Stephanie Gilbertson-White

Developmental cytokine response profiles and the clinical and immunologic expression of atopy during the first year of life

BACKGROUND Allergic diseases have been linked to abnormal patterns of immune development, and this has stimulated efforts to define the precise patterns of cytokine dysregulation that are associated with specific atopic phenotypes. OBJECTIVE Cytokine-response profiles were prospectively analyzed over the first year of life and compared with the clinical and immunologic expressions of atopy. METHODS Umbilical cord and 1-year PBMCs were obtained from 285 subjects from allergic families. PHA-stimulated cytokine-response profiles (IL-5, IL-10, IL-13, and IFN-gamma) were compared with blood eosinophil counts and total and specific IgE levels (dust mites, cat, egg, Alternaria species, peanut, milk, and dog) at age 1 year and at the development of atopic dermatitis and food allergy. RESULTS For the cohort as a whole, cytokine responses did not evolve according to a strict TH1 or TH2 polarization pattern. PHA-stimulated cord blood cells secreted low levels of IL-5 (2.1 pg/mL), moderate levels of IFN-gamma (57.4 pg/mL), and greater amounts of IL-13 (281.8 pg/mL). From birth to 1 year, IL-5 responses dramatically increased, whereas IL-13 and IFN-gamma responses significantly decreased. Reduced cord blood secretion of IL-10 and IFN-gamma was associated with subsequent sensitization to egg. In addition, there was evidence of TH2 polarization (increased IL-5 and IL-13 levels) associated with blood eosinophilia and increased total IgE levels by age 1 year. CONCLUSION These findings demonstrate that cytokine responses change markedly during the first year of life and provide further evidence of a close relationship between TH2 skewing of immune responses and the incidence of atopic manifestations in children.

Relationships among specific viral pathogens, virus-induced interleukin-8, and respiratory symptoms in infancy.

Both virus‐mediated damage to airway tissues and induction of pro‐inflammatory cytokines such as interleukin‐8 (IL‐8) could contribute to symptom severity during viral respiratory infections in children. To test the hypothesis that IL‐8 contributes to the pathogenesis of respiratory symptoms during naturally acquired respiratory viral infections in children, nasal wash samples collected from infants with acute viral infections (n = 198) or from healthy uninfected infants (n = 31) were analysed for IL‐8. Nasal wash IL‐8 was positively related to age in uninfected children (rs = 0.36, p < 0.05). Respiratory syncytial virus (RSV) infection caused more severe respiratory symptoms compared to infections with influenza A, parainfluenza viruses, or rhinoviruses. In addition, RSV, parainfluenza and rhinovirus infections increased levels of IL‐8 in nasal lavage fluid, and there were some differences in the ability of the viruses to induce IL‐8 production (RSV>influenza, p < 0.05). Finally, there were significant correlations between nasal wash IL‐8 levels and symptom scores during infections with rhinovirus (rs = 0.56, p < 0.001) or influenza A (rs = 0.45, p < 0.05), but not with parainfluenza virus or RSV. These findings provide evidence of a close relationship between the generation of IL‐8 and symptoms during acute community‐acquired infections with rhinovirus or influenza A. In contrast, for RSV and parainfluenza infections, factors in addition to IL‐8 production appear to contribute to the generation of clinical symptoms.

A review of the literature on multiple symptoms, their predictors, and associated outcomes in patients with advanced cancer

OBJECTIVE The findings from several studies suggest that palliative care patients with advanced cancer experience multiple symptoms, and that these symptoms may be related to demographic and clinical factors as well as to patient outcomes. However, no systematic review has summarized the findings from studies that assessed multiple symptoms, predictors, and outcomes in these patients. The purposes of this review, focused on palliative care patients with advanced cancer, are to: 1) describe the relationships among multiple symptoms; 2) describe the predictors of multiple symptoms; and 3) describe the relationships between multiple symptoms and patient outcomes. METHOD Comprehensive literature searches were completed using the following databases: PubMed, Cumulative Index to Nursing and Allied Health Literature, and PsychInfo. The key words: cancer or advanced cancer or neoplasm, AND palliative care or terminal care or hospice or end-of-life, AND symptoms or multiple symptoms or symptom clusters were combined. RESULTS Twenty-two studies met the inclusion criteria and examined at least one of our purposes. The majority of these studies were descriptive and used one of four common symptom assessment scales. Fifty-six different signs and symptoms were evaluated across various dimensions (i.e., prevalence, severity, distress, frequency, control). Pain, dyspnea, and nausea were the only symptoms measured in all 22 studies. Relationships among concurrent symptoms were examined in nine studies. Relationships among symptoms and predictors (i.e., demographics, cancer type, healthcare delivery environment) were examined in seven studies. Relationships among symptoms and outcomes (i.e., functional status, psychological status, quality-of-life, survival time) were examined in 14 studies. Significant methodological variation was found among these studies. SIGNIFICANCE OF RESULTS It is difficult to draw conclusions about the relationships among multiple symptoms, predictors, and outcomes due to the heterogeneity of these studies. Future research is needed to determine which symptoms and symptom dimensions to assess in order to better understand how multiple symptoms relate to each other as well to as predictors and outcomes in palliative care patients with advanced cancer.

Viral infections, cytokine dysregulation and the origins of childhood asthma and allergic diseases.

Background: The origins of asthma and allergic disease begin in early life for many individuals. It is vital to understand the factors and/or events leading to their development. Methods: The Childhood Origins of Asthma project evaluated children at high risk for asthma to study the relationships among viral infections, environmental factors, immune dysregulation, genetic factors, and the development of atopic diseases. Consequently wheezing illnesses, viral respiratory pathogen identification, and in vitro cytokine response profiles were comprehensively evaluated from birth to 3 years of age, and associations of the observed phenotypes with genetic polymorphisms were investigated. Results: For the entire cohort, cytokine responses did not develop according to a strict T helper cell 1 or T helper cell 2 polarization pattern during infancy. Increased cord blood mononuclear cell phytohemagglutin-induced interferon-γ responses of mononuclear cells were associated with decreased numbers of moderate to severe viral infections during infancy, especially among subjects with the greatest exposure to other children. In support of the hygiene hypothesis, an increased frequency of viral infections in infancy resulted in increased mitogen-induced interferon-γ responses at 1 year of age. First year wheezing illnesses caused by respiratory viral infection were the strongest predictor of subsequent third year wheezing. Also, genotypic variation interacting with environmental factors, including day care, was associated with clinical and immunologic phenotypes that may precede the development of asthma. Conclusions: Associations between clinical wheezing, viral identification, specific cytokine responses and genetic variation provide insight into the immunopathogenesis of childhood asthma and allergic diseases.

Methodologic issues in the measurement of cytokines to elucidate the biological basis for cancer symptoms

Multiple concurrent symptoms are highly prevalent in patients with cancer. However, little is known about the relationships among these symptoms and their underlying mechanisms. A number of cytokines that are involved in the development of sickness behavior are hypothesized to be a mechanism for symptom clusters. Measurement of these cytokines would provide valuable information that could be used to elucidate mechanisms underlying the development of symptom clusters and the identification of potential targets for intervention studies. In this article, the authors explore several issues that warrant careful consideration when designing a research study involving the use of a cytokine as a biomarker in symptom cluster research. These issues include which molecules to measure, which specimens to collect, the timing of specimen collection and processing, and which technologies to use to measure the biomarker and the sensitivity and specificity of the assay system. The article begins with a brief discussion of cytokines and sickness behavior and the role of the cytokines in cancer-related symptoms.

Determination of Cutpoints for Low and High Number of Symptoms in Patients with Advanced Cancer

While patients with advanced cancer experience a wide range of symptoms, no work has been done to determine an optimal cutpoint for a low versus a high number of symptoms. Analytic approaches that established clinically meaningful cutpoints for the severity of cancer pain and fatigue provided the foundation for this study. The purpose of this study was to determine the optimal cutpoint for low and high numbers of symptoms using a range of potential cutpoints and to determine if those cutpoints distinguished between the two symptom groups on demographic and clinical characteristics and depression, anxiety, and quality of life (QOL). Patients with advanced cancer (n=110) completed a symptom assessment scale, and measures of depression, anxiety, and QOL. Combinations of cutpoints were tested to yield one- and two-cutpoint solutions. Using analysis of variance for QOL scores, the F-ratio that indicated the highest between-group difference was determined to be the optimal cutpoint between low and high number of symptoms. A cutpoint of ≤ 12 symptoms (i.e., 0-12 is low, 13-32 is high) was the optimal cutpoint for total number of symptoms. Significant differences in depression, anxiety, and QOL scores validated this cutpoint. Psychological symptoms had higher occurrence rates in the high symptom group. Findings suggest that a threshold exists between a low and a high number of symptoms in patients with advanced cancer. Psychological symptoms were significantly different between patients in the low versus high symptom groups and may play an important role in QOL outcomes in patients with advanced cancer.