What is lymphopenia?

Your immune system is constantly working to protect you against countless threats every day, ranging from simple colds to life-threatening diseases. The cells that make up our immune system act like the body’s defense team when they come across potential threats. Among these, white blood cells, also called leukocytes, play a crucial role in identifying threats and responding to them. 

Immune system disorders can result from infections, allergies, immune deficiencies, or autoimmune conditions. Individuals affected by them experience immune system malfunctions, which compromise the body’s ability to defend against threats, making them vulnerable to a range of health problems. 

Lymphopenia, also known as lymphocytopenia, is a condition where the number of lymphocytes, a type of white blood cell (WBCs) in an individual’s blood, is abnormally low.¹ The name of the condition derives from”penia”, meaning deficiency, specifically of lymphocytes. 

Lymphocytes can be distinguished into three main cell types, based on their function:

• B cells - responsible for antibody production 
• T cells - responsible for overall immune regulation and eradication of abnormal cells 
• NK cells (Natural Killer cells)

In most cases of lymphopenia, T cells are predominantly affected, particularly Helper (CD4+) T cells. As a result, those affected by the condition usually show a reduced number of T cells in blood tests.^1,2 

It is important to understand that lymphopenia describes the deficiency of lymphocytes and is more of a haematological finding rather than a standalone disease. To better understand the disease profile, lymphopenia is categorised into two main types: primary lymphopenia and secondary lymphopenia. This article will explore lymphopenia and compare the causes, symptoms, and diagnosis, as well as available treatment options for both primary and secondary lymphopenia. 

Primary lymphopenia

Primary lymphopenia is often associated with a group of immune disorders, called primary immunodeficiencies (PIs). These disorders are called “primary” due to their genetic or congenital (present from birth) origin. Primary lymphopenia has been linked to several genetic conditions.³ 

Causes

Primary lymphopenia results from a genetic mutation that could be inherited (i.e., passed from parents) or occur newly in an individual. The resulting primary immunodeficiency impairs the development of lymphocytes, ultimately causing a low lymphocyte count. 

The primary immunodeficiencies that are most commonly associated with primary lymphopenia include:

Severe Combined Immunodeficiency (SCID)

SCID is used to describe a group of rare disorders that significantly weaken the immune system. SCID causes impaired development and production of immune cells, mostly T cells.⁴ This condition is often diagnosed in infancy, following recurrent infections that have a severe impact on the infant’s health.

WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome

This rare condition, named after the four clinical outcomes it causes, leads to chronic lymphopenia and subsequently to a high susceptibility to life-threatening infections.⁵

Wiskott-Aldrich Syndrome (WAS)

Individuals with WAS carry mutations in the WAS gene, which is located on their X chromosome, and is important for the cytoskeletal function of immune cells, as well as cell signalling. As a result, WAS leads to impaired immune cell function and impaired maturation of lymphocytes, contributing to lymphopenia.⁶

DiGeorge syndrome

This congenital condition can cause a wide range of complications that significantly affect the individual’s quality of life, with one of them being impaired T cell maturation and resulting lymphopenia due to defective development of the thymus.⁷ 

Onset

Given that primary lymphopenia is almost always caused by primary immunodeficiencies with a genetic or congenital molecular basis, symptoms typically appear in early childhood or infancy. 

Symptoms

Primary lymphopenia directly affects the immune system, leading to a high risk of infection and a low level of protection against threats.¹ As a general rule, individuals with primary lymphopenia experience frequent recurrent and unusual infections that can be of mild to extreme severity. In affected children or infants, the constant battle against infections prevents adequate nourishment of the body, leading to poor growth and failure to thrive. In addition, symptoms specific to the associated primary immunodeficiencies, such as eczema and heart defects, may be apparent in these individuals.

Diagnosis

Diagnosis of primary lymphopenia usually relies on clinical suspicion as a result of recurrent or unusual infections. Common diagnostic tools used in the laboratory include:⁸

• Complete Blood Count (CBC) test with differential, where the absolute lymphocyte count is measured
• Flow Cytometry test, where specific immune cell types, like CD4+ T-cells are measured. Results from this method help identify which primary immunodeficiency is responsible for the condition
• Serum Immunoglobulin Level testing, which measures levels of antibodies such as IgG, IgA, IgM etc., which are normally produced by B-cells. Low antibody counts suggest a low lymphocyte population
• Genetic testing, where specific mutated genes are identified and the specific immunodeficiency responsible for the abnormally low lymphocyte count is confirmed

Treatment 

Therapeutic options for primary lymphopenia often focus on controlling infections and treating the underlying immunodeficiency. Treatment usually includes:

• Appropriate medication for infections (antimicrobials)
• Immunoglobulin replacement therapy- for cases where low antibody levels are detected, immunoglobulin infusions offer a significant boost against infections⁹ 
• Bone marrow transplant- for individuals with severe underlying conditions, as in the case of SCID, this approach stands as a great curative treatment because of its ability to directly replace impaired immune cells with healthy new ones¹⁰
• Gene therapy- another promising treatment for genetic defects, that aims tos correct or replace the impaired gene responsible for the disease¹¹

Secondary lymphopenia

Secondary lymphopenia differs from the primary form in that it is “acquired”. While primary lymphopenia is caused by rare genetic conditions, secondary lymphopenia is caused by various medical conditions, infections, as a response to medication, or due to other external factors. For this reason, secondary lymphopenia is more common compared to the primary type. 

It is important to distinguish that, contrary to primary lymphopenia, people with secondary lymphopenia might have a healthy baseline for their immune system, which later becomes affected by an external factor.

Causes

The underlying causes of secondary lymphopenia are diverse and the most common triggers can generally be divided into the following groups.

Infections

Viral infections often deplete the body of immune cells, as in the case of HIV, where T cells are directly targeted, causing severe lymphocyte depletion and therefore lymphopenia. Additionally, viruses like influenza, Epstein-Barr virus (EBV), and more recently, COVID-19, have been shown to cause a substantial temporary decline in lymphocytes.¹²

Bacterial infections are a less common culprit for secondary lymphopenia; however, severe infections like sepsis or tuberculosis can lead to a range of problems, with lymphopenia being one of them.^13,14 

Medications 

Several medications suppress the immune system and contribute to lymphopenia, including:^15,16

• Corticosteroids- may temporarily cause lymphocyte depletion due to strong anti-inflammatory action.
• Chemotherapy / Radiation Therapy- while these are used to kill rapidly dividing cancer cells, they can also affect cells of the immune system.
• Immunosuppressive medication- used after organ transplants or for autoimmune diseases, these drugs intentionally suppress the function of the immune system. 

Autoimmune diseases 

Conditions, such as rheumatoid arthritis (RA), Systemic Lupus Erythematosus (SLE), and Hodgkin lymphoma, may trigger the immune system to attack its own tissues, sometimes destroying lymphocytes during this process, leading to lymphopenia.¹ 

Lifestyle influence

Dietary deficiencies due to poor nutrition (e.g., zinc and vitamin deficiencies), chronic alcohol use, and stress may sometimes contribute to suppression and damage of the immune system, leading to decreased lymphocyte populations.¹⁷ 

Onset

The onset of secondary lymphopenia depends entirely on the underlying cause and, therefore, is not limited to a specific age group. The onset can be sudden as with infections or medications, or could be more gradual when it is triggered by long-term autoimmune diseases or lifestyle choices.

Symptoms

Symptoms of secondary lymphopenia show an overlap with the symptoms of the underlying condition, alongside general symptoms of immunosuppression, which include:

• Increased susceptibility to infections 
• Slow wound healing
• Fever
• Fatigue

In certain instances, secondary lymphopenia may not show any symptoms at all, especially in the milder forms or in cases where the underlying condition is temporary. 

Diagnosis

Diagnosis of secondary lymphopenia involves a combination of medical and drug history reviews and blood workup. 

Treatment 

Management of secondary lymphopenia lies in addressing the underlying causes of the condition. For infections, treatment with appropriate antibiotics, antivirals, or antifungals can eliminate symptoms. For medication-induced lymphopenia, the dosage of the drug may need to be adjusted, or switching to a different medication with discontinuation of the offending drug may be required. Secondary lymphopenia driven by autoimmune disorders is harder to treat due to the complicated nature of the trigger; however, controlling the autoimmune process can significantly help restore lymphocyte populations. Lastly, lifestyle choices leading to lymphopenia may need to be changed by improving nutrition through a proper diet, cessation of alcohol, and stress reduction to regain proper immune function. 

What are the main differences between primary and secondary lymphopenia?

Summary

Lymphopenia is a serious health condition that arises as a result of an underlying cause. Based on the nature of this cause, lymphopenia is categorised into primary and secondary forms. Primary lymphopenia is due to genetic or inherited factors, while secondary lymphopenia arises from acquired causes such as infections, medications, and autoimmune conditions. Understanding the distinction between these two types is crucial for accurate diagnosis and for choosing the correct management plan. If you or someone you know experiences frequent infections that seem unusual, do not hesitate to consult a healthcare professional, as an early diagnosis can significantly help combat symptoms of lymphopenia and lead to a better long-term prognosis.