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The changing epidemiology of hospitalized pediatric patients in three measles outbreaks
Journal of Infection (2007) 54, 167e172
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The changing epidemiology of hospitalized pediatric patients in three measles outbreaks Kyung-Yil Lee*, Hyung-Shin Lee, Jae-Kyun Hur, Jin-Han Kang, Byung-Churl Lee Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Accepted 23 February 2006 Available online 18 April 2006
KEYWORDS Anti-measles IgM antibody; Epidemiology; Epidemic; Measles; Vaccine failure
Summary Objectives: To assess the demographic and clinical findings of measles patients during three epidemics from 1989 to 2001. Methods: A total 520 medical records of measles patients were analyzed retrospectively and divided into three groups; those who were admitted during 1989e1990 (group I, 116 patients), those admitted during 1993e1994 (group II, 127 patients), and those admitted during 2000e2001 (group III, 277 patients). Results: For the age distribution, there was no difference in the proportion of <2 years of age (61%, 58% and 57%, respectively) for the three groups. However, in each outbreak, there were significant differences in the distribution of 2 years children who had mostly received one-dose measlesemumpserubella (MMR) vaccination. The age distribution had changed with a significant increase in older children in subsequent outbreaks. In the last 2000e 2001 outbreak, there was a pattern for increased attack rates with increasing interval since the initial vaccination. There was no statistical difference between the three groups in gender ratio, MMR vaccination rate in 2 years of age, duration of fever, and complications. No difference was found in all the clinical and laboratory parameters between the anti-measles IgM antibody negative patients and the positive patients. Conclusions: The age distribution of admitted children with measles in each outbreak has changed over time since the introduction of one-dose MMR vaccination. This finding suggests that the secondary vaccine failure may have played a large role in the last measles outbreak. ª 2006 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary’s Hospital, 520-2 Daeheungdong, Jung-gu, Daejeon 301-723, Republic of Korea. Tel.: þ82 42 220 9541; fax: þ82 42 221 2925. E-mail address: [email protected] (K.-Y. Lee). 0163-4453/$30 ª 2006 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2006.02.016
168
Introduction Although the incidence of measles has significantly decreased in many countries due to the widespread use of effective vaccines, this disease still causes significant morbidity and mortality worldwide.1,2 The measles vaccine was introduced in Korea in 1965 and routine measlesemumpse rubella (MMR) vaccination became the general health care practice since 1985; this has led to the decreased incidence of measles.3e5 Nonetheless, three nationwide measles epidemics were reported in 1989e1990, 1993e1994, and in 2000e 2001.3e7 Although measles generally affected young children in the prevaccine era in Korea, the measles patients in the recent epidemics after the introduction of the MMR vaccine have included school-aged children and young adults.3e14 The changes in age distribution pattern in the postvaccine era suggest that vaccine failures play an important role in each epidemic. Although the immunity induced by live measles vaccine has been considered to be lifelong, w5% of vaccinees are affected during measles outbreaks in developed countries.8,10,11,14 We experienced three measles outbreaks in Daejeon over a decade in accordance with nationwide epidemics. We analyzed and compared the demographic characteristics with other findings for the children with measles during three outbreaks.
Patients and methods We retrospectively reviewed 520 medical charts of children with measles who were admitted to The Catholic University of Korea, Daejeon St. Mary’s Hospital, during the measles outbreaks of 1989e 1990, 1993e1994 and 2000e2001. Daejeon is one of the largest cities in South Korea with a population well over 1.3 million, and located in the central part of the nation. Most of the measles patients were admitted to four general hospitals including ours and the proportion of admitted children in our hospital was approximately one-fourth of all admitted patients in the city during this study period. The number of reported measles patients in Daejeon during the 2000e2001 epidemics was 1350, of which 277 children patients were admitted to our department. In Korea, measles has traditionally been regarded as a severe disease and most parents are well aware of the importance of having their children inoculated with the MMR vaccination. In Daejeon, most measles patients were recommended to receive admission care during the study period. Thus, a large numbers of uncomplicated
K.-Y. Lee et al. measles cases were included in this study, and the bias according to the severity of measles might be considered as negligible. The patients were classified by their hospitalization periods into three groups, i.e., group I included 116 patients admitted during 1989e 1990, group II included 127 patients admitted during 1993e1994, and group III included 277 patients admitted during 2000e2001. For the purpose of disease surveillance, the clinical criteria for a diagnosis of measles were (1) at least 2 days of prodromic symptoms of fever, cough, conjunctivitis, and the Koplik spots, followed by (2) a generalized maculopapular rash lasting 3 or more days associated with (3) a fever of 38.3 C or greater.15 Groups II and III underwent additional diagnostic test for the anti-measles IgM antibody, as measured using enzyme-linked immunosorbent assay (Measles IgM EIA Well, Radim, Italy). The age distribution of each outbreak was compared by dividing the patients into four subgroups with their ages ranging from 0 to 1 year old, 2 to 5 years old, 6 to 9 years old and 10 to 15 years old, respectively. The following parameters were examined in each group: the duration of fever, duration of hospitalization and complications, white blood cell (WBC) count and differential, and the value of transaminases. The patient was considered to have a complication when he or she was hospitalized for 6 days, and we analyzed a variety of complications shown by these patients among all the groups. MMR vaccination history was obtained from parent statements, in part based on vaccination records. From the patients of groups II and III, we evaluated the anti-measles IgM levels and compared the clinical and laboratory parameters between the anti-measles IgM positive and the negative groups.
Statistical analysis Statistical analysis was conducted with using SPSS 10.0 for Windows. The means that all continuous variables were compared by analysis of variance and one-way ANOVA test. The Chi-square test was used for categoric data. Continuous variables are reported as mean standard deviation (SD). A P 0.05 was considered statistically significant.
Results The age distributions in each outbreak are shown in Table 1 and Fig. 1. The mean age was significantly different between the groups. The proportions of the patients under 2 years of age in the three groups were 61%, 58% and 57%, respectively,
The changing epidemiology during three measles outbreaks Table 1
169
Characteristics of hospitalized patients in three measles outbreaks
Characteristics
1989e1990 (n ¼ 116)
1993e1994 (n ¼ 127)
2000e2001 (n ¼ 277)
Age (years) 0e1 y (n, %) 2e5 y 6e9 y 10e15 y Gender (M:F ratio) Duration of fever (days) Hospitalization (days) Complications (n, %)b MMR vaccination WBC (103/mm3) Abnormal LFT (n, %) Anti-measles IgM
2.5 3.5* 71 (61) 24 (21)** 14 (12) 7 (6) 69:47 (1.5:1) 5.3 1.9 6.4 2.9a 64 (55.2) 41/92 (44.6) 7.9 4.5 5 (4.3) ND
3.0 3.4* 73 (58) 15 (12) 36 (28)** 3 (2) 79:48 (1.6:1) 5.4 2.2 6.2 2.0 78 (61.4) 53/113 (46.9) 7.8 4.3 6 (4.7) 54/62 (87.1)
4.0 4.9* 156 (57) 23 (8) 39 (14) 59 (21)** 156:121 (1.3:1) 5.0 1.9 5.7 2.2 136 (49.1) 78/222 (35.1) 6.9 3.9 14 (5.1) 199/242 (82.2)
P 0.002 NS 0.005 0.001 <0.001 NS NS 0.02 NS NS NS NS NS
LFT, liver function test, cases above two-folds of normal values for aspartate aminotransferase and alanine aminotransferase; MMR, one-dose measlesemumpserubella vaccine; ND, Not determined; NS, Statistically non-specific. *Statistically significant for each group; **statistically significant for each subgroup (see Fig. 1). a Statistically significant compared to that of the 2000e2001 outbreak. b Number of cases who were hospitalized 6 days.
with no statistical differences. However, there were significant differences in the age distribution for patients above 2 years of age: 21% in 2e5 years of group I, 28% in 6e9 years of group II and 21% in >10 years of group III (Fig. 1). No differences were present between the three groups in the male: female ratio (total 1.4:1). To compare clinical features, we chose to use the duration of fever and hospitalization to quantify these parameters. There was no difference in the total duration of fever and the complication rates, but the length of hospitalization was significantly different for the group I as compared to group III (P ¼ 0.02, Table 1). Among the patients hospitalized for 6 70 60
(%)
50 40
*
30 20
*
*
10 0
0~1 2~5 6~9 >10
0~1 2~5 6~9 >10
0~1 2~5 6~9 >10
1989 - 90
1993 - 94
2000 - 01
(yr)
Figure 1 Age distributions of hospitalized patients in three measles outbreaks. ) Marks represent the second peak age subgroups and there were significant differences in each subgroup.
days, 60e70% of children were identified to have complications such as pneumonia, croup and bronchiolitis; however, none of the patient except one in group I was admitted to intensive care unit (ICU) as a result of serious complications. There were very few malnourished children with complicated measles, and some children had more than one complication. Meningoencephalopathy without sequelae as a severe complication of measles was noted in two patients in the group I, one patient in the group II and two patients in the group III (Table 2). The MMR vaccination history was investigated in a majority of patients (427 of 520, 82%). Forty-one of 92 (45%) patients in the group I, 53 of 113 (47%) in the group II, and 78 of 222 (35%) in the group III had a positive history of one-dose MMR vaccination. The evaluated MMR vaccination rates in the 2 years of age and the four different age subgroups were not significantly different among the three groups (Table 3). As for laboratory indices, WBC counts and the number of cases of elevated transaminases (AST and ALT levels each above 40 IU/L) were not statistically different among the three groups. The number of children who tested positive for anti-measles IgM was 54 of 62 (87.1%) patients in the group II, and 199 of 242 (82.2%) patients in the group III, with no difference. To determine if anti-measles IgM positivity led to a different clinical course, we evaluated a total of 306 patients in the groups I and II (253 were anti-measles IgM positive and 51 were negative). No difference was found in all the clinical and laboratory parameters between the groups (Table 4).
170 Table 2
K.-Y. Lee et al. Complications in three measles outbreaks
Complications
1989e1990 (n ¼ 116)
1993e1994 (n ¼ 127)
2000e2001 (n ¼ 277)
P
Total (n, %)a
64 (55.2)
78 (61.4)
136 (49.1)
NS
16 13 3 4 3 2 0 2 2 3
25 7 6 5 4 1 2 2 1 4
Pneumonia Croup Bronchiolitis Gastroenteritis Gingivostomatitis Febrile seizure Keratoconjunctivitis Hepatitisb Meningoencephalitis Otitis media
(18.8) (11.2) (2.6) (3.4) (2.6) (1.7) (1.7) (1.7) (2.6)
(19.7) (5.5) (4.7) (3.9) (3.1) (0.8) (1.6) (1.6) (0.8) (3.1)
41 6 4 10 4 2 2 6 2 6
(14.8) (2.2) (1.4) (3.6) (1.4) (0.7) (0.7) (2.2) (0.7) (2.2)
NS <0.01 NS NS NS NS NS NS NS NS
a Number of cases that were hospitalized 6 days, and the identified complications in these cases. Some patients had more than one complication. b Cases with values > 100 IU/L for aspartate aminotransferase and alanine aminotransferase.
Table 3
One-dose MMR vaccination rates
Age (n, %)
1989e1990 (n ¼ 92)
Total
41/92 (44.6) 53/113 (46.9) 78/222 (35.1) NS
1993e1994 (n ¼ 113)
0e1 y 9/54 (16.7) 12/69 (17.4) 2e5 y 17/19 (89.5) 10/11 (90.9) 6e9 y 11/12 (91.7) 28/30 (93.3) 10e15 y 4/7 (51.7) 3/3 (100)
2000e2001 (n ¼ 222)
15/141 13/18 19/25 31/38
(10.6) (72.2) (76) (81.6)
P
NS NS NS NS
Discussion Since the introduction of measles vaccine to Korea in 1965, the vaccination schedule has changed along with nationwide epidemics. The Korean Pediatrics Society and the Government of Korea recommended measles vaccination at 12 months of age in 1965
and at 15 months of age in 1976, and there was a nationwide MMR vaccination program started in 1985. The two-dose vaccination at 9 months with the measles vaccine and at 15 months with the MMR vaccine was recommended in 1991 after 1989e1990 epidemic, and two-dose MMR vaccination at 15 months and at 4e6 years of age has been recommended since 1995 after 1993e1994 epidemic. A large number of measles cases in vaccinees have occurred globally in the recent measles outbreaks. Although measles vaccination commenced in the early 1960s and the vaccination rate for susceptible population had been >90% in the Western countries, regional or nationwide measles outbreaks have been reported in 1980e 1990s.8e14 In one study in the United States,12 the age distribution of a measles outbreak in 1989e1990 showed that 45% of the cases was in <4 years of age (20% of the measles vaccination
Table 4 Characteristics of measles patients according to anti-measles IgM in 1993e1994 and 2000e2001 outbreaks Characteristics
Anti-measles IgM () (n ¼ 51)
Anti-measles IgM (þ) (n ¼ 253)
P
Age (years) 0e1 y (n, %) 2e5 y 6e9 y 10e15 y Gender (M:F ratio) Duration of fever (days) Hospitalization (days) MMR vaccination Complications (n, %) WBC (103/mm3) Hepatitis (n, %)
4.5 5.2 27 (52.9) 5 (9.8) 5 (9.8) 14 (27.5) 35:16 (1.9:1) 5.1 1.9 6.4 2.4 20/47 (42.6) 28 (55.9) 7.2 4.7 3 (5.9)
3.6 4.6 148 (58.5) 22 (8.7) 44 (17.4) 39 (15.4) 138:115 (1.2:1) 5.1 2.0 5.8 1.7 71/208 (34.1) 128 (50.1) 7.2 4.1 7 (2.8)
NS NS NS NS 0.04 NS NS NS NS NS NS NS
The changing epidemiology during three measles outbreaks coverage), 35% of the cases were between 5 and 19 year old (these patients were mostly assumed to have measles vaccination), and 20% of the cases were adults. Korean National Institute of Health reported that in the 2000 epidemic, 15,852 of 21,188 (74.8%) patients with measles, mainly older than 2 years, received the one-dose MMR vaccine on or after their first birthday.3 The age distribution showed two peaks; the children under 2 years of age and school aged children around the age of 10. The seroprevalence of measles antibody in school age children evaluated nationwide in 2001 was 89.4%,3,4 and the one-dose MMR vaccination coverage has been reported also around 90% or less for any children group born after 1987, including the rural area.4,5 Therefore, the seroprevalence of school age children in Korea did not reach the preventable level (>95% of population). In this study, the one-dose MMR vaccination rate in patients 2 years of age, regardless of the age subgroups in all outbreaks, was similar to that reported in Korea (Table 3).3e7 The age distribution, especially for the patients who received one-dose MMR vaccine (2 years of age), in each measles outbreak has changed during a decade. Interestingly, the 2e5 year age group during the 1989e1990 outbreak, which was the second peak age group, continued to show the second highest incidence in two subsequent outbreaks (Fig. 1). Although this age population had a relatively higher MMR vaccination rate (w90%) in each outbreak and they had experienced repeated exposure to wild virus during the repeated outbreaks, they were still the most prevalent age group as the 10e15 years of age group in the last outbreak. This may be partly explained by the possibility of low vaccine coverage or problems in vaccine products for Daejeon during those years. However, this is unlikely and difficult to demonstrate.7 The epidemiologic and clinical studies conducted during the three epidemics in other locations in Korea have reported a similar pattern of age distribution and MMR vaccination rate.3e7 Several studies have investigated for the possibility of waning immunity by determining risk of disease as a function of time that elapsed since vaccination (secondary vaccine failure).10,16 In contrast to these studies conducted during a single outbreak, we evaluated three outbreaks that occurred within a decade. In this study, the age distribution in the last outbreak showed a pattern for increased frequency of measles with increasing time after one-dose MMR vaccination (Fig. 1). These findings suggest that secondary vaccine failure as well as primary vaccine failure may play an important role in the last measles epidemic in Korea.17
171
The anti-measles IgM antibody has been studied for determining the vaccine failures. A positive anti-measles IgM has been regarded as an indication of primary vaccine failure in some studies,10,11,18 although there is some controversy.17,19 In addition, the vaccinees who subsequently develop measles have been reported to have a milder illness than the non-vaccinees in some studies,20,21 whereas other studies reported that there were no differences for clinical illness between the two groups.8,22e24 In this study, we found that there were no differences between the anti-measles IgM antibody positive and negative groups in regard to the examined parameters including the MMR vaccination rate and the duration of fever (Table 4). In addition, the seropositivity rate for anti-measles IgM between the 1993e1994 outbreak and the 2000e2001 outbreak was not different. We also found no differences in the clinical and laboratory parameters between the MMR vaccinees and the non-vaccinees in the <2 years of age group in 2000e2001 outbreaks.24 It has been well documented that in some cases, diagnostic antibodies may be negative during the early stage of an infectious disease. Thus, early measles antibody testing may be responsible for the seronegativity of antimeasles IgM antibody in this study. In this study, we used the duration of fever and hospitalization for quantifying the clinical manifestations including complications. None of the patients except for one required ICU care for any serious complications such as respiratory distress or meningoencephalitis. As previously stated, nearly all patients diagnosed or suspected of having measles received early admitted care and there were few malnourished children. These might partly explain the lower rate of serious complications. The minor antigenic variations in the measles virus have been reported, but the major antigenic type of measles virus has not changed.25 Although the duration of hospitalization in 1989e1990 outbreak was longer than those in 2000e2002 outbreak, there are some limitations for interpreting the result when considering such factors as the possibility of changes in discharge policy and the definition of complications. After the occurrence of measles outbreaks in postvaccine era, a routine two-dose vaccination was recommended in many countries.3,14,26,27 Although the Korean Pediatrics Society has recommended two-dose MMR vaccination since the 1993e1994 epidemic, two-dose MMR vaccination coverage in school age children was approximately 40% before the recent epidemic.3 Therefore, the Korean Government planned to eradicate measles by 2005 and a ‘catch-up campaign’ has been
172 performed since May 2001. As a result of this campaign, there have been few measles cases reported since August 2001.4,24 Our results may be helpful for the measles control programs for explaining that the second dose vaccination is required not only to decrease the small number of primary vaccine failures, but also to boost the immune response. In conclusion, we found that the age distribution of children who were admitted with measles has changed since the introduction of one-dose MMR vaccination in Korea. Routine two-dose vaccination for all children and also for older children and young adults who previously received onedose vaccination may be helpful to eliminate the scourge of measles.
K.-Y. Lee et al.
12.
13. 14.
15.
16.
17.
References
18.
1. Hopkins DR, Hinman AR, Koplan JP, Lane JM. The case for global measles eradication. Lancet 1982;6:1396e8. 2. Perry RT, Halsey NA. The clinical significance of measles: a review. J Infect Dis 2004;189(Suppl. 1):S4e16. 3. National Institute of Health of Korea. The results of evaluation of nationwide measles outbreak in 2000. Commun Dis Monthly Rep (Korea) 2001;12:33e8. 4. National Institute of Health of Korea. Measles in 2000e2001. The results of mass measles vaccination. Commun Dis Monthly Rep (Korea) 2002;13:19e24. 5. Choi YM, Kim CW, Seo JK, Shon YM, Oh SH, Lee WJ, et al. Reassessment of the current measles immunization policy in Korea. J Korean Pediatr Soc 1991;34:435e40. 6. Sohn YM, Hong CH, Lee SK. A measles outbreak in the Kangnam district of Seoul in 1989e1990. J Korean Med Assoc 1991;38:960e8. 7. Kim SK, Son BK, Chung CY, Ahn YM, Park CY, Lee HJ. Efficacy of measles vaccine during the 1993 measles epidemic in Korea. Pediatr Infect Dis J 1995;14:346e9. 8. Markowitz LE, Orenstein WA. Measles vaccines. Pediatr Clin North Am 1990;37:603e49. 9. Morse D, O’Shea M, Hamilton G, Soltanpoor N, Leece G, Miller E, et al. Outbreak of measles in a teenage school population: the need to immunize susceptible adolescents. Epidemiol Infect 1994;113:355e65. 10. Davis RM, Whiteman ED, Orenstein WA, Preblud SR, Markowitz LE, Hinman AR. A persistent outbreak of measles despite appropriate control measures. Am J Epidemiol 1987;126:438e49. 11. Gustafson TL, Lievens AW, Brunell PA, Moellenberg RG, Buttery CM, Sehulster LM. Measles outbreak in a full
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immunized secondary school population. N Engl J Med 1987;316:771e4. Gindler JS, Atkinson WL, Markowitz LE, Hutchins SS. Epidemiology of measles in the United States in 1989 and 1990. Pediatr Infec Dis J 1992;11:841e6. Heinonen OP, Paunio M, Peltola H. Total elimination of measles in Finland. Ann Med 1998;30:131e3. van den Hof S, Conyn-van Spaendonck MA, van Steenbergen JE. Measles epidemic in the Netherlands, 1999e2000. J Infect Dis 2002;186:1483e6. Centers for Disease Control. Classification of measles cases and categorization of measles elimination programs. MMWR 1983;31:707e11. Hutchins SS, Markowitz LE, Mead P, et al. School-based measles outbreak: the effect of a selective revaccination policy and risk factors for vaccine failure. Am J Epidemiol 1990;132:157e68. Markowitz LE, Preblud SR, Fine PM, Orenstein WA. Duration of live measles vaccine-induced immunity. Pediatr Infect Dis J 1990;9:101e10. Linnenman CC, Hegg ME, Rotte TC, Phair JP, Schiff GM. Measles IgM response during reinfection of previously vaccinated children. J Pediatr 1973;82:798e801. Hirose M, Hidaka Y, Miyazaki C, Ueda K, Yoshikawa H. Five cases of measles secondary vaccine failure with confirmed seroconversion after live measles vaccination. Scand J Infect Dis 1997;29:187e90. Smith FR, Curran AS, Raciti KA, Black FL. Reported measles in persons immunologically primed by prior vaccination. J Pediatr 1982;101:391e3. Aaby P, Bukh J, Leerhoy J, Lisse IM, Mordhorst CH, Pedersen IR. Vaccinated children get milder measles infection: a community study from Guinia-Bissau. J Infect Dis 1986;154:858e63. Baratta RO, Ginter MC, Price MA, Walker JW, Skinner RG, Prather EC, et al. Measles (rubeola) in previously immunized children. Pediatrics 1970;46:397e402. Knowane BM, Bart SW, Orenstein WA, Baltier M. Measles outbreak in a vaccinated school population: epidemiology, chains of transmission and the role of vaccine failures. Am J Public Health 1987;77:434e8. Lee KY, Lee HS, Hur JK, Kang JH, Lee BC. Clinical features of measles according to age in a measles epidemic. Scand J Infect Dis 2005;37:471e5. Bellini WJ, Rota JS, Rota PA. Viology of measles virus. J Infect Dis 1994;170(Suppl.1):S15e23. Center for disease control and prevention. Measles prevention. Recommendation of the immunization practice advisory committee (ACIP). MMWR 1989;38:5e9. Peltola H, Heinonen OP, Valle M, Paunio M, Virtanen M, Karanko V, et al. The elimination of indigenous measles, mumps, and rubella from Finland by a 12-year, twodose vaccination program. N Engl J Med 1994;331: 1397e402.
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The changing epidemiology of hospitalized pediatric patients in three measles outbreaks Kyung-Yil Lee*, Hyung-Shin Lee, Jae-Kyun Hur, Jin-Han Kang, Byung-Churl Lee Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Accepted 23 February 2006 Available online 18 April 2006
KEYWORDS Anti-measles IgM antibody; Epidemiology; Epidemic; Measles; Vaccine failure
Summary Objectives: To assess the demographic and clinical findings of measles patients during three epidemics from 1989 to 2001. Methods: A total 520 medical records of measles patients were analyzed retrospectively and divided into three groups; those who were admitted during 1989e1990 (group I, 116 patients), those admitted during 1993e1994 (group II, 127 patients), and those admitted during 2000e2001 (group III, 277 patients). Results: For the age distribution, there was no difference in the proportion of <2 years of age (61%, 58% and 57%, respectively) for the three groups. However, in each outbreak, there were significant differences in the distribution of 2 years children who had mostly received one-dose measlesemumpserubella (MMR) vaccination. The age distribution had changed with a significant increase in older children in subsequent outbreaks. In the last 2000e 2001 outbreak, there was a pattern for increased attack rates with increasing interval since the initial vaccination. There was no statistical difference between the three groups in gender ratio, MMR vaccination rate in 2 years of age, duration of fever, and complications. No difference was found in all the clinical and laboratory parameters between the anti-measles IgM antibody negative patients and the positive patients. Conclusions: The age distribution of admitted children with measles in each outbreak has changed over time since the introduction of one-dose MMR vaccination. This finding suggests that the secondary vaccine failure may have played a large role in the last measles outbreak. ª 2006 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary’s Hospital, 520-2 Daeheungdong, Jung-gu, Daejeon 301-723, Republic of Korea. Tel.: þ82 42 220 9541; fax: þ82 42 221 2925. E-mail address: [email protected] (K.-Y. Lee). 0163-4453/$30 ª 2006 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2006.02.016
168
Introduction Although the incidence of measles has significantly decreased in many countries due to the widespread use of effective vaccines, this disease still causes significant morbidity and mortality worldwide.1,2 The measles vaccine was introduced in Korea in 1965 and routine measlesemumpse rubella (MMR) vaccination became the general health care practice since 1985; this has led to the decreased incidence of measles.3e5 Nonetheless, three nationwide measles epidemics were reported in 1989e1990, 1993e1994, and in 2000e 2001.3e7 Although measles generally affected young children in the prevaccine era in Korea, the measles patients in the recent epidemics after the introduction of the MMR vaccine have included school-aged children and young adults.3e14 The changes in age distribution pattern in the postvaccine era suggest that vaccine failures play an important role in each epidemic. Although the immunity induced by live measles vaccine has been considered to be lifelong, w5% of vaccinees are affected during measles outbreaks in developed countries.8,10,11,14 We experienced three measles outbreaks in Daejeon over a decade in accordance with nationwide epidemics. We analyzed and compared the demographic characteristics with other findings for the children with measles during three outbreaks.
Patients and methods We retrospectively reviewed 520 medical charts of children with measles who were admitted to The Catholic University of Korea, Daejeon St. Mary’s Hospital, during the measles outbreaks of 1989e 1990, 1993e1994 and 2000e2001. Daejeon is one of the largest cities in South Korea with a population well over 1.3 million, and located in the central part of the nation. Most of the measles patients were admitted to four general hospitals including ours and the proportion of admitted children in our hospital was approximately one-fourth of all admitted patients in the city during this study period. The number of reported measles patients in Daejeon during the 2000e2001 epidemics was 1350, of which 277 children patients were admitted to our department. In Korea, measles has traditionally been regarded as a severe disease and most parents are well aware of the importance of having their children inoculated with the MMR vaccination. In Daejeon, most measles patients were recommended to receive admission care during the study period. Thus, a large numbers of uncomplicated
K.-Y. Lee et al. measles cases were included in this study, and the bias according to the severity of measles might be considered as negligible. The patients were classified by their hospitalization periods into three groups, i.e., group I included 116 patients admitted during 1989e 1990, group II included 127 patients admitted during 1993e1994, and group III included 277 patients admitted during 2000e2001. For the purpose of disease surveillance, the clinical criteria for a diagnosis of measles were (1) at least 2 days of prodromic symptoms of fever, cough, conjunctivitis, and the Koplik spots, followed by (2) a generalized maculopapular rash lasting 3 or more days associated with (3) a fever of 38.3 C or greater.15 Groups II and III underwent additional diagnostic test for the anti-measles IgM antibody, as measured using enzyme-linked immunosorbent assay (Measles IgM EIA Well, Radim, Italy). The age distribution of each outbreak was compared by dividing the patients into four subgroups with their ages ranging from 0 to 1 year old, 2 to 5 years old, 6 to 9 years old and 10 to 15 years old, respectively. The following parameters were examined in each group: the duration of fever, duration of hospitalization and complications, white blood cell (WBC) count and differential, and the value of transaminases. The patient was considered to have a complication when he or she was hospitalized for 6 days, and we analyzed a variety of complications shown by these patients among all the groups. MMR vaccination history was obtained from parent statements, in part based on vaccination records. From the patients of groups II and III, we evaluated the anti-measles IgM levels and compared the clinical and laboratory parameters between the anti-measles IgM positive and the negative groups.
Statistical analysis Statistical analysis was conducted with using SPSS 10.0 for Windows. The means that all continuous variables were compared by analysis of variance and one-way ANOVA test. The Chi-square test was used for categoric data. Continuous variables are reported as mean standard deviation (SD). A P 0.05 was considered statistically significant.
Results The age distributions in each outbreak are shown in Table 1 and Fig. 1. The mean age was significantly different between the groups. The proportions of the patients under 2 years of age in the three groups were 61%, 58% and 57%, respectively,
The changing epidemiology during three measles outbreaks Table 1
169
Characteristics of hospitalized patients in three measles outbreaks
Characteristics
1989e1990 (n ¼ 116)
1993e1994 (n ¼ 127)
2000e2001 (n ¼ 277)
Age (years) 0e1 y (n, %) 2e5 y 6e9 y 10e15 y Gender (M:F ratio) Duration of fever (days) Hospitalization (days) Complications (n, %)b MMR vaccination WBC (103/mm3) Abnormal LFT (n, %) Anti-measles IgM
2.5 3.5* 71 (61) 24 (21)** 14 (12) 7 (6) 69:47 (1.5:1) 5.3 1.9 6.4 2.9a 64 (55.2) 41/92 (44.6) 7.9 4.5 5 (4.3) ND
3.0 3.4* 73 (58) 15 (12) 36 (28)** 3 (2) 79:48 (1.6:1) 5.4 2.2 6.2 2.0 78 (61.4) 53/113 (46.9) 7.8 4.3 6 (4.7) 54/62 (87.1)
4.0 4.9* 156 (57) 23 (8) 39 (14) 59 (21)** 156:121 (1.3:1) 5.0 1.9 5.7 2.2 136 (49.1) 78/222 (35.1) 6.9 3.9 14 (5.1) 199/242 (82.2)
P 0.002 NS 0.005 0.001 <0.001 NS NS 0.02 NS NS NS NS NS
LFT, liver function test, cases above two-folds of normal values for aspartate aminotransferase and alanine aminotransferase; MMR, one-dose measlesemumpserubella vaccine; ND, Not determined; NS, Statistically non-specific. *Statistically significant for each group; **statistically significant for each subgroup (see Fig. 1). a Statistically significant compared to that of the 2000e2001 outbreak. b Number of cases who were hospitalized 6 days.
with no statistical differences. However, there were significant differences in the age distribution for patients above 2 years of age: 21% in 2e5 years of group I, 28% in 6e9 years of group II and 21% in >10 years of group III (Fig. 1). No differences were present between the three groups in the male: female ratio (total 1.4:1). To compare clinical features, we chose to use the duration of fever and hospitalization to quantify these parameters. There was no difference in the total duration of fever and the complication rates, but the length of hospitalization was significantly different for the group I as compared to group III (P ¼ 0.02, Table 1). Among the patients hospitalized for 6 70 60
(%)
50 40
*
30 20
*
*
10 0
0~1 2~5 6~9 >10
0~1 2~5 6~9 >10
0~1 2~5 6~9 >10
1989 - 90
1993 - 94
2000 - 01
(yr)
Figure 1 Age distributions of hospitalized patients in three measles outbreaks. ) Marks represent the second peak age subgroups and there were significant differences in each subgroup.
days, 60e70% of children were identified to have complications such as pneumonia, croup and bronchiolitis; however, none of the patient except one in group I was admitted to intensive care unit (ICU) as a result of serious complications. There were very few malnourished children with complicated measles, and some children had more than one complication. Meningoencephalopathy without sequelae as a severe complication of measles was noted in two patients in the group I, one patient in the group II and two patients in the group III (Table 2). The MMR vaccination history was investigated in a majority of patients (427 of 520, 82%). Forty-one of 92 (45%) patients in the group I, 53 of 113 (47%) in the group II, and 78 of 222 (35%) in the group III had a positive history of one-dose MMR vaccination. The evaluated MMR vaccination rates in the 2 years of age and the four different age subgroups were not significantly different among the three groups (Table 3). As for laboratory indices, WBC counts and the number of cases of elevated transaminases (AST and ALT levels each above 40 IU/L) were not statistically different among the three groups. The number of children who tested positive for anti-measles IgM was 54 of 62 (87.1%) patients in the group II, and 199 of 242 (82.2%) patients in the group III, with no difference. To determine if anti-measles IgM positivity led to a different clinical course, we evaluated a total of 306 patients in the groups I and II (253 were anti-measles IgM positive and 51 were negative). No difference was found in all the clinical and laboratory parameters between the groups (Table 4).
170 Table 2
K.-Y. Lee et al. Complications in three measles outbreaks
Complications
1989e1990 (n ¼ 116)
1993e1994 (n ¼ 127)
2000e2001 (n ¼ 277)
P
Total (n, %)a
64 (55.2)
78 (61.4)
136 (49.1)
NS
16 13 3 4 3 2 0 2 2 3
25 7 6 5 4 1 2 2 1 4
Pneumonia Croup Bronchiolitis Gastroenteritis Gingivostomatitis Febrile seizure Keratoconjunctivitis Hepatitisb Meningoencephalitis Otitis media
(18.8) (11.2) (2.6) (3.4) (2.6) (1.7) (1.7) (1.7) (2.6)
(19.7) (5.5) (4.7) (3.9) (3.1) (0.8) (1.6) (1.6) (0.8) (3.1)
41 6 4 10 4 2 2 6 2 6
(14.8) (2.2) (1.4) (3.6) (1.4) (0.7) (0.7) (2.2) (0.7) (2.2)
NS <0.01 NS NS NS NS NS NS NS NS
a Number of cases that were hospitalized 6 days, and the identified complications in these cases. Some patients had more than one complication. b Cases with values > 100 IU/L for aspartate aminotransferase and alanine aminotransferase.
Table 3
One-dose MMR vaccination rates
Age (n, %)
1989e1990 (n ¼ 92)
Total
41/92 (44.6) 53/113 (46.9) 78/222 (35.1) NS
1993e1994 (n ¼ 113)
0e1 y 9/54 (16.7) 12/69 (17.4) 2e5 y 17/19 (89.5) 10/11 (90.9) 6e9 y 11/12 (91.7) 28/30 (93.3) 10e15 y 4/7 (51.7) 3/3 (100)
2000e2001 (n ¼ 222)
15/141 13/18 19/25 31/38
(10.6) (72.2) (76) (81.6)
P
NS NS NS NS
Discussion Since the introduction of measles vaccine to Korea in 1965, the vaccination schedule has changed along with nationwide epidemics. The Korean Pediatrics Society and the Government of Korea recommended measles vaccination at 12 months of age in 1965
and at 15 months of age in 1976, and there was a nationwide MMR vaccination program started in 1985. The two-dose vaccination at 9 months with the measles vaccine and at 15 months with the MMR vaccine was recommended in 1991 after 1989e1990 epidemic, and two-dose MMR vaccination at 15 months and at 4e6 years of age has been recommended since 1995 after 1993e1994 epidemic. A large number of measles cases in vaccinees have occurred globally in the recent measles outbreaks. Although measles vaccination commenced in the early 1960s and the vaccination rate for susceptible population had been >90% in the Western countries, regional or nationwide measles outbreaks have been reported in 1980e 1990s.8e14 In one study in the United States,12 the age distribution of a measles outbreak in 1989e1990 showed that 45% of the cases was in <4 years of age (20% of the measles vaccination
Table 4 Characteristics of measles patients according to anti-measles IgM in 1993e1994 and 2000e2001 outbreaks Characteristics
Anti-measles IgM () (n ¼ 51)
Anti-measles IgM (þ) (n ¼ 253)
P
Age (years) 0e1 y (n, %) 2e5 y 6e9 y 10e15 y Gender (M:F ratio) Duration of fever (days) Hospitalization (days) MMR vaccination Complications (n, %) WBC (103/mm3) Hepatitis (n, %)
4.5 5.2 27 (52.9) 5 (9.8) 5 (9.8) 14 (27.5) 35:16 (1.9:1) 5.1 1.9 6.4 2.4 20/47 (42.6) 28 (55.9) 7.2 4.7 3 (5.9)
3.6 4.6 148 (58.5) 22 (8.7) 44 (17.4) 39 (15.4) 138:115 (1.2:1) 5.1 2.0 5.8 1.7 71/208 (34.1) 128 (50.1) 7.2 4.1 7 (2.8)
NS NS NS NS 0.04 NS NS NS NS NS NS NS
The changing epidemiology during three measles outbreaks coverage), 35% of the cases were between 5 and 19 year old (these patients were mostly assumed to have measles vaccination), and 20% of the cases were adults. Korean National Institute of Health reported that in the 2000 epidemic, 15,852 of 21,188 (74.8%) patients with measles, mainly older than 2 years, received the one-dose MMR vaccine on or after their first birthday.3 The age distribution showed two peaks; the children under 2 years of age and school aged children around the age of 10. The seroprevalence of measles antibody in school age children evaluated nationwide in 2001 was 89.4%,3,4 and the one-dose MMR vaccination coverage has been reported also around 90% or less for any children group born after 1987, including the rural area.4,5 Therefore, the seroprevalence of school age children in Korea did not reach the preventable level (>95% of population). In this study, the one-dose MMR vaccination rate in patients 2 years of age, regardless of the age subgroups in all outbreaks, was similar to that reported in Korea (Table 3).3e7 The age distribution, especially for the patients who received one-dose MMR vaccine (2 years of age), in each measles outbreak has changed during a decade. Interestingly, the 2e5 year age group during the 1989e1990 outbreak, which was the second peak age group, continued to show the second highest incidence in two subsequent outbreaks (Fig. 1). Although this age population had a relatively higher MMR vaccination rate (w90%) in each outbreak and they had experienced repeated exposure to wild virus during the repeated outbreaks, they were still the most prevalent age group as the 10e15 years of age group in the last outbreak. This may be partly explained by the possibility of low vaccine coverage or problems in vaccine products for Daejeon during those years. However, this is unlikely and difficult to demonstrate.7 The epidemiologic and clinical studies conducted during the three epidemics in other locations in Korea have reported a similar pattern of age distribution and MMR vaccination rate.3e7 Several studies have investigated for the possibility of waning immunity by determining risk of disease as a function of time that elapsed since vaccination (secondary vaccine failure).10,16 In contrast to these studies conducted during a single outbreak, we evaluated three outbreaks that occurred within a decade. In this study, the age distribution in the last outbreak showed a pattern for increased frequency of measles with increasing time after one-dose MMR vaccination (Fig. 1). These findings suggest that secondary vaccine failure as well as primary vaccine failure may play an important role in the last measles epidemic in Korea.17
171
The anti-measles IgM antibody has been studied for determining the vaccine failures. A positive anti-measles IgM has been regarded as an indication of primary vaccine failure in some studies,10,11,18 although there is some controversy.17,19 In addition, the vaccinees who subsequently develop measles have been reported to have a milder illness than the non-vaccinees in some studies,20,21 whereas other studies reported that there were no differences for clinical illness between the two groups.8,22e24 In this study, we found that there were no differences between the anti-measles IgM antibody positive and negative groups in regard to the examined parameters including the MMR vaccination rate and the duration of fever (Table 4). In addition, the seropositivity rate for anti-measles IgM between the 1993e1994 outbreak and the 2000e2001 outbreak was not different. We also found no differences in the clinical and laboratory parameters between the MMR vaccinees and the non-vaccinees in the <2 years of age group in 2000e2001 outbreaks.24 It has been well documented that in some cases, diagnostic antibodies may be negative during the early stage of an infectious disease. Thus, early measles antibody testing may be responsible for the seronegativity of antimeasles IgM antibody in this study. In this study, we used the duration of fever and hospitalization for quantifying the clinical manifestations including complications. None of the patients except for one required ICU care for any serious complications such as respiratory distress or meningoencephalitis. As previously stated, nearly all patients diagnosed or suspected of having measles received early admitted care and there were few malnourished children. These might partly explain the lower rate of serious complications. The minor antigenic variations in the measles virus have been reported, but the major antigenic type of measles virus has not changed.25 Although the duration of hospitalization in 1989e1990 outbreak was longer than those in 2000e2002 outbreak, there are some limitations for interpreting the result when considering such factors as the possibility of changes in discharge policy and the definition of complications. After the occurrence of measles outbreaks in postvaccine era, a routine two-dose vaccination was recommended in many countries.3,14,26,27 Although the Korean Pediatrics Society has recommended two-dose MMR vaccination since the 1993e1994 epidemic, two-dose MMR vaccination coverage in school age children was approximately 40% before the recent epidemic.3 Therefore, the Korean Government planned to eradicate measles by 2005 and a ‘catch-up campaign’ has been
172 performed since May 2001. As a result of this campaign, there have been few measles cases reported since August 2001.4,24 Our results may be helpful for the measles control programs for explaining that the second dose vaccination is required not only to decrease the small number of primary vaccine failures, but also to boost the immune response. In conclusion, we found that the age distribution of children who were admitted with measles has changed since the introduction of one-dose MMR vaccination in Korea. Routine two-dose vaccination for all children and also for older children and young adults who previously received onedose vaccination may be helpful to eliminate the scourge of measles.
K.-Y. Lee et al.
12.
13. 14.
15.
16.
17.
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