Introduction

When you get an infection, your body fights it using your immune system.Your body has lots of different white blood cells that help fight infections, and one such type of white cells is lymphocytes. If your body is fighting an infection, you might find a higher number of lymphocytes in your blood than normal, and this increase is known as lymphocytosis.¹ It often shows when medical professionals carry out blood tests to diagnose you. Most often, viral infections cause lymphocytosis, but bacteria and parasites can also make the number of lymphocytes go up.²

Role of lymphocytes and mechanisms of lymphocytosis in viral infections

Viruses can infect different types of cells; some viruses infect lymphocytes directly causing different changes in lymphocyte levels.³ Viruses have small surface proteins called antigens. Our immune cells, including lymphocytes, can recognise these antigens as things that don’t belong in our body naturally and use them to attack the viruses.⁴ Lymphocytes usually make up between 20%-40% of the total white blood cell count (WBC). However, if there is an infection present, lymphocytes can increase in number to make up more than 40% of the WBC (i.e. lymphocytosis).¹ They may become larger in size and change shape slightly to create atypical lymphocytes; they are distinct under a microscope helping diagnosis.⁵

The two main types of lymphocytes include T cells and B cells, and they both have different methods of attack. T cells directly destroy any cells that are infected by foreign pathogens such as viruses (i.e. cell-mediated immunity). B cells indirectly attack viruses by first producing proteins known as antibodies.⁴ Antibodies stick to surface proteins (antigens) to block the viruses from doing further harm and can act as a marker so that cells from the immune system can recognise them and destroy them. Lymphocytes can also turn into memory cells that remember that specific virus or foreign pathogen and quickly grow in number if they come across the same pathogen during a subsequent infection.⁴ 

Many cells also release proteins called cytokines, which work as chemical messengers, sending signals to other immune cells, such as lymphocytes, to multiply or go to where the infection is and fight the virus.⁶

Common viral infections associated with lymphocytosis

Infectious mononucleosis

Infectious mononucleosis, also known as “mono” or glandular fever, is a sickness caused by Epstein-Barr virus (EBV). It often affects teenagers and young people from 15 to 24.⁷ EBV is passed around by being in contact with body fluids, most often saliva (e.g., by kissing or sharing drinks).⁸ EBV specifically infects B cells found in the throat, leading to symptoms such as a sore throat (pharyngitis), fever, tiredness and sore, swollen lymph nodes (lymphadenopathy).⁷ This is a classic example of lymphocytosis with atypical lymphocytes,^1,9 caused by infection of lymphocytes directly. The number of lymphocytes can go above 50% of the WBC.⁷

Cytomegalovirus (CMV)

Cytomegalovirus (CMV) is a common virus that typically spreads through close contact with body fluids (e.g., saliva, pee (urine), poo (stool), breast milk, blood and semen through sex) of someone who has it already.¹⁰ It usually doesn’t cause any harm, but it can cause mild symptoms in people who get this sickness for the first time. More severe symptoms may appear in babies who got it through their mother during pregnancy (i.e. congenital CMV) or people who have weaker immune systems (immunocompromised).¹¹ CMV, like EBV, causes lymphocytosis with atypical lymphocytes, with similar symptoms (e.g., sore throat, fever and fatigue) and clinical signs.¹

Adenovirus

Adenoviruses are a group of viruses that mainly affect your airways but can infect many organ systems within your body. Adenoviruses spread through close contact with someone who has it already, by touching surfaces with adenoviruses on it and touching your nose, eyes and mouth without washing your hands or via cough/sneeze droplets.¹² Most infections come with no symptoms, but there is a possibility of flu- or cold-like symptoms, including fever, sore throat (pharyngitis) and pneumonia.¹³ Lymphocytosis occurs as a normal immune response against the viral infection.¹

Human Immunodeficiency Virus (HIV)

The Human Immunodeficiency Virus (HIV) is a virus that causes harm to your lymphocytes, specifically T cells.¹⁴ It spreads from one person to another by being in close direct contact with the body fluids like blood, breast milk, semen and vaginal fluids, of someone who has HIV.¹⁵ When HIV first infects your body (acute infection), lymphocytosis with atypical lymphocytes often occurs which is a normal sign of your immune system fighting the virus. However, as HIV keeps destroying your T cells, your body loses lymphocytes over time (i.e. lymphopenia), making your immune system weaker.¹ If this isn’t treated, the HIV infection eventually leads to acquired immunodeficiency syndrome (AIDS). To stop the development of AIDS, early diagnosis and proper treatment is needed.¹⁵

Hepatitis viruses (Hepatitis A and B)

Hepatitis is the inflammation of the liver and this can occur because of viruses like hepatitis A, B, and C.¹⁶ Hepatitis can be short-term (i.e. acute) as the viral infection comes and resolves within a short period of time.¹⁷ Lymphocytosis may occur in acute hepatitis because of a normal immune response to the infection. The lymphocyte number will come back to normal once the infection is cleared. 

Hepatitis can also be long-lasting (i.e. chronic hepatitis), and this can lead to serious conditions such as liver scarring (cirrhosis).¹⁷ In long-lasting chronic hepatitis B and C, lymphocytosis can be persistent as the immune system tries to fight off the virus within the body.¹⁸ This might also show that the drugs being used as treatment are not working well.¹⁹

Rubella (german measles) and measles (rubeola)

Rubella is a contagious viral infection that usually affects young children or young adults.²⁰ It causes mild symptoms like a rash on the body, fever, sore throat and swollen lymph nodes.²¹ Measles is also a contagious infection and is caused by a virus different from the rubella virus.²² It shows similar symptoms to rubella, including the rash and cold-like symptoms, but these signs tend to be more severe.²³ Lymphocytosis occurs as a normal response while the immune system fights the viral infection. However, with measles, first there will be a drop in the number of lymphocytes (i.e. lymphopenia) because the virus mainly attacks and destroys these cells.²⁴

Varicella-zoster virus (VZV)

The varicella-zoster virus causes chickenpox in children and young adults and shingles in the elderly and those with poor immunity. Both diseases are very easy to catch from other people who have it (i.e. it is highly contagious). Chickenpox gives rise to a distinct skin rash that itches and forms blisters.²⁵ The virus spreads through the air via droplets produced when someone who is sick with this virus coughs or sneezes , or by close contact (e.g., touching the rash) with a person who has the infectiont.²⁶ Lymphocytosis also occurs during this infection as a normal response to fighting the viral infection. These levels usually go back to normal as the virus clears and chickenpox fades.

Other viral infections

Other viral infections that have been found to also cause lymphocytosis include:

• Mumps virus¹
• Influenza virus¹
• Dengue virus²⁷
• COVID-19 (SARS-CoV-2)²⁸

Differential diagnosis and clinical clues

To receive proper treatment and thereby get the lymphocyte count back to normal, it is important to find out what type of virus is causing the infection. Many viral infections have the same, non-specific symptoms and signs such as a fever, sore throat, or cold-/flu-like symptoms, but there are sometimes ways to tell them apart during a check-up. Some viral infections give rise to skin rashes that are specific to the virus causing it (e.g., measles and chickenpox rashes present differently). However through laboratory tests, it is much easier to detect the virus responsible for the infection, especially if symptoms and clinical presentations don’t help. PCR or antigen tests can tell you the specific virus causing the infection,²⁹ as each virus has its specific antigen.³⁰ Monospot tests can be done for EBV analysis.³¹ If hepatitis is suspected, then liver function tests can be carried out to see if there are abnormalities with the function.³²

It is important to identify different viral infections apart, but it is also important to see if there are other potential causes. Lymphocytosis can also be a result of a bacterial or parasitic infection.¹ Getting the right diagnosis is important as this helps the professionals to give you the correct treatment. Therefore, you should tell your doctor/medical examiner about your past health, what you feel, what symptoms you have and any other information that would help figure out the cause for the lymphocytosis.

Summary

Lymphocytosis means the number of lymphocytes (a type of white blood cell) has increased beyond the normal level as the body’s immune system works to fight off the infection. It is most commonly seen in infections caused by viruses, but can also be present during bacterial and parasitic infections. The number of lymphocytes drops back to normal once the infection has cleared. Some common viral infections that are associated with lymphocytosis include infectious mononucleosis (EBV), CMV, early-stage HIV, hepatitis viruses, measles and chickenpox (varicella-zoster virus). A common feature of lymphocytosis from viral infections that helps during diagnosis is seeing atypical lymphocytes (larger and slightly misshapen lymphocytes) in a blood smear when examined under a microscope. A lot of these viral infections show mild signs like fever, sore throat and cold/flu signs. However, some may have specific, clear signs, such as a characteristic type of rash, that can help identify the virus causing the infection for the right diagnosis and treatment. Testing in labs (e.g., antigen testing and PCR) can help find the specific virus if the signs and symptoms are of not much help.