The Reemergence of Measles.

OBJECTIVES: Present-day pathologists may be unfamiliar with the histopathologic features of measles, which is a reemerging disease. Awareness of these features may enable early diagnosis of measles in unsuspected cases, including those with an atypical presentation. Using archived tissue samples from historic patients, a unique source of histopathologic information about measles and other reemerging infectious diseases, we performed a comprehensive analysis of the histopathologic features of measles seen in commonly infected tissues during prodrome, active, and late phases of the disease. METHODS: Subspecialty pathologists analyzed H&E-stained slides of specimens from 89 patients accessioned from 1919 to 1998 and correlated the histopathologic findings with clinical data. RESULTS: Measles caused acute and chronic histopathologic changes, especially in the respiratory, lymphoid (including appendix and tonsils), and central nervous systems. Bacterial infections in lung and other organs contributed significantly to adverse outcomes, especially in immunocompromised patients. CONCLUSIONS: Certain histopathologic features, especially Warthin-Finkeldey cells and multinucleated giant cells without inclusions, allow pathologists to diagnose or suggest the diagnosis of measles in unsuspected cases.

Enfermedades exantemáticas virales: aspectos clinicoepidemiológicos y de laboratorio / Exanthematous viral diseases: clinical and laboratory aspects

Los cuadros exantemáticos tienen frecuentemente origen infeccioso; los virus son una causa importante de exantema. Los exantemas más relevantes son, entre los maculopapulosos, el sarampión, la rubéola, el eritema infeccioso y el exantema súbito y, entre los vesiculoampollosos, la varicela, el zóster y la enfermedad boca-mano-pie. Algunas de las anteriores, y otras infecciones virales, causan exantemas purpúricos que pueden ser de mayor gravedad. El diagnóstico de laboratorio se realiza de forma directa, mediante el aislamiento, la detección de antígenos o la detección del ácido nucleico viral, siendo esta última la aproximación más adecuada; o, serológicamente, por detección de IgM específica, que proporciona diagnóstico temprano, o de seroconversión. En general, ambas herramientas metodológicas se complementan para mejorar el rendimiento diagnóstico. La caracterización molecular es una importante actividad de laboratorio, especialmente para los virus del sarampión y de la rubéola, en el contexto del plan de eliminación de estas enfermedades (AU)

Exanthematous diseases frequently have an infectious origin; viruses are a major cause of rashes. The most notable maculopapular rashes are measles, rubella, infectious erythema and exanthem subitum, while the vesicular rashes include varicella (and zoster) and hand-foot-and-mouth disease. Some of the above and other viral infections cause purpuric rashes, which may be more severe. Laboratory diagnosis is performed directly, by viral isolation, antigen detection or viral nucleic acid detection, the latter being the best approach; or serologically, by detection of specific IgM (providing rapid diagnosis) or seroconversion. Both methodological tools generally complement each other to improve diagnostic performance. Molecular characterization is an important laboratory procedure, especially for the measles and rubella viruses, in the context of the plan for the elimination of these diseases (AU)

Vigilancia microbiológica del sarampión y la rubéola en España. Red de laboratorios / Microbiological surveillance of measles and rubella in Spain. Laboratory network

El laboratorio es un elemento imprescindible en la vigilancia del sarampión y la rubéola, ya que los casos han de ser adecuadamente confirmados para poder estimar la incidencia de forma precisa, las cepas han de ser caracterizadas genéticamente para conocer el patrón de circulación de los virus y estudiar de forma completa los brotes y las cadenas de transmisión y la susceptibilidad de la población debe de ser determinada mediante encuestas de seroprevalencia. El diagnóstico de laboratorio de las infecciones agudas por estos agentes se basa en la detección de la respuesta inmune específica de clase IgM, que debe de complementarse con la detección del genoma del virus en exudado faríngeo y/u orina para poder alcanzar un rendimiento diagnóstico óptimo, especialmente si la recogida de las muestras es muy temprana. El genotipado de la cepa se realiza por secuenciación genómica de acuerdo a protocolos de referencia de la OMS. La vigilancia de laboratorio de sarampión y rubéola en España se estructura en forma de red, con laboratorios autonómicos de capacidades diferentes y un Laboratorio Nacional de Referencia (LNR), que es el Centro Nacional de Microbiología, que garantiza la disponibilidad de las técnicas en todo el territorio nacional, vela por la calidad de los resultados y representa a la Red Nacional en la Red Europea de laboratorios. El LNR está actualmente implantando nuevas herramientas de caracterización molecular basadas en regiones hipervariables del genoma para la caracterización de las cepas a nivel subgenotípico y su aplicación a la vigilancia (AU)

The Laboratory is a fundamental component on the surveillance of measles and rubella. Cases need to be properly confirmed to ensure an accurate estimation of the incidence. Strains should be genetically characterized to know the transmission pattern of these viruses and frequently, outbreaks and transmission chains can be totally discriminated only after that. Finally, the susceptibility of the population is estimated on the basis of sero-prevalence surveys. Detection of specific IgM response is the base of the laboratory diagnosis of these diseases. It should be completed with genomic detection by RT-PCR to reach an optimal efficiency, especially when sampling is performed early in the course of the disease. Genotyping is performed by genomic sequencing according to reference protocols of the WHO. Laboratory surveillance of measles and rubella in Spain is organized as a net of regional laboratories with different capabilities. The National Center of Microbiology as National Reference Laboratory (NRL), supports regional laboratories ensuring the availability of all required techniques in the whole country and watching for the quality of the results. The NRL is currently working in the implementation of new molecular techniques based on the analysis of genomic hypervariable regions for the strain characterization at sub-genotypic levels and use them in the surveillance (AU)

Level of immunization coverage and associated factors among children aged 12-23 months in Lay Armachiho District, North Gondar Zone, Northwest Ethiopia: a community based cross sectional study.

BACKGROUND: Immunization against childhood disease is one of the most important public health interventions with cost effective means to preventing childhood morbidity, mortality and disability. However, complete immunization coverage remains low particularly in rural areas of Ethiopia. This study aimed to assess the level of immunization coverage and associated factors in Lay Armachiho District, North Gondar zone, Northwest Ethiopia. A community based cross-sectional study was conducted in March, 2014 among 751 pairs of mothers to children aged 12-23 months in Lay Armachiho District. A two stage sampling technique was employed. Logistic regression analysis was carried out to compute association between factors and immunization status of children. Backwards stepwise regression method was used and those variables significant at p value 0.05 were considered statistically significant. RESULTS: Seventy-six percent of the children were fully immunized during the study period. Dropout rate was 6.5% for BCG to measles, 2.7% for Penta1 to Penta3 and 4.5% for Pnemonia1 to Pnemonia3. The likelihood of children to be fully immunized among mothers who identified the number of sessions needed for vaccination were higher than those who did not [AOR = 2.8 (95% C1 = 1.89, 4.2)]. Full immunization status of children was higher among mothers who know the age at which the child become fully immunized than who did not know [AOR = 2.93 (95% CI = 2.02, 4.3)]. Taking tetanus toxoid immunization during pregnancy showed statistically significant association with full immunization of children [AOR 1.6 (95% CI = 1.06, 2.62)]. Urban children were more likely to be fully immunized than rural [AOR = 1.82 (95% CI = 1.15, 2.80)] and being male were more likely to be fully immunized than female [AOR = 1.80 (95% CI = 1.26, 2.6)]. CONCLUSION AND RECOMMENDATION: Vaccination coverage was low compared to the Millennium Development Goals target. It is important to increase and maintain the immunization level to the intended target. Efforts should be made to promote women's' awareness on tetanus toxoid immunization, when the child should start vaccination, number of sessions needed to complete immunization, and when a child become complete vaccination to improve immunization coverage through health development army and health professionals working at antenatal care, postnatal care and immunization units.

Resurgence of measles in a country of elimination: interim assessment and current control measures in the Republic of Korea in early 2014.

Since the beginning of 2014, the Republic of Korea has experienced a resurgence of measles cases. Among the 220 cases confirmed as measles during epidemiological weeks 1-20 (December 29, 2013 to May 17, 2014), 10 imported cases were identified. The predominant genotype was B3, which reflects the circulating measles virus in adjacent countries. Even with the verification of measles elimination in March 2014 by the World Health Organization, recent importation has been related to international travel. Targeted control measures have been implemented in addition to proper isolation and patient care. A vigilant surveillance system and high levels of vaccine coverage should be maintained to sustain the measles elimination status.

Brote de 22 casos de sarampión autóctono en la zona norte de Madrid / Outbreak of measles in the population of Spanish origin in North Madrid

Tras estar prácticamente erradicado en Europa, en los últimos 3 años han aparecido miles de casos de sarampión autóctono. Se describen los casos ocurridos en la zona norte de Madrid (enero-junio de 2011).Se informa de 22 casos, 18 de ellos agrupados en 2 brotes (2 escuelas infantiles). La tasa de ataque del principal fue del 29%.Todos fueron en pacientes no vacunados (mediana=14 meses). El genotipo predominante fue el D4 (95%). Hubo un 45% de complicaciones y un 45% de ingresos. El Servicio de Salud Pública recomendó aislar a los casos y vacunó anticipadamente a los contactos susceptibles. En los centros sanitarios se estableció un circuito específico para atender a los casos sospechosos. Se ha adelantado la vacunación triple vírica de los 15 a los 12 meses en la Comunidad de Madrid. El sarampión es una enfermedad re-emergente en Europa. El manejo coordinado entre Salud Pública y los centros asistenciales es fundamental para limitar los brotes(AU)

After being virtually eradicated in Europe, thousands of cases of measles in the population of Spanish origin have appeared in the last 3 years. We describe the cases diagnosed in the north of Madrid between January and June 2011. A total of 22 cases are reported, 18 of them grouped in 2 outbreaks (2 nurseries). The primary attack rate was 29% in the main outbreak. All cases were in unvaccinated patients (median = 14 months). Genotype D4 was predominant (95%). There was a 45% complication rate and 45% were admitted to hospitals. The Public Health Service recommended isolating cases and vaccinating susceptible contacts in advance. Health Centres established a specific protocol to respond to suspected cases. The Measles vaccination has been brought forward from 15 to 12 months in Madrid. Measles is a re-emerging disease in Europe. The coordinated management between public health and health facilities is essential to limiting outbreaks(AU)

[Clinical value of CD64 expression in adults with measles complicating bacterial pneumonia].

OBJECTIVE: To study the clinical value of expression of peripheral blood neutrophil CD64 in adults with measles complicating pneumonia. METHODS: 106 patients were divided into two groups by clinical manifestation and bacteria study: measles complicating bacterial pneumonia group and measles complicating viral pneumonia, using flow cytometry determination of CD64, C-reactive protein (CRP) and white blood cell (WBC) count. RESULTS: The expression of CD64 in the bacterial pneumonia group with eruptive stage was (32.15 +/- 11.07) MFI, which was significantly higher than that in the group of with recovery stage (10.6 +/- 3.23) MFI (P < 0.01) and viral pneumonia (9.55 +/- 3.48) MFI (P < 0.01). These markers were considered positive if CD64 > or = 8.5 MFI, CRP > or = 10 mg/L and WBC > or = 9.05 x 10(9)/L. Their sensitivity was 78.12%, 80.48% and 59.37%. Their specificity was 76.19% ,67.67% and 64.28%. Their accuracy rate was 77.35%, 74.52%, 61.32%; CD64 has a positive relationship with CRP. CONCLUSION: Compared to CRP, expression of peripheral blood neutrophil CD64 can be a better marker in the early diagnosis of patients with measles complicating bacterial pneumonia and as one of the indicators of disease conditions.

Rubella and measles seroprevalence among women of childbearing age, Argentina, 2002.

To assess rubella and measles susceptibility among women of childbearing age we conducted a cross-sectional seroprevalence study in four cities and one rural area in Argentina. A convenience sample of women aged 15-49 years seeking care in public health-care institutions was selected (n=2804). Serum specimens were tested for rubella and measles IgG antibody titres. The overall susceptibility to rubella and measles was 8.8 and 12.5% respectively. Seroprevalence differences were found for both rubella (P<0.001) and measles (P=0.002) across sites. Rubella seroprevalence was higher in women aged >or=40 years than in younger women (P=0.04). Measles seroprevalence tended to increase with age (P<0.001). Approximately 15% of women aged 15-29 years were not immune to measles. No risk factors were associated with rubella seronegativity; however, age (P<0.001) and having less than four pregnancies (P<0.001) were factors associated with measles seronegativity. Our findings support the introduction of supplemental immunization activities targeting adolescents and young adults to prevent congenital rubella syndrome and measles outbreaks over time.

Severe measles in a young female patient with chronic, generalized Trichophyton rubrum infection showing type 2 helper T cell-dominant immunologic reactivity.

An obese 18-year-old girl without a history of atopic dermatitis or a systemic immunosuppressive disorder had severe measles with liver dysfunction and pneumonia. For the previous 3 years she had had a chronic untreated generalized Trichophyton rubrum infection. The rash of the measles tended to spare the fungal lesions, where numerous fungi grew in the stratum corneum. Serum IgE level was markedly elevated (>16,000 IU/mL) and decreased after effective antifungal therapy. Delayed skin hypersensitivity reactions to trichophytin and tuberculin were negative, but the immediate skin hypersensitivity to trichophytin was positive. These data indicate that the patient had acquired hyperproduction of IgE with suppression of cell-mediated immunity, that is, acquired impairment of the balance between type 1 and type 2 helper T cells. In this case, chronic T rubrum infection was thought to have a role in driving a normal balance between type 1 and type 2 helper T cells toward type 2 helper T cell-dominant immunity. The result was deterioration of the measles infection and prolongation of the dermatophytosis.

Novel measles virus genotype, East Timor and Australia.

Measles outbreaks in 1999 in Queensland and Victoria, Australia, were caused by a novel strain of clade G virus (proposed name g3). Epidemiologic and molecular evidence supports independent circulation of this virus in Queensland, northern Australia, in addition to importation of the virus by East Timor refugees seeking safe haven in Australia.

[Specific features of the epidemic process of measles and epidemic parotitis in territories with ecologically unfavorable conditions]. / Osobennosti épidemicheskogo protsessa pri kori i épidemicheskom parotite na ékologocheski neblagopoluchnykh territoriiakh.

Differences in the epidemic process of measles and epidemic parotitis in cities situated at territories with ecologically unfavorable conditions have been established. The intensity of the epidemic process of measles and epidemic parotitis is higher in those cities where a higher total level of pollution has been established. A high level of morbidity in these infections is due to disturbances in the immunological resistance of children living in such cities and, as a consequence, having insufficient postvaccinal immunity. A higher percentage of seronegative children among those immunized against the corresponding infections and a higher morbidity level among this category of the population have been established. To decrease morbidity in measles and epidemic parotitis to the level, sporadic for such cities, a greater coverage of children with immunization (up to 99-99.5%) is necessary.

Viral replication and development of specific immunity in macaques after infection with different measles virus strains.

Cynomolgus monkeys (Macaca fascicularis) were experimentally infected with a wild type measles virus (MV) strain (MV-BIL). Following intratracheal inoculation with different infectious doses, the virus could be isolated from peripheral blood mononuclear cells (PBMC), lung lavage cells, and pharyngeal cells. The kinetics of the cell-associated viremia was similar in all infected animals. They developed specific serum IgM, IgG, and neutralizing antibody responses as well as MV-specific T cell-mediated immunity. Monkeys infected intratracheally or intramuscularly with the wild type MV-Edmonston or the attenuated MV-Schwartz strain showed a lower level of PBMC-associated viremia and less pronounced specific IgM responses. Nine months after infection with MV strains, all of the monkeys were protected from intratracheal reinfection with MV-BIL. This monkey model is suitable for study of new generations of vaccines and vaccination strategies for measles.

Measles virus-specific functional antibody responses and viremia during acute measles.

Antibody titers measured in functional and immunofluorescent assays were compared with proportions of peripheral blood mononuclear cells infected with measles virus in 8 adults with measles. In addition, a syncytium inhibition assay (SIA) for measuring neutralizing antibody using low-passage virus was compared with a standard plaque neutralization test (PNT). Antibody-dependent cellular cytotoxicity (ADCC) antibody rose later but attained higher titer than neutralizing, antibody-dependent complement-mediated lysis, IgM, or IgG antibodies. When titer changes between specimens from each patient obtained on different days were compared, only ADCC (r = .81, P = .026) and IgM (r = .81, P = .027) antibodies correlated with reductions in viremia. SIA and PNT correlated well (r = .93, P < .001). ADCC may be an important defense against measles. The delay in ADCC antibody relative to other antibodies is unique among viruses studied. The SIA is a useful alternative to the PNT for measuring measles neutralizing antibody.

Transcription inhibition and other properties of matrix proteins expressed by M genes cloned from measles viruses and diseased human brain tissue.

Ribonucleoprotein (RNP) cores extracted from virions of wild-type (Edmonston strain) measles virus (MV) or obtained from MV-infected cells (cRNP) were shown to be capable of transcribing RNA in vitro but at relatively low efficiency. The tightly bound matrix (M) protein could be effectively removed from virion RNP (vRNP) and from cRNP by exposure to buffers of high ionic strength (0.5 to 1.0 M KCl) but only at pH 8.0 or higher. The vRNP and cRNP cores complexed with M protein exhibited markedly reduced transcriptional activity at increasing concentrations, whereas vRNP and cRNP cores free of M protein exhibited linear and substantially higher transcriptional activity; these data suggest that M protein is the endogenous inhibitor of MV RNP transcription. M-gene cDNA clones derived from three strains of wild-type (wt) MV and 10 clones from mRNAs isolated from the brain tissue of patients who had died from subacute sclerosing panencephalitis (SSPE) and from measles inclusion body encephalitis (MIBE) were recloned in the pTM-1 expression vector driven by the bacteriophage T7 RNA polymerase expressed by a coinfecting vaccinia virus recombinant. All 10 mutant SSPE and MIBE clones expressed in vitro and in vivo M proteins that reacted with monospecific anti-M polyclonal antibody and migrated on polyacrylamide gels to positions identical to or only slightly different from those of the M proteins expressed by wt MV clones. When reconstituted with cRNP cores, the three expressed wt M proteins and 6 of the 10 mutant-expressed M proteins showed equivalent capacity to down-regulate MV transcription. Three of the M proteins from SSPE clones and one from the MIBE clone showed little or no capacity to down-regulate transcription when reconstituted with cRNP cores. The only plausible explanations for loss of transcription inhibition activity by the four SSPE/MIBE M proteins were exceedingly high degrees of hypermutations leading to U-->C transitions and cloning-corrected mutations in the initiator codon (ATG-->ACG) of the four M genes. However, only the hypermutated M protein expressed by the MIBE cDNA clone exhibited virtually no capacity to bind cRNP cores in a reconstitution assay. These experiments provide some preliminary data to support the hypothesis that MV encephalitis may result from certain selective mutations in the M gene.

Detection of measles virus from clinical samples using the polymerase chain reaction.

OBJECTIVE: To evaluate the usefulness of the polymerase chain reaction to detect the measles virus sequence using clinical samples. DESIGN: Centers for Disease Control and Prevention case definition of measles with or without IgM serology as a standard. SETTING: A laboratory in the Department of Pediatrics of the Hokkaido University Hospital, Sapporo, Japan. PATIENTS: Thirty-two serum samples, 16 throat swab samples, and nine cerebrospinal fluid samples from 32 patients with measles, including four patients with central nervous system involvement, and one serum sample and two throat swab samples from two patients with modified courses of measles were obtained. Ten serum samples, 10 throat swab samples, and 10 cerebrospinal fluid samples were obtained from patients without apparent measles infection as negative controls. MEASUREMENTS AND MAIN RESULTS: Sensitivity and specificity were comparable with those as obtained by culture or other methods reported in the literature. The polymerase chain reaction was positive in 24 (75.0%) of 32 by serum samples and in 13 (81.3%) of 16 by throat swab samples from the patients with measles, in contrast to none within the negative control group. In three of the four patients with central nervous system involvement, the measles virus sequence was detected in cerebrospinal fluid samples obtained within 1 day following the onset of the manifestations. All three samples from the patients with modified measles yielded positive results. CONCLUSIONS: The polymerase chain reaction can be used with sufficient sensitivity and specificity to detect the measles virus sequence using clinical samples. Transient and direct invasion of the central nervous system by this virus at the initial stage of the central nervous system involvement was strongly suggested.

Increased brain quinolinic acid production in mice infected with a hamster neurotropic measles virus.

In order to examine the status of quinolinic acid (QUIN) metabolism in a model of delayed excitotoxic neurodegeneration, the de novo production of QUIN from 3-hydroxyanthranilic acid was assessed in brain homogenates and brain slices of mice injected with hamster neurotropic measles virus. In the hippocampus, which presents exclusive nerve cell loss in this model, the activity of 3-hydroxyanthranilic acid oxygenase, an astrocytic enzyme responsible for the biosynthesis of QUIN, was increased 3.3-fold by 7 days after virus inoculation. Less dramatic increases were observed in the cerebral cortex and the striatum, while cerebellar enzyme activity was not different from control values. In the same brain homogenates, no changes occurred in the activities of kynurenine aminotransferase, the biosynthetic enzyme of the neuroprotectant kynurenic acid, and of the astrocytic marker glutamine synthetase. At 7 days postinoculation, hippocampal slices from virus-treated animals, when exposed to 3-hydroxyanthranilic acid, produced 18 times more QUIN than slices from control animals. Notably, a significant increase was also seen 3 days postinoculation, i.e., at a time when astrocytes had started to proliferate but prior to the onset of neurodegeneration (Eur. J. Neurosci. 3:66-71, 1991). These data suggest that astrocyte-derived QUIN may play a causative role in the occurrence of hippocampal nerve cell loss in measles virus-infected mice.

Laboratory diagnosis of measles infection and monitoring of measles immunization: memorandum from a WHO meeting.

Measles infection continues to be a major global health problem, and in many countries the disease is frequently diagnosed on clinical grounds alone, although it is easily confused with other conditions. In order to discuss approaches to improving this situation, a WHO Consultation on Laboratory Diagnosis of Measles Infection and Monitoring of Measles Immunization was held in Glasgow on 7-8 August 1993. The discussions and recommendations made by the participants are summarized in this Memorandum.

PIP: Measles infection remains a major global health problem. Although it may be easily confused with other conditions, the disease is frequently diagnosed in many countries on clinical grounds alone. A World Health Organization Consultation on Laboratory Diagnosis of Measles Infection and Monitoring of Measles Immunization was held in Glasgow August 7-8, 1993, to discuss ways to improve the situation. This brief summarizes the discussions and recommendations made by the participants. It is recommended that since only limited efforts have been made in recent years to develop tools for the diagnosis and surveillance of measles virus infection, focus should be given to techniques for the rapid diagnosis of measles using inexpensive techniques and technologies currently employed in other immunological and molecular diagnostic methods, with priority given to assay systems which determine parameters associated with current and recent infection; an international network of laboratories involved in the diagnosis and surveillance of measles should be established; and to evaluate next-generation diagnostic tools and establish criteria for their use, panels of serum samples should be established from individuals with a well-defined history of vaccination and/or wild-type measles virus infection. A bank of clinical specimens from monkeys experimentally infected or vaccinated with different measles viruses should also be established. Ongoing efforts will require a sound financial base. The proposed laboratory network is described, followed by sections on the laboratory diagnosis of measles in clinical materials, the direct detection of measles virus antigens in clinical specimens, and the detection of specific nucleic acids.