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Incidence of narcolepsy before and after MF59-adjuvanted influenza A(H1N1)pdm09 vaccination in South Korean soldiers
Vaccine 33 (2015) 4868–4872
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Vaccine journal homepage: www.elsevier.com/locate/vaccine
Incidence of narcolepsy before and after MF59-adjuvanted influenza A(H1N1)pdm09 vaccination in South Korean soldiers Woo Jung Kim a,b , Sang Don Lee c , Eun Lee b,d,e , Kee Namkoong b,d , Kang-Won Choe f , Joon Young Song g , Hee Jin Cheong g , Hye Won Jeong h , Jung Yeon Heo h,∗ a
Department of Psychiatry, Eulji Addiction Institute, Gangnam Eulji Hospital, Eulji University, Seoul, South Korea Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea c Department of Psychiatry, The Armed Forces Capital Hospital, Seongnam, Gyeonggi, South Korea d Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea e Sleep Health Center, Severance Hospital, Seoul, South Korea f Department of Internal Medicine, The Armed Forces Capital Hospital, Seongnam, Gyeonggi, South Korea g Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea h Department of Internal Medicine, Chungbuk National University, Cheongju, Chungbuk, South Korea b
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Article history: Received 6 May 2015 Received in revised form 18 July 2015 Accepted 20 July 2015 Available online 1 August 2015 Keywords: Narcolepsy Incidence H1N1 influenza A Vaccination Adjuvants MF59
a b s t r a c t Background: Previous reports mostly from Europe suggested an association between an occurrence of narcolepsy and an influenza A(H1N1)pdm09 vaccine adjuvanted with AS03 (Pandemrix® ). During the 2009 H1N1 pandemic vaccination campaign, the Korean military performed a vaccination campaign with one type of influenza vaccine containing MF59-adjuvants. This study was conducted to investigate the background incidence rate of narcolepsy in South Korean soldiers and the association of the MF59adjuvanted vaccine with the occurrence of narcolepsy in a young adult group. Methods: To assess the incidence of narcolepsy, we retrospectively reviewed medical records of suspicious cases of narcolepsy in 2007–2013 in the whole 20 military hospitals of the Korean military. The screened cases were classified according to the Brighton Collaboration case definition of narcolepsy. After obtaining the number of confirmed cases of narcolepsy per 3 months in 2007–2013, we compared the crude incidence rate of narcolepsy before and after the vaccination campaign. Results: We included 218 narcolepsy suspicious cases in the initial review, which were screened by the diagnostic code on the computerized disease registry in 2007–2013. Forty-one cases were finally diagnosed with narcolepsy in 2007–2013 (male sex, 95%; median age, 21 years). The average background incidence rate of narcolepsy in Korean soldiers was 0.91 cases per 100,000 persons per year. During the 9 months before vaccination implementation (April to December 2009), 6 narcolepsy cases occurred, whereas during the next 9 months (January to September 2010) including the 3-month vaccination campaign, 5 cases occurred. Conclusions: The incidence of narcolepsy in South Korean soldiers was not increased after the pandemic vaccination campaign using the MF59-adjuvanted vaccine. Our results suggest that the MF59-adjuvanted H1N1 vaccine did not contribute to the occurrence of narcolepsy in this young adult group. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Abbreviations: DMSIS, Defense Medical Statistics Information System; ICD, International Classification of Diseases and Related Health Problems; SPSS, Statistical Package for the Social Science; IQR, interquartile range; MSLT, multiple sleep latency test; SOREMP, sleep-onset rapid eye movement period; ICSD, International Classification of Sleep Disorders; DSM, Diagnostic and Statistical Manual of Mental Disorders. ∗ Corresponding author. Tel.: +82 43 269 7634; fax: +82 43 273 3252. E-mail address: [email protected] (J.Y. Heo). http://dx.doi.org/10.1016/j.vaccine.2015.07.055 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
Narcolepsy is a rare sleep disorder characterized by the recurrent, irresistible need to sleep, with or without cataplexy. In patients with cataplexy in particular, narcolepsy is known to be caused by a hypocretin deficiency resulting from an autoimmune mechanism [1–3]. Although the precise cause of narcolepsy remains unknown, it is believed that an autoimmune process might be triggered by exposure to environmental factors such as infections or vaccinations in genetically susceptible individuals
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[4,5]. Accordingly, both influenza infections and vaccinations may influence the increase of narcolepsy in a situation such as an influenza pandemic. Several reports have generated concern that an influenza A(H1N1)pdm09 vaccine containing the adjuvant AS03 (Pandemrix® ) was associated with an increased risk of narcolepsy in childhood and adolescence [6–13]. In addition to the multinational epidemiological study [14], these concerns have recently been extended to the MF59-adjuvanted H1N1 vaccine and the nonadjuvanted influenza H1N1 vaccine itself [15–17]. During the 2009 pandemic influenza outbreak in South Korea, inactivated monovalent H1N1 vaccine was used with just two types of vaccine formulations, of which one was the nonadjuvanted vaccine (GREENFLU-S® , Green Cross Corp., Hwasoon, South Korea) and the other was the MF59-adjuvanted vaccine (GREENFLU-S plus® ; the adjuvant produced by Novartis Vaccines and Diagnostics Inc., Emeryville, CA, USA) [18]. The recipients of the MF59-adjuvanted H1N1 vaccine included adults aged ≥19 years except for healthcare workers, essential social service workers, and pregnant women. In particular, Korean military personnel (623,771 of 750,000; 83.2%) were vaccinated solely with the MF59-adjuvanted H1N1 vaccine between January and March 2010 [18]. Korean soldiers are almost exclusively between 18 and 25 years of age. A previous study in South Korea did not find increased narcolepsy incidence during the 2009 H1N1 pandemic vaccination campaign [15]. However, the study results were limited to verifying narcolepsy cases that were not reviewed through medical records and to clinical information such as the presence of cataplexy or polysomnography results. Our aim was to examine whether the MF59-adjuvanted H1N1 vaccine was associated with an increased risk of narcolepsy in a young adult group. Through a retrospective chart review, we (1) investigated the background incidence of narcolepsy in Korean soldiers, which is mainly composed of young adults in their late teens and early 20s and (2) compared its incidence before and after the 2009 H1N1 pandemic vaccination campaign using the MF59-adjuvanted vaccine. 2. Methods 2.1. Characteristics of study population The study population included all active duty soldiers and military officers in the Korean military. In South Korea, military service is mandatory for healthy males older than 18 years. The service period is generally 21–24 months. Annually, more than 300,000 healthy young adults become duty soldiers and a comparable number of soldiers complete their military service. In the Korean military, any soldier who needs to be tested for narcolepsy or its related conditions should at least once visit an outpatient clinic in the one of the 20 military hospitals. Since 2007, a computerized disease registry of all Korean military hospitals (Defense Medical Statistics Information System, DMSIS) has been available.
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cataplexy (G47.4),” clinicians may diagnose some narcolepsy cases (e.g., especially without cataplexy) using the other diagnoses codes. Thus, we must have included all possible cases with the previously mentioned diagnostic codes. 2.3. Case classification By reviewing the screened cases’ medical records, two sleep specialists (W.J.K. and S.D.L.) independently classified the diagnostic certainty of each case according to the Brighton Collaboration case definition of narcolepsy [19], and then excluded cases with insufficient evidence to meet the case definition (i.e., level 4–5). Unambiguous cataplexy was determined as follows: (1) sudden and unexpected onset of episodes and (2) concomitant presence of (a) partial/generalized muscle weakness, (b) preserved consciousness during the episodes, and (c) at least two attacks with clear emotional triggers [19]. One additional criterion for defining unambiguous cataplexy – that the duration of each episode lasted less than 30 seconds – could not be applied in the current study because few medical records described attack duration. 2.4. Data analysis We obtained the raw number of newly diagnosed narcolepsy cases in each 3-month period and per year in 2007–2013. By doing so, we assessed the crude incidence rate of narcolepsy by season, and by year as well. The vaccination campaign against influenza A(H1N1)pdm09, which used only one MF59-adjuvant vaccine, was implemented between January and March 2010 in the Korean military. To compare the incidence of narcolepsy before and after the pandemic vaccination campaign, we defined the prevaccination campaign period as April to December 2009 (9 months) [15,18] and the vaccination campaign (3 months) and the 6 months following as January to September 2010 [6,19,20]. For defining incidence, the date of disease onset was regarded as the first date of a clinical visit related to narcolepsy. In calculating the annual background incidence rates of narcolepsy diagnosis, denominators were calculated as the approximate number of soldiers from the biennial reports of the Korean military as follows: 650,000 in 2007–2008 [21]; 653,000 in 2009–2010 [22]; 636,000 in 2011–2012 [23]; and 639,000 in 2013 [24]. We also examined the demographic and clinical factors of available cases such as follows: sex, age, height, weight, reported symptoms, results of confirmatory tests, psychiatric/neurological comorbidities, and any other significant medical illness. Descriptive analyses of the demographic and clinical factors were conducted using the Statistical Package for the Social Science (SPSS) for Windows, version 20 (IBM Corp., Armonk, NY, USA). This study was approved by the Institutional Review Board of the Armed Forces Medical Command (Seongnam, Gyeonggi, South Korea). 3. Results
2.2. Case identification 3.1. Identification of narcolepsy cases We retrospectively reviewed the medical records of suspected narcolepsy cases in military hospitals from January 2007 to December 2013. We screened possible cases of narcolepsy with the following diagnostic codes: narcolepsy and cataplexy (G47.4); disorders of excessive somnolence (hypersomnias) (G47.1); nonorganic hypersomnia (F51.1); other nonorganic sleep disorders (F51.8); nonorganic sleep disorder, unspecified (F51.9); other sleep disorders (G47.8); and sleep disorder, unspecified (G47.9), using DMSIS and based on the International Classification of Diseases and Related Health Problems (ICD), 10th revision. Because the diagnostic code of ICD-10 for narcolepsy is limited to “narcolepsy and
Through DMSIS, 218 cases of narcolepsy and its related conditions were identified in Korean soldiers from January 2007 to December 2013. Of these, the medical records of 216 cases were reviewed and excluded two duplicate cases registered to different hospitals (Fig. 1). A total of 41 cases met the Brighton Collaboration case definition of narcolepsy: level 1, two cases (4.9% of 41 cases); level 2, 17 cases (41.0%); and level 3, 22 cases (53.7%). The other 175 cases, which corresponded to the diagnostic certainty level 4–5, were excluded from this study (level 4a, 40 cases; level 4b, 71 cases; and level 5, 64 cases). In DMSIS, the 41 eligible
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16 (39.0%) had unambiguous cataplexy defined by the Brighton Collaboration definition. There was no narcolepsy case in which symptoms could be explained by another significant medical illness, including psychiatric/neurological disorders. In the results of the multiple sleep latency test (MSLT), the median time of the mean sleep latency was 2.1 min (IQR = 1.9–3.3), and the number of sleep-onset rapid eye movement period (SOREMP) were 2 or more in 40 cases (97.6%). These results showed that the classification of narcolepsy cases were relevant (Table 1). We also ascertained that all 41 cases were on narcolepsy medication (i.e., modafinil or methylphenidate). Seventeen cases were additionally medicated with an antidepressant for their cataplexy, of which 11 received venlafaxine.
3.3. Incidence rate of narcolepsy in South Korean soldiers
Fig. 1. Study flow chart. After the screening, two cases were identified as the duplicates that were diagnosed in two different military hospitals. DMSIS, Defense Medical Statistics Information System.
Table 1 Demographic and clinical characteristics of narcolepsy cases in South Korean soldiers, 2007–2013. Variables
Confirmed narcolepsya (n = 41)
Male sex, n (%) Age, years, median (IQR) Reported age of symptom onset,b years, median (IQR) Body mass index ≥25, n (%) Symptoms Excessive daytime sleepiness, n (%) Unambiguous cataplexy,a n (%) Hypnagogic hallucination, n (%) Sleep paralysis, n (%) ESS score, median (IQR) PSG/MSLT findings PSG sleep latency, min, median (IQR) PSG REM sleep latency, min, median (IQR) MSLT mean sleep latency, min, median (IQR) MSLT number of SOREMP ≥2, n (%) Obstructive sleep apnea, n (%) Periodic leg movements, n (%)
39 21.0 17.0
(95.1) (20.9–25.5) (15.7–20.3)
21
(51.2)
41 16 19 31 17.0
(100) (39.0) (46.3) (75.6) (14.4–21.0)
1.5 45.3
(0.7–5.2) (19.8–60.7)
2.1 40 20 12
Fig. 2 depicts the number of narcolepsy cases per every 3-month period and the background incidence rates of narcolepsy diagnosis per 100,000 persons per year in South Korean soldiers. There were 6 narcolepsy cases during the 9-month prevaccination campaign period (April–December 2009), whereas there were 5 cases during the next 9-month period (January–September 2010). Overall, the number of narcolepsy cases was not increased in the vaccination campaign and the following 6-month period compared with the prevaccination campaign period. The incidence rates of each 9month period were 0.92 per 100,000 persons (the prevaccination campaign period) and 0.77 per 100,000 persons (the vaccination campaign and the following period). In 2007–2013, the average incidence rate of narcolepsy diagnosis in Korean soldiers was 0.91 cases per 100,000 persons per year. In detail, the incidence rate for Brighton Collaboration level 1 and 2, except level 3, was 0.42 cases per 100,000 persons per year at the same period. The highest rate of narcolepsy diagnosis was observed in 2011 (1.10 cases per 100,000). Conversely, the lowest rate of narcolepsy was in 2013 (0.63 cases per 100,000). Although the highest incidence of narcolepsy was observed in 2011, among the diagnosed cases in 2011, we could not find any case which were vaccinated during the military vaccination campaign (Jan–Mar 2010) considering the period of service. Therefore, there was no case of confirmed narcolepsy in our sample which received the MF59-adjuvanted H1N1 vaccine. We did not find any recognizable pattern for the occurrence of narcolepsy (e.g., seasonal variation).
(1.9–3.3) (97.6) (48.8) (29.3)
IQR, interquartile range; ESS, Epworth Sleepiness Scale; PSG, polysomnography; MSLT, multiple sleep latency test; REM, rapid eye movement; SOREMP, sleep-onset REM period. a Defined by the Brighton Collaboration case definition of narcolepsy. b Identifiable in 35 cases.
narcolepsy cases were coded originally with narcolepsy and cataplexy (G47.4; 39 cases) and nonorganic hypersomnia (F51.1; 2 cases). 3.2. Characteristics of narcolepsy cases Demographic and clinical characteristics of the 41 narcolepsy cases are presented in Table 1. Almost all were male (39 cases, 95.1%) and in their early 20s (median age, 21.0 years, interquartile range [IQR] = 20.9–25.5). Based on the medical records, while all the 41 cases reported excessive daytime sleepiness symptom,
4. Discussion To the best of our knowledge, this is the first study to investigate narcolepsy incidence in a young adult group who received the MF59-adjuvanted H1N1 vaccine and to investigate the background incidence of narcolepsy in South Korean soldiers. The incidence of narcolepsy in Korean soldiers did not increase after the pandemic vaccination campaign. Our results suggest that the MF59-adjuvanted H1N1 vaccine was not associated with the risk of narcolepsy in a young adult group. This is in accordance with a previous ecological study in South Korea [15] in which no increase was found in narcolepsy incidence in health insurance data during and after the 2009 pandemic H1N1 vaccination campaign. Although it should be considered that our study population was mostly young adult males, these findings together suggest that the MF59-adjuvanted H1N1 vaccine might not be associated with an increased risk for narcolepsy in South Korea. Nevertheless, prospective studies with various age and sex groups are needed to confirm the association between a specific vaccination and narcolepsy occurrence.
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Fig. 2. Numbers of incident narcolepsy cases per 3 months and the annual incidence rates of narcolepsy in South Korean soldiers between 2007 and 2013. Each bar graph indicates the number of incident cases per 3 months, and a line graph presents the changing pattern of the crude incidence rates of narcolepsy per 100,000 South Korean soldiers per year in 2007–2013. The dot-lined boxes show two 9-month periods separated by the beginning of the 2009 H1N1 pandemic vaccination campaign (January 2010): left box indicates the pre-vaccination campaign period and right box includes the 3-month vaccination campaign and 6-month following period. The table within the figure shows the number of cases per each 3 months based on the Brighton Collaboration level 1, 2, 3, and all (defined as narcolepsy). Each bar graph corresponds to the “Total” value in the table.
In interpreting the result, an important consideration is the lag time between symptom onset and the first clinical visit. According to the recent comprehensive review of the post-vaccination narcolepsy [17], there might have been information biases in some of European studies which showed the significantly shortened lag time. Because narcolepsy is rare and its onset is usually insidious, a delay of diagnosis is common. If a greater public awareness of narcolepsy arises, the opportunity of diagnosing the unwitting illness will be increased; and the number of delayed diagnosis will decrease as shown in some earlier studies. In this study, the median lag time was 5.0 years (IQR, 1.5–7.0) in the available 33 cases in 2007–2013. Even though it resembled the result of another epidemiological study of narcolepsy not related to the vaccination [25], indeed, the diagnosed cases in 2011 displayed the shortest lag time (2.0 years, IQR = 0.25–3.75). However, there was no sudden surge of cases in 2011, compared with the number of cases in the other years. Therefore, the lag time shortening, possibly followed by increasing public awareness of narcolepsy, would not have affected our results. In a situation such as an influenza pandemic, some delay between a pandemic outbreak and the implementation of a mass vaccination campaign may be inevitable because of the vaccine manufacturing process [26]. This delay can be reduced by using a vaccine containing an adjuvant (i.e., AS03 or MF59), which can save the amount of virus antigen used in the manufacturing process. Although AS03 and MF59 are both squalene-based adjuvants, a major difference between them is whether ␣-tocopherol is included [27]. The AS03 adjuvant containing ␣-tocopherol is able to promote immune system activation to the nonregional lymph nodes [28], whereas MF59 enhances the cellular immune response at the injection site and regional lymph nodes [29]. Moreover, a recent in vitro study demonstrated that ␣-tocopherol can induce higher hypocretin expression and increase proteasomal activity [30]. This suggests that overproduction of hypocretin fragments can conduce antigen presentation via human leukocyte antigens, resulting in an autoimmune process that can destroy hypocretin-producing neurons. These biological indications, which were discovered in clinical and epidemiological studies, can
partially explain the different effects in the occurrence of narcolepsy between AS03 and MF59. The background incidence rates of narcolepsy in South Korean soldiers were estimated at 0.63–1.10 cases per 100,000 persons per year, whereas the rates among the Korean adult population in similar periods ranged from 1.05 to 3.83 cases per 100,000 persons per year [15]. Given that only “healthy” young “male” adults in South Korea have mandatory military service obligations, the overall lower incidence rate of narcolepsy in this study makes sense. Furthermore, the incidence rates of the current study were evaluated by sleep specialists who reviewed medical records according to the Brighton Collaboration case definition of narcolepsy. If we assessed the rate according to the diagnostic code only, a higher incidence rate of narcolepsy might be expected. Although the incidence rates of narcolepsy in our study were roughly similar to those in an earlier population-based study in US, the incidence rate of cases with cataplexy was lower in ours than the US study in which cases with cataplexy were more than half of all narcolepsy cases [25]. The stringent definition of unambiguous cataplexy [19] might affect the reversed composition (with and without cataplexy) in this study. Additionally, by sorting of cases per 3-month period, there was no seasonal or cyclical pattern in narcolepsy occurrence in Korean soldiers. This result differs from a previous Chinese study in which narcolepsy onset was highly associated with seasonal patterns of upper respiratory tract infections, including H1N1 influenza [20]. A different pattern of narcolepsy occurrence could also be partially explained by difference in methods between studies, such as narcolepsy definition and symptom onset measurement. Further investigation, such as a comparative study in different areas of East Asia, is needed. There are some limitations to this study. First, the true time of symptom onset might be somewhat discrepant from our defined date of disease onset, which was the first date of a clinical visit related to narcolepsy. In fact, the median lag time between symptom onset and the first visit was 5.0 years in our study; however, this degree of lag time is generally unavoidable which is also common in other studies because of the insidious characteristics of narcolepsy. Second, we could not examine directly the confounding
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effect of H1N1 influenza infection itself on narcolepsy occurrence. Yet we did not observe a seasonal pattern of narcolepsy occurrence. Third, we could not include cases that were discharged upon completing their military service just after the vaccination. Fourth, the incidence presented in this study might be different from one that depended on clinical diagnostic criteria (e.g., ICD, the International Classification of Sleep Disorders [ICSD], or the Diagnostic and Statistical Manual of Mental Disorders [DSM]). Last, as best as we could, we tried to examine all clinical manifestations and their information in the medical record system, but some details (e.g., duration of cataplexy attack) were missing more frequently than expected. Despite the limitations of the study’s retrospective characteristics, we included the most possible cases of narcolepsy in the entire military hospital system in South Korea; therefore, this study could be considered a population-based incidence study in South Korean soldiers. In addition, our study has a strength of which could distinguish the proper sleep disorder – narcolepsy – from some other psychiatric/neurological illnesses by our reviewing process of medical records. In conclusion, this retrospective study showed the incidence of narcolepsy before and after the 2009 H1N1 pandemic vaccination campaign using only the MF59-adjuvanted vaccine in South Korean soldiers. The incidence of narcolepsy in Korean soldiers did not increase after the vaccination campaign. The current study suggested that the MF59-adjuvanted H1N1 vaccine was not associated with the risk of narcolepsy. An international study on the association of narcolepsy and AS03-/MF59-adjuvanted H1N1 vaccines is in progress [31]. Our study has a significant provision for evidence for the safety of adjuvant MF59. Of note, our data will be useful for establishing a policy in a global context for pandemic influenza infections in the future.
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Acknowledgements
[21]
This was not an industry supported study. The authors have indicated no financial conflicts of interest.
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Incidence of narcolepsy before and after MF59-adjuvanted influenza A(H1N1)pdm09 vaccination in South Korean soldiers Woo Jung Kim a,b , Sang Don Lee c , Eun Lee b,d,e , Kee Namkoong b,d , Kang-Won Choe f , Joon Young Song g , Hee Jin Cheong g , Hye Won Jeong h , Jung Yeon Heo h,∗ a
Department of Psychiatry, Eulji Addiction Institute, Gangnam Eulji Hospital, Eulji University, Seoul, South Korea Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea c Department of Psychiatry, The Armed Forces Capital Hospital, Seongnam, Gyeonggi, South Korea d Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea e Sleep Health Center, Severance Hospital, Seoul, South Korea f Department of Internal Medicine, The Armed Forces Capital Hospital, Seongnam, Gyeonggi, South Korea g Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea h Department of Internal Medicine, Chungbuk National University, Cheongju, Chungbuk, South Korea b
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Article history: Received 6 May 2015 Received in revised form 18 July 2015 Accepted 20 July 2015 Available online 1 August 2015 Keywords: Narcolepsy Incidence H1N1 influenza A Vaccination Adjuvants MF59
a b s t r a c t Background: Previous reports mostly from Europe suggested an association between an occurrence of narcolepsy and an influenza A(H1N1)pdm09 vaccine adjuvanted with AS03 (Pandemrix® ). During the 2009 H1N1 pandemic vaccination campaign, the Korean military performed a vaccination campaign with one type of influenza vaccine containing MF59-adjuvants. This study was conducted to investigate the background incidence rate of narcolepsy in South Korean soldiers and the association of the MF59adjuvanted vaccine with the occurrence of narcolepsy in a young adult group. Methods: To assess the incidence of narcolepsy, we retrospectively reviewed medical records of suspicious cases of narcolepsy in 2007–2013 in the whole 20 military hospitals of the Korean military. The screened cases were classified according to the Brighton Collaboration case definition of narcolepsy. After obtaining the number of confirmed cases of narcolepsy per 3 months in 2007–2013, we compared the crude incidence rate of narcolepsy before and after the vaccination campaign. Results: We included 218 narcolepsy suspicious cases in the initial review, which were screened by the diagnostic code on the computerized disease registry in 2007–2013. Forty-one cases were finally diagnosed with narcolepsy in 2007–2013 (male sex, 95%; median age, 21 years). The average background incidence rate of narcolepsy in Korean soldiers was 0.91 cases per 100,000 persons per year. During the 9 months before vaccination implementation (April to December 2009), 6 narcolepsy cases occurred, whereas during the next 9 months (January to September 2010) including the 3-month vaccination campaign, 5 cases occurred. Conclusions: The incidence of narcolepsy in South Korean soldiers was not increased after the pandemic vaccination campaign using the MF59-adjuvanted vaccine. Our results suggest that the MF59-adjuvanted H1N1 vaccine did not contribute to the occurrence of narcolepsy in this young adult group. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Abbreviations: DMSIS, Defense Medical Statistics Information System; ICD, International Classification of Diseases and Related Health Problems; SPSS, Statistical Package for the Social Science; IQR, interquartile range; MSLT, multiple sleep latency test; SOREMP, sleep-onset rapid eye movement period; ICSD, International Classification of Sleep Disorders; DSM, Diagnostic and Statistical Manual of Mental Disorders. ∗ Corresponding author. Tel.: +82 43 269 7634; fax: +82 43 273 3252. E-mail address: [email protected] (J.Y. Heo). http://dx.doi.org/10.1016/j.vaccine.2015.07.055 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
Narcolepsy is a rare sleep disorder characterized by the recurrent, irresistible need to sleep, with or without cataplexy. In patients with cataplexy in particular, narcolepsy is known to be caused by a hypocretin deficiency resulting from an autoimmune mechanism [1–3]. Although the precise cause of narcolepsy remains unknown, it is believed that an autoimmune process might be triggered by exposure to environmental factors such as infections or vaccinations in genetically susceptible individuals
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[4,5]. Accordingly, both influenza infections and vaccinations may influence the increase of narcolepsy in a situation such as an influenza pandemic. Several reports have generated concern that an influenza A(H1N1)pdm09 vaccine containing the adjuvant AS03 (Pandemrix® ) was associated with an increased risk of narcolepsy in childhood and adolescence [6–13]. In addition to the multinational epidemiological study [14], these concerns have recently been extended to the MF59-adjuvanted H1N1 vaccine and the nonadjuvanted influenza H1N1 vaccine itself [15–17]. During the 2009 pandemic influenza outbreak in South Korea, inactivated monovalent H1N1 vaccine was used with just two types of vaccine formulations, of which one was the nonadjuvanted vaccine (GREENFLU-S® , Green Cross Corp., Hwasoon, South Korea) and the other was the MF59-adjuvanted vaccine (GREENFLU-S plus® ; the adjuvant produced by Novartis Vaccines and Diagnostics Inc., Emeryville, CA, USA) [18]. The recipients of the MF59-adjuvanted H1N1 vaccine included adults aged ≥19 years except for healthcare workers, essential social service workers, and pregnant women. In particular, Korean military personnel (623,771 of 750,000; 83.2%) were vaccinated solely with the MF59-adjuvanted H1N1 vaccine between January and March 2010 [18]. Korean soldiers are almost exclusively between 18 and 25 years of age. A previous study in South Korea did not find increased narcolepsy incidence during the 2009 H1N1 pandemic vaccination campaign [15]. However, the study results were limited to verifying narcolepsy cases that were not reviewed through medical records and to clinical information such as the presence of cataplexy or polysomnography results. Our aim was to examine whether the MF59-adjuvanted H1N1 vaccine was associated with an increased risk of narcolepsy in a young adult group. Through a retrospective chart review, we (1) investigated the background incidence of narcolepsy in Korean soldiers, which is mainly composed of young adults in their late teens and early 20s and (2) compared its incidence before and after the 2009 H1N1 pandemic vaccination campaign using the MF59-adjuvanted vaccine. 2. Methods 2.1. Characteristics of study population The study population included all active duty soldiers and military officers in the Korean military. In South Korea, military service is mandatory for healthy males older than 18 years. The service period is generally 21–24 months. Annually, more than 300,000 healthy young adults become duty soldiers and a comparable number of soldiers complete their military service. In the Korean military, any soldier who needs to be tested for narcolepsy or its related conditions should at least once visit an outpatient clinic in the one of the 20 military hospitals. Since 2007, a computerized disease registry of all Korean military hospitals (Defense Medical Statistics Information System, DMSIS) has been available.
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cataplexy (G47.4),” clinicians may diagnose some narcolepsy cases (e.g., especially without cataplexy) using the other diagnoses codes. Thus, we must have included all possible cases with the previously mentioned diagnostic codes. 2.3. Case classification By reviewing the screened cases’ medical records, two sleep specialists (W.J.K. and S.D.L.) independently classified the diagnostic certainty of each case according to the Brighton Collaboration case definition of narcolepsy [19], and then excluded cases with insufficient evidence to meet the case definition (i.e., level 4–5). Unambiguous cataplexy was determined as follows: (1) sudden and unexpected onset of episodes and (2) concomitant presence of (a) partial/generalized muscle weakness, (b) preserved consciousness during the episodes, and (c) at least two attacks with clear emotional triggers [19]. One additional criterion for defining unambiguous cataplexy – that the duration of each episode lasted less than 30 seconds – could not be applied in the current study because few medical records described attack duration. 2.4. Data analysis We obtained the raw number of newly diagnosed narcolepsy cases in each 3-month period and per year in 2007–2013. By doing so, we assessed the crude incidence rate of narcolepsy by season, and by year as well. The vaccination campaign against influenza A(H1N1)pdm09, which used only one MF59-adjuvant vaccine, was implemented between January and March 2010 in the Korean military. To compare the incidence of narcolepsy before and after the pandemic vaccination campaign, we defined the prevaccination campaign period as April to December 2009 (9 months) [15,18] and the vaccination campaign (3 months) and the 6 months following as January to September 2010 [6,19,20]. For defining incidence, the date of disease onset was regarded as the first date of a clinical visit related to narcolepsy. In calculating the annual background incidence rates of narcolepsy diagnosis, denominators were calculated as the approximate number of soldiers from the biennial reports of the Korean military as follows: 650,000 in 2007–2008 [21]; 653,000 in 2009–2010 [22]; 636,000 in 2011–2012 [23]; and 639,000 in 2013 [24]. We also examined the demographic and clinical factors of available cases such as follows: sex, age, height, weight, reported symptoms, results of confirmatory tests, psychiatric/neurological comorbidities, and any other significant medical illness. Descriptive analyses of the demographic and clinical factors were conducted using the Statistical Package for the Social Science (SPSS) for Windows, version 20 (IBM Corp., Armonk, NY, USA). This study was approved by the Institutional Review Board of the Armed Forces Medical Command (Seongnam, Gyeonggi, South Korea). 3. Results
2.2. Case identification 3.1. Identification of narcolepsy cases We retrospectively reviewed the medical records of suspected narcolepsy cases in military hospitals from January 2007 to December 2013. We screened possible cases of narcolepsy with the following diagnostic codes: narcolepsy and cataplexy (G47.4); disorders of excessive somnolence (hypersomnias) (G47.1); nonorganic hypersomnia (F51.1); other nonorganic sleep disorders (F51.8); nonorganic sleep disorder, unspecified (F51.9); other sleep disorders (G47.8); and sleep disorder, unspecified (G47.9), using DMSIS and based on the International Classification of Diseases and Related Health Problems (ICD), 10th revision. Because the diagnostic code of ICD-10 for narcolepsy is limited to “narcolepsy and
Through DMSIS, 218 cases of narcolepsy and its related conditions were identified in Korean soldiers from January 2007 to December 2013. Of these, the medical records of 216 cases were reviewed and excluded two duplicate cases registered to different hospitals (Fig. 1). A total of 41 cases met the Brighton Collaboration case definition of narcolepsy: level 1, two cases (4.9% of 41 cases); level 2, 17 cases (41.0%); and level 3, 22 cases (53.7%). The other 175 cases, which corresponded to the diagnostic certainty level 4–5, were excluded from this study (level 4a, 40 cases; level 4b, 71 cases; and level 5, 64 cases). In DMSIS, the 41 eligible
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16 (39.0%) had unambiguous cataplexy defined by the Brighton Collaboration definition. There was no narcolepsy case in which symptoms could be explained by another significant medical illness, including psychiatric/neurological disorders. In the results of the multiple sleep latency test (MSLT), the median time of the mean sleep latency was 2.1 min (IQR = 1.9–3.3), and the number of sleep-onset rapid eye movement period (SOREMP) were 2 or more in 40 cases (97.6%). These results showed that the classification of narcolepsy cases were relevant (Table 1). We also ascertained that all 41 cases were on narcolepsy medication (i.e., modafinil or methylphenidate). Seventeen cases were additionally medicated with an antidepressant for their cataplexy, of which 11 received venlafaxine.
3.3. Incidence rate of narcolepsy in South Korean soldiers
Fig. 1. Study flow chart. After the screening, two cases were identified as the duplicates that were diagnosed in two different military hospitals. DMSIS, Defense Medical Statistics Information System.
Table 1 Demographic and clinical characteristics of narcolepsy cases in South Korean soldiers, 2007–2013. Variables
Confirmed narcolepsya (n = 41)
Male sex, n (%) Age, years, median (IQR) Reported age of symptom onset,b years, median (IQR) Body mass index ≥25, n (%) Symptoms Excessive daytime sleepiness, n (%) Unambiguous cataplexy,a n (%) Hypnagogic hallucination, n (%) Sleep paralysis, n (%) ESS score, median (IQR) PSG/MSLT findings PSG sleep latency, min, median (IQR) PSG REM sleep latency, min, median (IQR) MSLT mean sleep latency, min, median (IQR) MSLT number of SOREMP ≥2, n (%) Obstructive sleep apnea, n (%) Periodic leg movements, n (%)
39 21.0 17.0
(95.1) (20.9–25.5) (15.7–20.3)
21
(51.2)
41 16 19 31 17.0
(100) (39.0) (46.3) (75.6) (14.4–21.0)
1.5 45.3
(0.7–5.2) (19.8–60.7)
2.1 40 20 12
Fig. 2 depicts the number of narcolepsy cases per every 3-month period and the background incidence rates of narcolepsy diagnosis per 100,000 persons per year in South Korean soldiers. There were 6 narcolepsy cases during the 9-month prevaccination campaign period (April–December 2009), whereas there were 5 cases during the next 9-month period (January–September 2010). Overall, the number of narcolepsy cases was not increased in the vaccination campaign and the following 6-month period compared with the prevaccination campaign period. The incidence rates of each 9month period were 0.92 per 100,000 persons (the prevaccination campaign period) and 0.77 per 100,000 persons (the vaccination campaign and the following period). In 2007–2013, the average incidence rate of narcolepsy diagnosis in Korean soldiers was 0.91 cases per 100,000 persons per year. In detail, the incidence rate for Brighton Collaboration level 1 and 2, except level 3, was 0.42 cases per 100,000 persons per year at the same period. The highest rate of narcolepsy diagnosis was observed in 2011 (1.10 cases per 100,000). Conversely, the lowest rate of narcolepsy was in 2013 (0.63 cases per 100,000). Although the highest incidence of narcolepsy was observed in 2011, among the diagnosed cases in 2011, we could not find any case which were vaccinated during the military vaccination campaign (Jan–Mar 2010) considering the period of service. Therefore, there was no case of confirmed narcolepsy in our sample which received the MF59-adjuvanted H1N1 vaccine. We did not find any recognizable pattern for the occurrence of narcolepsy (e.g., seasonal variation).
(1.9–3.3) (97.6) (48.8) (29.3)
IQR, interquartile range; ESS, Epworth Sleepiness Scale; PSG, polysomnography; MSLT, multiple sleep latency test; REM, rapid eye movement; SOREMP, sleep-onset REM period. a Defined by the Brighton Collaboration case definition of narcolepsy. b Identifiable in 35 cases.
narcolepsy cases were coded originally with narcolepsy and cataplexy (G47.4; 39 cases) and nonorganic hypersomnia (F51.1; 2 cases). 3.2. Characteristics of narcolepsy cases Demographic and clinical characteristics of the 41 narcolepsy cases are presented in Table 1. Almost all were male (39 cases, 95.1%) and in their early 20s (median age, 21.0 years, interquartile range [IQR] = 20.9–25.5). Based on the medical records, while all the 41 cases reported excessive daytime sleepiness symptom,
4. Discussion To the best of our knowledge, this is the first study to investigate narcolepsy incidence in a young adult group who received the MF59-adjuvanted H1N1 vaccine and to investigate the background incidence of narcolepsy in South Korean soldiers. The incidence of narcolepsy in Korean soldiers did not increase after the pandemic vaccination campaign. Our results suggest that the MF59-adjuvanted H1N1 vaccine was not associated with the risk of narcolepsy in a young adult group. This is in accordance with a previous ecological study in South Korea [15] in which no increase was found in narcolepsy incidence in health insurance data during and after the 2009 pandemic H1N1 vaccination campaign. Although it should be considered that our study population was mostly young adult males, these findings together suggest that the MF59-adjuvanted H1N1 vaccine might not be associated with an increased risk for narcolepsy in South Korea. Nevertheless, prospective studies with various age and sex groups are needed to confirm the association between a specific vaccination and narcolepsy occurrence.
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Fig. 2. Numbers of incident narcolepsy cases per 3 months and the annual incidence rates of narcolepsy in South Korean soldiers between 2007 and 2013. Each bar graph indicates the number of incident cases per 3 months, and a line graph presents the changing pattern of the crude incidence rates of narcolepsy per 100,000 South Korean soldiers per year in 2007–2013. The dot-lined boxes show two 9-month periods separated by the beginning of the 2009 H1N1 pandemic vaccination campaign (January 2010): left box indicates the pre-vaccination campaign period and right box includes the 3-month vaccination campaign and 6-month following period. The table within the figure shows the number of cases per each 3 months based on the Brighton Collaboration level 1, 2, 3, and all (defined as narcolepsy). Each bar graph corresponds to the “Total” value in the table.
In interpreting the result, an important consideration is the lag time between symptom onset and the first clinical visit. According to the recent comprehensive review of the post-vaccination narcolepsy [17], there might have been information biases in some of European studies which showed the significantly shortened lag time. Because narcolepsy is rare and its onset is usually insidious, a delay of diagnosis is common. If a greater public awareness of narcolepsy arises, the opportunity of diagnosing the unwitting illness will be increased; and the number of delayed diagnosis will decrease as shown in some earlier studies. In this study, the median lag time was 5.0 years (IQR, 1.5–7.0) in the available 33 cases in 2007–2013. Even though it resembled the result of another epidemiological study of narcolepsy not related to the vaccination [25], indeed, the diagnosed cases in 2011 displayed the shortest lag time (2.0 years, IQR = 0.25–3.75). However, there was no sudden surge of cases in 2011, compared with the number of cases in the other years. Therefore, the lag time shortening, possibly followed by increasing public awareness of narcolepsy, would not have affected our results. In a situation such as an influenza pandemic, some delay between a pandemic outbreak and the implementation of a mass vaccination campaign may be inevitable because of the vaccine manufacturing process [26]. This delay can be reduced by using a vaccine containing an adjuvant (i.e., AS03 or MF59), which can save the amount of virus antigen used in the manufacturing process. Although AS03 and MF59 are both squalene-based adjuvants, a major difference between them is whether ␣-tocopherol is included [27]. The AS03 adjuvant containing ␣-tocopherol is able to promote immune system activation to the nonregional lymph nodes [28], whereas MF59 enhances the cellular immune response at the injection site and regional lymph nodes [29]. Moreover, a recent in vitro study demonstrated that ␣-tocopherol can induce higher hypocretin expression and increase proteasomal activity [30]. This suggests that overproduction of hypocretin fragments can conduce antigen presentation via human leukocyte antigens, resulting in an autoimmune process that can destroy hypocretin-producing neurons. These biological indications, which were discovered in clinical and epidemiological studies, can
partially explain the different effects in the occurrence of narcolepsy between AS03 and MF59. The background incidence rates of narcolepsy in South Korean soldiers were estimated at 0.63–1.10 cases per 100,000 persons per year, whereas the rates among the Korean adult population in similar periods ranged from 1.05 to 3.83 cases per 100,000 persons per year [15]. Given that only “healthy” young “male” adults in South Korea have mandatory military service obligations, the overall lower incidence rate of narcolepsy in this study makes sense. Furthermore, the incidence rates of the current study were evaluated by sleep specialists who reviewed medical records according to the Brighton Collaboration case definition of narcolepsy. If we assessed the rate according to the diagnostic code only, a higher incidence rate of narcolepsy might be expected. Although the incidence rates of narcolepsy in our study were roughly similar to those in an earlier population-based study in US, the incidence rate of cases with cataplexy was lower in ours than the US study in which cases with cataplexy were more than half of all narcolepsy cases [25]. The stringent definition of unambiguous cataplexy [19] might affect the reversed composition (with and without cataplexy) in this study. Additionally, by sorting of cases per 3-month period, there was no seasonal or cyclical pattern in narcolepsy occurrence in Korean soldiers. This result differs from a previous Chinese study in which narcolepsy onset was highly associated with seasonal patterns of upper respiratory tract infections, including H1N1 influenza [20]. A different pattern of narcolepsy occurrence could also be partially explained by difference in methods between studies, such as narcolepsy definition and symptom onset measurement. Further investigation, such as a comparative study in different areas of East Asia, is needed. There are some limitations to this study. First, the true time of symptom onset might be somewhat discrepant from our defined date of disease onset, which was the first date of a clinical visit related to narcolepsy. In fact, the median lag time between symptom onset and the first visit was 5.0 years in our study; however, this degree of lag time is generally unavoidable which is also common in other studies because of the insidious characteristics of narcolepsy. Second, we could not examine directly the confounding
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effect of H1N1 influenza infection itself on narcolepsy occurrence. Yet we did not observe a seasonal pattern of narcolepsy occurrence. Third, we could not include cases that were discharged upon completing their military service just after the vaccination. Fourth, the incidence presented in this study might be different from one that depended on clinical diagnostic criteria (e.g., ICD, the International Classification of Sleep Disorders [ICSD], or the Diagnostic and Statistical Manual of Mental Disorders [DSM]). Last, as best as we could, we tried to examine all clinical manifestations and their information in the medical record system, but some details (e.g., duration of cataplexy attack) were missing more frequently than expected. Despite the limitations of the study’s retrospective characteristics, we included the most possible cases of narcolepsy in the entire military hospital system in South Korea; therefore, this study could be considered a population-based incidence study in South Korean soldiers. In addition, our study has a strength of which could distinguish the proper sleep disorder – narcolepsy – from some other psychiatric/neurological illnesses by our reviewing process of medical records. In conclusion, this retrospective study showed the incidence of narcolepsy before and after the 2009 H1N1 pandemic vaccination campaign using only the MF59-adjuvanted vaccine in South Korean soldiers. The incidence of narcolepsy in Korean soldiers did not increase after the vaccination campaign. The current study suggested that the MF59-adjuvanted H1N1 vaccine was not associated with the risk of narcolepsy. An international study on the association of narcolepsy and AS03-/MF59-adjuvanted H1N1 vaccines is in progress [31]. Our study has a significant provision for evidence for the safety of adjuvant MF59. Of note, our data will be useful for establishing a policy in a global context for pandemic influenza infections in the future.
[9]
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[12]
[13]
[14]
[15]
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[19]
[20]
Acknowledgements
[21]
This was not an industry supported study. The authors have indicated no financial conflicts of interest.
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