Steven C. Castle

Clinical Relevance of Age-Related Immune Dysfunction

Immunosenescence is the state of dysregulated immune function that contributes to the increased susceptibility to infection of the elderly. Extensive studies of inbred laboratory animals and very healthy elderly humans have identified changes in immunity; these studies have identified limited phenotypic and functional changes in the T cell component of adaptive immunity. However, no compelling scientific evidence has shown that these changes have direct relevance to the common infections seen in the aged population. This perspective will attempt to shed light on this dilemma. First, it will review clinically relevant infections in the elderly, focusing on influenza and influenza virus vaccination and how chronic illness contributes to increased risk and severity of infection and/or failed vaccine response. Second, key changes in immunity will be reviewed, keeping a perspective of the impact of confounding variables in addition to age but focusing on age-related changes in the interaction of the innate and acquired components of immunity. If the goal is to prevent serious infections in the elderly, it appears that the field of geriatric immunology and/or infectious diseases is faced with the tremendous challenge of studying a very diverse population, including mildly immunocompromised/chronically ill individuals and very healthy elderly.

Fever Response in Elderly Nursing Home Residents: Are the Older Truly Colder?

Objective To test the hypothesis that many nursing home residents with an apparently blunted fever response (maximum temperature <101°F) may actually have a significant change in temperature (ΔT ≥ 2.4°F) which is not recognized because of a low baseline temperature.

Evidence of enhanced type 2 immune response and impaired upregulation of a type 1 response in frail elderly nursing home residents

Peripheral blood mononuclear cells (PBMC) of frail elderly nursing home residents had significantly higher PHA-induced interleukin-10 (IL-10) production compared to PBMCs from young control subjects. No correlation was observed between IL-10 production and interleukin-12 (IL-12) p40 production, proliferative response or with the proportion of CD28-negative T cells. To better characterize the host response to a ubiquitous pathogen, the dose response and time-dependent (kinetic) production of IL-10 and IL-12 p40 of PBMC stimulated with Staphylococcus aureus Cowan (SAC) was studied. IL-10 production continued to increase at 48 h, while IL-12 p40 levels declined or remained stable, in both young and elderly subjects. In analyzing how excessive IL-10 production might influence antigen presenting cell functions, IL-12 was markedly inhibited by recombinant IL-10 (rIL-10), while anti-IL-10 enhances IL-12 p40 production in cultures from young controls; but the PBMC cultured from an elderly cohort were not able to generate similar absolute levels of IL-12 p40 even in the presence of anti-IL-10. These preliminary data suggest that there may be both over production of IL-10 in some individuals, as well an an impaired ability to upregulate a T Helper 1 (type 1) reaction. These age-related changes could even be more dramatic at the tissue level and contribute to the impaired delayed type hypersensitivity (DTH) and failed host defense to infection, such as to primary and reactivation tuberculosis.

Immunosenescence and Vaccination in Nursing Home Residents

The elderly population continues to increase in most countries. Concomitantly, the number of individuals who are institutionalized is also increasing, unfortunately, with more and more individuals being institutionalized at greater ages. These elderly individuals are very different from healthy, community-dwelling elderly individuals, in that many are considered to be frail and have various chronic diseases. It is apparent that the immune response diminishes even in healthy elderly people and that the pathologies that occur in nursing home patients, together with malnutrition, further impair immunity required for an effective vaccine response. Therefore, it is important to take secondary age-related effects, attributable to factors such as chronic diseases, inflammation, frailty, nutrition, functional status, and stress, into account when assessing vaccination strategies. Despite these alterations that can affect immune function and their potential interaction with vaccination, vaccination is still worthwhile and is recommended for elderly nursing home residents. Research efforts should continue attempts to elucidate the immunological basis of impaired immunity in nursing home residents to design improved prevention strategies for this vulnerable group.

Host Resistance and Immune Responses in Advanced Age

Immunosenescence results in populating immune tissues with less functional T cells, and perhaps B cells dendritic cells, that do not function well and produce more type 2 cytokines and fewer type 1 cytokines. Impaired immunity, distinct from immunosenescence, correlates more with disease burden than chronologic age. Older adults who have chronic diseases or chronic infections are more susceptible to common infections and have poor vaccine responses. Understanding specific mechanisms and targeting interventions are dependent on research to resolve the relationship between frailty-associated impaired immunity and the role of chronic infection versus immunosenescence in developing impaired immunity.

Antigen presenting cell function is enhanced in healthy elderly

Aging is associated with a progressive decline in T cell-mediated immune responses. Little is known about the effect of aging on antigen presenting cells (APC). We have recently reported an age-related decline in proliferative response of peripheral blood mononuclear cells from elderly volunteers to Staphylococcus enterotoxin B (SEB). Since SEB-induced stimulation of T cells is not restricted by major histocompatibility complex, experiments were conducted in which T cells and APC from young and healthy elderly subjects were combined. We initially demonstrated the decreased SEB-induced proliferative capacity of elderly T cell elderly APC co-cultures when compared with young T cell young APC co-cultures. Combination of purified T cells from elderly donors with APC from young donors maintained a reduced T cell proliferative response. Age-related decline in T cell function was also established by the reduced proliferative capacity of elderly T cells co-cultured with a reference monocyte cell line. Surprisingly, co-culture of APC from healthy elderly donors with purified T cells from young donors enhanced T cell proliferation. APC from elderly donors also marginally enhanced the proliferative response of an SEB-specific T cell line.

Comorbidity is a better predictor of impaired immunity than chronological age in older adults.

Objectives: To determine whether high level of comorbidity, measured using a standardized instrument, can predict impaired immunity in older adults.

MEGESTROL ACETATE SUSPENSION THERAPY IN THE TREATMENT OF GERIATRIC ANOREXIA/CACHEXIA IN NURSING HOME PATIENTS

nence, and patients regained the confidence and dignity needed to resume their social lives. Many factors (anxiety, loose stool, certain foods, inaccessibility to the bathroom, etc.) may play a role in each case. However, regardless of the causes, patients suffer from loss of confidence and may be unable to continue social activities. We want to emphasize that patients frequently do not voluntarily admit to fecal incontinence, and we may miss the true underlying cause (fecal incontinence) that explains a variety of secondary complaints and symptoms.

Immune dysfunction in the elderly and its reversal by antihistamines

The decline in immunity seen in the elderly is a significant contributor to disease burden. This decline has largely been attributed to alterations in T cell immunity and contributes to an overall increased risk and severity of infection in the elderly. A key component of T cell immunity involves antigen presentation, an event where an antigen is processed and presented to specific immune cells for destruction. This event has been found to be crucial to immune function. Recent research has focused on a key antigen presenting cell (APC), the dendritic cell (DC), and changes within its function associated with aging. DCs are considered to be the most professional APCs, and are responsible for the initiation and outcome of effector T cells and their resultant immune response. DCs capture antigens and undergo a maturation process and polarize into either type 1 dendritic cells (DC1) or type 2 dendritic cells (DC2), based upon their ability to favor a T helper1 (Th1) or T helper 2 (Th2) T cell response, respectively. Evidence suggests that in normal healthy adults, a Th1 type response predominates, and in frail elders, a Th2 response predominates. It has been proposed that this change from a predominately Th1 type to a predominate Th2 type response is a possible mechanism for age-associated immune dysfunction. In addition, recent research has focused on how histamine, an inflammatory mediator, promotes a Th2 response. Histamine has also been shown to polarize human DCs into Th2 cell-promoting effector DCs or DC2s. This has been shown to occur via interaction with the H2 receptor. Therefore, we theorize that use of an H2 selective antihistamine will reverse this polarization back to a Th1 type response and therefore improve immune function of the frail elderly.

The Equivalency of Infrared Tympanic Membrane Thermometry with Standard Thermometry in Nursing Home Residents

Objective: To compare the equivalence of infrared tympanic membrane (TM) measure of body temperature with standard electronic oral (PO) and rectal (R) measures in a nursing home population.