Studies have shown that fungal infections are significantly higher in patients with severe COVID-19 and low lymphocyte levels than in patients with high lymphocyte levels, indicating that patients with lymphopenia may be more susceptible to microbial infections. Additionally, microbial infection has been shown to increase disease progression and severity. 

Clinical Implications of SARS-CoV-2-induced Lymphopenia: Microbial Infection 

There are several proposed mechanisms for lymphocyte depletion and exhaustion:

- Direct entry of SARS-CoV-2 into T cells and macrophages due to interactions between S proteins on the virus and ACE2 receptors on lymphocytes (especially T cells)
- Increased inflammatory cytokines may cause T cell depletion and exhaustion
- Destruction of lymphatic organs, inducing lymphopenia
- Increased levels of lactic acid, which may inhibit lymphocyte proliferation  

Potential Mechanisms of SARS-CoV-2-induced Depletion and Exhaustion of Lymphocytes 

Cytokine and SARS-CoV-2 entry into the median eminence of the hypothalamus could activate the autonomic nervous system and the release of adrenal catecholamines and steroids. These effectors could act on the bone marrow to release immunosuppression neutrophils and myeloid cells, leading to immunosuppression and lymphopenia. 

The Hypothalamus: Potential Role in Immune Dysregulation and Lymphopenia

Decreased levels of lymphocytes, or lymphopenia, is a key indicator of severe COVID-19. While T cell and NK cell levels have been found to be significantly reduced, B cell count remains within a normal range. Because lymphopenia is so distinctive of COVID-19, it has been proposed as a tool to measure both the severity of COVID-19 and the prognosis of the patient. 

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Patients with severe COVID-19 are known to exhibit uncontrolled pro-inflammatory responses to SARS-CoV-2. As a result, these patients have lymphopenia, lymphocyte activation and dysfunction, granulocyte and monocyte abnormalities, high cytokine levels, and elevated immunoglobulin G and total antibodies. 

The Immunopathology of COVID-19

Yang, Li, et al. “COVID-19: Immunopathogenesis and Immunotherapeutics.” Signal Transduction and Targeted Therapy, vol. 5, no. 1, 2020, doi:10.1038/s41392-020-00243-2.

https://www.nature.com/articles/s41392-020-00243-2

COVID-19: Immunopathogenesis and Immunotherapeutics

Lymphopenia 

Studies have shown that T cells are very active in response to SARS-CoV-2. As a result, patients with COVID-19 can show evidence of T cell exhaustion. In severe cases, apoptosis in CD8+ T cells is unusually frequent, also reducing functional diversity. 

Lymphocyte Activation and Dysfunction 


The relative number of neutrophils compared to lymphocytes is much higher in severe cases of COVID-19 than in non-severe cases. However, there is a decreased percentage of eosinophils (indicates parasitic infections), basophils (indicates allergic reactions), and monocytes in severe patients. A low monocyte count makes it difficult to fight off viral infections, and neutrophils aid in bacterial infections, not viral.

Abnormalities of Granulocytes and Monocytes 

While IgM and IgG are both SARS-CoV-2-specific antibodies, the level of IgG is more closely correlated with the severity of the disease and therefore can be used to evaluate severity and prognosis. However, a quicker test can be done on the total antibody level, in which higher levels are indicative of worse patient outcomes.

Increased Antibodies

Even though SARS-CoV-2 and SARS-CoV infection is initiated by similar innate and adaptive immune responses, there is no strong evidence that would indicate that lymphopenia, lymphocyte dysfunction, and granulocyte and monocyte abnormalities are associated with SARS-CoV, therefore making these abnormalities unique to SARS-CoV-2. 


Comparison with SARS-CoV-induced Immunopathology 


Severe cases of COVID-19 tend to exhibit a “cytokine storm”, which is an extreme increase in certain inflammatory cytokines. While patients with non-severe COVID-19 have an upregulated level of some of the same cytokines, the amount and diversity of cytokines are much less than that of severe cases. 

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