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

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.

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 chi-square 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.

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.

We identified 49 patients aged ≥18 years who were hospitalized for tetanus, of whom 32 required invasive MV. Table 1 lists the baseline characteristics and clinical presentation of the MV and nonMV groups. Among the 49 patients with tetanus, 32 (57.1%) were women, and the median age was 67.0 years (IQR, 53.0–80.0). The demand for MV increased significantly among the older patients (median age, 72.5 years [IQR, 59.0–82.0 years] and 53.0 years [IQR, 46.0–67.0 years] for the MV and nonMV groups, respectively; P = 0.002). The incubation time was shorter for the nonMV group than for the MV group but did not differ significantly (median, 6.0 days [IQR, 3.0–8.0 days] vs. 2.0 [IQR, 1.0–6.0 days]; P = 0.237). All the patients developed generalized tetanus. 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.

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 group, and three (17.7%) were reported in the nonMV group.

Thirty-two (84.2%) of the 38 patients admitted to the intensive care unit (ICU) required MV. The median MV duration was 33.0 days (IQR, 22.0–40.5 days), and the hospital stay was longer for the MV group than for the nonMV group (median, 46.5 days [IQR, 39.5–52.5 days] vs. 8.0 days [IQR, 5.0–21.0 days]; P <  0.001). Eleven patients (34.4%) in the MV group required rehabilitation, whereas only one patient (5.9%) in the nonMV group required rehabilitation. The median rehabilitation period was 30.0 days (IQR, 13.0–39.0 days) for the MV group. 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).

As shown in Table 3, age > 65 years and the presence of dyspnea were identified as risk factors for the need of MV support in the multivariate regression logistic analysis (age 65 years: odds ratio [OR], 4.63; 95% confidence interval [CI], 1.22–19.99; P = 0.029; dyspnea: OR, 5.44; 95% CI, 1.44–23.43; P = 0.016).

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).

Table 5 shows the clinical outcomes and features of the older adult patients. Thirty patients were aged > 60 years, and all of the deceased were in older adult group. The need for MV was significantly greater for those aged ≥60 years than for those aged < 60 years (24 cases [80.0%] vs. 8 cases [42.1%]; P = 0.016). The patients aged > 60 years had longer hospitalizations than those aged < 60 years (median stay, 40.5 days [IQR, 22.0–51.0 days] vs. 21.0 days [IQR, 7.0–46.5 days]; P = 0.109).