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As WHO recommends vitamin A supplementation (VAS) at vaccination contacts after age 6 months, many children receive VAS together with measles vaccine (MV). We aimed to investigate the immunological effect of VAS given with MV. Within a randomised placebo-controlled trial investigating the effect on overall mortality of providing VAS with vaccines in Guinea-Bissau, we conducted an immunological sub-study of VAS v. placebo with MV, analysing leucocyte counts, whole blood in vitro cytokine production, vitamin A status and concentration of C-reactive protein (CRP). VAS compared with placebo was associated with an increased frequency of CRP≥5 mg/l (28 v. 12 %; P=0·005). Six weeks after supplementation, VAS had significant sex-differential effects on leucocyte, lymphocyte, monocyte and basophil cell counts, decreasing them in males but increasing them in females. Mainly in females, the effect of VAS on cytokine responses differed by previous VAS: in previous VAS recipients, VAS increased the pro-inflammatory and T helper cell type 1 (Th1) cytokine responses, whereas VAS decreased these responses in previously unsupplemented children. In previous VAS recipients, VAS was associated with increased IFN-γ responses to phytohaemagglutinin in females (geometric mean ratio (GMR): 3·97; 95 % CI 1·44, 10·90) but not in males (GMR 0·44; 95 % CI 0·14, 1·42); the opposite was observed in previously unsupplemented children. Our results corroborate that VAS provided with MV has immunological effects, which may depend on sex and previous VAS. VAS may increase the number of leucocytes, but also repress both the innate and lymphocyte-derived cytokine responses in females, whereas this repression may be opposite if the females have previously received VAS.

Abstract 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.

The interplay between autophagy and intracellular pathogens is intricate as autophagy is an essential cellular response to fight against infections, whereas numerous microbes have developed strategies to escape this process or even exploit it to their own benefit. The fine tuned timing and/or selective molecular pathways involved in the induction of autophagy upon infections could be the cornerstone allowing cells to either control intracellular pathogens, or be invaded by them. We report here that measles virus infection induces successive autophagy signallings in permissive cells, via distinct and uncoupled molecular pathways. Immediately upon infection, attenuated measles virus induces a first transient wave of autophagy, via a pathway involving its cellular receptor CD46 and the scaffold protein GOPC. Soon after infection, a new autophagy signalling is initiated which requires viral replication and the expression of the non-structural measles virus protein C. Strikingly, this second autophagy signalling can be sustained overtime within infected cells, independently of the expression of C, but via a third autophagy input resulting from cell-cell fusion and the formation of syncytia. Whereas this sustained autophagy signalling leads to the autophagy degradation of cellular contents, viral proteins escape from degradation. Furthermore, this autophagy flux is ultimately exploited by measles virus to limit the death of infected cells and to improve viral particle formation. Whereas CD150 dependent virulent strains of measles virus are unable to induce the early CD46/GOPC dependent autophagy wave, they induce and exploit the late and sustained autophagy. Overall, our work describes distinct molecular pathways for an induction of self-beneficial sustained autophagy by measles virus.

Background. We investigated a measles outbreak among healthcare workers (HCWs) by assessing laboratory characteristics, measles vaccine effectiveness, and serological correlates for protection. Methods. Cases were laboratory-confirmed measles in HCWs from hospital X during weeks 12-20 of 2014. We assessed cases' severity and infectiousness by using a questionnaire. We tested cases' sera for measles immunoglobulin M, immunoglobulin G, avidity, and plaque reduction neutralization (PRN). Throat swabs and oral fluid samples were tested by quantitative polymerase chain reaction. We calculated attack rates (ARs) by vaccination status and estimated measles vaccine effectiveness as 1 - [ARvaccinated/ARunvaccinated]. Results. Eight HCWs were notified as measles cases; 6 were vaccinated with measles vaccine twice, 1 was vaccinated once, and 1 was unvaccinated. All 6 twice-vaccinated cases had high avidity and PRN titers. None reported severe measles or onward transmission. Two of 4 investigated twice-vaccinated cases had pre-illness PRN titers of >120 mIU/mL. Among 106 potentially exposed HCWs, the estimated effectiveness of 2 doses of measles vaccine was 52% (95% confidence interval [CI], –207%-93%). Conclusions. Measles occurred in 6 twice-vaccinated HCWs, despite 2 having adequate pre-exposure neutralizing antibodies. None of the twice-vaccinated cases had severe measles, and none had onward transmission, consistent with laboratory findings suggesting a secondary immune response. Improving 2-dose MMR coverage among HCWs would have likely reduced the size of this outbreak.

Measles is an extremely contagious, vaccine-preventable infection that was officially declared eradicated in the US in 2000. However, measles outbreaks are increasingly occurring in the US. Measles cases have considerable morbidity requiring hospitalization, yet little is known about hospitalization and complications from measles in recent years. To analyze the frequency, predictors, costs and other outcomes of hospitalization for measles in the US. The 2002-2016 Nationwide Inpatient Sample, containing a 20% sample of US hospitalizations (n = 96,568,625), was analyzed. Measles and comorbidities were defined by International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) or ICD-10-CM codes. Multivariable survey logistic regression and linear regression models controlling for sociodemographic demographic factors were constructed to understand associations with organ-specific complications, and cost of care and length of stay, respectively. Overall, 1,018 measles hospitalizations occurred in 2002-2016, and hospitalizations increased over time. In multivariable logistic regression models, measles was associated with higher odds of gastrointestinal, hematologic, infectious, neurologic, ophthalmologic, pulmonary, and renal complications, with the strongest association observed with encephalitis (39.84 [16.51-96.12], P<0.0001). Increased length of stay (LOS) and similar cost of care (mean [95% CI]; 4.8 [4.4-5.4]; $7,438 [$6,446-$8,582]) were observed versus (vs.) all other admissions (4.5 [4.4-4.5]; P<0.01; $7,854 [$7,774-$7,935], P>0.05). There were 34 deaths in hospitalized measles patients; inpatient mortality was numerically higher in those with vs. without measles (proportion ± SEM: 3.3±1.2% vs. 2.3±0.01%, P = 0.333). Lack of outpatient or prescription data. Measles continues to pose a substantial and preventable health care burden, with serious complications, hospitalization and inpatient mortality. Further studies are needed to improve the prevention and management of measles.

Abstract Measles remains one of the most important causes of child morbidity and mortality worldwide with the greatest burden in the youngest children. Most acute measles deaths are owing to secondary infections that result from a poorly understood measles-induced suppression of immune responses. Young children are also vulnerable to late development of subacute sclerosing panencephalitis, a progressive, uniformly fatal neurologic disease caused by persistent measles virus (MeV) infection. During acute infection, the rash marks the appearance of the adaptive immune response and CD8+ T cell-mediated clearance of infectious virus. However, after clearance of infectious virus, MeV RNA persists and can be detected in blood, respiratory secretions, urine, and lymphoid tissue for many weeks to months. This prolonged period of virus clearance may help to explain measles immunosuppression and the development of lifelong immunity to re-infection, as well as occasional infection of the nervous system. Once MeV infects neurons, the virus can spread trans-synaptically and the envelope proteins needed to form infectious virus are unnecessary, accumulate mutations, and can establish persistent infection. Identification of the immune mechanisms required for the clearance of MeV RNA from multiple sites will enlighten our understanding of the development of disease owing to persistent infection. Measles is an acute virus infection that is associated with prolonged virus clearance and risk of persistent infection.

  Resolution of MV infection is associated with increased lymphoproliferation [8], [24] and enlargement of lymph nodes [13]. [...]the immune system efficiently restricts MV replication and clears MV-infected cells. Do Dendritic Dells Play a Crucial Role? DC subsets have been shown susceptible to MV infection in vitro [15]-[17] and in nonhuman primates in vivo [11], [19]. [...]it is likely that infection, depletion, or functional modulation of DCs contributes to measles-associated immune suppression.

An outbreak of measles in the Netherlands in 2013–2014 provided an opportunity to assess the effect of MMR vaccination on severity and infectiousness of measles. Measles is notifiable in the Netherlands. We used information on vaccination, hospitalisation, complications, and most likely source(s) of infection from cases notified during the outbreak. When a case was indicated as a likely source for at least one other notified case, we defined it as infectious. We estimated the age-adjusted effect of vaccination on severity and infectiousness with logistic regression. Of 2676 notified cases, 2539 (94.9%) were unvaccinated, 121 (4.5%) were once-vaccinated and 16 (0.6%) were at least twice-vaccinated; 328 (12.3%) cases were reported to have complications and 172 (6.4%) cases were hospitalised. Measles in twice-vaccinated cases led less often to complications and/or hospitalisation than measles in unvaccinated cases (0% and 14.5%, respectively, aOR 0.1 (95% CI 0–0.89), 𝑃 = 0.03). Of unvaccinated, once-vaccinated and twice-vaccinated cases, respectively, 194 (7.6%), seven (5.1%) and 0 (0%) were infectious. These differences were not statistically significant (𝑃 > 0.05). Our findings suggest a protective effect of vaccination on the occurrence of complications and/or hospitalisation as a result of measles and support the WHO recommendation of a two-dose MMR vaccination schedule.

Measles is characterized by fever and a maculopapular skin rash, which is accompanied by immune clearance of measles virus (MV)-infected cells. Histopathological analyses of skin biopsies from humans and non-human primates (NHPs) with measles rash have identified MV-infected keratinocytes and mononuclear cells in the epidermis, around hair follicles and near sebaceous glands. Here, we address the pathogenesis of measles skin rash by combining data from experimentally infected NHPs, ex vivo infection of human skin sheets and in vitro infection of primary human keratinocytes. Analysis of NHP skin samples collected at different time points following MV inoculation demonstrated that infection in the skin precedes onset of rash by several days. MV infection was detected in lymphoid and myeloid cells in the dermis before dissemination to the epidermal leukocytes and keratinocytes. These data were in good concordance with ex vivo MV infections of human skin sheets, in which dermal cells were more targeted than the epidermal cells. To address viral dissemination to the epidermis and to determine whether the dissemination is receptor-dependent, we performed experimental infections of primary keratinocytes collected from healthy donors. These experiments demonstrated that MV infection of keratinocytes is mainly nectin-4-dependent, and differentiated keratinocytes, which express higher levels of nectin-4, are more susceptible to MV infection than proliferating keratinocytes. Based on these data, we propose a model to explain measles skin rash: migrating MV-infected lymphocytes initiate the infection of dermal skin-resident CD150+ immune cells. The infection is subsequently disseminated from the dermal papillae to nectin-4+ keratinocytes in the basal epidermis. Lateral spread of MV infection is observed in the superficial epidermis, most likely due to the higher level of nectin-4 expression on differentiated keratinocytes. Finally, MV-infected cells are cleared by infiltrating immune cells, causing hyperemia and edema, which give the appearance of morbilliform skin rash.

Measles inclusion-body encephalitis (MIBE) is rare, with insights largely from case studies. We systematically analyzed subacute Sclerosing Panencephalitis (SSPE) cases in immunocompromised patients, identifying distinctive clinical and neuroimaging features. These findings could facilitate MIBE diagnosis without the need for brain biopsies. Our systematic review on MIBE and HIV-related SSPE adhered to PRISMA guidelines and was registered with PROSPERO. We searched multiple databases and followed a detailed inclusion process with independent reviews and quality assessment. Data on patient demographics, clinical features, and outcomes were compiled. A review of 39 studies on 49 MIBE patients and 8 reports on HIV-positive SSPE patients was conducted. Acute lymphoblastic leukemia, HIV, organ transplants, and malignancies were common precursors to MIBE. Perinatal HIV was prevalent among SSPE cases. Seizures were the primary symptom in MIBE, often drug-resistant and progressing to status epilepticus or epilepsia partialis continua, whereas periodic myoclonus was universal in SSPE. Neuroimaging showed distinct patterns for each group, and histopathology confirmed measles virus presence in 39% of MIBE cases. MIBE patients typically progressed to coma and death. In conclusion, MIBE and SSPE in HIV-infected patients present with distinct clinical pictures but identical brain pathological abnormalities.