1/ #Lymphopenia has recently been under the spotlight with the ongoing COVID-19 pandemic.

This is a quick #Tweetorial attempting to decypher the mechanisms behind lymphopenia, its causes and potential consequences.

What is the most common cause of transient lymphopenia?

2/ Lymphocytes are predominantly T cells (~70%, CD4/8), followed by B cells (~10-20%) and NK cells (~10%).

Normal ALC (absolute lymphocyte count) ranges between 4000 and 10000 cells/microL.

Lymphopenia (or lymphocytopenia) is defined by an ALC of <1000 cells/microL for adults.

3/ Lymphopoiesis:
- Production in the bone marrow. All lymphocytes arise from a CLP (common lymphoid progenitor).
- Differentiation, selection of T cells in the thymus.
- All lymphocytes (B, T, NK) then continue their maturation in the periphery (lymph nodes, spleen, MALT).

4/ As you can imagine, any insult (central or peripheral) during this process can lead to decreased production of mature lymphocytes (known as lymphopenia).

Mechanisms of lymphopenia:
- immune damage of progenitor/blood cells or impaired lymphopoiesis (e.g. viral diseases)

5/
- direct infection of blood cells, inducing cell apoptosis and growth inhibition (e.g. viral diseases)
- antibody-dependent cytotoxicity (ADCC) (e.g. SLE)
- complement mediated cytolysis of lymphocytes (e.g. SLE)
- lymphocyte sequestration (e.g. siponimod)
- apoptosis

6/ Common causes of lymphopenia:

- Infection: HIV, coronavirus, influenza, hepatitides, rubeola, polioviruses, varicella-zoster, typhoid fever, brucellosis, malaria, widespread TB, rickettsia, ehrlichia.

Sepsis is the most common cause of transient ALC.

7/
- Auto-immune diseases: SLE, RA, Sjogren's disease, sarcoidosis
- Malignancy: lymphoma, metastatic solid tumors
- Severe malnutrition (most common cause worldwide, related to reduced production.)
- Severe trauma
- Alcohol abuse
- Cushing's syndrome
- Zinc deficiency

8/
- Organ transplants
- GVHD
- Medication-induced: chemotherapy (fludarabine, cladribine), steroids (even inhaled), MTX, AZA, rituximab, carbamazepine, MS drugs (siponimod, NTZ), etc.
- Total body irradiation
- Congenital immunodeficiencies (SCID, DiGeorge syndrome)
- Idiopathic

9/ Lymphopenia is usually reversible and most frequently associated with acute illness (sepsis, trauma, major surgery).

There is a diurnal variation in lymphocyte counts, probably related to a change in corticosteroid levels.

10/ Early morning venous sampling from patients resting in bed has important physiological influences on the lymphocyte count and subset numbers.

Careful with interpretation of moderately-low ALC in hospitalized patients in early AM (nadir): doi:10.3109/00365513.2011.602422

11/ Prolonged and severe lymphopenia (~6% of total cases) predisposes to opportunistic viral (PML, CMV reactivation, hepatitis B reactivation, VZV reactivation), fungal (PJP, disseminated Cryptococcus & Candida) and mycobacterial infections (TB, MAC).

12/ When faced with prolonged lymphopenia:

Evaluate medication list for unnecessary medications that could be contributing to the problem.
Assess HIV status.
Measure lymphocyte subpopulations by flow cytometry and immunoglobulin levels to further characterize deficiency.

13/ No interventions are generally necessary for patients with asymptomatic lymphocytopenia without an associated illness.

Degree of #COVID19-related lymphopenia is proportional to severity of disease (more common with ARDS) & improves with resolution of disease.

14/ Remember that lymphopenia is not specific to #COVID19. Ask for medication list and look for underlying immunosuppression.

15/ For further reading:

Kipps TJ. Chapter 81. Lymphocytosis and Lymphocytopenia. Williams Hematology, 8e New York, NY: McGraw-Hill; 2010.

Castelino et. al: https://www.ncbi.nlm.nih.gov/pubmed/9145181 

Davids:
https://www.uptodate.com/contents/approach-to-the-adult-with-lymphocytosis-or-lymphocytopenia