INTRODUCTION — Normal functions of the immune system include defense against infections and detection and destruction of malignant or autoreactive cells. As the immune system ages and these capabilities decline, there is increased susceptibility to infections and cancer and an increased incidence of autoimmune disorders. The study of age-related changes in immune function is a relatively new area of investigation, which is limited by incomplete understanding of the complexities of immune mechanisms in general [1]. Most research is focused on defining normal changes in immune function at the basic science level, and much of the available data are from animal studies. In addition, there are no clinical interventions that have been definitively shown to counter immunologic aging.
This topic will review the changes observed in different components of the immune system with aging. Normal aging is reviewed elsewhere. (See "Normal aging".)
IMMUNOSENESCENCE — Immunosenescence refers to the changes that occur in the immune system with increasing age. By 2050, there will be more than 1.6 billion adults 65 years and older worldwide, making age-related diseases and conditions a growing public health concern [2]. One cannot examine immunosenescence in isolation as it is part of biological senescence that is inevitable with aging. Much of the data on immunosenescence and reversal of aging are generated in mouse models, although there are increasing human studies and clinical trials [2]. Immunosenescence is characterized by an increased risk of inflammation, infections, malignancy, and autoimmune disorders.
Terms that are routinely used in the literature of immunity in older adults include:
●Inflammaging [3]: Chronic low-grade (sub-clinical) inflammation that increases with age. This is usually associated with elevated inflammation markers.
●Cellular senescence [4]: Processes that occur as cells age, including division arrest, apoptosis resistance, and the acquisition of a senescence-associated secretory phenotype (SASP). Cells undergoing these processes can be targeted in future trials aimed at slowing aging.
●Senolytics [5]: Compounds intended to eliminate senescent cells.
●Senomorphics or senostatics [5]: Compounds intended to modulate proinflammatory senescent cells
Infections — Pneumonia and influenza are among the top 10 causes of death in individuals aged 65 and older [6]. Nosocomial infections are also significantly increased in older adults. An age over 65 years is considered a poor prognostic marker for coronavirus disease 2019 (COVID-19) infection. Increased susceptibility to infection could be the result of decreased immunologic function, in addition to a decreased efficacy of vaccines in older adults. However, there are several other factors that are likely to contribute to increased infections in older adults, including malnutrition, comorbid conditions (eg, diabetes, chronic obstructive pulmonary disease), diminished mucosal barriers, decreased cough reflex, and mechanical changes to the urinary tract system, among others [7].
The clinical presentation of infections in older patients may be different from that in younger patients. Older adults with severe infections tend to have fewer symptoms, and fever is absent or blunted in 20 to 30 percent. This suggests a decreased ability to mount inflammatory cytokine responses in the face of infection. Signs of infection in older adults can be nonspecific and include falls, delirium, anorexia, or generalized weakness [8]. (See "Approach to infection in the older adult".)
"Failure to thrive" is a term that has been extrapolated from the pediatric description. In older adults, it is used to describe a gradual decline in physical and/or cognitive function, usually accompanied by weight loss and social withdrawal that occurs without immediate explanation. Failure to thrive in older adults has been defined as a syndrome manifested by weight loss greater than 5 percent of baseline, decreased appetite, poor nutrition, and inactivity, often accompanied by dehydration, depressive symptoms, impaired immune function, and low cholesterol levels [9]. Failure to thrive is not considered a normal consequence of aging, an equivalent to dementia, or a descriptor of the later stages of a terminal disease [10]. One important treatable cause of failure to thrive is an undetected chronic infection, such as tuberculosis, endocarditis, or bronchiectasis. (See "Failure to thrive in older adults: Evaluation" and "Failure to thrive in older adults: Management".)
Malignancy — Cancer incidence and mortality increase markedly after age 65, leveling off around age 85 to 90. Both the innate and adaptive arms of the immune system are involved in the defense against aberrant tumor cells. Patients with primary and acquired immunodeficiency are at increased risk for certain tumors, which is an indication of the immune system's role in defense against malignancy. However, carcinogenesis is a complex phenomenon, and the exact role of immunosenescence is difficult to establish. An increased mutational load and carcinogen exposure are likely other contributors to increased malignancy in older adults [11].
Autoimmune disorders — There is an increase in the production of autoantibodies with age [12]. In one study of healthy older adults, 28 percent had a positive antiphospholipid antibody, 22 percent had a positive rheumatoid factor, and 14 percent had elevated antinuclear antibodies [13]. The mechanisms for heightened autoantibody production are not clear, but decreased T regulatory cell function and decreased clearance of apoptotic cells by macrophages are two potential explanations.
As is the case with infections, autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome, may present with atypical symptoms in older adults. SLE can present as vague symptoms of weight loss, muscle pain, and cognitive or affective deterioration [13]. In a study of patients with RA, older patients were more likely than younger patients to present with symptoms similar to polymyalgia rheumatica and were less likely to have subcutaneous nodules or rheumatoid factor at disease onset [14]. Joint scores were also lower.
Effect of malnutrition — Adequate nutrition is fundamental to healthy aging. Malnutrition is not uncommon in older adults and is associated with increased morbidity and mortality [15,16]. In a Swedish study, malnutrition was present in 60 to 80 percent of patients over 60 years of age admitted to the hospital [17]. In general, energy requirements decrease with age due to a decline in lean body mass and decreased physical activity. Despite this, older adults are at risk for malnutrition due to dental or swallowing problems that might interfere with eating, loss of smell or taste sensations, chronic illnesses that interfere with digestion or absorption of food and increase nutritional requirements, medication side effects, depression and social isolation, functional/visual/cognitive impairments, and economic barriers to obtaining high-quality food [18]. (See "Geriatric nutrition: Nutritional issues in older adults".)
Malnutrition is associated with immune defects, in particular, a decrease in T cell function [19]. Malnutrition is also associated with an increased risk of and a worse outcome with infections [20]. Deficiencies of vitamins A and E [21], vitamin C [22], vitamin B12 and folate [23,24], vitamin B6 [25], vitamin D [26], as well as zinc, selenium, magnesium [27], and copper [28], have been described in older adults, although the precise effects of these deficiencies on immune function are not well-defined. (See 'Nutritional supplements and diet' below.)
CHANGES IN SPECIFIC COMPONENTS OF THE IMMUNE SYSTEM — All immune cells originate from hematopoietic stem cells (HSCs) in the bone marrow, and there is a general decline in the total bone marrow hematopoietic tissue with aging [29]. HSCs, like other cells, undergo progressive loss of telomeric DNA with successive divisions. It is estimated that 50 to 200 base pairs of telomeric DNA is lost with each cell division [30]. The sequential loss and shortening of telomeric DNA with advancing age lead to an increase in apoptosis (noninflammatory, programmed cell death). In addition to telomere shortening, acquired defects in genomic or mitochondrial DNA also contribute to the decline in HSCs. Overall, the proliferative capacity of HSCs from older people is two to four times less than those from younger subjects [29]. Differences in regenerating capacity are particularly important during times of illness or other physiologic stress.
Production of pro-B cells is significantly decreased with aging, resulting in a smaller number of B cells leaving the bone marrow, while T cell precursors seem to be less affected [31]. In contrast, age-related changes do not affect erythroid and myeloid progenitors, and enhanced myelopoiesis is observed [32]. Other age-related changes in the bone marrow are discussed separately. (See "Normal aging", section on 'Hematopoietic system'.)
The immune system is divided into innate and adaptive immunity. Innate immunity refers to immune responses that are present from birth and not learned, adapted, or refined as a result of exposure to micro-organisms/antigens. In contrast, adaptive immunity, which consists of the responses of T and B lymphocytes, differentiates and matures during the lifetime of an individual as a result of antigen exposure. Aging affects both innate and adaptive immunity, although innate immune mechanisms are better preserved overall [33].
Innate immunity — The innate immune system consists of epithelial barriers (skin, gastrointestinal and respiratory mucosa), macrophages, neutrophils, natural killer (NK) cells, natural killer T (NKT) cells, dendritic cells (DCs), and complement proteins. Nonspecific defense mechanisms, such as production of mucus in the proper quantity and viscosity, local antimicrobial peptides, and normal ciliary function, are also part of normal defenses. Several age-related changes in the components of the innate immune system have been characterized (table 1).
Overall, although some innate immune mechanisms are decreased, other mechanisms appear to be more active in older individuals. The result of these changes is a propensity to develop chronic inflammatory states. Thus, the result of aging of the innate immune system may be most accurately characterized as a state of immune dysregulation characterized by low-grade, chronic inflammatory changes [34]. Chronic viral infections, such as cytomegalovirus (CMV) infection, may also contribute to this phenomenon, as discussed below (see 'Immune risk profile and herpesviruses' below):
●Toll-like receptors – Toll-like receptors (TLRs) are receptors that are responsible for the recognition of pathogen-associated molecular patterns and thus play a very important role in recognizing infecting organisms. It is unclear as to whether TLR expression is reduced with aging. However, TLR function was found to be decreased in aged mice [35]. In humans, cytokine production by monocytes as a result of TLR-1/2 activation decreases with age [36]. (See "Toll-like receptors: Roles in disease and therapy".)
●Macrophages – Macrophages are an important first-line defense against invading micro-organisms. Macrophages function by recognizing, ingesting, and killing organisms, presenting processed antigens to T cells, and releasing mediators that activate other inflammatory cells. (See "An overview of the innate immune system", section on 'Monocytes and macrophages' and "Antigen-presenting cells", section on 'Professional APCs'.)
There is a significant decrease in bone marrow macrophage precursors with aging [37]. In addition, macrophages from aged rats and mice were found to have reduced production of nitric oxide and the reactive oxygen species that are essential for their killing activity [38]. The decreased macrophage activity in older adults may result in a longer duration of infection by extracellular bacteria, as well as delayed wound healing. Deficient production of tumor necrosis factor (TNF)-alpha by skin macrophages was found to underlie impaired responses to delayed-type hypersensitivity testing with age [39].
●Neutrophils – Neutrophils are short-lived cells, important in acute inflammation and in defense against bacterial and fungal organisms. Aging does not affect the total number of neutrophil precursors in the bone marrow or the number of circulating neutrophils in the blood. However, the phagocytic ability of neutrophils is reduced in older adults as compared with younger adults. Studies of superoxide generation by neutrophils in older adult patients have reached varying conclusions, depending upon the conditions used in vitro [40,41].
●Natural killer cells – Natural killer (NK) cells are large, granular lymphocytes that secrete cytokines and are capable of destroying tumor cells and viral-infected cells. They are defined as being CD56+ CD3-. Peripheral blood NK cells are comprised of around 10 percent CD56bright and 90 percent CD56dim subsets. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Biology of NK cells'.):
•CD56bright CD16dim NK cells function primarily in producing cytokines, such as interferon (IFN)-gamma and chemokines, and have minimal cytotoxic activity.
•CD56dim CD16bright NK cells are highly cytotoxic and produce lower amounts of cytokines.
Unlike other lymphocytes, the NK cell percentage and number tend to increase with age [42]. More than one study noted that the percentage and number of CD56bright NK cells gradually decline with age, while CD56dim NK cells progressively increase [43-45]. Consequently, the ability to produce IFN-gamma was modestly impaired in NK cells from older subjects compared with adult controls, while NK cell cytolytic activity, as well as antibody-dependent cellular toxicity, were preserved in the older population [46].
NK cells may play an important role in controlling infections in older adults. A study on 108 older adults in nursing homes found a correlation between a low NK cell activity, and both increased infection rate and death due to infections [47]. In another study, centenarians had preserved or increased NK cell activity, consistent with the concept that these cells are important for successful aging [48].
●Natural killer T cells – Natural killer T (NKT) cells are a subset of T cells (ie, CD3+) that shares some characteristics of NK cells [49]. NKT cells are heterogeneous, but the majority express an invariant T cell receptor alpha chain encoded by V-alpha-24/J-alpha-Q gene segments (these cells are called invariant NKT cells [iNKT]) [50]. NKT cells can be a potent source of IFN-gamma and interleukin (IL)-4 and can thus modulate adaptive immune responses. Lymphocytes from older adults were reported to have a decreased percentage of iNKT, and these iNKT were more likely to secrete IL-4 rather than IFN-gamma, compared with lymphocytes from young subjects [51-53]. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Biology of NK cells'.)
●Dendritic cells – Dendritic cells (DCs) are the most potent antigen-presenting cells. They play a critical role in the initiation of the immune response by capturing and processing antigens and presenting the processed antigens to other immune cells. They also stimulate the immune system by secreting a number of cytokines and form an important link between innate and adaptive immunity. (See "Antigen-presenting cells", section on 'Professional APCs'.)
The number of DCs (both myeloid and plasmacytoid DC subsets) does not seem to be affected by aging (table 1) [42]. The extent of immunosenescence of human DCs remains an area of uncertainty [54]. There is a suggestion, however, that aging is associated with a numeric and functional decline in plasmacytoid but not myeloid DCs, that the TLR function in DCs from older adults may be decreased, and that such a decrease might determine the adequacy of response to influenza vaccine [55,56].
One study suggested that upon TLR7 stimulation, DCs from old mice have a reduced ability to upregulate costimulatory molecules and to cross-prime naïve CD8+ T cells. This may have a negative impact on the generation of a robust CD8+ T cell cytotoxic immune response and may provide an insight as to why severe influenza infection is common in older adults [57].
Adaptive immunity — Adaptive immunity consists of T and B lymphocytes, which mediate cellular and humoral immune responses, respectively.
Cellular immunity: T cells — There are several key changes that occur to T cells during aging (table 2). One of the most striking changes of immunosenescence is the involution of the thymus gland.
Thymic involution — Naïve T cells are generated from precursors that leave the bone marrow and migrate to the thymus for maturation. (See "Normal B and T lymphocyte development", section on 'T cell development'.)
The thymus gland is most active early in life, reaches maximum size within the first year of life, and then undergoes a steady decline with age. By age 7, the part of the thymus with active cell replication (thymopoietic space) represents less than 10 percent of the total thymic space. The functional thymic cortex and medulla are progressively replaced by fatty tissue. These changes are almost complete by age 40 to 50 [58]. As a result of thymic involution, the number of naïve T cells exiting the thymus is significantly decreased and gets progressively lower between the age groups of 40 to 54, 55 to 69, and 70 to 90 [59].
Changes in T cell subsets — An overall decline in T cell function is apparent with aging, as evidenced by a decline in T cell number and diversity and reduced T cell expansion, differentiation, and signaling intensity (table 2). Specific changes include the following:
●T cell receptor diversity dramatically decreases after age 65, resulting in a significantly reduced repertoire [59]. A diverse repertoire is critical for protection from a variety of new infections, especially viral infections. As a result, the ability of T cells to mount an immune response against new antigens declines with age. A study of 44 centenarians found that 84 percent had nondetectable T cell receptor excision circles (biomarkers for de novo T cell synthesis) and that these subjects had a low number of naïve T cells [60]. In contrast, numbers of terminally differentiated cells in centenarians were not different from those in young or middle-aged subjects. These findings suggest that production of new T cells is dramatically reduced in the very old, and T cell populations are largely composed of persistent long-lived lymphocytes. Age-related defects in the signaling pathways of naïve CD4 T cells have been identified [61].
●There is a decrease in the numbers of CD4 T cells, an increase in CD8 T cells, and a decrease in the costimulatory molecule CD28 with aging. Reduction in CD28 results in an impaired ability of T cells to proliferate and secrete IL-2 [62]. Because CD4 (helper) T cells are important in stimulating B cells, the ability of T cells to help B cells proliferate and produce antibodies diminishes with age [63]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'T cell activation via the two-signal model'.)
●T regulatory cells (Tregs) are a subset of T cells that keep the immune system "in check" by maintaining homeostasis, limiting autoimmune responses, and modulating the inflammatory response to infectious agents and tumors. There is a decrease in Treg function after the age of 50, which may be a contributing factor to the increase in autoimmunity and malignancy seen in older individuals (table 2) [64]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Suppression'.)
Studies have been conflicting about the types of cytokines produced by aging T cells. One study showed an increased number of both T helper type 1 (Th1) and T helper type 2 (Th2) cells in older adults (70 to 90 years) and nonagenarians when compared with young individuals, with a decrease in the Th2/Th1 ratio [65]. Other studies suggested an increase in Th2 cytokines in older adults [66,67], while previous studies had suggested increased Th1 cytokines [68]. Another study examined the correlation of inflammatory cytokines (IL-6, TNF-alpha, and the 75kDa soluble TNF-alpha receptor II [sTNF-RII]) and T cell subsets with frailty in older adults [69]. Inflammatory cytokines were more closely related to frailty than were lymphocyte subpopulations. In particular, sTNF-RII levels had a high accuracy in the predictive value for frailty.
Humoral immunity: B cells — B cells produce their own surface membrane immunoglobulin and differentiate into plasma cells, which then make immunoglobulin for the blood or secretions. These immunoglobulins are the mediators of humoral immunity. B cells respond to antigen exposure (ie, through infections or vaccinations) by producing antibodies, which then bind to antigens to fight concurrent infections or prevent future infections. Naïve B cells produce primarily immunoglobulin (Ig)M. Upon stimulation with antigen, B cells switch to the production of IgG, IgA, or IgE. The ability of B cells to respond to antigens and produce antibodies is a main measure of their functional capacity. (See "The adaptive humoral immune response".)
The numbers of B cells precursors in the bone marrow (pre-B cells), as well as peripheral B cells, decrease with age [70]. Immunoglobulin levels, on the other hand, do not change with aging, and may actually increase [71]. However, quantities of specific antibodies (ie, those generated by encounters with antigens through infection or vaccination) decline with age [72]. Some studies have shown that, similar to T cells, the diversity of the B cell repertoire decreases with age. This decreased repertoire also correlated with a poor health status or "frailty" [73].
Memory B and T cells — The generation of long-lasting protective memory is one of the most unique and important characteristics of the adaptive immune system. Memory is essential in allowing individuals to defend themselves from infections to which they have previously been exposed. As the thymic output declines, individuals rely more on re-expansion of experienced memory cells for defense against infections.
Memory responses to recall challenge appear to be relatively well-preserved with aging, compared with responses of naïve B and T cells [74]. Data suggest that memory B and T cells, once elicited by antigen during youth, are quite resilient to the impact of immunosenescence [75,76]. An example of this phenomenon was seen during the 2009 H1N1 influenza pandemic, in which older adults were better protected from H1N1 infection than middle-aged adults, probably because of the persistence of memory lymphocytes producing neutralizing cross-reactive antibodies generated in response to an H1N1 virus that circulated prior to 1957 [77]. The antibody avidity for 2009 H1 was higher in older adults than in middle-aged adults [78].
Conversely, animal studies suggest that T cell memory generated for the first time in old animals is defective [79].
Functional response — T and B cells may be less responsive to stimulation with antigen in older adults. One study compared the adaptive immune responses to a neoantigen, the Japanese encephalitis virus vaccine, in 30 older adults (mean age 68.6, range 61 to 78 years) and 30 younger individuals (mean age 24.3, range 18 to 30 years) [80]. Antibody production and interferon-gamma production were both significantly reduced in the older adult group. Notably, CMV-seropositive older adult individuals also had significantly lower antibody titers in response to vaccination. Another study examined primary and secondary responses to hepatitis B vaccine volunteers younger and older than 60 years of age and found a decreased response to the primary but not the booster hepatitis B vaccination in older adults [81]. In addition, only the older adult group had individuals who did not respond after the three-dose primary vaccination series.
ASSESSING IMMUNOSENESCENCE — Immunosenescence is part of normal aging, and as such, it would be assumed to be present to varying degrees in all older adults. Assays for quantifying immunosenescence are largely research tools.
Genetics versus epigenetics — It is becoming increasingly apparent that epigenetics, or the heritable changes in phenotypes or gene expression (active versus inactive genes) that do not involve changes to the underlying DNA sequence, play a major role in many aspects of human health and disease. A recurring question in the older adults is how much of their longevity is determined by inheritance and how much is determined by lifestyle. Studies of monozygotic twins are valuable in answering this question. One seminal study involved an analysis of 105 pairs of healthy twins (78 monozygotic and 27 dizygotic pairs) between 8 and 82 years of age and measured 204 different parameters, including cell population frequencies, cytokine responses, and serum proteins [82]. They found that nonheritable influences dominated 77 percent of these parameters and almost completely dominated 58 percent of the parameters. Twin discordance increased steadily with age, suggesting that the effects of environmental exposures on the immune system are cumulative. Interestingly, the discordance was most apparent in measurements relating to T and B cells. In addition to the in vitro parameters, this study measured serologic responses to seasonal influenza vaccination and found them to be determined largely by nonheritable factors. The importance of infections across a lifespan is also illustrated by the finding that monozygotic twins discordant for cytomegalovirus (CMV) infection showed greatly reduced correlations for many immune cell frequencies, such as effector CD8 and gamma-delta T cells. (See 'Immune risk profile and herpesviruses' below.)
Proteome profile in aging — Several studies have suggested that blood from young mice might reverse at least some aspects of aging in older mice [83,84]. There is a suggestion that blood factors might transfer beneficial effects of exercise on neurogenesis and cognition of the aged brain [85]. The study of proteomics in aging is still in its infancy. In a study of the plasma proteome profile across the lifespan, 2925 plasma proteins obtained from 4263 subjects ranging in age from 18 to 95 years old were measured [86]. Rather than linear changes in the proteomic profile, three waves of changes were detected. These occurred during the fourth, seventh, and eight decades of life and affected different biological pathways. These waves might be associated with genetic/epigenetic modulation of clinical phenotypes.
Inflammasome — Inflammasomes are cytosolic protein complexes that serve as the framework for the activation of the same proteases that lead to activation of proinflammatory cytokines. The inflammasome gene molecules of older individuals were able to be stratified into two subsets in one study [87]. One subset had constitutive expression of proinflammatory cytokines including IL-1b, elevated oxidative stress, high rates of hypertension and arterial stiffness. The other subset did not have constitutive expression of IL-1b and did not have the comorbidities of the other subset. This work may lead to future studies targeting inflammasome components to minimize inflammaging.
Leukocyte telomere length — Telomeres are protein-DNA complexes, 10 to 20 kb long, characterized by tandem repeats (TTAGGG). Telomeres play a role in preventing DNA degradation by protecting the chromosome end from recombination and fusion with another telomere or DNA end. The telomere length is an indication of the cell replication history and replicative capacity of normal somatic cells [88]. Leukocyte telomere length is sometimes used as a biomarker of oxidative stress and injury [89]. Telomere length and inflammation markers were examined in a study of 1554 Japanese individuals, including 684 centenarians and semi-super centenarians (105 or older), 167 pairs of centenarian offspring and spouses (100 to 104 years old), and 536 very old (85 to 99 years) [90]. Inflammation was a more significant predictor of all-cause mortality for the very old and semi-super centenarians, respectively. Inflammation was also a better predictor than telomere length for capability and cognition. Interestingly, the inflammation score was lower in centenarian offspring compared with age-matched controls. Another study examined DNA methylation level, a general marker of epigenetic effects, in 82 semi-super centenarians, 63 of their offspring, and 47 age-matched controls and found that the offspring of semi-super centenarians had a lower epigenetic age than age-matched controls [91].
Immune risk profile and herpesviruses — Although most studies look at the effects of aging on the immune system, other lines of research suggest that immunosenescence itself may be a major contributor to the process of aging. One hypothesis is that ongoing antigenic stimulation by herpesviruses (CMV or possibly also Epstein-Barr virus) may have a depleting effect on the immune system over time, which in turn contributes to the immunologic changes associated with aging and frailty [92]. Older adult women had higher CMV viral loads as compared with younger women, and frailty levels were associated with higher viral reactivation and viral loads [93].
The "immune risk profile" (IRP) is a term used to describe a combination of immunologic findings, including poor T cell proliferative response to mitogens, low numbers of B cells, inverted CD4:CD8 T cell ratio (ie, ratio <1), and CMV seropositivity. The IRP has been proposed to predict survival, although results from different cohorts are not consistent, and further studies are required. Studies that support this concept include the following:
●Older adults (86 to 94 years of age) with an IRP demonstrated high mortality at two, four, and six years of follow-up [94-96].
●Studies of individuals from long-lived families and those who reached 100 years of age found a low incidence of the immune changes that comprise the IRP, suggesting that people of extreme longevity may be less susceptible to CMV-accelerated immunosenescence [97,98].
However, the findings of other studies have not supported the utility of the IRP:
●No relationship between frailty and either IRP or CMV seropositivity was found in one study of 845 persons aged 85 and older [99]. Instead, frailty was associated with elevations in certain inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) and neutrophil counts and inversely correlated with albumin levels.
●In the BELFRAIL study, older adults with a phenotype of CMV seropositivity and CD4:CD8 ratio of >5 (rather than <1) had a higher risk of impaired physical activity [100].
A 2013 longitudinal study identified immune findings similar to the IRP in a cohort of 66-year-old individuals [101]. A five year-follow up of the individuals in this study found that a CD4/CD8 ratio <1 was associated with CMV infection and with increases in the levels of T Effector Memory RA (TEMRA) cells, CD8+ T cells being higher [102]. Increased levels of TEMRA and decreased levels of naïve T cells were associated with seropositivity for CMV. Interestingly, the levels of CMV IgG were stable throughout the five year follow-up period. In a longitudinal study of 684 Japanese centenarians and semi-supercentenarians, lower indices of inflammation were a better predictor of successful aging than telomere length, and inflammation scores were lower in the centenarians' offspring compared with age-matched controls [90].
POTENTIAL INTERVENTIONS TO COUNTER IMMUNOSENESCENCE — Human history is replete with various strategies to increase longevity, although a more desirable goal would be increased longevity without infections, autoimmunity, or cancer. Adequate nutrition is likely essential for optimizing immune function, and there are some data indicating that regular, moderate exercise is also important. However, there are no pharmacologic therapies that have been convincingly shown to counter normal immunosenescence.
Nutritional supplements and diet — Studies demonstrating that vitamin or mineral supplements can boost immune function are lacking. Available data do indicate that vitamins (A, D, E, B6, B12, folate, and C) and trace elements (selenium, zinc, copper, and iron) are necessary for normal immune function [103-105]. In addition, the prevalence of certain nutritional deficiencies (eg, vitamins D and B12) is sufficiently high in the geriatric population, that certain supplements are indicated. However, beyond achieving the recommended daily amounts of nutrients, there are no data to suggest that further supplementation can improve immune function.
Few studies have evaluated the effect of dietary practices on specific immune functions. One study suggested that fruit and vegetable consumption improved antipneumococcal antibody response in subjects aged 65 to 85 years, although there were technical issues with the measurement of immune response, and more work is needed [106].
Nutritional issues in older adults are reviewed in more detail elsewhere. (See "Geriatric nutrition: Nutritional issues in older adults".)
Exercise — There is some evidence that long-term, moderate exercise may improve aspects of immune functioning in older adults:
●Available data suggest that CD8+ T cells and natural killer (NK) cell numbers (but not function) may be transiently elevated by acute exercise [107,108].
●One small controlled trial (14 patients in each arm) suggested that regular aerobic exercise can increase the immune response to influenza vaccination [109].
●Another small study reported that acute exercise in 20 octogenarians resulted in increased numbers of granulocytes, monocytes, and CD4+ T lymphocytes, while T cell proliferation and CD56dim NK cell numbers decreased postexercise [110].
●Sixty sedentary older adult volunteers (ages 61 to 67 years) were randomized to a 40-minute supervised aerobic treadmill exercise versus resistance training three times per week for six months. The aerobic exercise group had a significant reduction in mean values of TNF-alpha, IL-6, lymphocytes (CD3, CD4, and CD8), and CD4/CD8 ratio, as well as an increase in serum IL-10, compared with the resistance training group. This suggests that longer-term aerobic exercise might contribute to reducing inflammation in older adults [111].
●The effect of cycling (as a representative of a high level of physical activity) was studied in 125 adults aged 55 to 79 years and compared to 75 age-matched older adults and 55 young adults who did not do regular exercise [112]. Cyclists had a higher frequency of naïve T cells and recent thymic emigrants compared to the inactive control group. In addition, the frequency of recent thymic emigrants in older adults who exercised was not different from young adults. Active older adults also had a lower level of IL-6, which is a pro-inflammatory cytokine, and higher levels of IL-7, which is thymoprotective. However, cyclists did not have any significant difference in the frequency of the immunosenescent CD8 T cells.
On the other hand, strenuous exercise can be immunosuppressive, and the impact of exercise probably depends upon the patient's underlying state of health, as well as the intensity and type of exercise performed [113]. In addition, studies examining the clinically relevant endpoint of reductions in the frequency of infections are needed.
Stress reduction — There are some data suggesting that chronic stress is associated with accelerated immunosenescence and that stress management therapies including psychosocial support and coping skills might reverse some features of immunosenescence [114].
Attention to vaccinations — Most vaccinations that are recommended for older adults are provided to boost pre-existing immune memory from previous vaccination or natural infection. Impaired vaccine response in older individuals could be due to reduced quantitative and functional memory T cells and decreased functional vaccine-specific antibodies [2]. However, some of the effective vaccine strategies described below may be able to overcome the abundance of senescent T cells. Recommendations have been issued for routine vaccination of healthy older adults (figure 1). Vaccines to protect against tetanus, diphtheria, pertussis, influenza, pneumococcal infections, and zoster are particularly relevant to individuals older than 65.
Other information regarding the administration of specific vaccines to older adults includes the following:
●Tdap – In 2010, the Advisory Committee on Immunization Practices (ACIP) began recommending that adults aged 65 years and older who anticipate having close contact with infants younger than one year of age (eg, grandparents, childcare providers, health care providers) and who have not previously received Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) should receive a single dose of this vaccine. This is reviewed in more detail separately. (See "Tetanus-diphtheria toxoid vaccination in adults", section on 'Indications for Td or Tdap vaccination in adults' and "Geriatric health maintenance", section on 'Immunizations'.)
●Pneumococcal vaccination – Pneumococcal vaccination is recommended for adults over the age of 65 years and has been shown to be effective in this group. Specific recommendations for use of the 23-valent pneumococcal polysaccharide vaccine (PPV-23) and 13-valent pneumococcal conjugate vaccine (PCV-13) in older adults are reviewed elsewhere.
There is mounting evidence that older adults may respond better to certain adjuvants and types of vaccines [115-117]. Specifically, protein-conjugated vaccines, which have traditionally been preferred in young children, may offer advantages in older adults as well. In a study of vaccine-naïve individuals older than 70, subjects were initially given either the 7-valent pneumococcal conjugate vaccine (PCV-7) or PPV-23 [118]. One year after receiving the first vaccine, subjects in each group received a booster with either the PCV-7 or PPV-23 vaccine. Immune responses were compared for each of the seven serotypes common to both vaccines. Antibody concentrations and opsonophagocytic activity were higher in those who received an initial dose of PCV-7, suggesting that an initial dose of PCV-7 is likely to elicit higher and potentially more effective levels of antipneumococcal antibodies than an initial dose of PPV-23. In addition, PPV-23 induced a state of hyporesponsiveness for subsequent vaccination, which was not observed with the PCV-7 vaccine. However, a caveat of the hyporesponsiveness is that there was no control group that received PPV-23 followed by a repeat dose of PPV-23. Moreover, the hyporesponsiveness was checked only for the serotypes in PCV-7 and not all of the serotypes in PPV-23. This is an important point given the clinical reports suggesting that, in children, PCV-7, while inducing protection against the seven serotypes, may be associated with higher susceptibility to infection with the nonvaccine serotypes [119,120].
Data are inconsistent regarding the effectiveness of pneumococcal vaccination in the "older old," in terms of antibody generation or incidence of invasive pneumococcal disease. In one study, persons >85 years of age generated adequate antibody responses to the PPV-23 vaccine [121], while in another, persons >80 years of age demonstrated a decreased IgG antibody response to PPV-23, and the opsonophagocytic activity of these antibodies was relatively poor [122]. A third study of patients >80 years of age found that vaccination with PPV-23 did not significantly reduce invasive pneumococcal disease [123].
Of note, even the effectiveness of the conjugated pneumococcal vaccine may be reduced with age, as suggested in a study of immunocompetent adults aged ≥65 years. This study suggested that the efficacy of PCV-13 in preventing community-acquired pneumonia or invasive pneumococcal disease declined with increasing age from 65 percent in 65-year-olds to 40 percent in 75-year-olds [124]. In another study, overall efficacy of PPV23 was 27 percent in individuals older than 65, with higher effectiveness in those without underlying medical conditions [125].
●Influenza – Vaccine studies suggest that older individuals have significantly reduced influenza-specific antibody responses compared with young adults, and/or fail to maintain durable antibody titers. In addition, antibodies in older individuals have a lower ability to neutralize infection [126].
●Herpes zoster – In 2017, the ACIP recommended the two-dose recombinant zoster vaccine (RZV) for adults ≥50 years, including those individuals who previously received the zoster vaccine live (ZVL) and those who have a history of herpes zoster [127]. The efficacy or RZV in preventing herpes zoster was high regardless of age: 96.6 percent (50 to 59 years), 97.4 percent (60 to 69 years), and 91.3 percent (≥70 years). In persons aged ≥70 years, vaccine efficacy was 97.6 percent in the first year and 84.7 percent for the remaining three years of the study. Efficacy for prevention of postherpetic neuralgia was 91.2 percent (≥50 years) and 88.8 percent (≥70 years). RZV estimates of efficacy against herpes zoster were higher than ZVL estimates in all age categories, the difference being most pronounced among recipients aged ≥70 years [128]. The use of a novel VZV subunit plus adjuvant in the RZV seems to be promising in overcoming age-related reductions in immune responses. (See "Vaccination for the prevention of shingles (herpes zoster)", section on 'Recombinant zoster vaccine'.)
Use of higher dose vaccines — Increasing the dose of certain vaccines may improve effectiveness in older adults. A study of patients with asthma suggested that patients aged 60 and older produced adequate levels of seroprotective antibody to H1N1 vaccine in response to a 30 mcg dose but not a 15 mcg dose [115]. In response to this and other studies showing that the conventional vaccine produced marginal protection in older adults, the US Food and Drug Administration approved a seasonal flu vaccine for the 2010 fall flu season that was specifically designed for people aged 65 and over. This preparation, Fluzone High-Dose (brand name), contains four times as much of the active antigen component as a conventional flu shot, resulting in a stronger antibody response in older adults [129]. (See "Seasonal influenza vaccination in adults".)
Role of vaccine boosters — In a study evaluating pre- and postimmunization titers for the tetanus, diphtheria, pertussis, and polio vaccines in 252 older adults compared with a group of younger adults, protective titers were lower for the inactivated vaccines compared with the live polio vaccine [130]. For the inactivated vaccines, postimmunization titers were significantly higher in patients with higher preimmunization titers, indicating that routine booster programs for these vaccines could help achieve better protection in older adults.
Investigational vaccine techniques — There are several other strategies that could improve vaccine response in older adults:
●Use of different adjuvants and vaccine formulations – Older adults may respond better to certain adjuvants and types of vaccines [115-117]. As an example, young children are believed to respond to protein-conjugated vaccines better than polysaccharide vaccines, and conjugate vaccines have been traditionally used in children. However, these preparations may offer advantages in older adults as well. In a study of vaccine-naïve individuals older than 70, subjects were initially given either PCV-7 or PPV-23 [118]. One year after receiving the pneumococcal vaccine, subjects in each group received a booster with either the PCV-7 or PPV-23 vaccine. Immune responses were compared for each of the seven serotypes common to both vaccines. Antibody concentrations and opsonophagocytic activity were higher in those who received an initial dose of PCV-7. The authors concluded that an initial dose of PCV-7 is likely to elicit higher and potentially more effective levels of antipneumococcal antibodies than is PPV-23. In addition, PPV-23 induced a state of hyporesponsiveness for subsequent vaccination, which was not observed with the PCV-7.
The use of an adjuvant (AS03) in the trivalent influenza vaccine in adults ≥65 years resulted in a higher frequency of CD4 T cells specific to the three vaccine strains [131].
Clinical trials also suggest that toll-like receptor ligands can be safe and effective vaccine adjuvants, but studies are needed to assess their efficacy in older adults [132].
●Refining vaccination schedules – Another general strategy for optimizing the response to vaccines that create long-lasting immunity is to administer these earlier in life, when the immune system can create a more vigorous and lasting memory response [130].
●Changing the routes of administration – At least one study documented higher protective antibody levels to influenza vaccine in older adults with intradermal, rather than intramuscular, administration [133]. However, specific preparations are needed for intradermal administration.
●Novel vaccines – Vaccines to prevent chronic viral infections, such as cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and perhaps also HIV are of interest in the field of immunosenescence because these chronic infections are believed to contribute to the chronic inflammatory changes of aging, as well as to "immunologic exhaustion" [16].
Cytokine therapies — Recombinant interleukin (IL)-7 is under investigation as an agent to increase thymic output of T cells [134]. The use of this drug in aged mice resulted in reversal of thymic atrophy and increased thymic output. Simian IL-7 in aged rhesus macaques resulted in increased numbers of naïve CD4 and CD8 cells, central memory CD8 T cells, and T cell receptor excision circles, which are biomarkers for de novo T cell synthesis.
A phase I study of recombinant human IL-7 (rhIL-7) done on 16 human subjects with refractory cancer (age 20 to 71) suggested that rhIL-7 disproportionately increased the numbers of naïve and central memory cells (but not effector T cells). CD8+ T cell repertoire diversity also increased. These effects were age-independent and persisted after therapy (for the study duration of 28 days) [135]. It has also been studied in patients with HIV infection [136], although not in normal-aging adults.
Investigational pharmacologic interventions — Two groups of drugs that have been evaluated for possible anti-aging effects include mammalian target of rapamycin (mTOR) inhibitors and statins.
mTOR inhibitors — Agents that inhibit the mammalian target of rapamycin (mTOR) suppress T cell proliferation and proliferative responses induced by several cytokines. These drugs have been studied for their effects on lifespan (in animal models) and immune function.
●Animal studies have found that mTOR inhibitors variably extend lifespan and partially reverse aging to immune cells. Studies in mice showed that the mTOR inhibitor rapamycin extended lifespan by 9 to 14 percent, even when treatment was started later life, an effect that was sex-dependent and unrelated to dietary restriction [137,138]. However, a study in marmosets found that long-term (14 months) administration of rapamycin did not increase lifespan [139].
●Human studies of mTOR inhibitors suggest that these agents may counter some measures of immunosenescence. In a single-blind, placebo-controlled trial, 218 volunteers >65 years of age with no unstable medical conditions were randomized to receive placebo or one of three doses of an oral mTOR inhibitor [140]. Subjects were treated for six weeks, followed by a two-week hiatus, and then given influenza vaccine. The mTOR inhibitor enhanced the response to influenza vaccine by about 20 percent and reduced the percentage of CD4 and CD8 lymphocytes that expressed the programmed death-1 (PD-1) receptor. A separate study in mice showed that aged mice have increased numbers of exhausted T cells and that T cell function could be partially restored by in vitro blockade of the PD-1 pathway [141]. It remains to be seen as to whether blockade of the PD-1 pathway will have an effect on lifespan and immunosenescence.
Statins — Preliminary studies suggest that statin drugs may have a beneficial effect of the process of aging by two mechanisms: an anti-inflammatory effect and an effect on telomere shortening. However, further study is needed before statins can be recommended as anti-aging therapy.
Statins are known to have anti-inflammatory effects [142,143]. A rat model suggested that atorvastatin prevents age-related and amyloid B-induced microglial activation by blocking interferon-gamma release from NK cells in the brain [144]. Other evidence suggests that statins may have anti-aging effects that are linked to their ability to inhibit telomere shortening by reducing oxidative telomeric DNA damage, as well as by a telomere capping mechanism [145]. (See 'Leukocyte telomere length' above.)
Metformin — Metformin is widely used for glucose control in type 2 diabetes. It acts by increasing the activity of AMP-activated protein kinase (AMPK) [146]. In a retrospective observational study, the survival of type 2 diabetics treated with metformin or sulfonylureas was examined and compared to age matched controls [147]. Those treated with metformin had longer survival than matched non-diabetic controls and also longer survival than diabetics receiving sulfonylureas. Several clinical trials are either underway or getting ready to start with the goal of examining the effect of metformin on life span, frailty, and immunosenescence.
EVALUATION OF THE IMMUNE SYSTEM IN OLDER ADULTS — Many older adults have mild degrees of immunosuppression as a result of immunosenescence, and it can be difficult to determine if an evaluation of immune function is in order. However, immune dysfunction would present with the same types of disorders in an older adult as in a younger adult, and clinicians should be vigilant for certain patterns:
●The hallmark of a weak immune system is recurrent infections. In patients of any age, several characteristics of infections raise the suspicion of an immunodeficiency: higher than expected frequency, severity, duration, complications, and infections with unusual organisms. However, the presentation of infections in older individuals can be subtle and atypical. In older adults, unexplained bronchiectasis may be a sign that the patient experienced multiple pulmonary infections throughout life.
●The combination of infectious, autoimmune, and malignant disease is an indicator of immune dysregulation and should prompt consideration of an immune evaluation in a patient of any age.
●Chronic diarrhea or malabsorption and poor wound healing are other potential presentations of immunodeficiency.
The approach to a patient with possible immunodeficiency begins with the consideration of whether a primary or secondary immune problem is more likely. In all age groups, secondary causes of immunodeficiency are more common than primary causes, and this is especially true in older adults.
Secondary causes of immunodeficiency — Secondary causes of immunodeficiency are much more common than primary immunodeficiency disorders in older adults. Common causes of secondary immunodeficiency include:
●Malnutrition (see "Geriatric nutrition: Nutritional issues in older adults")
●Malignancy and drugs to treat malignancy
●Immunosuppressive drugs
●Immunomodulatory agents (eg, rituximab [affecting B cells], infliximab, etanercept, adalimumab, anakinra [affecting cellular immunity]) (see "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab')
●Drug-induced hypogammaglobulinemia (eg, certain antiepileptic medications) (see "Primary humoral immunodeficiencies: An overview", section on 'Differential diagnosis')
●Protein loss (especially if presenting with low IgG but normal IgA and IgM) (eg, nephrotic syndrome, protein-losing enteropathy)
●Metabolic disease (diabetes, severe liver disease, uremia)
●HIV infection
●Functional or surgical asplenia
Evaluation of the immune system in older adults therefore starts with screening for causes of secondary immunodeficiency. As in any area of medicine, the most important initial evaluation is a thorough history: detailed history regarding infections (location, complications, frequency, etc), weight loss (suggesting malnutrition, malignancy, or chronic inflammatory disease), a review of any chronic medical problems (eg, poorly-controlled diabetes mellitus), and detailed medication history (including immunosuppressive and immunomodulatory medications, as well as antiepileptics, with particular attention to drug interactions).
Primary causes of immunodeficiency — Although primary immunodeficiency disorders commonly present in childhood or early adulthood, they can initially present in older adults or may be recognized for the first time in later life, once multiple manifestations of immune dysfunction have developed. The most common example would be common variable immunodeficiency. Specific antibody deficiency (ie, the inability to mount an antipolysaccharide antibody response) may also be diagnosed later in life. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Specific antibody deficiency".)
Initial screening tests for immunodeficiency — Once suspected, evaluation for immunodeficiency in older adults is similar to that in younger adults, with the exception that the emphasis should be on underlying malignancies and other causes of secondary immunodeficiency. We suggest the following initial tests to evaluate immune function in an older adult.
●Complete blood count with differential and smear. Total circulating numbers of white blood cells as well as the differential of the white blood cell count do not change significantly with age.
●Creatinine, electrolytes, liver function tests, blood glucose.
●Urinalysis (to detect proteinuria).
●Total serum protein, prealbumin, albumin, cholesterol (decreased in malnutrition).
●Plasma zinc and selenium levels.
●Serum IgG, IgM, IgA, IgE. Levels of IgG, IgA, and IgM typically do not change with age and may increase slightly. An elevated IgE level is usually seen in atopic diseases but can also serve as a surrogate marker for a skewing of the immune system toward a T helper type 2 response, which would be less efficient at fighting infections. Moreover, IgE can be elevated in parasitic infestations, lymphomas, HIV, and some inflammatory diseases. (See "The biology of IgE".)
●Lymphocyte subsets; this includes enumeration of T, B, and NK cells via flow cytometry.
Expected changes are discussed above (see 'Adaptive immunity' above). The interpretation of immunologic studies is discussed in detail separately. (See "Laboratory evaluation of the immune system".)
Vaccine response — The ability of a patient to respond to vaccination is the next step in evaluating immune function. Response to both protein and polysaccharide antigens is assessed. (See "Laboratory evaluation of the immune system", section on 'Measurement of antibody function'.)
Selective polysaccharide nonresponse is the most common form of functional antibody defect and is best demonstrated by an inability to respond to 23-valent pneumococcal polysaccharide vaccine (PPV-23). However, a clear definition of a normal response to PPV-23 in patients >65 years of age has not been established, and studies are somewhat conflicting, although most have found that responses to PPV-23 are diminished. Relevant studies include the following [121-123,148-151]:
●One group reported that the 30-day response and 5-year persistence of antibodies to pneumococcal polysaccharide vaccine serotypes was preserved irrespective of age [151]. Similarly, in another study of persons >85 years of age, subjects generated adequate antibody responses to the PPV-23 vaccine [121].
●In contrast, another study found that persons >80 years of age demonstrated a decreased IgG antibody response to PPV-23, and the opsonophagocytic activity of these antibodies was relatively poor [122].
●Frailty appeared to impact the quantitative response to vaccines more than numeric age in one report [143,152]. Older adults who responded to the vaccine with titers that were slightly lower than protective sometimes generated protective titers after a second (booster) dose. In this clinical setting, it is reasonable to boost with another dose of PPV-23. However, antibody titers before and after immunization should be compared in order to ensure adequate response and to exclude specific antibody deficiency.
If no abnormalities are uncovered by the testing described above and suspicion is still high for an immunodeficiency, then further work-up would be targeted toward underlying malignancies, presenting symptoms, and less common forms of primary immunodeficiency disorders.
SUMMARY
●Immunosenescence refers to the changes that occur in the immune system with increasing age. The clinical consequences of immunosenescence include an increased risk of infections, malignancy, and autoimmune disorders. Malnutrition is relatively common among older adults and can contribute to declining immune function. (See 'Immunosenescence' above.)
●Aging affects both innate and adaptive immunity, although adaptive processes are affected more dramatically. (See 'Changes in specific components of the immune system' above.)
●The innate immune system consists of epithelial barriers, antimicrobial peptides and mucus, as well as macrophages, neutrophils, natural killer cells, natural killer T cells, dendritic cells, and complement proteins. Some innate immune mechanisms decline with age, while others appear to become more active. The clinical consequence of this increased activity results in a state of immune dysregulation characterized by low-grade, chronic proinflammatory changes. (See 'Innate immunity' above.)
●The adaptive immune system consists of B and T cell responses. With aging, naïve T and B cells decline, while the functions of memory cells are relatively preserved. (See 'Adaptive immunity' above.)
•T cells originate from the thymus, which is active in youth and then undergoes dramatic involution by middle age, with a continued gradual decline in function thereafter. The number of naïve T cells exiting the thymus is significantly decreased, and naïve T cells capable of responding to new infections and antigens drop in number, reducing the T cell repertoire. There is a corresponding decrease in the number of T regulatory cells, which keep the immune system "in check" by maintaining homeostasis, limiting autoimmune responses, and modulating the inflammatory response to infectious agents and tumors. (See 'Cellular immunity: T cells' above.)
•B cells numbers decrease with age, although immunoglobulin levels do not change or sometimes increase. Despite the preservation of the overall amount of immunoglobulin, specific antibody production declines, and the ability of B and T cells to interact and respond vigorously to vaccinations and new infections becomes limited. (See 'Humoral immunity: B cells' above.)
●Immunosenescence is not routinely measured in clinical practice, although several parameters, such as leukocyte telomere length and the "immune risk profile," are used in research settings. (See 'Assessing immunosenescence' above.)
●There are no specific therapies that have been convincingly shown to counter normal immunosenescence. However, adequate nutrition is important, and there may be a role for regular, moderate exercise. In addition, research into how older adults respond to vaccination has resulted in several changes in vaccination guidelines and several potential strategies for creating vaccine preparations that are more effective in this age group. In addition, vaccination against common herpesviruses, such as cytomegalovirus and Epstein-Barr virus, may someday limit the contribution of these viruses to "immunologic exhaustion." (See 'Potential interventions to counter immunosenescence' above.)
●Evaluation of the immune system in older adults is similar to that in younger adults, with a greater emphasis on disorders leading to secondary immunodeficiency. (See 'Evaluation of the immune system in older adults' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.