culminating in 30,027 reported cases in 2019.⁸ Alarmingly, the incidence of pertussis in Hangzhou escalated to 21.46 per 100,000 individuals in 2022, marking the apex since 2010.

Pertussis results in a significant healthcare resource utilization (HCRU) and imposes a considerable economic burden. A study by Stojanov et al. highlighted that 4.5% of pertussis patients required hospitalization.⁹ Among these hospitalized patients, half experienced complications, with an average duration of hospital stay of 8 d. In Germany, the direct cost of treating a pertussis patient in primary care was estimated at 120 euros. However, for those in employment, the indirect cost escalated to 2443 euros.¹⁰

The prevention and control of pertussis is essential since the resurgence of pertussis has grown to be a significant public health concern. In the 1960s, the Diphtheria, Tetanus, Whole-Cell Pertussis vaccine (DTwP) was introduced in China for infants aged 3–5 months. However, the landscape of immunization shifted with the introduction of the Diphtheria-Tetanus-Acellular Pertussis vaccine (DTaP) in 2005, which progressively replaced DTwP by 2010.^11,12 According to estimates, incidence and fatalities of pertussis reduced by 21.2% and 58.8% by 2014 as a consequence of expanded pertussis vaccination.¹³

To the best of our knowledge, there exists a notable dearth of rigorous research addressing the economic burden of pertussis in China.¹⁴ In this study, we conducted a hospital-based study to estimate the economic burden to households with children with pertussis. We evaluated the HCRU and direct medical cost associated with pertussis treatment and care to raise the awareness of pertussis and provide evidence to inform health intervention strategies that aim at bolstering pertussis prevention in China.

Methods

Design, participants, and data source

We have collected the retrospective data of children with a diagnosis of pertussis in outpatient clinics and those hospitalized at the Children’s Hospital, Zhejiang University School of Medicine from January 1, 2022 to December 31, 2022. Three databases were used to extract data on pertussis patients reported in Hangzhou from January 1, 2022 to December 31, 2022, i.e., China Information System for Disease Control and Prevention (CISDCP), hospital information system (HIS) of the children’s hospital, and Hangzhou Immunization Information System (HZIIS). The residence area was divided into urban, suburban and rural areas. In Hangzhou, the district of Shangcheng, Gongshu, Xihu and Binjiang were considered as the urban area; the district of Xiaoshan, Yuhang, Linping, Qiantang, Fuyang and Linan and their counties were defined as the suburban area. The district of Tonglu, Jiande and Chunan and their counties were regarded as the rural area. A confirmed diagnosis of pertussis was confirmed by one laboratory test, regardless of the laboratory technique utilized (serology, PCR, or culture), which is consistent with recommendations by the World Health Organization (WHO).¹⁵

In 2022, the Children’s Hospital, Zhejiang University School of Medicine reported 62.0% of all pertussis cases in Hangzhou. Data regarding healthcare resource utilization and direct medical costs of pertussis patients were extracted from the HIS, utilizing the number of identification card of the patient. These information included the frequency of outpatient visits, instances of hospitalization, and the duration of hospital stay at each time. The direct medical cost referred to costs due to outpatient and inpatient medications, examinations and other items(such as outpatient registration fee, inpatient bed fee and nursing fee, operation fee, treatment fee, etc.) that incurred as a result of pertussis treatment. The HZIIS was developed in 2005 by the Hangzhou Center for Disease Control and Prevention, including statistics on vaccinations and demographic data. The HZIIS was used to verify the status of the pertussis vaccination status by the date and dose of vaccination.

Statistical analysis

The average frequency of outpatient visits as a continuous variable was presented as mean ± standard deviation (SD) and was examined using the two independent samples t tests and one-way ANOVA. Due to the skewed distribution of the cost data, medians and interquartile ranges (IQRs) were calculated. The comparison between costs was performed by univariate analysis using the Wilcoxon test or Kruskal-Wallis H test. The factors with statistical significance in univariate analysis were included in the generalized linear regression model to further analyze the factors associated with the direct medical costs among pertussis patients. The results from the generalized linear regression model was expressed by the equation, i.e., Y=β₀+β₁X₁+β₂X₂+…+β_nX_n+ε. In addition, pertussis population was stratified as subgroups by complications. We analyzed the costs and the factors associated with the direct medical costs between pertussis patients with and without complications. Regarding the missing data, 13 patients missed data of medical expense records or the vaccination records. We did not impute missing values. Statistical analyzes were performed using SPSS 24.0 (Chicago, United States) software, and p < .05 indicated the statistical significance. Children’s Hospital, Zhejiang University School of Medicine Ethics Committee reviewed and approved this protocol and informed consent was obtained from each subject (2022-IRB-0301-P-01).

Results

Socio-demographic characteristics of the study population

In 2004, China began to implement direct online reporting of infectious diseases, all medical institutions should report pertussis through CISDCP that collected information on patient identification card number, date of birth, gender, onset date, current residence address, etc. Hangzhou City, which is an economically developed city in Zhejiang Province of China, with a population of about 10 million in 14 districts. A total of 1110 patients were included into the study. The range of age was from 1 month to 15 y. 333 (30%) patients were aged 0–4 y, 672(60.5%) aged 5–9 y, and 105 (9.5%) aged 10–15 y. 50.8% were male, 74.8% resided in suburban areas, and 86.2% had received four doses of the pertussis vaccination (Table 1). Regarding the temporal distribution, we observed a surge in patient numbers starting from March, peaking in June, with May to July collectively accounting for 51.3% of all cases (Figure 1).

Figure 1. Temporal distribution of pertussis cases in 2022.

Table 1. Socio-demograhic and frequency of outpatient visits due to pertussis.

Characteristics	No. (n)	frequency of outpatient visits	p-value
Sex			.24
Male	564	5.59
Female	546	5.39
Age group (years)			.26
0–4	333	5.63
5–9	672	5.48
10–15	105	5.11
Area			<.001
Rural	38	4.58
Suburban	830	5.29
Urban	242	6.30
With complications			.003
No	993	5.38
Yes	117	6.42
With hospitalization			.82
No	1060	5.50
Yes	50	5.34
Doses of pertussis vaccination			.87
No pertussis vaccination	67	5.28
With 1 dose of pertussis vaccination	23	6.00
With 2 doses of pertussis vaccination	15	5.27
With 3 doses of pertussis vaccination	48	5.54
With 4 doses of pertussis vaccination	957	5.49

Healthcare resource utilization

On average, each patient had 5.49 times of outpatient visits, and the mean duration of hospital stay was 7.96 d. Although there were 117 instances of complications, no fatality was recorded. The overall hospitalization rate attributed to pertussis was 4.5%. Eighty percent of hospitalization happened among the age group of 0–4 y; 72% were either unvaccinated or had incomplete vaccinations; and 54% had complications. Notably, individuals aged 0–4 y, residing in rural areas, presenting with complications, and receiving no pertussis vaccination are more likely hospitalized compared to their counterparts (p values < .05) (Table 2). As delineated in Table 1, urban residents and individuals with complications more often visited the outpatient clinics (p values < .05). There was no statistically significant difference regarding the average frequency of outpatient visits across subgroups (p values > .05).

Table 2. Factors associated with hospitalization.

Characteristics	With hospitalization (%)	Without hospitalization (%)	p-value
Sex			.86
Male	26(4.6)	538(95.4)
Female	24(4.4)	522(95.6)
Age group (years)			<.001
0–4	40(12)	293(88)
5–9	8(1.2)	664(98.8)
10–15	2(1.9)	103(98.1)
Area			.03
Rural	11(28.9)	27(71.1)
Suburban	34(4.1)	796(95.9)
Urban	5(2.1)	237(97.9)
With complications			<.001
No	23(2.3)	970(97.7)
Yes	27(23.1)	90(76.9)
Doses of pertussis vaccination			<.001
No pertussis vaccination	27(40.3)	40(59.7)
With 1 dose of pertussis vaccination	6(26.1)	17(73.9)
With 2 doses of pertussis vaccination	1(6.7)	14(93.3)
With 3 doses of pertussis vaccination	2(4.2)	46(95.8)
With 4 doses of pertussis vaccination	14(1.5)	943(98.5)

Direct medical cost (Table 3)

The average direct medical cost per person due to pertussis was ¥1878.70 ($279.33), more specifically, ¥577.00 ($85.79) was used for medication, ¥525.75 ($78.17) for examinations, and ¥775.95 ($115.37) for other costs. Notably, the direct medical cost for patients who had complications was approximately three times higher than that that for those without complications (¥4756.90 vs. ¥1539.57, p value < .05).

Table 3. The direct medical cost per capita due to pertussis (¥).

Characteristics	No. (n)	Direct medical cost per capita (median, IQR)	p-value
Sex			.88
Male	564	1190.91(639.79,2005.15)
Female	546	1167.74(654.97,1929.51)
Age group (years)			<.001
0–4	333	1376.33(785.44,2347.34)
5–9	672	1101.34(611.12,1866.84)
10–15	105	963.03(606.00,1561.74)
Area			<.001
Rural	38	1240.99(617.42,2448.67)
Suburban	830	1115.30(612.04,1833.53)
Urban	242	1376.77(780.58,2354.77)
With complications			<.001
No	993	1088.72(615.76,1822.60)
Yes	117	2019.80(1414.26,3576.68)
With hospitalization			<.001
No	1060	1128.44(634.80,1831.25)
Yes	50	7104.08(4810.80,17610.75)
Number of medical visits			<.001
With 1 medical visit	23	422.79(207.75,2979.17)
With 2 medical visits	68	475.26(317.23,662.52)
With ≥3 medical visits	1019	1230.76(713.23,1998.56)
Doses of pertussis vaccination			<.001
No pertussis vaccination	67	2325.42(1115.82,5885.05)
With 1 dose of pertussis vaccination	23	1898.74(948.61,3417.73)
With 2 doses of pertussis vaccination	15	1479.70(349.10,2357.49)
With 3 doses of pertussis vaccination	48	1179.24(768.78,2244.10)
With 4 doses of pertussis vaccination	957	1128.76(634.97,1846.24)

The direct medical cost was higher in individuals aged 0–4 y, residing in urban areas, having complications, being hospitalized, having three or more medical visits, and not having pertussis vaccination, compared to their counterparts (p values < .05).

Table 4 presented urban residence (OR:1.27, 95%CI:1.02–1.60, p = .04), presence of complications (OR:1.40, 95%CI:1.23–1.59, p < .001), hospitalization (OR:10.04, 95%CI:7.89–12.77, p < .001), and three or more times of medical visits (OR:3.71, 95%CI:2.77–4.98, p < .001) were significantly associated with the increased direct medical cost. Conversely, receiving four doses of pertussis vaccination was significantly associated with the reduced direct medical cost (OR:0.81, 95%CI:0.66–0.99, p = .04).

Table 4. Factors associated with the direct medical cost per capita among pertussis patients.

Characteristics	B	SE	χ^2	P	OR
Age group (years)
0–4					1.00
5–9	−0.05	0.05	0.86	.35	0.95(0.86–1.05)
10–15	−0.09	0.08	1.28	.26	0.92(0.79–1.07)
Area
Rural					1.00
Suburban	<0.001	0.11	<0.001	.98	1.00(0.80–1.24)
Urban	0.24	0.12	4.37	.04	1.27(1.02–1.60)
With complications
No					1.00
Yes	0.34	0.07	25.93	<.001	1.40(1.23–1.59)
With hospitalization
No					1.00
Yes	2.31	0.12	352.17	<.001	10.04(7.89–12.77)
Number of medical visits
With 1 medical visit					1.00
With 2 medical visits	0.30	0.17	3.27	.07	1.35(0.98–1.86)
With ≥3 medical visits	1.31	0.15	76.28	<.001	3.71(2.77–4.98)
Doses of pertussis vaccination
No pertussis vaccination					1.00
With 1 dose of pertussis vaccination	−0.23	0.16	2.01	.16	0.79(0.58–1.09)
With 2 doses of pertussis vaccination	0.30	0.20	2.28	.13	1.34(0.92–1.97)
With 3 doses of pertussis vaccination	−0.21	0.13	2.37	.12	0.81(0.63–1.06)
With 4 doses of pertussis vaccination	−0.21	0.10	4.31	.04	0.81(0.66–0.99)

Table 5 revealed significant disparities in direct costs between patients with and without complications (p values < .05). The direct medical cost, medication cost, examination cost, and other costs of patients with complications were higher than those without complications.

Table 5. Comparison of medical cost (¥) between pertussis patients with and without complications.

Medical cost	Overall	Non-complications	Complications	p-value
Direct medical cost				<.001
Mean(SD)	1878.70 (3495.80)	1539.57 (2264.85)	4756.90 (7976.65)
Median	1183.20	1088.72	2019.80
Min	25.00	25.00	426.00
Max	49362.00	40038.00	49362.00
Medication cost				<.001
Mean(SD)	577.00 (726.31)	509.56 (642.09)	1149.34 (1071.61)
Median	344.62	287.87	822.19
Min	0.00	0.00	9.00
Max	10545.00	10545.00	5348.00
Examination cost				<.001
Mean(SD)	525.75 (1076.13)	419.89 (614.34)	1424.21 (2633.19)
Median	341.00	330.00	481.00
Min	0.00	0.00	80.00
Max	18880.00	11990.00	18880.00
Other costs				<.001
Mean(SD)	775.95 (2151.99)	610.12 (1410.50)	2183.34 (5002.75)
Median	399.70	366.66	681.02
Min	0.00	0.00	92.73
Max	35643.22	29700.87	35643.22

SD, standard deviation; Min, minimum; Max, maximum.

Table 6 showed results of the univariate analysis regarding the direct medical costs across subgroups. Males, hospitalization, and a lack of pertussis vaccination were correlated with higher direct medical costs among patients with complications (p values < .05). For patients without complications, those aged 0–4 y, residing in urban areas, being hospitalized, having three or more times of medical visits, and receiving no pertussis vaccination were correlated with higher direct medical costs(p values < .05).

Table 6. Factors associated with the direct medical cost per capita between pertussis patients with and without complications (¥).

Characteristics	With Complications		Without Complications
	Direct medical cost per capita(median, IQR)	p-value	Direct medical cost per capita(median, IQR)	p-value
Sex		.04		.98
Male	2531.72(1432.61,5705.93)		1107.86(604.77,1876.20)
Female	1888.40(1379.35,2876.34)		1078.88(631.96,1786.46)
Age group (years)		.09		.001
0–4	2652.89(1466.92,5705.93)		1240.99(735.89,2162.69)
5–9	1918.24(1291.36,2620.74)		1017.78(596.63,1727.48)
10–15	2405.81(1725.89,6627.90)		939.93(603.26,1517.44)
Area		.66		<.001
Rural	2041.95(956.97,2911.25)		1174.50(513.93,2400.04)
Suburban	1972.96(1380.69,3473.02)		1005.45(601.15,1660.94)
Urban	2408.18(1601.75,4682.37)		1289.60(751.65,2222.92)
With hospitalization		<.001		<.001
No	1787.43(1267.97,2392.74)		1070.24(609.19,1748.94)
Yes	7965.29(4520.82,21849.63)		6896.79(4892.17,12708.08)
Number of medical visits		.42		<.001
With 1 medical visit	3003.68(2979.17,-)		358.83(167.91,476.12)
With 2 medical visits	3173.25(498.33,21813.71)		423.44(293.76,618.69)
With ≥3 medical visits	1989.41(1432.61,3399.27)		1164.81(678.36,1894.06)
Doses of pertussis vaccination		.004		.002
No pertussis vaccination	4750.57(1677.93,23031.80)		1593.71(772.56,3806.87)
With 1 dose of pertussis vaccination	3507.39(1124.59,16448.61)		1473.67(948.61,3171.80)
With 2 doses of pertussis vaccination	–		1479.70(349.10,2357.49)
With 3 doses of pertussis vaccination	1918.37(1473.21,2501.90)		1113.91(708.34,2248.69)
With 4 doses of pertussis vaccination	1903.19(1357.59,2620.30)		1050.06(607.29,1747.51)

Discussion

The decline in the incidence and mortality of pertussis was largely attributed to the introduction and widespread administration of the pertussis vaccine.¹⁶ However, in recent years, there has been a resurgence of pertussis occurring in China and other countries, such as the United States,^17–19 which has caused heavy disease burden. With a population of around 10,000,000, Hangzhou is a developed Chinese metropolis located in the Zhejiang Province. A total of 38,295 cases of pertussis were reported in China in 2022, including 37,648 cases in the 0–15 age group. In Hangzhou, 1,830 pertussis cases were reported, with 1,795 of those cases occurring in the 0–15 age range. The present study evaluated the economic burden due to pertussis among pediatric patients in Hangzhou, and found factors for the increased direct medical costs, such as urban residence, having complications, hospitalization, and having three or more medical visits. In contrast, receiving four doses of pertussis vaccination was associated with the reduced direct medical costs. These findings will enhance public awareness and inform health policy and preventive strategies in China.

We observed that the overall hospitalization rate was 4.5% and the mean duration of hospital stay about 8 d, which aligned with previous research.⁹ Infants younger than one year, due to their limited immunity, were particularly vulnerable to hospitalization when contracting pertussis. A majority of hospitalizations were noted among patients younger than one year (69.2%), which is a consistent finding with the study by Skoff et al.²⁰ There was no fatality during the study period, the fatality rate in our study was lower than that reported in Japanese infants, i.e., 0.15%.²¹ Maternal vaccination during pregnancy is an effective intervention to protect against pertussis infection in newborns,^22,23 while maternal immunization has not been implemented yet in China. Therefore, it is important supplementary strategy to carry out pertussis vaccine immunization during pregnancy in order to reduce the disease burden and to protect susceptible individuals. Among the 50 patients who were hospitalized in our study, complications were noted in 27 cases, while the pneumonia complication accounted for 54%, which was higher than that reported in Germany, i.e., 28.1%.²⁴ The characteristics of the study populations may explain the inconsistency in study findings, such as a different distribution of age and sex as well as varying vaccination coverage.

The mean direct medical costs for pertussis were estimated at ¥1878.70 ($279.33), with per hospitalization costs averaging ¥7104.08 ($1056.23). Geographic and temporal variations influence the economic burden of pertussis; for instance, the mean direct medical cost per pertussis episode is €120 in Germany and $300 in Brazil.^10,25 Our study echoed findings of increased costs associated with pertussis-related complications¹⁰ and hospitalizations,²⁶ with direct expenses per hospitalization ranging from €368 in Brazil²⁷ to €4814 in a U.S. study focusing on newborns.²⁸ In Portugal, the median estimated cost for a hospital stay was €549.²⁹ Vaccination not only conferred protection against pertussis but also mitigated disease severity and associated costs.³⁰ In Vietnam, the cost for hospitalization of pertussis non-vaccinated patients was significantly greater than for the group of vaccinated patients ($826 vs. $582 per patient).³¹ As reported by others,³² in our study, the disease burden was higher among the population without pertussis vaccination. The costs obtained may be understated since other direct or indirect costs, such as those resulting from productivity losses, were not considered. The current study solely assessed the direct medical expenses collected from the HIS of ZCH. Owing to the inherent disparities in insurance frameworks, pricing structures, and economic development across different countries and regions, exercising caution is paramount when attempting to draw direct comparisons from the results of these diverse studies.

Our study has several limitations, including its single-center design, which, while encompassing a broad area, may not yield universally representative data. The selection of variables was constrained, and clinical manifestations of patients were not extensively explored. With only 50 patients hospitalized in this study, the economics were skewed toward ambulatory treatment cost. The omission of indirect costs might lead to an underestimation of the total economic burden of pertussis. Consequently, while offering insights, the findings should be interpreted considering these limitations and the inherent challenges in comparing studies across diverse healthcare, economic, and insurance landscapes. More accurate economic burden of pertussis are expected to be obtained in future longer-term studies.

Conclusion

The present study showed that the economic burden of pertussis is substantial for children in Hangzhou, especially among patients residing in urban areas, those experiencing complications, requiring hospitalization, multiple medical consultations, or lacking comprehensive pertussis vaccination.

Author contributions

Yan Liu and Chunzhen Hua: conceptualization. Yingying Yang, Jinsi Zhou and Xuechao Zhang: methodology. Yan Liu, Yingying Yang and Jinsi Zhou: formal analysis, data curation, visualization, writing, review, and editing. Lintao Gu, Yuyang Xu and Zhaojun Lu: investigation. Chunzhen Hua, Xiaoping Zhang and Qixin Xie: resources. Chunzhen Hua and Yan Liu: supervision. Xuechao Zhang: project administration and funding acquisition. All authors contributed to the article and approved the submitted version.

Availability of data and materials

The dataset used in the study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The ethics committee of Children’s Hospital, Zhejiang University School of Medicine approved this study protocol and informed consent was obtained from each subject.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This study was supported by Natural Science Foundation of Zhejiang Province, China [LGF18H010001], the Science and Technology Program of Zhejiang Province [2021KY267] and Hangzhou health science and technology plan [A20230202].