Measles infection was confirmed by detection of serum measles IgM antibodies using a commercial measles IgM enzyme-linked immunosorbent assay (Wampole Laboratories, Princeton, NJ) and CDC antibody-capture enzyme immunoassay,11 detection of viral RNA by conventional and real-time reverse-transcription polymerase chain reaction (RT-PCR), or culture of measles virus on Vero/human signaling lymphocytic activation molecule cells.12 Testing for serum measles IgG antibodies (Wampole Laboratories Measles IgG enzyme-linked immunosorbent assay II) was used as a surrogate measure of measles immunity among selected contacts. Nasopharyngeal, oropharyngeal, or urine specimens were collected from persons with suspected measles for RT-PCR testing and viral culture.
Real-time RT-PCR to detect measles virus RNA was performed using a previously described protocol.13 Templates for sequence analysis of measles viruses were prepared by conventional RT-PCR using the SuperScript One-step RT-PCR kit (Invitrogen, Carlsbad, CA).14 Sequencing reactions were performed using the BigDye Terminator sequence reaction kit version 1.1 (ABI, Forest City, CA). Sequencing reactions were cleaned using the CleanSeq magnetic bead cleanup kit (Agencourt, Beverly, MA) and analyzed by an ABI 3100 automated sequencer (ABI). Nested PCR was applied if conventional RT-PCR was unable to produce a product for sequence analysis. In these cases, a 640-nucleotide PCR product derived from the region of the genome coding for the carboxyl terminus of the nucleocapsid (N) protein was first amplified by RT-PCR, followed by conventional PCR amplification of the standard genotyping target sequence.
Sequences were edited using Sequencher version 4.7 (Gene Codes, Ann Arbor, MI). Data from edited sequences were analyzed and compared with World Health Organization measles reference strains15 using version 10.3 of the Genetics Computer Group Package (Accelrys, San Diego, CA). Phylogenetic analyses were performed using PAUP version 4.01 (Sinauer Associates, Sunderland, MA).
Seven epidemiologically linked measles cases were identified through contact tracing of 1250 persons in California, Georgia, Illinois, Indiana, Maryland, Michigan, Pennsylvania, and Texas.
The index case occurred in a Japanese boy, aged 12 years, who had been exposed to a sibling with a measles-like illness in Japan in late July 2007. He was unable to provide immunization records, and his vaccination status was classified as unknown. On August 13, 2007, he traveled with the Japanese and Chinese-Taipei teams by commercial airline from Tokyo, Japan, to Detroit, MI, where they cleared immigration and customs. They boarded a commercial flight from Detroit to Baltimore, MD, and then traveled by chartered bus from Baltimore to central Pennsylvania (Fig. 1). In Pennsylvania, the index patient stayed in a residential compound at the sporting event site, sharing recreational and dining facilities with coaches, staff, and 200 players (boys aged 12–13 years) representing 8 US and 8 international teams. Access to the residential compound was restricted to team members, event staff, and corporate representatives.
On August 15, ∼60 hours after commencing travel, the index patient had onset of maculopapular rash and fever. Measles was suspected when he was evaluated at the event infirmary the next day. The Pennsylvania Department of Health was contacted; a serum specimen was obtained; and he was placed in isolation at the compound. On August 17, measles was confirmed by detection of serum measles IgM antibodies (Table 3). Because the communicable period for measles extends from 4 days before to 4 days after rash onset, he was considered infectious during August 12–19, a period that included his international and domestic travel and his initial stay at the event compound. The incubation period for measles, from exposure to rash onset, ranges from 7 to 18 days.
Contact tracing conducted among all 471 players, coaches, translators, and event staff with access to the event compound identified 193 (41%) persons without evidence of presumptive measles immunity. These 193 persons were offered MMR vaccine or serologic testing for measles IgG antibodies (Table 4); 102 (53%) elected to receive vaccine, 90 (47%) underwent serologic testing, and 1 was lost to follow-up. Among the 102 persons who elected to receive MMR vaccine without serologic testing, 38 (37%) received vaccine on August 18, within 72 hours of isolation of the index patient; the remaining 64 persons (63%) received MMR vaccine during August 21–23. Among 90 persons tested, 16 (18%) had undetectable serum measles IgG antibodies and subsequently received MMR vaccine during August 21–23. Four seronegative persons were non-US-resident players (aged 13 years) from Canada (1), the Netherlands (1), and Venezuela (2). Twelve seronegative persons were adults; 9 (75%) were US residents (median age, 39 years; range, 21–45 years) and 3 (aged 39, 40, and 48 years) were from the Netherlands, Canada, and Saudi Arabia.
Although participant vaccination records had been routinely requested by event organizers, responses were initially incomplete for most players, and an additional request was made after identification of the index case. In response to this second request, documentation of measles vaccination was received for all 96 US players, compared with only 23 (22%; P < 0.001) of 103 international team players. Among the 25 players from the teams that had traveled with the index patient, 24 (96%) elected to receive MMR vaccine on August 18 without undergoing serum measles IgG antibody testing. A higher proportion of the US-resident adults, compared with non-US-resident adults, had documentation of presumptive measles immunity (62% vs. 30%; P = 0.001).
Corporate representatives who had visited the event compound were notified of potential measles exposure and advised to visit a healthcare provider for postexposure prophylaxis if they lacked evidence of immunity. Local healthcare providers were notified of the case and given information on measles. National public health notifications were posted through the Epidemic Information Exchange, and public announcements were made through the mass media. As additional cases were identified, contact tracing was expanded to notify other exposed persons.
On August 24, an emergency department near the event site reported another suspected measles case in a Japanese boy, aged 12 years, who had presented with fever and maculopapular rash; his mother had no documentation or recollection of his having received measles vaccine, and he was considered unvaccinated. He had been exposed to the index patient on August 12 during practice in Japan, and had traveled to the US on August 15 to attend the event as a spectator. He was isolated in his hotel room. Measles was confirmed by detection of serum measles IgM antibodies (Table 3). Because rash onset occurred on August 23, he was considered noninfectious during his travel. The 29 members of his travel group and all 27 hotel staff were interviewed at their hotel; 38 (68%) persons lacked evidence of presumptive measles immunity and received MMR vaccine. Persons staying at the hotel during his infectious period were notified of potential measles exposure through letters mailed to 109 registered guests, advising them to contact physicians and local health departments in the event of illness. The patient had no other known public contact during his communicable period, and no cases were identified among his contacts.
Cases 3 and 4: Air Travel-associated Transmission
Case 3 occurred in a federal airport officer, aged 25 years, who had worked in the Detroit airport customs area on August 13 when the index patient had arrived. Although he had been born in the US and believed that he had been vaccinated against measles, no documentation of measles or MMR vaccination was found on review of his school records. On August 23, he experienced cough, coryza, wheezing, diaphoresis, and abdominal pain, followed by rash onset on August 27. Measles was confirmed by serum measles IgM antibodies; measles virus RNA was detected by RT-PCR in an oropharyngeal specimen. However, efforts to amplify the larger region of the N gene necessary for genotyping were unsuccessful. Although no additional cases were definitively linked, a coworker at the same airport experienced laboratory-confirmed measles more than 1 incubation period later (rash onset on September 27); genotyping was also unsuccessful in that case.
Case 4 occurred in a woman, aged 53 years, who had been seated 1 row in front of the index patient on the 1.5-hour Detroit to Baltimore flight on August 13. Born in the US in 1954, she had neither record of prior measles vaccination nor clinical measles history, and received immunoglobulin 6 days after exposure. On August 25, she experienced fever, cough, and coryza, followed by rash on August 28. Serum measles IgM antibodies were detected (Table 3). No additional cases were identified among her contacts.
One of the 9 corporate representatives exposed to the index patient at the sporting event subsequently developed measles. He was a US-born man, aged 40 years, who had greeted the index patient on August 14. After returning to Texas, he was contacted by public health authorities, informed of his exposure, and advised to see his physician because he had no documentation or recollection of prior measles illness or having received vaccination against measles. On August 26, he experienced cough, coryza, conjunctivitis, and fever. He visited 3 Houston-area colleges on August 28, the day of his rash onset. At his physician's office on August 29, his temperature was 40.9°C, and he experienced a generalized seizure; he was hospitalized for 4 days with pneumonia and recovered. Specimens collected on August 31 confirmed measles through detection of serum IgM antibodies (Table 3).
Cases 6 and 7
Two additional cases (6 and 7, respectively) occurred in male college students aged 20 and 21 years, who recalled being in close proximity to the corporate representative (case 5) when he was coughing during an August 28 college visit. They were US-born, roommates, and from the same town. Each had documentation of 2 appropriately timed routine childhood doses of MMR vaccine from different health centers. They experienced fevers, chills, and myalgias on September 9 and 10. Maculopapular rash appeared 2 days after fever onset, was generalized in case 6, and limited to the trunk in case 7. Both were laboratory-confirmed, although neither met the Council of State and Territorial Epidemiologists clinical case definition for measles,9 lacking cough, coryza, or conjunctivitis (Table 3). Both students had assisted at a youth baseball camp during their potential infectious period, and 189 persons were subsequently notified of possible measles exposure. No additional cases were identified among their contacts.
Clinical characteristics and laboratory results for all 7 measles cases are summarized in Table 3. Viral genotype was determined for 6 (86%) cases and identified measles genotype D5 with identical sequences (Fig. 2). Nested PCR was necessary to determine genotype in 3 cases.
This international sporting event-associated measles outbreak demonstrated susceptibility among US adults, nonclassical clinical presentations in previously vaccinated patients, air travel-associated transmission, and the successful application of nested PCR for determining viral genotype. The findings from this outbreak remind healthcare providers of the potential for measles importation. Since the elimination of endemic measles transmission in the US, failure to consider the diagnosis of measles has resulted in documented outbreaks, as in 2008.16,17 Continuing importations of measles also highlight the importance of maintaining high 2-dose vaccine coverage in the US population.
Sporting events and other types of international mass gatherings provide opportunities for measles transmission.6,18,19 The index patient in this outbreak had been exposed in Japan where measles vaccination rates are low,8 measles is still endemic, and large outbreaks are documented periodically.19–21 This outbreak also highlights the importance of maintaining and having readily available immunization records for US residents and travelers. Such records are critical for rapidly evaluating presumptive immunity during an outbreak investigation. Immunization records had been requested by event organizers before this sporting event, and 2-dose MMR vaccination was subsequently documented among all US players during the contact investigation. However, the majority of participating adults and non-US players lacked available documentation of vaccination. Serologic testing was extensively used in assessing measles immunity among persons exposed at the event site and identified adults and non-US players who lacked evidence of measles immunity. International event organizers should encourage participants and attendees to be fully vaccinated against measles and should enhance efforts to improve immunization documentation among all players, event staff, and coaches. Since this outbreak, health department personnel now participate actively on the event planning committee. To minimize the likelihood of future problems, information is shared with event organizers on emerging health threats in participating countries, public health information is sent to participating teams before traveling to the event, and health department personnel assess health-related data supplied by the teams beforehand and upon arrival.
The number of cases in this outbreak was small relative to the large number of potentially exposed persons. Effective surveillance and prompt public health response by state and local health authorities likely prevented additional cases. Sixteen exposed persons at the sporting event residential compound had undetectable measles IgG antibodies. However, this likely underestimates the number of measles-susceptible persons at the compound because >100 persons followed public health recommendations to receive MMR vaccine without first undergoing serologic testing. On the basis of a previously documented 90% measles attack rate among exposed susceptible persons,22 it is likely that multiple additional measles cases were prevented through prompt implementation of patient isolation and postexposure vaccination of exposed contacts. Additional measles cases at this event might have resulted in further spread domestically and internationally by event attendees returning to many US states and participating countries (Canada, Curaçao, Japan, Mexico, the Netherlands, Saudi Arabia, Taiwan, and Venezuela).
High levels of measles immunity in the US population probably also limited transmission during this outbreak. Larger measles outbreaks (consisting of 34 and 12 cases) have been documented in US communities with low measles vaccination rates.6,16 In contrast to subsequent US measles cases during January to June 2008 that occurred primarily among school-aged children whose parents declined vaccination,17 this outbreak illustrates that US-born adults may also be at risk of imported measles. A national seroprevalence survey revealed that US adults born during 1967–1976 have the lowest prevalence (92.4%) of measles IgG antibody among persons born during 1949–1998.23 Five (71%) patients in this outbreak lacked evidence of prior vaccination. These findings underscore the importance of reviewing measles immune status for adults and children, and administering MMR vaccine in accordance with Advisory Committee on Immunization Practices recommendations.10 In August 2009, revised Advisory Committee on Immunization Practices provisional recommendations for measles, mumps, and rubella evidence of immunity for healthcare personnel were made available.24
This and previous outbreaks among highly vaccinated populations demonstrate that measles cases might not meet standard measles clinical case definitions, especially if they occur among previously vaccinated persons.25,26 Persons born in the US before 1957 are presumed to have measles immunity through exposure to wild virus, but also may remain susceptible. These findings highlight the importance of testing all exposed persons with febrile rash illness (suspected case definition; Table 19) during a measles outbreak.
Measles transmission occurred in an airplane passenger and an airport worker. Although risk of measles transmission aboard commercial aircraft is considered low,27 instances of suspected aircraft transmission have been reported.5,28–31 Although the passenger who contracted measles (case 4) may have also been exposed before or after the flight, she had been seated 1 row in front of the index patient and was identified by the CDC measles airline contact investigation protocol at the time of the investigation. CDC has since revised the measles contact investigation protocol for flights with >30 passengers to include persons seated in the same row and 2 rows in front and behind (across all aisles), all flight crew serving the same cabin, and all babies in the arms of an adult seated anywhere on the flight (CDC, unpublished protocol, December 2008). Airport workers may also be at increased risk for measles exposure. The measles case that occurred 1 month later in another Detroit airport officer may have been linked to this outbreak through an unidentified chain of transmission, or may have resulted from exposure to an unidentified infected traveler. Persons planning international travel or who are regularly exposed to international travelers are highly encouraged to confirm measles immunity and to receive vaccination, if indicated.10
Measles genotype identification is important for tracing the likely source of imported virus in the postelimination era32–35; genotype information confirmed epidemiologic associations in this outbreak. Measles genotype D5 was identified in 6 cases, and the identical sequences were consistent with a single chain of transmission. Viruses with the same sequence circulated in Japan during 2007.20,21 An identical sequence was also obtained from a case imported from Japan to Oregon in May 2007 (CDC, unpublished data, 2007). Nested PCR was a useful technique for genotyping when conventional PCR amplification methods were unsuccessful in this outbreak, possibly because of low quantities of viral RNA.
Limitations of this investigation included absence of immediate follow-up for travelers who returned to other countries after possible measles exposure. Contact tracing may have failed to identify additional US cases, although this seems unlikely given the national public health notifications about this outbreak and the sensitivity of US measles surveillance during outbreaks.36 Viral genotyping was unsuccessful for the Detroit airport officer (case 3), and his epidemiologic link to the outbreak was not confirmed by molecular methods.
Ongoing measles transmission in many parts of the world, including industrialized nations in Asia and Europe,17,37–39 will likely result in continuing measles importation to the US. The risk of imported measles highlights the necessity of maintaining high population levels of immunity to limit the size of importation-associated outbreaks and to maintain measles elimination in the US. Supporting local and state public health surveillance and response capacity is critical for early identification of measles cases and containment of outbreaks. Improving global measles control through expanded vaccination coverage will reduce morbidity and mortality in other countries and also will reduce the burden of measles in the US.
The authors acknowledge H. Stafford, J. Bart, A. Gray, V. Urdaneta, J. Battin, D. Fontaine, J. Mincer, C. Nicolardi, M. Dincher, J. Clodgo, A. Regec, M. Strohecker, and S. Reynolds, Pennsylvania Department of Health, Pennsylvania; R. Pestronk, Genesee County Health Department, Michigan; K. Lokar, S. Tremonti, and L. Childers, Macomb County Public Health, Michigan; C. Bird, S. Bies, and K. Burdinie, Oakland County Health Division, Michigan; R. Potter and E. Wells, Michigan Department of Community Health, Michigan; D. Blythe, Maryland Department of Health and Mental Hygiene, Maryland; J. Butwin, C. Jones, and V. Caine, Marion County Health Department, Indiana; K. Buffin and W. Staggs, Indiana State Department of Health, Indiana; A. Siston, Chicago Department of Public Health, Illinois; C. Kilborn, D. Martinez, C. Fruthaler, U. Shah, H. Palacio, R. Obey, and M. Garza, Harris County Public Health and Environmental Services, Texas; M. Lowrey, A. Awosika-Olumo, S. Khuwaja, M. Chin, and T. Fasoranti, City of Houston Health and Human Services, Texas; T. Kram, and W. Sessions, Texas Department of State Health Services, Texas; D. Kodagoda and V. Nguyen, Los Angeles County Department of Public Health, California; M. McDonald, Orange County Health Agency, California; R. Shaikh, California Department of Public Health, California; E. Ward, Georgia Division of Public Health, Georgia; A. Ferraro, Council of State and Territorial Epidemiologists; M. Thorley, Global Immunization Division, CDC; A. Barskey, D. Payne, and E. Lopareva, Division of Viral Diseases, CDC; C. Kim, F. Averhoff, J. Thomas, S. Blumensaadt, K. Marienau, and G. Palumbo, Division of Global Migration and Quarantine, CDC.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
measles; disease outbreaks; genotype classification; travel; sports