Overlapping Signs and Symptoms Between Recurrent Varicella and Pityriasis rosea Gibert.

BACKGROUND: Pityriasis rosea Gibert (PRG) has features similar to those of common infectious childhood diseases, suggesting a viral cause, but no agent has been identified to date. We describe 4 children with PRG and 2 with recurrent varicella who were studied using photochronography, virology and immunology. METHODS: The 6 patients with skin rashes visited our pediatric clinic from April 2012 to May 2016. Photographs of their skin lesions were taken; blood, skin lesions, and/or nasal lavage samples were collected to detect varicella-zoster virus (VZV) DNA and antibodies; and skin tests were carried out to measure cell-mediated immunity to VZV. RESULTS: Herald patches were confirmed in 2 of 4 PRG patients. No specimen cultures were positive for infectious VZV. However, VZV-DNA was detected in skin lesions of 3 PRG patients. During the acute phase, 5 patients had IgG antibodies to VZV, and skin-test reactions were positive in 5 patients. CONCLUSIONS: IgG antibody titers to VZV at rash onset were high, suggesting that they were already rising at the appearance of the rash and that reinfection with VZV must have occurred during the prodromal stage or several weeks before rash appearance in PRG patients whose immunity had declined below the threshold. Our study suggests a new pathogenesis of PRG that might help to address incongruities of past theories on PRG sites of viral entry and replication, incubation period and variations in the clinical course of PRG from prodrome to healing.

Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection.

The mucosal immune system is the largest component of the entire immune system, having evolved to provide protection at the main sites of infectious threat: the mucosae. As SARS-CoV-2 initially infects the upper respiratory tract, its first interactions with the immune system must occur predominantly at the respiratory mucosal surfaces, during both inductive and effector phases of the response. However, almost all studies of the immune response in COVID-19 have focused exclusively on serum antibodies and systemic cell-mediated immunity including innate responses. This article proposes that there is a significant role for mucosal immunity and for secretory as well as circulating IgA antibodies in COVID-19, and that it is important to elucidate this in order to comprehend especially the asymptomatic and mild states of the infection, which appear to account for the majority of cases. Moreover, it is possible that mucosal immunity can be exploited for beneficial diagnostic, therapeutic, or prophylactic purposes.

Immunology of Human Milk and Lactation: Historical Overview.

The development of the mammary glands and the process of lactation is an integral component of mammalian evolution, and suckling has been essential for the survival of the neonates of most mammalian species. The colostrum and milk, the major products of lactation, contain a wealth of biologically active products derived from the immunologic and microbiological experiences in the maternal circulation and in the maternal mucosal surfaces. These include major immunoglobulin isotypes in the maternal circulation, secretory IgA, a variety of soluble proteins, casein, nutritional components, hormones, a large number of cellular elements and their secreted functional products (cytokines and chemokines), several peptides, lipids, polysaccharides and oligosaccharides, and a diverse spectrum of microorganisms. During the past few decades, significant new information has become available about the evolutionary biology of mammalian lactation, the functional characterization of antibody and cellular immunologic products, the role of oligosaccharides and other proteins and peptides, and about the distribution and biologic functions of the microbiome observed in human products of lactation. This workshop explores this information in some detail in a series of presentations. A brief overview of the earlier observations on the immunologic aspects of lactation is presented here, and detailed reviews of more recent observations are reported in subsequent presentations in this workshop.

Mucosal immunity to poliovirus.

The Global Polio Eradication Initiative (GPEI) currently based on use of oral poliovirus vaccine (OPV) has identified suboptimal immunogenicity of this vaccine as a major impediment to eradication, with a failure to induce protection against paralytic poliomyelitis in certain population segments in some parts of the world. The Mucosal Immunity and Poliovirus Vaccines: Impact on Wild Poliovirus Infection, Transmission and Vaccine Failure conference was organized to obtain a better understanding of the current status of global control of poliomyelitis and identify approaches to improve the immune responsiveness and effectiveness of the orally administered poliovirus vaccines in order to accelerate the global eradication of paralytic poliomyelitis.

Mucosal immunity and poliovirus vaccines: impact on wild poliovirus infection and transmission.

Since the resolution of the World Assembly in 1988 to eradicate polio globally, substantial progress toward this target has been achieved, but the final goal remains elusive. India and other tropical developing countries present a unique challenge because of the much lower oral poliovirus vaccine (OPV) immunogenicity compared to industrialized countries, both in terms of humoral and mucosal immunity. To overcome this challenge, further research is needed to elucidate the causes for the suboptimal OPV immunogenicity, better defining the optimal vaccine schedules and delivery strategies, developing and evaluating adjuvants to boost OPV immunogenicity, and improving the methods for directly measuring mucosal immunity.

Ageing and its possible impact on mucosal immune responses.

The development, structural diversification, and functional maturation of mammalian immunologic repertoire at mucosal surfaces and the systemic lymphoid tissue is a remarkably dynamic and continuous process, which begins in early fetal life and eventually culminates in variable degree of senescence or cellular death with advancing age. This brief overview will highlight the status of our current understanding of the ontogeny of mucosal immunologic response. The role of mucosal microflora and other environmental macromolecules in the regulation of mucosal immunity relative to the process of ageing will also be reviewed.

Concluding remarks. The Window of Opportunity: Pre-Pregnancy to 24 Months of Age.

This symposium focused on the window of opportunity for nutritional interventions to prevent chronic disease. Following a recommendation by the UN Standing Committee on Nutrition, 2006, the window of opportunity was defined as the period from conception to 2 years after birth. We discussed what is known and what needs to be known about (a) growth during this window, (b) critical periods of development, (c) the effects of nutrition, and (d) possible interventions to improve nutrition.

Effects of early environment on mucosal immunologic homeostasis, subsequent immune responses and disease outcome.

During the neonatal period, the mammalian host is exposed through mucosal surfaces for the first time to a plethora of environmental macromolecules and microbial agents. The neonatal mucosa is endowed with all major elements of innate and adaptive immunologic repertoire. Rudimentary Peyer's patches and mucosal lymphoid follicles expressing HLA-DR+ and CD4+ cells can be observed as early as 10-11 weeks of gestation. CD5+ and IgA+ B cells can be detected in Peyer's patches by 16-18 weeks. CD7+ CD3+ T lymphocytes have been observed in fetal Peyer's patches, epithelial surfaces as well as in the lamina propria. Interestingly, however, the early neonatal period is also characterized by a relative deficiency in antigen-presenting cell functions, altered cell-mediated immune responses, and a relative increase in apoptosis and eosinophilic responses. After birth, each human being may be colonized by over 100 trillion bacteria, representing over 500 bacterial species. The ratio of bacterial to human cells in a normal adult may exceed 10:1. The nature and the species of microflora acquired in the first few months of life is determined by many factors including, external environmental microflora, introduction of cow's milk, use of antibiotics and immunomodulatory agents, and use of breastfeeding. Recent Investigations have shown that the nature of mucosal microflora acquired in early infancy determines the outcome of mucosal inflammation and the subsequent development of mucosal disease, autoimmunity and allergic disorders later in life. It appears that altered mucosal microflora in early childhood alters signaling reactions which determine T cell differentiation and/or the induction of tolerance. Reduced Th1 and increased Th2 cytokine expression in the respiratory tract associated with increased allergic disease has been correlated with reduced exposure to microbial agents associated with Th1 responses. In contrast, reduced exposure to helminthes in the gut associated with reduced Th2 expression appears to correlate well with dominant Th1 cytokine expression and inflammatory bowel disease. These observations suggest that the nature of interaction between the external environment and the mucosal tissues in the early neonatal period and infancy may be critical in directing and controlling the expression of disease-specific responses in later life.

Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses.

BACKGROUND: Respiratory syncytial virus (RSV) and influenza virus are common causes of infantile lower respiratory tract infection (LRTI). It is widely believed that both viral replication and inappropriately enhanced immune responses contribute to disease severity. In infants, RSV LRTI is known to be more severe than influenza virus LRTI. METHODS: We compared cytokines and chemokines in secretions of infants surviving various forms of respiratory illness caused by RSV or influenza viruses, to determine which mediators were associated with more-severe illness. We analyzed lung tissue from infants with fatal cases of RSV and influenza virus LRTI to determine the types of inflammatory cells present. Autopsy tissues were studied for the lymphotoxin granzyme and the apoptosis marker caspase 3. RESULTS: Quantities of lymphocyte-derived cytokines were minimal in secretions from infants with RSV infection. Concentrations of most cytokines were greater in influenza virus, rather than RSV, infection. Lung tissues from infants with fatal RSV and influenza virus LRTI demonstrated an extensive presence of viral antigen and a near absence of CD8-positive lymphocytes and natural killer cells, with marked expression of markers of apoptosis. CONCLUSIONS: Severe infantile RSV and influenza virus LRTI is characterized by inadequate (rather than excessive) adaptive immune responses, robust viral replication, and apoptotic crisis.

A comparison of epidemiologic and immunologic features of bronchiolitis caused by influenza virus and respiratory syncytial virus.

We studied epidemiologic and immunologic factors in infants with bronchiolitis caused by influenza virus. The proportion of these infants who were male and who had an immediate family member with a history of asthma was similar to that of a control group of infants with respiratory syncytial virus (RSV) bronchiolitis. In subjects with influenza virus infection, concentrations of the beta chemokine macrophage inflammatory protein-1alpha (MIP-1alpha), but not other beta chemokines, in nasopharyngeal secretions (NPS) were greater among infants with more severe, hypoxic bronchiolitis than in subjects with mild, nonhypoxic bronchiolitis, or upper respiratory tract infection alone. Quantities of MIP-1alpha were also correlated with lower values of oxygen saturation. These findings point out epidemiologic and immunologic similarities between bronchiolitis caused by influenza and RSV, and suggest that host factors are more important than the nature of the infecting virus in the development of severe forms of bronchiolitis caused by influenza and RSV.

In vivo effects of bifidobacteria and lactoferrin on gut endotoxin concentration and mucosal immunity in Balb/c mice.

The aim of the present study was to examine the effects of oral supplementation of newborn Balb/c mice with bifidobacteria (B. infantis, B. bifidum) and iron-free apo-lactoferrin (bovine, human) on gut endotoxin concentration and mucosal immunity. Endotoxin concentration was measured in ileocecal filtrates at 7, 14, 21, and 28 days postdelivery by a quantitative limulus amebocyte lysate test. While endotoxin levels in bifidobacteria-fed mice showed a steady rise over time, they were consistently lower than that observed in control animals. Results of lactoferrin supplementation varied depending on the specific time point, but overall by day 28, all treatment groups showed lower intestinal endotoxin concentrations compared to saline fed animals. Neither bifidobacteria nor lactoferrin stimulated an increase in B or T cells, or in cytokine production (IL-6, TNF-alpha, INF-gamma), in Peyer's patches as measured by flow cytometry. Bifidobacteria and lactoferrin were well tolerated as dietary supplements and showed promising potential to reduce gut endotoxin levels.

Production of interferon gamma in respiratory syncytial virus infection of humans is not associated with interleukins 12 and 18.

In order to understand early events in the immune response to respiratory syncytial virus (RSV) infection, we studied the presence of various chemokines and cytokines in respiratory secretions of human infants with RSV infection. Interferon gamma (IFNgamma) was present in 30/39 (76.9%) subjects tested, but the IFNgamma-inducing cytokines interleukin (IL)12 and IL18 were detectable in 6/40 (15%) and 11/38 (28.9%) subjects, respectively. Quantities of IL12 and IL18 did not correlate with those of IFNgamma. IL18, but neither IFNgamma nor IL12 was found in significantly greater concentrations in subjects with mild, nonhypoxic forms of bronchiolitis than in those with upper respiratory illness alone or hypoxic bronchiolitis. The findings suggest that IFNgamma may be induced independently of the activities of IL12 and IL18 during RSV infection. Immune responses characterized by relatively greater release of IL18 may be associated with milder forms of bronchiolitis.

Respiratory syncytial virus: the virus, the disease and the immune response.

RSV is the primary cause of hospitalisation in the first year of life for children in most parts of the world, and nearly 100% of children in the USA are infected with the virus by 2 to 3 years of age. The agent is an enveloped RNA virus with a non-segmented single-stranded negative-sense genome. The viral genome encodes 8 structural and 2 non-structural proteins. Important structural proteins include the fusion (F) protein and the attachment (G) protein which are essential for viral penetration and attachment to the host cells. Both proteins are important in development of immune responses. The virus is estimated to cause 3000 to 4000 deaths annually. Primary infections are as a rule symptomatic. The spectrum of clinical manifestations ranges from mild upper tract illness, infection in middle ear which progresses to acute otitis media, croup, to apnoea in premature infants, pneumonia and bronchiolitis. Premature babies born at 30-35 weeks of gestation, infants with cyanotic congenital heart disease, HIV-infected subjects, and patients on intensive immunosuppressive therapy especially after bone marrow transplant are considered to be at risk for increased mortality and morbidity during RSV infection. The virus does not normally replicate outside of the bronchopulmonary tree and the infection is exquisitely restricted to the respiratory mucosa. However, development of extrapulmonary disease has been observed in certain T and B cell immunodeficiency states. The association of RSV with asthma and reversible reactive airway disease in early childhood has attracted significant attention. Recurrent wheezing for up to 5 to 7 years of age and established airway disease has been observed in a significant number of children with a strong family history of allergy, after primary infection or reinfection with RSV. Immune response to primary infection is relatively small but on reinfection, a significant booster effect with sustained immunologic reactivity is observed in serum and respiratory mucosa. Both CD(4)- and CD(8)-specific as well as Th(1)- and Th(2)-cell specific immune responses have been observed during human infection. In addition, proinflammatory as well as immunoregulatory cytokines and chemokines are induced in the respiratory tract after natural and induced (in vitro) infection. Significant progress has been made in understanding the role of Th(1) vs. Th(2), IgE, viral induced cytokines and chemokines in the mechanisms of pathogenesis of the disease, development of wheezing and in the prevention and treatment of the infection and its sequelae. Respiratory syncytial virus (RSV) is one of the commonest human viral infections, and virtually every child is infected by the third birthday. Because of its restricted mucosal immunopathology, and frequent association with bronchial hyperreactivity and development of wheezing, RSV has served as an important model to investigate mechanisms of mucosal immune responses and development of mucosal disease following infection. The importance of RSV in bronchopulmonary disease and development of bronchial hyperreactivity has been the focus of several recent symposia [Kimpen JL, Simoes EAF. Am J Respir Crit Care Med 2001; 163:S1-S6]. This brief report will only summarise, based on selected references, the historical landmarks of its discovery and current understanding of the mechanisms of immunity, and their possible role in the pathogenesis of bronchopulmonary disease.