A Mechanism for Severity of Disease in Older Patients with COVID-19: The Nexus between Telomere Length and Lymphopenia

AbstractBackgroundLymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count.MethodsOur sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres.ResultsLymphocyte count (109/L) was 0.91 ± 0.42 in COVID-19 patients and 1.50 ± 0.50 in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients.ConclusionsThese results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

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The Nexus Between Telomere Length and Lymphocyte Count in Seniors Hospitalized With COVID-19

The Journals of Gerontology Series A ◽

10.1093/gerona/glab026 ◽

2021 ◽

Cited By ~ 1

Author(s):

Athanase Benetos ◽

Tsung-Po Lai ◽

Simon Toupance ◽

Carlos Labat ◽

Simon Verhulst ◽

...

Keyword(s):

T Cell ◽

Telomere Length ◽

Lymphocyte Count ◽

Older Persons ◽

Southern Blotting ◽

Mononuclear Cells ◽

The Novel ◽

Peripheral Blood Mononuclear ◽

T Cell Lymphopenia ◽

Registration Number

Abstract Profound T-cell lymphopenia is the hallmark of severe coronavirus disease 2019 (COVID-19). T-cell proliferation is telomere length (TL) dependent and telomeres shorten with age. Older COVID-19 patients, we hypothesize, are, therefore, at a higher risk of having TL-dependent lymphopenia. We measured TL by the novel Telomere Shortest Length Assay (TeSLA), and by Southern blotting (SB) of the terminal restriction fragments in peripheral blood mononuclear cells of 17 COVID-19 and 21 non-COVID-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. TeSLA tallies and measures single telomeres, including short telomeres undetected by SB. Such telomeres are relevant to TL-mediated biological processes, including cell viability and senescence. TeSLA yields 2 key metrics: the proportions of telomeres with different lengths (expressed in %) and their mean (TeSLA mTL), (expressed in kb). Lymphocyte count (109/L) was 0.91 ± 0.42 in COVID-19 patients and 1.50 ± 0.50 in non-COVID-19 patients (p < .001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kb (p = .005) and positively correlated with TeSLA mTL (p = .03). Lymphocyte count was not significantly correlated with SB mTL in either COVID-19 or non-COVID-19 patients. We propose that compromised TL-dependent T-cell proliferative response, driven by short telomere in the TL distribution, contributes to COVID-19 lymphopenia among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons. Clinical Trials Registration Number NCT04325646.

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Measurement of Proinflammatory Cytokines and T-Cell Proliferative Response in Superantigen-Activated Human Peripheral Blood Mononuclear Cells

Superantigen Protocols ◽

10.1385/1-59259-367-4:137 ◽

2003 ◽

pp. 137-149

Author(s):

Teresa Krakauer

Keyword(s):

T Cell ◽

Proinflammatory Cytokines ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Proliferative Response ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Peripheral Blood Mononuclear ◽

Cell Proliferative Response ◽

Blood Mononuclear Cells

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Prostaglandin E2 is Variably Induced by Bacterial Superantigens in Bovine Mononuclear Cells and Has a Regulatory Role for the T Cell Proliferative Response

Immunobiology ◽

10.1016/s0171-2985(00)80069-8 ◽

2000 ◽

Vol 201 (5) ◽

pp. 493-505 ◽

Cited By ~ 20

Author(s):

Anke Hendricks ◽

Wolfgang Leibold ◽

Volkhard Kaever ◽

H.-Joachim Schuberth

Keyword(s):

T Cell ◽

Prostaglandin E2 ◽

Proliferative Response ◽

Mononuclear Cells ◽

Regulatory Role ◽

Cell Proliferative Response ◽

Bacterial Superantigens

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Influence of the conformation of a macromolecule on the generation of T-cell proliferative response A study with model polypeptides

FEBS Letters ◽

10.1016/0014-5793(94)00708-x ◽

1994 ◽

Vol 349 (3) ◽

pp. 380-384 ◽

Cited By ~ 2

Author(s):

E. Lacassie ◽

A. Delmas ◽

Y. Trudelle

Keyword(s):

T Cell ◽

Proliferative Response ◽

Cell Proliferative Response

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Impairment of Antigen-Specific T Cell Proliferative Response in B Cell Suppressed Mice

In Vivo Immunology - Advances in Experimental Medicine and Biology ◽

10.1007/978-1-4684-9066-4_84 ◽

1982 ◽

pp. 609-615 ◽

Cited By ~ 1

Author(s):

Yacov Ron ◽

Patrick De Baetselier ◽

Julius Gordon ◽

Michael Feldman ◽

Shraga Segal

Keyword(s):

T Cell ◽

B Cell ◽

Proliferative Response ◽

Cell Proliferative Response

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Mechanisms of age-related decline in antigen-specific T cell proliferative response: IL-2 receptor expression and recombinant IL-2 induced proliferative response of purified tac-positive T cells

Mechanisms of Ageing and Development ◽

10.1016/0047-6374(86)90089-8 ◽

1986 ◽

Vol 36 (3) ◽

pp. 223-241 ◽

Cited By ~ 89

Author(s):

Shigeru Negoro ◽

Hideki Hara ◽

Susumu Miyata ◽

Osamu Saiki ◽

Toshio Tanaka ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Proliferative Response ◽

Receptor Expression ◽

Cell Proliferative Response ◽

Age Related

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FUNCTIONAL ROLES OF HUMAN CLASS II ANTIGENS IN T CELL PROLIFERATIVE RESPONSE COMPARISON OF THE DR AND DQ MOLECULES USING MOUSE MONOCLONAL ANTIBODIES

European Journal of Immunogenetics ◽

10.1111/j.1744-313x.1986.tb01125.x ◽

1986 ◽

Vol 13 (5-6) ◽

pp. 401-414 ◽

Cited By ~ 4

Author(s):

R.-F. Chen ◽

H. Maeda

Keyword(s):

Monoclonal Antibodies ◽

T Cell ◽

Proliferative Response ◽

Class Ii ◽

Human Class ◽

Functional Roles ◽

Cell Proliferative Response ◽

Class Ii Antigens

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Is the subcutaneous route an alternative for administering ertapenem to older patients? PHACINERTA study

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz385 ◽

2019 ◽

Vol 74 (12) ◽

pp. 3546-3554 ◽

Cited By ~ 2

Author(s):

Claire Roubaud Baudron ◽

Rachel Legeron ◽

Julien Ollivier ◽

Fabrice Bonnet ◽

Carine Greib ◽

...

Keyword(s):

Older Patients ◽

Older Persons ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Antibiotic Administration ◽

Subcutaneous Route ◽

Final Model ◽

Once Daily ◽

The Mean ◽

Pharmacodynamic Data

Abstract Background Antibiotic administration by subcutaneous (SC) injection is common practice in French geriatric wards as an alternative to the intravenous (IV) route, but few pharmacokinetic/pharmacodynamic data are available. Ertapenem is useful for the treatment of infections with ESBL-producing enterobacteria. Objectives To report and compare ertapenem pharmacokinetic data between IV and SC routes in older persons. Methods Patients >65 years of age receiving ertapenem (1 g once daily) for at least 48 h (IV or SC, steady-state) were prospectively enrolled. Total ertapenem concentrations [residual (C0), IV peak (C0.5) and SC peak (C2.5)] were determined by UV HPLC. Individual-predicted AUC0–24 values were calculated and population pharmacokinetic analyses were performed. Using the final model, a Monte Carlo simulation involving 10 000 patients evaluated the influence of SC or IV administration on the PTA. Tolerance to ertapenem and recovery were also monitored. ClinicalTrials.gov identifier: NCT02505386. Results Ten (mean ± SD age=87±7 years) and 16 (age=88±5 years) patients were included in the IV and SC groups, respectively. The mean C0 and C2.5 values were not significantly different between the IV and SC groups (C0=12±5.9 versus 12±7.4 mg/L, P=0.97; C2.5=97±42 versus 67±41 mg/L, P=0.99). The mean C0.5 was higher in the IV group compared with the SC group (C0.5=184±90 versus 51±66 mg/L, P=0.001). The mean individual AUCs (1126.92±334.99 mg·h/L for IV versus 1005.3±266.0 mg·h/L for SC, P=0.38) and PTAs were not significantly different between groups. No severe antibiotic-related adverse effects were noted. Conclusions SC administration of ertapenem is an alternative to IV administration in older patients.

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