We describe the occurrence of measles in an 18 monthold
patient in Sicily, Italy, in March 2015, who received
the first dose of a measles-containing vaccine seven
days before onset of prodromal symptoms. Measles
virus infection was confirmed by PCR and detection of
specific immunoglobulin; viral genotyping permitted
the confirmation of a vaccine-associated illness. The
patient had a concurrent influenza virus infection, during
a seasonal epidemic outbreak of influenza

Casuccio, N.

Dones, P.

D’Angelo, C.

TRAMUTO, Fabio

VITALE, Francesco

Eurosurveillance

We describe the occurrence of measles in an 18 month-old patient in Sicily, Italy, in March 2015, who received the first dose of a measles-containing vaccine seven days before onset of prodromal symptoms. Measles virus infection was confirmed by PCR and detection of specific immunoglobulin; viral genotyping permitted the confirmation of a vaccine-associated illness. The patient had a concurrent influenza virus infection, during a seasonal epidemic outbreak of influenza.
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F Tramuto

P Dones

C D’Angelo

N Casuccio

F Vitale

Crossref

Post-vaccine measles in a child with concomitant influenza, Sicily, Italy, March 2015

Archivio istituzionale della ricerca - Università di Palermo

1www.eurosurveillance.orgRapid communicationsPost-vaccine measles in a child with concomitant influenza, Sicily, Italy, March 2015F Tramuto (fabio.tramuto@unipa.it)1,2, P Dones3, C D’Angelo4, N Casuccio4, F Vitale1,21. Department of Sciences for the Health Promotion and Mother-Child Care “G. D’Alessandro” – Hygiene section, University of Palermo, Palermo, Italy2. Regional Reference Laboratory for Molecular Surveillance of Measles and Rubella, Clinical Epidemiology Unit, University Hospital “Paolo Giaccone”, Palermo, Italy3. Paediatric Infectious Disease Unit, ARNAS Ospedali Civico, Di Cristina, Benfratelli, Palermo, Italy4. Public Health, Epidemiology and Preventive Medicine Unit, Azienda Sanitaria Provinciale, Palermo, ItalyCitation style for this article: Tramuto F, Dones P, D’Angelo C, Casuccio N, Vitale F. Post-vaccine measles in a child with concomitant influenza, Sicily, Italy, March 2015. Euro Surveill. 2015;20(20):pii=21134. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=21134 Article submitted on 07 May 2015 / published on 21 May 2015We describe the occurrence of measles in an 18 month-old patient in Sicily, Italy, in March 2015, who received the first dose of a measles-containing vaccine seven days before onset of prodromal symptoms. Measles virus infection was confirmed by PCR and detection of specific immunoglobulin; viral genotyping permitted the confirmation of a vaccine-associated illness. The patient had a concurrent influenza virus infection, dur-ing a seasonal epidemic outbreak of influenza.Case descriptionIn early March 2015, measles-mumps-rubella-varicella zoster (MMRV) vaccine was administered to an appar-ently healthy 18-month-old child living in Sicily, Italy. Seven days later, the child presented to the family pae-diatrician with fever (40.1 °C), catarrhal cough, runny nose and eyelid oedema. Macular rash appeared over the body two days later, starting on the trunk and then spreading to the neck and face. By day 13, the rash was fading, but due to the persistence of symptoms, the child was admitted to a children’s hospital and reported as a possible case of vaccine-related measles to the Epidemiology Department of the Regional Public Health.The local health authority carried out an epidemiologi-cal investigation: a standard measles notification form was sent to the regional health authorities and imme-diately forwarded to the Ministry of Health and to the Infectious Diseases Epidemiology Unit of the National Institute of Health. No direct link was identified with other measles cases in the community and the fam-ily had no history of travel outside Sicily. Moreover, contact investigation revealed no household mem-bers or pre-school contacts with symptoms consistent with measles. One of the child’s parents developed influenza-like illness (ILI) symptoms (fever (> 38 °C) and cough, which lasted for three consecutive days) one day after administration of MMRV vaccine to the patient.Urine and throat swab specimens were collected from the child and submitted to the Regional Reference Laboratory in Palermo for nucleic acid-based testing for measles, mumps, rubella and varicella zoster viruses and genotyping of any detected viruses. Given that this patient with suspected vaccine-associated mea-sles developed symptoms during a seasonal epidemic outbreak of influenza viruses, and taking into account reports of morbilliform rash associated in patients with influenza B who tested negative for measles virus infection [1,2], testing was also requested for influenza and other respiratory viruses.While no viruses could be detected in the urine speci-men, measles, influenza A(H3N2) and respiratory syn-cytial viruses were detected in the throat swab.On day 17, the patient’s symptoms resolved without complications and the patient was discharged from hospital (Figure).Measles virus was detected in throat swabs taken on days 17, 19, 21 and 25, but no influenza or other res-piratory viruses were detectable in these specimens.Measles virus was not detected on day 28 from a throat swab and urine specimen. A blood sample was taken at this time for serological testing for measles, mumps, rubella and varicella zoster viruses. A time line of events is shown in the Figure.Seroconversion following MMRV immunisation was evaluated through the detection of specific measles, rubella, mumps and varicella zoster IgM and IgG anti-bodies by chemiluminescent immunoassay (CLIA) (mea-sles virus: IgM = 3.1 arbitrary units (AU)/mL, IgG > 300 2 www.eurosurveillance.orgAU/mL; mumps virus: IgM = 1.3 AU/mL, IgG = 78.9 AU/mL; rubella virus: IgM = 1.97 AU/mL, IgG = 18.0 interna-tional units (IU)/mL; varicella zoster: IgM = 0.71 AU/mL, IgG = 271.8 mIU/mL).The measles virus was determined to be the Schwarz vaccine strain, genotype A, MVs/Palermo.ITA/12.15 [A] (VAC) [3] by sequence analysis of the genome.Laboratory investigationsSerological and nucleic acid-based tests were per-formed for surveillance of measles and rubella, and genotype determination at the Regional Reference Laboratory of Palermo, formerly a member of the national network for influenza surveillance and geno-typing (INFLUNET).For the detection of specific measles, rubella, mumps and varicella zoster IgM and IgG antibodies, com-mercial CLIA tests were used (LIAISON (DiaSorin) and VITROS (Ortho Clinical Diagnostics)), which have the following cut-off values: measles IgM ≥ 1.0; measles IgG ≥ 13.5; mumps IgM ≥ 1.0; mumps IgG ≥ 10.0; rubella IgM ≥ 1.2; rubella IgG ≥ 15.0; varicella zoster IgM ≥ 1.0; varicella zoster IgG ≥ 100.0.Throat swabs and the sediment of urine samples were tested using a real-time PCR instrument (QuantStudio 7 Flex Real-Time PCR system, Applied Biosystems), using specific primer/TaqMan probe sets for measles [4], mumps [5], rubella [4] and varicella zoster [6,7] viruses after extraction of total RNA using QIAmp Viral RNA Mini Kit (Qiagen).Measles genotyping was conducted to distinguish wild-type from vaccine-associated measles viral strains. PCR products, targeting either the N gene or the H gene [8], were obtained from throat swab and sequenced using BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems).FigureTime line of symptoms and physical signs in a child with post-vaccine measles and concomitant influenza, case management, specimen collection and laboratory results, Sicily, Italy, March 2015MMRV: measles-mumps-rubella-varicella zoster; neg: negative; pos: positive. Discharged fromhospitalMolecular testing of urine sediment:Measles virus negRubella virus negMolecular testing of throat swab:Measles virus posInfluenza A(H3N2) posRespiratory syncytial virus posRubella virus negMumps virus negVaricella zoster virus negAdenovirus negParainfluenza virus 1/2/3 negMolecular testing of throat swab:Measles virus posInfluenza A(H3N2) virus negMolecular testing of throat swab and urine sediment:Measles virus negSerum immunoassay:Measles virus IgM and IgG posMumps virus IgM and IgG posRubella virus IgM and IgG posVaricella zoster virus IgM and IgG posAdministration of first dose of MMRV vaccineRapid fading of macular rash Pharynx hyperaemicSerous rhinorrhoeaCatarrhal coughRegression of macular rashPharynx hyperaemicSerous rhinorrhoeaAcute otitis mediaOnsetof macular rashRhinitisSerous rhinorrhoeaTonsillarhypertrophyEmergency room accessHospital admissionReport to the Epidemiology Departmentof Regional Public HealthOnset of fever (40.1 °C)Catarrhal coughRunny noseEyelid oedemaDay 0 7 9 13 14 17 19 21 25 283www.eurosurveillance.orgSuperScript One-Step RT-PCR kit with Platinum Taq (Invitrogen) were used for both endpoint reverse tran-scription RT-PCR and real-time RT-PCR reactions.Sequences were confirmed as measles virus following comparison with the BLAST algorithm and they were phylogenetically analysed to assign genotype and clus-ter. The sequences were identified as Schwarz vaccine strain (genotype A) and were submitted to GenBank (accession numbers KR262162 (gene N) and KR262161 (gene H)).BackgroundIn Italy, vaccination against measles is included in the national vaccination schedule. Two doses of mea-sles-mumps-rubella (MMR) vaccine have been rec-ommended in all regions since the early 1990s [9], sometimes in association with varicella vaccination. The first dose is given at 13–15 months-old and the second at the age of 5–6 years [10].In accordance with the national measles elimination plan [11], an enhanced surveillance system was intro-duced in 2007 [12] with the aim of improving timeliness, completeness of case reporting and case investigation, including laboratory confirmation of diagnosis and viral genotyping.As the incidence of wild-type measles decreases in countries with high levels of vaccination coverage, vaccine-associated cases could be misreported [13,14], suggesting that there is a need to improve the ability to distinguish between vaccine-associated measles and ‘true’ wild-type measles virus infection [15].Post-marketing surveillance of vaccines is manda-tory in Italy and adverse reactions observed after the administration of vaccines are reported through the national pharmacovigilance network. According to the latest data available [16], these are mainly represented by fever, skin rash and febrile seizures, while post-vaccination viral shedding is a very uncommon event, which has been rarely documented so far [17,18].DiscussionWith an estimated more than 500 million doses admin-istered in over 60 countries since the 1970s, the benefit of measles vaccination in preventing illness, disability and death appear unchallengeable [19,20].Moreover, vaccine safety is annually validated by accu-rate post-marketing surveillance of adverse reactions conducted by the Italian Medicines Agency (AIFA). As for other live attenuated vaccines, adverse reactions following MMR or MMRV immunisation rarely present with clinically significant illness [16]: such illness is indistinguishable from wild-type measles. In this con-text, the reference laboratory for molecular surveillance plays a fundamental role in measles virus characteri-sation, through viral sequencing and genotyping, in order to promptly differentiate between wild-type and vaccine-related strains [14,18].In this report, we documented the pharyngeal excretion of the Schwarz measles vaccine virus in an apparently healthy child with a febrile rash after measles vaccina-tion and with laboratory-confirmed influenza A(H3N2) coinfection.On the basis of our data, some points can be noted.Firstly, although unlikely, measles after MMRV vaccina-tion is possible, and this can mimic wild-type infection, leading to potential measles case misclassification. The application of molecular techniques for viral gen-otyping is helpful to correctly classify a case and to drive the decisions of public health authorities at the local level.Secondly, this is the first report of a measles case with concurrent influenza and respiratory syncyt-ial virus detection: we cannot exclude the possibility that the co-presence of other viral natural infections in a very young child, showing a slight hypogamma-globulinaemia in serum protein electrophoresis, may have favoured, or even determined, the occurrence of vaccine-related measles virus in pharyngeal secre-tions. Unfortunately, the parent showing ILI symptoms was not tested for influenza virus, making us unable to assess, although very likely, an intrafamilial transmis-sion of influenza virus infection.Notably, virus excretion was demonstrated over a 25-day period after vaccination, which is longer than previously reported [17,21,22]. Interference with other coinfecting viruses or a defective host immune response could play a role in this unexpected persis-tence of measles virus, although this hypothesis will require further investigation.Thirdly, virus excretion was repeatedly detected in the throat, but not in urine sediment. This finding partially contrasts with World Health Organization (WHO) guid-ance for laboratory diagnosis for measles virus infec-tion, which suggests to test preferentially for the virus in the sediment of urine samples that have been col-lected within at least five days after the onset of rash [23]. In the case presented here, in accordance with WHO guidance, matched urine and throat specimens were collected on the fifth day after the onset of macu-lar rash. Detection of measles virus in respiratory samples up to 16 days after the onset of rash suggests that other host cell pathways or viral mechanisms, potentially related to other concomitant viral infections, might be respon-sible for such an event. However, also in this case, fur-ther studies are necessary to better explain such an anomaly.In conclusion, development of measles in individuals who have received MMR or MMRV vaccine is a possible, 4 www.eurosurveillance.orgalthough extremely rare, event. Therefore, especially in geographical areas with a low incidence of measles, maintenance of efficient molecular surveillance sys-tems and the improvement of the timeliness of both case reporting and virus genotyping is of paramount importance, to ensure correct differentiation between vaccine-related illness and natural measles infection [24].Conflict of interestNone declared.Authors’ contributionsConceived and designed the study: FT, FV. Collected clinical and epidemiological data: PD, CD, NC. Analysed data: FT. Wrote the paper: FT, FV.References1. ProMED-mail. Influenza-associated rash - USA: CDC request for information. Archive Number: 20150318.3238651. 18 Mar 2015. Available from: http://promedmail.org2. Skowronski DM, Chambers C, Osei W, Walker J, Petric M, Naus M, et al. Case series of rash associated with influenza B in school children. Influenza Other Respi Viruses. 2015;9(1):32-7. http://dx.doi.org/10.1111/irv.12296 PMID:253820643. Measles virus nomenclature update: 2012. Wkly Epidemiol Rec. 2012;87(9):73-81. PMID:224621994. Hübschen JM, Kremer JR, De Landtsheer S, Muller CP. A multiplex TaqMan PCR assay for the detection of measles and rubella virus. J Virol Methods. 2008;149(2):246-50. http://dx.doi.org/10.1016/j.jviromet.2008.01.032 PMID:183534515. Rota JS, Rosen JB, Doll MK, McNall RJ, McGrew M, Williams N, et al. 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Post-vaccine measles in a child with concomitant influenza, Sicily, Italy, March 2015

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