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National Public Health Institute and Helsinki University Central Hospital, Hospital for Children and Adolescents, Helsinki, Finland
The possible viral etiology of mumps-like illnesses in patients vaccinated for measles, mumps, and rubella (MMR) was studied by use of serum samples prospectively collected, during 19831998, from 601 acutely ill Finnish children and adolescents with mumps-like symptoms. Mumps virus was excluded by testing serum samples for mumps antibodies, and the serum samples were further tested for antibodies to adenovirus, enterovirus, Epstein-Barr virus, parainfluenza virus types 13, and parvovirus B19. The serum samples of 114 children <4 years old were also tested for antibodies to human herpesvirus 6 (HHV-6). A viral etiology was verified in 84 cases (14%), most commonly Epstein-Barr virus (7%), followed by parainfluenza virus types 1, 2, or 3 (4%) and adenovirus (3%). HHV-6 infection was found in 5 children <4 years old (4%). This study confirms that mumps-like symptoms in MMR-vaccinated children and adolescents are often not caused by mumps virus infection. Careful laboratory-based diagnostic testing of MMR-vaccinated children and adolescents who develop clinical symptoms compatible with those of mumps is important in the treatment of individual patients, in the comprehension of the true epidemiology of these illnesses, and in the evaluation of the impact of MMR vaccination programs.
In Finland, suspected cases of measles, mumps, and rubella (MMR) must be reported to the National Public Health Institute, and, since 1987, laboratory-based diagnostic tests have been used to confirm or refute the diagnoses of all such illnesses. In 1982, the nationwide MMR vaccination program and a system for intensified follow-up of MMR cases were introduced [1]. Soon after the MMR vaccination campaign was launched, the number of cases of mumps in Finland declined rapidly, from 12,000 cases in 1980 to 400 cases in 1985. The last outbreak of mumps, in 1987, involved 75 cases, mostly high school students in 1 community [2]. Since 1996, no indigenous cases of mumps and only a few imported cases of mumps have been diagnosed annually [2]. Although confirmed cases of MMR became very rare by the beginning of the 1990s [2, 3], clinically suspected cases of mumps that could not be confirmed by laboratory-based diagnostic tests continued to occur. Therefore, a study of the possible viral etiology of these illnesses was undertaken.
Mumps is difficult to differentiate clinically from other conditions that cause swelling of the major salivary glands (the parotid gland being the one most commonly involved) [4]. Several viral agents can induce symptoms that mimic those of mumps [47], and parotid-gland swelling can be caused by various bacterial infections [4] and noninflammatory [6, 8] conditions.
We studied the possible viral etiology of mumps-like symptoms in a large group of MMR-vaccinated children and adolescents. Serum samples collected when patients were ill were analyzed for antibodies to Epstein-Barr virus (EBV), parainfluenza virus types 13, enterovirus, adenovirus, and parvovirus. Serum samples from young children (<4 years old) were also tested for antibodies to human herpesvirus 6 (HHV-6). Our research group previously had completed a similar analysis of MMR-vaccinated children presenting with measles-like and rubella-like illnesses [9].
SUBJECTS, MATERIALS, AND METHODS
Background
A national campaign to eliminate MMR was launched in Finland during 1982 [3]. So that the impact of MMR vaccination could be followed, clinicians were urged to report to the National Public Health Institute suspected cases of mumps that occurred >3 months after vaccination and, for each such case, to submit pairedacute-phase and convalescent-phaseserum samples taken 13 weeks apart [1].
Case Selection
By 1998, serum samples had been obtained from 848 patients who were reported to have a mumps-like illness (usually with symptoms that included swelling of the parotid gland and low-grade fever) and who had been vaccinated for MMR. Serologic analysis showed that only 17 (2%) of these patients actually had a mumps virus infection; mumps was serologically confirmed if IgM antibodies to mumps virus were present and/or a significant intrapair increase in IgG antibodies to mumps was observed.
For the 831 nonmumps cases, paired serum samples that were adequately collected and stored were available from 601 children and adolescents (1.619 years old); the first sample in each pair had been taken, on average, 4 days after the onset of illness; the second had been taken 16 days later. Of these 601 patients, 279 (46%) were <6 years old, 266 (44%) were 611 years old, and 56 (9%) were 12 years old; 228 (38%) were female and 373 (62%) were male. HHV-6 tests were performed on 114 children <4 years old. Serum samples had been kept frozen at -20°C until used in this study.
Methods
Mumps antibody tests.
Until 1990, IgG antibodies to mumps virus were measured with a commercial hemolysis-in-gel test (Orivir Mumps; Orion); thereafter, they were measured with a commercial EIA kit (Enzygnost Anti-Mumps/IgG; Dade Behring). IgM antibodies to mumps virus were measured with a commercial EIA kit (Enzygnost Anti-Mumps/Ig; Dade Behring).
Epstein-Barr virus antibody tests.
IgM antibodies to EBV were measured with a commercial EIA kit (Enzygnost Anti-EBV/IgM; Dade Behring). Paired serum samples that tested positive for IgM antibodies to EBV were then tested for IgG antibodies to EBV and for avidity (Enzygnost EBV/IgG-Avidity; Dade Behring), to distinguish between a polyclonal IgM response and recent infection. A low avidity index (<20%) was considered to be indicative of a recent infection.
Parainfluenza virus antibody test.
IgG antibodies to the parainfluenza viruses were measured with a commercial EIA kit able to detect all 3 types of parainfluenza virus (Parainfluenza 1/2/3 IgG-ELISA; IBL). The manufacturer of this kit did not provide diagnostic criteria, but we considered a 2-fold intrapair increase in EIA units to be diagnostic [10].
Parvovirus antibody tests.
IgM antibodies to human parvovirus B19 were measured with a commercial EIA kit (Parvovirus B19 IgM EIA; Biotrin).
Adenovirus antibody test.
Adenovirus infection was confirmed by an in-house EIA technique to detect IgG antibodies, as described elsewhere [9]. We used purified adenovirus (type 2) hexon protein [11] as the antigen. A diagnosis of adenovirus infection was confirmed if a 4-fold increase in EIA units between paired serum samples was observed.
Enterovirus antibody test.
IgG antibodies to enterovirus were measured by an EIA that used, as an antigen, a synthetic peptide derived from an immunodominant region of capsid protein VP1 known to be a common antigenic determinant for most enteroviruses [12]. The assay procedure, previously validated by concomitant isolations of enterovirus [13], was slightly modified and has been described elsewhere in more detail [9]. A 2-fold intrapair increase in the optical-density (OD) reading was considered to be a significant change; if the OD reading of the first sample in a pair was already high (1.500), an intrapair increase of 0.500 (3 times the interassay variation) was considered to be diagnostic.
HHV-6 antibody test.
The HHV-6 antibody assays were performed by use of an indirect immunofluorescence test [14]. The reciprocal of the highest dilution of a serum sample showing fluorescence was regarded as its antibody titer. A 4-fold intrapair increase in antibody titer was considered to be diagnostic.
RESULTS
Occurrence of different infections.
In 84 (14%) of the 601 patients, an acute infection with EBV; parainfluenza virus types 1, 2, or 3; adenovirus; enterovirus; parvovirus; or, in children <4 years old, HHV-6 was diagnosed serologically (table 1). EBV infection was diagnosed in 41 (7%) of the 601 patients. After serum samples were tested for IgM antibodies to EBV, the results for 49 patients were positive, and the results for 28 were equivocal, but 36 positive results were excluded after the serum samples were tested for IgG antibodies and avidity. Twenty-four cases (4%) met the diagnostic criteria for infection with parainfluenza types 1, 2, or 3. A significant intrapair increase in levels of IgG antibodies to either adenovirus or enterovirus was seen in 17 cases (3%) and 12 cases (2%), respectively. In addition, 141 patients (23%) had high (units, >70 EIA) levels of IgG antibodies to adenovirus, and 80 patients (13%) had high (OD, >2.0) levels of IgG antibodies to enterovirus, possibly reflecting a recent infection. Eighteen (3%) of these patients with high levels of IgG antibodies to either adenovirus or enterovirus were diagnosed with some other infection (usually EBV), and 19 (3%) had high levels of IgG antibodies to both adenovirus and enterovirus. Only 3 patients (0.5%) were diagnosed with human parvovirus B19; 2 of them were 13 years old, and 1 of them was 5 years old. Five children (4% of children <4 years old), all 2-3 years old, had evidence of acute HHV-6 infection. The criteria for simultaneous infection with 2 or 3 viral agents was met by 14 (2%) and 2 (0.3%) of the patients, respectively. The most common combinations were either adenovirus and enterovirus infections or EBV and parainfluenza virus infections. Both of the patients with a combination of 3 infections had diagnostic-level intrapair increases in the levels of antibodies to adenovirus, enterovirus, and the parainfluenza viruses.
Age-specific and seasonal trends.
EBV infections were most frequent in children 1 or 2 years old (2/10 and 13/45 children, respectively) and >11 years old (7/56 children). All 24 parainfluenza infections were diagnosed in children 9 years old. No enterovirus infections occurred in patients <5 years old. Adenovirus infections were quite evenly distributed among the different age groups (figure 1A).
EBV infections seemed to be somewhat more common in patients who had fallen ill during January than during other months (figure 1B). Parainfluenza virus infections were diagnosed more often during the first half of the year than during the last half of the year, with peaks in January and May. Enterovirus infections were diagnosed more frequently toward the end of the year than toward the beginning of the year, whereas adenovirus infections did not have any clear seasonal variation in frequency. The incidences of the other viral infections were too low to permit any conclusions with regard to age-specific or seasonal trends.
DISCUSSION
During 1982, the MMR vaccination program and a system for the intensified follow-up of all suspected cases of MMR were introduced [3]. Failures of the MMR vaccine have been rare in Finland [9]. During the last mumps epidemic, in 1987, only 2 of 75 cases were diagnosed as vaccine failures [2]. Indigenous cases of mumps were eliminated from Finland during 1996; since then, only a few (04) imported cases have been diagnosed annually [2].
When a disease such as mumps becomes rare, the positive predictive value for clinical diagnosis declines rapidly. Therefore, a specific diagnosis based on laboratory tests becomes important [15, 16]. In our study of >800 cases, only a very small portion (2%) proved to be true cases of mumps.
Establishing the etiology of mumps-like illnesses is not simple, because so many different infectious and noninfectious causes must be considered. In our study, an alternate viral etiology could be confirmed in 14% of the cases, and the diagnoses included EBV, parainfluenza virus, adenovirus, enterovirus, HHV-6, and parvovirus B19 infections. A relatively large proportion (86%) of the test group could not be diagnosed; however, the 2 groupsthose who had diagnoses and those who did not have diagnosesdid not differ from each other in any aspect, such as symptoms, age, or gender distribution.
In our study, the pathogen most commonly diagnosed (occurring in 7% of patients) was EBV. EBV infections are known to show some seasonal variation in frequency [17], and, in the present study, they were somewhat more common in January than in other months. EBV infection has been thought to occur during early childhood in people in developing countries, whereas it has seemed to be more common in older childhood and young adulthood, with a peak incidence during the teenage years, in people in developed countries [18]. It has been shown to be not as rare in young children as had generally been thought, because patients <2 years old may present with mild or atypical symptoms [18]. The present study has produced similar results, showing the highest incidence in children 1-2 years old and in those >11 years old.
Parainfluenza infection was diagnosed only in children <10 years old. The results of the present study are similar to those in the 16-year study by Knott et al. [19], in which most parainfluenza infections were diagnosed in children <5 years old. In the present study, parainfluenza infections were diagnosed primarily during the first half of the year. This seasonal variation in frequency accords with Finnish epidemiological data. The seasonal trends were not as clear as the age-specific trends, because the number of diagnosed cases was rather small and because the cases occurred over several years. However, we consider the seasonal trends to be indicative of the likelihood that a child is infected with a particular virus. One problem with interpreting the data by season is that the EIA that we used did not differentiate between parainfluenza types 1, 2, and 3, which may have different epidemiological patterns [19].
Adenovirus infections typically manifest as lymphonodular tenderness and swelling. Adenovirus infections associated with parotitis have previously been reported only in HIV-positive persons [4]. According to the results of the present study, adenovirus infection should be considered as a differential diagnosis for mumps-like symptoms in otherwise healthy children and adolescents. Adenovirus infections did not show any clear-cut seasonal variation in frequency.
Our research group has published elsewhere the results from a study of the etiology of measles-like and rubella-like illnesses in MMR-vaccinated children and adolescents, in which 37% of the suspected cases of measles or rubella were found to be caused by a virus different than what had been suspected [9]. In that study, serum samples were tested for antibodies to the same viral agents that were used in the present study. Interestingly, in the present study, no enterovirus infections occurred in patients <5 years old, whereas, in the study of measles-like and rubella-like illnesses, enterovirus infections had their highest prevalence in children <6 years old [9]. The seasonal trend was similar in both studies, with a higher frequency of enterovirus infections diagnosed toward the end of the year than toward the beginning of the year.
As the results of the present study indicate, when one is trying to establish the cause of mumps-like symptoms in a patient, it would be worthwhile to test at least for antibodies to EBV and the parainfluenza viruses, if not for antibodies to other viruses as well. An attempt to verify the etiology of mumps-like diseases is important for active surveillance in a population in which mumps is no longer endemic and also for evaluation of the success of an MMR vaccination program.
Acknowledgments
We thank Matti Waris, for providing the adenovirus hexon protein; Raija Vainionp, for collaborating on the adenovirus EIA; Kimmo Linnavuori, for collaborating on the HHV-6 test; Merja Roivainen, for providing synthetic peptides for the enterovirus EIA; and Seija Salmi, for her excellent work on the laboratory tests.
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