Why these health conditions make Covid-19 more deadly

These are the main at risk groups for poor outcomes to SARS-CoV-2. In this article I look at specifically why this is the case with regard to immune function.

Older age

Older people are more likely to show the severe form of Covid-19. In addition to less accurate immune responses in aged patients, comorbidities are inevitably more frequent with ageing.

In immune system terms, the number of leukocytes decreases and the ratio of immune cells in the peripheral blood and lungs changes with age. The number of CD8 T cells, proliferation, and granzyme + T cells, for example, have been shown to be significantly reduced in older monkeys.

The compensatory effect, however, of IL-7 (interleukin-7 is a cytokine that promotes lymphocyte development) stimulation on the number of T cells has recently been indicated. Immune B cell population decreases, followed by the reduction of neutralizing antibodies and mucosal IgA in the elderly, resulting in a more compromised immune response.

Decreased pulmonary dendritic cells and macrophages in old age are accompanied by a decrease in the frequency of co-stimulatory CD86 + cells through SARS infection. Senescence leads in the accumulation of Reactive  Oxygen Species due to the attenuated antioxidative defence system. Redox imbalance activates of redox-sensitive transcription factors, such as nuclear factor kappa B (NF-κB), which promote the expression of proinflammatory genes, including IL1β, IL6, TNFα, and adhesion molecules.

On the other hand, NF-κB activation negatively inhibits type I IFN signaling. In fact, the disease outcomes depend on the balance between the antiviral and proinflammatory responses, which are negatively influenced by aging. There is a correlation between ACE2 expression and COVID-19 fatality. Different expression of ACE2 during adulthood is another cause for the severity of SARS-CoV 2 disease in aged patients.


Sex Hormones

Decreased sensitivity of females to COVID-19 disease could be explained by sex hormones

  • Estrogen acts as an immunomodulatory factor in females, while
  • Testosterone is an immunosuppressor.
  • SARS-CoV-2 replication is suppressed by estrogen signaling in females, so they have a lower viral load.

During an inflammation, estrogens repress monocyte-macrophage infiltration and NFκβ activation via suppression of special micro-RNAs such as miR125 and let7a in macrophages.

Ovariectomy or estrogen receptor antagonists increase monocyte-macrophage and neutrophil recruitment into the lung of the SARS-CoV-2 infected female mice and increase disease severity and mortality.

Immune related genes on the X chromosome play a crucial role in feminine protection. For example, overexpression of TLR-7 in women, which is located on the X chromosome, upregulates IFN-β in plasmacytoid dendritic cells and improves antiviral protection. Estrogen also enhances the ACE2 mRNA levels and reduce disease fatality in women.


Obesity increases the secretion of various cytokines and adipokines, such as TNF-α, IL-6, TGF-β, leptin, and adiponectin, which causes an inflammatory basal state that delays innate and acquired immune responses and allows the virus to spread.

Suppressor of cytokine signaling (SOCS) proteins are upregulated in the peripheral blood mononuclear cell (PBMC) and lungs of obese individuals and inhibit the production of type I and type III IFNs and pro-inflammatory cytokines. In obese mice, alveolar macrophages are reduced and less capable to express type I IFN receptor and IFN-stimulated genes. CD4+ and CD8 + T cells of obese individuals produce more IL-5 and fewer IFN-γ, TNFα, granzyme B, and CD40 ligand.

Obesity also increases the risk of many comorbidities such as type II diabetes, cancer and cardiovascular disease, leading them to severe COVID-2019 infection. Diabetes, hypertension and cardiovascular disease are other risk factors for COVID-19 that are associated with obesity, as these disorders are more common in people with higher BMIs.

Renin–Angiotensin–Aldosterone System (RAAS) inhibitors, such as ACE inhibitors, angiotensin II type 1 receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) are conventional treatments for these conditions. RAAS inhibition increases expression of ACE2, so it enhances the viral load and prone individuals to the detrimental outcomes.

Different mechanisms are associated with immune paralysis in diabetes include: a) decrease the secretion of IFN-γ and TNF-α by T cells, NK cells, and macrophages, b) declined MHC-І expression and also antibody biological function because of glycation.

Intensive immunosuppressive drugs are used in cancer patients make them sensitive to various viral infections, including SARS-CoV-2. Lung macrophages in smokers suppress the immune system more than non-smokers. These macrophages secrete low levels of IL-1, IL-6 and TNF-α. NK cell activity and serum levels of IgG and IgA are reduced in smokers. ACE2 expression is also increased in tobacco users.