A hematology @tony_breu-style tweetorial:

Why does lymphopenia occur in #COVID19?

A normal WBC count and lymphopenia are seen in patients affected by COVID-19, but why it occurs has bothered me since the pandemic onset.

The potential answer is surprising and interesting.
First, what do you think the mechanism is?
Does the degree of lymphopenia correlate with survival?
At what lymphocyte percentage is there a worse likelihood of survival?
First, brief review time!

What types of cells are considered lymphocytes?
(Very) simply put, lymphocytes are comprised of and have the following functions:

B-cells = make antibodies

T-cells = cytotoxic and cytokine production

NK-cells = help destroy infected cells and cancer cells

(some) Dendritic cells = antigen presentation / cytokine production
Lymphopenia is common in the setting of acute infection.
Lymphocytopenia is a common occurrence in the setting of acute infection.

Though commonly ignored on the diff, neutrophilia seen in bacterial infections is often accompanied by lymphopenia.
It is also seen in many other conditions, including cancers, SLE, RA, MS, sarcoidosis.

Steroids, including high levels of cortisol, are lytic to lymphocytes and induce apoptosis.

Fewer lymphocytes = few auto-antibodies.

This is why we use steroids in autoimmune disease!
Certain chemotherapy agents (i.e. fludarabine, rituximab, melphalan) are known to cause lymphopenia.

This effect is used to therapeutic advantage in diseases such as CLL, lymphomas, and preparation for bone marrow transplants!
Certain viral infections cause lymphopenia:

HIV leads to an isolated CD4+ lymphocyte depletion.

H1N1 influenza led to lymphopenia with an associated monocytosis.

...and recently, SARS Cov2 has been associated with lymphopenia in 80+% of cases.
As you probably know, SARS Cov2 uses the ACE2 receptor.

What cell types express the ACE2 receptor?
ACE2 receptor expression occurs on numerous multiple tissue types, including type II pneumocytes, gastrointestinal endothelial cells, cardiac myocytes, along with many other cell types.

This creates a wide phenotype of illness, ranging from URI sx, cough, nausea, and diarrhea:
Mechansims of illness:

Type II pneumocytes → loss of surfactant → cough, hypoxia → ARDS → respiratory failure

GI tract → nausea, vomiting, diarrhea

Cytokine release → High TNFα, IL-6, and other pro-inflammatory cytokines can induce lymphocyte deficiency →fever/chills
...interestingly, the ACE2 receptor is expressed on lymphocytes, mainly those within oral mucosa, digestive system, and lungs.

Given these findings, this suggests the following mechanisms for lymphopenia:
1. Direct invasion / destruction of lymphocytes via ACE2 receptor

2. Disordered cytokine release → lymphocyte apoptosis

3. Lymphatic organ damage → damage to organs like the thymus and spleen may occur

4. Severe acidemia may suppress the proliferation of lymphocytes
However, which of the lymphocyte subgroups do you think is most predominantly affected by SARS Cov2?
Among lymphocyte subgroups, B cells exhibited the most significant differences from the non-COVID-19-infected pneumonia patients.

As B cells are responsible for the humoral immunity by producing antibodies, an inadequate B cell response may fail to restrict viral replication!
...so if this is true, does the severity of lymphopenia correlate with survival?
A recent study by Zheng et al. examined this and discovered that not only is the degree of lymphopenia correlated with disease severity, but is also correlated with probability of survival.

Survival was found to be lower particularly when lymphocyte count was <20%!
So, to summarize, what is the mechanism of lymphopenia?
Does the degree of lymphopenia correlate with survival?
At what threshold is there a worse likelihood of survival?

Lymphopenia occurs via direct viral invasion due to ACE2 expression on lymphocytes

Also cytokine and/or lactic-acid excess → apoptosis

B-cells are most affected → loss of humoral immunity may worsen infection

Lymphocyte count <20% = worse prognosis / survival
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