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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?
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.
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).
- 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)
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
- 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.
- 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
- 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
- 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.
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
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.
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.
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
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
