Clinical outcomes and healthcare costs of inpatients with tetanus in Korea, 2011–2019

Background Tetanus is a rare, vaccine-preventable but extremely serious disease. We investigated the recent trend of the clinical outcomes and medical costs for inpatients with tetanus in South Korea over 10 years. Methods We conducted a retrospective review to determine the clinical factors and medical costs associated with tetanus at two national university hospitals in South Korea between January 2011 and October 2019. Results Forty-nine patients were admitted for tetanus (mean age, 67.0 years [range, 53.0–80.0 years]; 32 women [57.1%]). All the patients had generalized tetanus, and 5 (10.2%) died during hospitalization. The median duration from symptom onset to hospital admission was 4 days. Trismus (85.7%) was the most common symptom, and the median hospital stay was 39 days. Thirty-two patients (65.3%) required mechanical ventilation, and 20 (40.8%) developed aspiration pneumonia. The median total healthcare cost per patient was US $18,011. After discharge, 35 patients (71.4%) recovered sufficiently to walk without disability. Conclusions Tetanus requires long hospital stays and high medical expenditures in South Korea; however, the vaccination completion rate is low. Medical staff should therefore promote medical advice and policies on the management of tetanus to the general South Korean population.


Background
Tetanus is a fatal but preventable infectious disease caused by Clostridium tetani. According to the US Centers for Disease Control and Prevention, tetanus vaccines have largely contributed to the reduced tetanus surveillance and morbidity since 1990 [1]. Similarly, the incidence of tetanus in South Korea has decreased since the introduction of the diphtheria and tetanus toxoid and acellular pertussis vaccine in 1982 [2].
As recommended by the Committee on Infectious Disease of the Korean Pediatric Society, the tetanus immunization schedule for children is five doses of diphtheria and tetanus toxoids and acellular pertussis vaccine at 2, 4, 6, 15, and 18 months of age, and then again at 4-6 years. This schedule should be followed by a tetanus toxoid, diphtheria, and acellular pertussis (Tdap) vaccine dose at 11-12 years of age, and a tetanus toxoid vaccine (Td) dose every 10 years [3]. However, insufficient tetanus vaccinations have been administered to adults in certain cases of tetanus. According to the Korea Centers for Disease Control and Prevention (KCDC), the nationwide incidence of tetanus increased to a mean of 23.9 cases per year between 2010 and 2019 as compared with the mean of 10.9 cases per year between 2000 and 2009. Given the steady increase in its incidence, tetanus remains difficult to prevent and treat. Unfortunately, studies are limited regarding tetanus cases in South Korea. The most recent study on the clinical manifestations of tetanus was conducted at Chonnam National University in 2003. It focused on the clinical and epidemiological findings of tetanus from 17 cases in South Korea, with no mention regarding the cost incurred for the treatment of the disease. We therefore aimed to investigate the clinical features and inpatient costs of tetanus within the past 10 years.

Data collection
This retrospective cohort study was conducted between January 1, 2011 and July 30, 2019 at Kyungpook National University Hospital and Chonnam National University Hospital. The definition of patients with tetanus was extracted from the nomenclature of the International Classification of Disease, Tenth Revision (ICD-10). Two physicians reviewed the patient data that included demographics, clinical characteristics, and laboratory findings retrieved from the hospital medical records and data. All the included patients were older than 18 years and diagnosed as having tetanus at 1 of 2 tertiary referral centers. We did not include neonatal tetanus. Tetanus was defined according to the clinical features, such as generalized or localized muscular spasm and contractures without other medical causes. As defined in this study, generalized tetanus is characterized by painful muscle spasms of the jaw and neck, muscular contraction unrelated to injury sites, or autonomic dysfunction, and patients who presented fluctuating systolic blood pressure or heart rate [4] or required inotropic agents or calcium channel blockers to control their blood pressure were defined as having autonomic dysfunction. The patients were divided into two groups, a non-mechanical ventilation (nonMV) group and a mechanical ventilation (MV) group. The MV group included patients who received invasive ventilation during hospitalization, while the nonMV group included patients who were not administered ventilation. We collected data on the patients' demographic characteristics, tetanus-related clinical features, hospital stay duration, rehabilitation treatment duration, infection source, complications during treatment, and medical costs for tetanus treatment. Aspiration pneumonia was confirmed by a radiologist by performing chest radiography or CT scans, the results of which were reviewed by a physician. The requirement for rehabilitation was determined by consultation with the rehabilitation professionals. We considered loss of immunization visits when the patients did not attend the arranged outpatient clinic visit on time and no medical referral was indicated in the electronic medical records. We also collected data on the laboratory results and expenditures during the tetanus treatment. The medical charts from most of the patients were reviewed during their first and last hospital visits.

Statistical analyses
All statistical data were analyzed using R statistics version 3.1. The categorical variables are expressed as numbers and percentages and were compared using the chisquare test or Fisher exact test. The continuous variables are expressed as mean ± standard deviation (SD) or median with the interquartile range (IQR) and were compared using the Mann-Whitney U test. Data that did not exhibit a normal distribution are represented as median with IQR. We used a multivariate logistic regression analysis to evaluate the risk factors associated with MV. P values < 0.05 were considered statistically significant.

Ethics statement
The institutional review board of Kyungpook National University Hospital and Chonnam National University Hospital reviewed and approved our study protocol (approval Nos. KNUH-201907031 and CNUH-2019235, respectively). Considering the retrospective nature of the study and the use of anonymous clinical data for the analysis, the requirement for informed consent was waived.

Patient characteristics and clinical features
We identified 49 patients aged ≥18 years who were hospitalized for tetanus, of whom 32 required invasive MV. Table 1  With regard to the entry site of the toxin, an unknown entry site (34.7%) was the most common, followed by the legs (24.5%) and arms (22.4%). The most common symptoms on admission were trismus (85.7%) and muscle stiffness (73.5%). Most patients developed autonomic nervous dysfunction, and half of the patients (51.0%) developed fever during their hospital stay.

Clinical findings of the patients who died
The median age of the five patients who died was 85 years (range, 77-89 years), and four (80%) of these patients were women. Four of the five patients had no definitive injuries and did not know the incubation time.
In one case, the dorsum of the right hand was injured 14 days prior to symptom onset. Before admission, none of the five patients remembered their tetanus vaccination history. Four patients were provided with MV, and one patient refused life-sustaining treatment, including MV and cardiopulmonary resuscitation because of their advanced age. The cause of death in all five patients was respiratory failure. The tetanus complications in this group included aspiration pneumonia in two patients, pulmonary thromboembolism in one patient, and multifocal infarction in one patient. Table 2 provides the details of the clinical outcomes and complications. Twenty patients (40.8%) experienced aspiration pneumonia, and 18 (36.7%) had concurrent ventilator-associated pneumonia. Twenty-one (65.6%) cases of nosocomial infection were reported in the MV  One patient in the nonMV group underwent rehabilitation for 54.0 days. Most of the patients recovered without impaired motor function after discharge, and the degree of recovery demonstrated no significant difference between the groups (P = 0.609). The proportion of secondary tetanus vaccinations was significantly higher in the MV group (65.6%) than in the nonMV group (17.6%; P = 0.004), whereas the proportion of third tetanus vaccinations was not significantly different between the MV (16.1%) and nonMV groups (6.2%; P = 0.617).

Clinical outcomes and significant factors of mechanical ventilation status
As shown in Table 3 Table 4 shows the economic burden according to the following details: The median total expenditure for the patients with tetanus was US $18,011 (range, US $2680-$34,497). In particular, the expenditure for the procedure and operation, including MV management, was the most expensive (median, US $5502), followed by the expenditures for drugs and injections (median, US $3861) and diagnostic blood tests (median, US $3764).

Discussion
Although the prevalence of tetanus has decreased with the introduction of tetanus vaccination, tetanus still causes approximately 60,000 deaths per year worldwide [5]. In this study, we reviewed the cases of 49 patients with tetanus in two tertiary referral centers. The median age of the 49 patients with tetanus was 67.0 years; of the patients, five died and 65.3% required MV. The median hospital stay of the patients with tetanus was 39.0 days. The older adult patients required more MV, longer-term hospital care, and higher treatment cost than the young patients. This study is comparable with previous studies in terms of the patients' clinical characteristics. Most of the patients with tetanus were older adults, a similar finding to previous reports in developed countries [1,[6][7][8]. The female predominance among the patients with tetanus was consistent with the results from France and Italy, possibly due to the essential immunizations administered to men during their compulsory military service [6,9,10]. In our study, the most common entry site was unknown, which was comparable with other reports [11,12]. However, other studies have reported that 90% of patients were aware of the entry site [8,13,14]. It is possible that the wound was too small for the patients to discover or was chronic and therefore overlooked given that an acute traumatic wound was the primary focus.
Five of our patients died during the study, resulting in a 10.2% mortality rate, which was comparable with the 13.2 and 16.5% in studies in the United States and Italy, respectively [1,6]. A previous study in France showed a relatively high mortality rate of up to 44.5% due to the inclusion of patients with severe tetanus who were admitted to the ICU [15]. In the present study, the clinical outcomes were consistent with those of a previously published national report in Japan [7]. Nakajima et al. showed that 53.5% of all patients required MV and that most deaths occurred in the older adult group, which could be explained by the similarity in the healthcare insurance system and medical accessibility between the two countries [16]. Studies have shown that tetanus severity is associated with older adult patients, even for different healthcare insurance systems. In the United States, age > 65 years was associated with a higher risk of fatal tetanus (OR, 9.6; 95% CI, 3.6-25) [1]. In a French study of older adult ICU patients with tetanus (median age, 80 years), only age was related to the 1-year mortality rate (mean age of the deceased vs. mean age of the survivors at 1 year: 83 years [range, 81-85 years] vs. 79 years [range, 73-84 years]; P = 0.03) [17]. As in previous reports, our results showed higher MV and mortality rates in the older adult group. This study of tetanus patients demonstrates that older age and dyspnea may be the cause of the tendency toward MV support in the multivariate logistic regression analysis, but we did not find any studies explaining the risk factor related to MV support in patients with tetanus. We thought that further research would need to define the risk factors of mortality through a multivariate adjusted method.
Our study showed relatively lower healthcare costs for tetanus than those reported in previous studies [18][19][20]. However, considering that the healthcare expenditures have been relatively lower in South Korea than in other   [22]. This does not even take into account the indirect costs of the disease, such as lost wages and productivity. To our knowledge, no studies have reported on the Tdap or Td vaccination rate in adults in South Korea. A previous report indicated that the estimated DTaP coverage among children aged < 7 years with five vaccinations was 56.6%, despite that the Korean National Immunization Program has financed the DTaP immunization, [23]. Other reports have shown that the proportion of antitetanus immunoglobulin-G titers ≥0.1 IU/mL steadily decreased in the older adult group and that the tetanus seroprevalence rate was 19.3% for the age group > 60 years in Korea [9,24]. The US National Center for Health Statistics in 2015 released a report that the tetanus vaccination rate for adults aged > 65 years was 56.9% over the past 10 years in the United States [25]. Choi et al. reported that all groups aged > 40 years responded with > 0.1-U/mL tetanus antibody levels after the third vaccine dose [26]. Our study showed a low vaccination rate even in patients who had experienced tetanus. Considering that the cost of three doses of the Td vaccine in South Korea is US $72 and the extraordinarily high medical cost of treating tetanus of US $18,010.5, a massive financial incentive is allotted to ensuring sufficient Td vaccination, thereby preventing tetanus and its consequent medical costs. We believe that further studies regarding the status of Tdap or Td vaccination in adults will be helpful to highlight the advantages of vaccination.
This study has a number of limitations. First, it was conducted at two local tertiary referral hospitals. Given that approximately 20 tetanus cases are reported annually in South Korea by the KCDC, the data in this study should be interpreted with caution because the cases represented approximately 20% of all tetanus cases in South Korea. Nevertheless, we believe that our data are noteworthy because the two tertiary university hospitals are national hospitals in Gyeongsangbuk-do, Jeollabuk-do, and a representative province in South Korea. Collecting data from a large number of cases would be helpful to further define the clinical manifestations and risk factors of mortality through a multivariate adjusted method. Second, the quality of the data depends on the historical data available in this retrospective cohort study. Third, we did not include healthcare costs and additional indirect costs, such as private nursing care and lost earnings during hospitalization. Nevertheless, our study is one of the few studies that have investigated the costs of treatment and economic burden caused by tetanus, and provides noteworthy information given the rarity of tetanus, which, to our knowledge, has not been investigated in a tertiary university hospital in the past 10 years.

Conclusion
In summary, tetanus remains a severe but preventable acute infection disease, and its treatment entails high medical costs, which could be challenging for many individuals. The study observed a high rate of MV and high medical costs due to the intensive care required for older adult patients; however, tetanus immunization in adults is often overlooked. Therefore, strategies to improve tetanus vaccination should be implemented, especially for older adults.