Epidemiology of mumps, mumps complications, and mumps orchitis in Korea using the National Health Insurance Service database

Owing to the widespread success of controlling the parotitis epidemic using measles, mumps, and rubella (MMR) vaccines, public health officials aimed to eradicate the spread of epidemic parotitis in the United States by 2010 in 1998 [1]. The introduction of the MMR vaccine in 1968 reduced the incidence of the virus by 99% in the United States by 2001 [2]. However, the resurgence of mumps has drawn attention again, with more than 56,000 cases reported in England and Wales in 2004 [3].

It is still not clear what causes the outbreak of mumps despite the high vaccine coverage in countries with sophisticated quarantine systems, such as the United States, Europe, and Korea. Infections from tourists traveling to various countries may be a factor. However, unlike epidemics caused by new viruses, such as severe acute respiratory syndrome coronavirus 2, infectious diseases controlled by existing vaccines show a resurgence in each cycle [4].

In the current environment, people may be exposed to the risk of respreading of former infectious diseases for which mass immunity has been established as they are easily exposed to various infectious diseases due to group lives, such as schools and workplaces, as those places are highly urbanized [5]. In particular, the Korea Centers for Disease Control and Prevention reported to the National Assembly in 2014 that the number of military personnel with infectious diseases had increased by more than 33%, among whom mumps accounted for the largest number of cases [6]. Therefore, we aimed to investigate the MMR vaccine status and understand the need for additional vaccines against mumps and other infectious diseases in Koreans by analyzing the outbreak of infectious diseases, such as mumps and mumps orchitis.

This research team obtained approval from the Institutional Review Board (IRB) of Korea University Ansan Hospital in 2019 and confirmation of exemption from deliberation (IRB no. 2019AS0129) in advance. Subsequently, the team requested data and obtained permission through the healthcare big data open system (https://opendata.hira.or.kr), received a virtual account and conducted the analysis (approval no. M20190602777), and attempted to determine the incidence rate based on the treatment code by identifying the number of patients with mumps within the population based on the initial, first, and second follow-up data from the received data and by extracting each diagnostic code.

The team extracted all patients with the B26.x diagnosis code (mumps) from those registered in the healthcare big data open system from 2007 to 2016. Subsequently, the following conditions were established to identify patients who were diagnosed and treated for mumps-related complications. First, the research team identified patients with mumps-related complications for at least two out-patient visits and one hospitalization with codes. The mumps-related complications and associated diagnostic codes included mumps orchitis (B26.0; N51.1x), mumps meningitis (B26.1; G02.0x), mumps encephalitis (B26.2; G05.1x), mumps pancreatitis (B26.3), arthritis (B26.8; M01.5x), myocarditis (I41.1x), nephritis (N08.0x), and polyneuropathy (G63.0x). Subsequently, to improve diagnostic accuracy and avoid selection bias, patients who had related complication codes between 1 day and 2 months after confirmation of the mumps diagnosis (B26.x) and did not have a related complication code previously were included. Lastly, the team classified the pattern of outbreaks by region into metropolitan cities and provinces based on the regional code in the data.

This study aimed to classify patients who underwent surgical treatment for mumps orchitis. Related surgical treatments included orchiectomy total (R3851), orchiectomy partial (R3853), repair of testis rupture (R3856), and scrotal reconstruction (R3903). Patients who had diagnostic codes related to testicular-related injury within 1 week of the above surgical code ([Contusion of Testis], S30.2E [open wound of the scrotum and testes], and S31.3 S31.5) were excluded because they were diagnosed with traumatic testicular rupture. We also analyzed the proportions of patients with the diagnostic codes of testicular atrophy (N50.0) and infertility (N46) separately by follow-up on the patient group until 2016. Data were analyzed using Statistical Analysis System (SAS for Windows, version 9.2, SAS Institute).

Mumps spreads through respiratory droplets sprayed when an infected patient coughs or sneezes. It can be transmitted through direct contact with a patient's saliva or respiratory secretions. As a result, mumps is more prevalent in schools, the military, and daycare centers where people live closely or in groups [7, 8].

There is currently no specific treatment for mumps. It is known to heal naturally after approximately a week; however, it can lead to serious complications, such as pancreatitis, cerebral meningitis, and orchitis [9]. Avoiding contact with patients is important for the prevention of mumps [10]. Although it is possible to prevent it with personal hygiene, such as hand washing, the best way to prevent it is to have most of the population vaccinated [10, 11]. The mumps vaccination is part of the MMR vaccine, and two doses are recommended during infancy [8].

In South Korea, the MMR vaccine is administered once between 12 and 15 months and once between 4 and 6 years (two doses in total), according to the national vaccination support project for children under the age of 12 years [12]. In the case of adults, if they do not have a record of vaccination and were not known to have been infected by mumps before or antibodies were not found, at least one vaccination (two doses, especially for university students, vocational training students, medical workers, and overseas travelers 4 weeks apart) is recommended [13].

Although measles was completely eradicated through vaccination, mumps (epidemic parotitis) occurred intermittently [14, 15]. Most patients with mumps are students, college students, and military personnel living in groups [6]. This study also showed that there was an epidemic of mumps in 2009, 2013, and 2014, and most of the patients were elementary, middle, and high school students aged between 8 and 19 years.

A South Korean research team suggested that intermittent mumps outbreaks, despite the high vaccination rates, could be due to weakened immunity to disease or antigenic differences between currently available vaccine strains and circulating wild-type viruses [12, 16]. The team measured mumps virus-specific immunoglobulin G and rapid focus reduction neutralization test (FRNT) thresholds in Korean isolates and serum obtained from 50 children between 1 and 2 years of age who received a single dose of the MMR vaccine [17]. It has been reported that the FRNT threshold after vaccination is significantly lower for genotypes F, H, and I than for genotype A. These facts may explain the likelihood of recurrence of mumps outbreaks in the vaccinated population, depending on the degree of genetic conservation of the HN gene.

In this study, the incidence pattern of mump-related complications was different from the overall incidence of mumps. During the study period, the incidence of mumps was predominant in the ages of 1–9 years and 10s, and the incidence of mumps-related complications was the highest among males in their 20s (5.15%), while those in their 10s and 30s showed similar rates. In contrast, less than 1% of people under 10 years of age had mumps. It can be inferred from the results of this study that despite the high incidence rate of mumps, children under 10 years of age showed a relatively low complication rate. In particular, when the annual incidence of mumps orchitis was divided by the age of 20 years, the incidence in males aged 20 years or older was generally higher than that in males under 20 years of age during the study period, and the incidence rate was highest in 2009, 2013, and 2014 when mumps outbreaks occurred. However, the overall incidence rate was less than 1.5% in those under 20 years of age, and the incidence of mumps orchitis did not increase during the year of the outbreak. This can be interpreted as that, although mumps occur mainly at a young age, complications appear more frequently in adults.

According to a study analyzing 62 patients with mumps orchitis from a single institution in South Korea from 2005 to 2012, testicular enlargement due to mumps orchitis was milder in South Korean patients than in patients of previous studies published in other countries, such as Spain and Turkey, where vaccination rates were lower [18]. Moreover, previous epidemiological studies conducted in other countries reported that complications, such as orchitis, pancreatitis, and cerebral meningitis, occurred in up to 42% of the patients with mumps [19, 20]. While the results of this study showed that only 3,872 (1.9%) of the 199,186 South Korean patients suffered from mump-related complications, this indicates that most patients had milder complications and symptoms due to their vaccination history, similar to previously mentioned studies on the pattern of mumps orchitis in South Korea. In addition, since most of the patients with complications were at an age that could have reduced previously acquired immunity, it could raise the possibility that the mass immunity acquired in the early stage may decrease to some extent in the late teens and 20s, considering that it occurred in age groups with a high frequency of long-term contact with others, such as school, military, and work, rather than in those in their 40s and older, who have a low frequency of group activities [14]. In other words, these facts may form the basis for the hypothesis that additional vaccination may be necessary for a specific group to reduce the outbreak of mumps infection and reestablish mass immunity.

Although this study used national health data, it had several limitations. First, since this study analyzed diagnosed patients based on diagnosis codes and claims data, there was a possibility of selection bias in not including patients with missing diagnosis codes. For example, previous studies have reported that mumps virus causes parenchymal damage in the testicles, resulting in testicular atrophy occurring in 30 to 50% of testicles affected by edema. [21, 22] On the other hand, in this study, only 45 of the 19,453 patients diagnosed with mumps orchitis were diagnosed with testicular atrophy, representing that the incidence was significantly lower than in previous studies. The reason for such results can be assumed that for future health information of a growing child and adolescent, patients or their guardians may try to avoid diagnosis of the disease, and doctors may not diagnose well. Therefore, the data may have had a lower prevalence than the actual one, and this study could not represent epidemiology of mumps, mumps complications, and mumps orchitis in Korea. Second, there is a possibility that diagnosis of mumps was not included in this study in cases of misdiagnosis due to similar clinical symptoms and medical history and false-positive and false-negative results. Third, the healthcare big data open system might contain code errors. Fourth, the follow-up period was limited to 11 years because the healthcare big data open system database used in this study provided data for only 11 years. This is because the maximum amount of data that can be provided to a virtual account in the current healthcare big data open system is less than two terabytes. If it were possible to conduct a long-term follow-up study for more than 20 years, it would have been possible to accurately calculate the probability of infertility and the rate of surgery due to testicular atrophy in patients diagnosed with mumps orchitis.

Nevertheless, this study provides the following remarkable results: first, this study reported that mumps complications occurred more frequently in males than in females for the first time. Moreover, previous studies have not reported differences in the age of patients with mumps and mumps complications. Lastly, the results of this study can be the basis for suggesting that additional vaccination may be necessary to form mass immunity in the age groups exposed to social or group life. However, the results of this study had some limitations as it was a large-scale retrospective cohort study at the national level, as mentioned previously. Therefore, it is believed that if a large-scale prospective study can be conducted to obtain more accurate results, the results of this study can be supported and lead to a discussion on the necessity for a change in national health policy.

Despite the high vaccination rate in Korea, mumps and mumps orchitis have shown periodic outbreaks. Mumps orchitis also shows periodic outbreaks but is particularly prevalent in adults. This may indicate the need for additional vaccinations against mumps.