Low Lymphocyte Levels Correlate with Greater Mortality in Late Life

Lymphopenia is the condition of having lower than normal levels of lymphocytes, a mix of cells of the adaptive and innate immune system, in blood samples. The immune system is of vital importance to health, and this is demonstrated here by data that shows raised mortality in the sizable fraction of older people with degrees of lymphopenia versus those without. Lymophocytes do not just respond to the presence of infectious pathogens, but also attack and destroy senescent cells and cancerous cells, among other important activities. A severely deficient immune system is a real threat to life, and as this work illustrates, even a modestly deficient immune system is something to worry about.

The near future should see the advent of approaches to restore immune function in the elderly. Regrowth of the atrophied thymus, where T cells of the adaptive immune system are trained; restoration of the declining hematopoietic stem cell population responsible for creating immune cells in the bone marrow; clearance of harmful populations of misconfigured, senescent, and exhausted T cells in the aged immune system; regeneration of fibrotic and structurally disrupted lymph nodes. These four approaches, as they are enacted, should go a long way towards ensuring a healthier, longer life for older people.

This study sought to (1) determine the associations among lymphocyte levels, other immunohematologic parameters, and survival and (2) establish the extent to which the associated risk of these variables is additive. In this large cohort of adults, we found that lymphopenia was associated with mortality risk independently of traditional clinical risk factors and other immunohematologic variables (red blood cell distribution width and C-reactive protein level). Individuals with multiple immunohematologic abnormalities had a strikingly high risk of mortality among this generally low-risk population. Approximately 20% of the general US population appears to have a high-risk immunohematologic profile, and these participants' 10-year mortality was 28%, compared with 4% in participants in the present study with a low-risk profile. The risk associated with this immunohematologic pattern is independent of (and thus additive to) traditional clinical risk factors. Together, these data suggest that immunohematologic risk may be viewed as a multidimensional entity and can be estimated using markers commonly available as part of routine clinical care.

We believe the results presented herein add to the growing body of evidence that immune status is associated with cardiovascular and noncardiovascular disease. Previous observational and prospective trials suggest that participants with overt or subacute inflammatory diseases have elevated risk of atherothrombotic disease, heart failure, malignant disease, and death. Comparatively few studies have evaluated absolute lymphocyte count as a prognostic biomarker. Herein, we found that lymphopenia is relatively common in the general population and is associated with reduced longevity independently of age, clinical risk factors, and other immunohematologic parameters. In our fully adjusted analyses, a bimodal relationship between lymphocyte counts and mortality emerged, suggesting that the expansion of lymphocytes may also introduce hazard in the general population.

Because mortality in this population was largely driven by noninfectious causes, these data support the notion that immune status is indeed associated with resilience against cancer and cardiovascular disease, and an adverse immune phenotype may precede clinical manifestations of these illnesses. Whether lymphocyte levels are themselves part of the causal pathways linking lymphopenia to death will require additional study. Cytotoxic T cells can eradicate cells with malignant potential, and thus an optimal absolute lymphocyte count may reflect an immune system capable of providing protection against tumor development. Lymphopenia can also induce compensatory proliferation of antigen-experienced T cells, which could increase the risk of cardiovascular disease. In those with lymphocytosis, dysregulated expansion of memory T cells, whether driven by indolent viral infections (eg, cytomegalovirus) or other mechanisms, may induce a proinflammatory milieu and similarly elevate the risk of incident cardiovascular disease.

Lymphopenia may also reflect adverse inflammatory, metabolic, or neuroendocrine stressors and thus be associated with survival as an epiphenomenon. The administration of tumor necrosis factor, interleukin 1β, or microbial products reduces levels of circulating T cells. Excess levels of cortisol and catecholamine also cause lymphopenia. In these disease and models systems, lymphopenia was caused by redistribution of T cells from the circulation to lymphoid tissues and an increased susceptibility of T cells to apoptosis. Thus, additional study is needed to characterize the immune, metabolic, and neuroendocrine profiles in those with dysregulated T-cell homeostasis and to explore the lines of causation and effect that may contribute to resilience and longevity in the primary prevention setting.

Link: https://doi.org/10.1001/jamanetworkopen.2019.16526

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