Introduction

A brief background on covid-19

Remember 2019, the COVID-19 experience that brought about lockdowns around the world? COVID-19 was caused by the virus SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2). It is a very infectious and fast-transmitting type of coronavirus, which was first noticed in Wuhan, China in late 2019. This incident was horrific as its effect placed a heavy burden on the health sector, making people at risk of other health issues and even death as a result of the virus.¹ The possible outcomes of COVID-19, especially in elderly people and those with other overlapping health conditions, include severe pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, and death; sometimes infection can be symptomless.²

How does the body’s immune system respond to viral infection?

In general, the human immune system has two processes in response to infections: innate and adaptive immunity. The innate immunity is fast and non-specific; it also contains the natural killer (NK) cells that provide early defence by targeting infected cells before the adaptive immune response is fully activated. On the other hand, adaptive immunity is slow and antigen-specific; it comprises B cells that generate virus-specific antibodies and then CD4+ helper and CD8+ cytotoxic T cells that are essential for identifying and destroying virus-infected cells.³ Lymphocytes include the T cells, B cells and NK cells; they are key players in viral clearance and immune control.⁴

Usually, during a viral infection, the body builds up a defence system to fight against the invading viral source through lymphocytosis, that is, an increase in the amount of circulating lymphocytes.⁵ This increase is a result of the stimulation and multiplication of lymphocytes in response to viral antigens. Although, depending on the particular virus and the immune status of the host, different changes in the lymphocyte subset may occur.⁵

Importance of understanding lymphocyte patterns in COVID-19

With COVID-19, the lymphocyte pattern (where there is a viral infection) is different because COVID-19 is often linked to lymphopenia, a state that marks a reduction in circulating lymphocyte counts, especially affecting the CD4+ and CD8+ T cells, regulatory T cells, and NK cells.^4,5 The level of lymphopenia has been shown to be connected with disease severity and prognosis; more severe lymphocyte reduction is seen in critically ill people and can lead to worse outcomes. Therefore, it is important to monitor lymphocyte counts; this helps provide valuable information that indicates COVID-19 and aids in disease management.^4,5

Definition and causes of lymphocytosis

Lymphocytosis is an abnormal rise in the blood's white blood cells, which are important for immune defence; they are called lymphocytes. The absolute lymphocyte count (ALC) in healthy adults normally falls between 1,300 and 4,000 cells per microlitre (µL) of blood. Although some sources and clinical contexts use a threshold of 3,000 cells/µL, lymphocytosis is typically diagnosed in adults when the ALC exceeds 4,000 cells/µL.^6,7 Higher values are regarded as normal in children, and an ALC above 8,000 cells/µL is typically used to define lymphocytosis, which reflects physiological changes associated with ageing.⁷ The diagnostic threshold for some blood disorders, like chronic lymphocytic leukaemia (CLL), might be set at an ALC higher than 5,000 cells/µL (5 × 10^9/L).

Numerous underlying health conditions can cause lymphocytosis, which can be broadly classified as follows:⁸

• Infections caused by viruses: The most frequent cause of transient lymphocytosis is acute viral infections. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV), which causes infectious mononucleosis, are two prominent examples. A significant rise in lymphocyte counts is a hallmark of both EBV and CMV infections, frequently with over 50% of the differential count's lymphocytes and at least 10% of them being reactive lymphocytes. Increased lymphocyte counts can also result from other viral infections like influenza, mumps, and rubella
• Long-Term Inflammatory Disorders: Sustained lymphocytosis can be brought on by ongoing immune activation brought on by autoimmune or chronic inflammatory conditions like rheumatoid arthritis or inflammatory bowel disease. In these situations, continuous immune system stimulation is reflected in the increase in lymphocyte count
• Haematologic Malignancies: Lymphocytosis may be a hallmark of certain blood cancers, particularly lymphoproliferative disorders. Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia and is defined by a persistent increase in monoclonal B lymphocytes, typically above 5,000 cells/µL, confirmed by flow cytometry. Other malignancies, such as lymphomas and acute lymphoblastic leukaemia, can also present with lymphocytosis

Atypical presentation: lymphocytosis in covid-19

Despite the disease's characteristic of decreased circulating lymphocyte counts, COVID-19 has shown atypical lymphocyte dynamics, with reports of lymphocytosis in particular clinical settings. For instance:

1. Chronic lymphocytic leukaemia (CLL) case studies: It is known as "COVID-19–induced lymphocytosis,"  here some people experiencing untreated CLL showed a three-fold increase in lymphocyte counts during the COVID-19 infection. In one instance, the lymphocyte count doubled over four weeks, from 26.7×10³/µL to 51.3×10³/µL, indicating that SARS-CoV-2 may hasten the expansion of clonal B-cells in susceptible people⁹
2. Reactive lymphocytosis in severe COVID-19: A study of 98 people who had COVID-19 and were hospitalised revealed that atypical lymphocytes were present in 16.3% of cases at first presentation and increased to 50% over the course of the clinical course. Ironically, in two-thirds of oxygen-dependent patients, these reactive lymphocytes preceded clinical improvement, despite having a correlation with pneumonia¹⁰
3. Population-level data: Leukocytosis, including lymphocytosis, is present in cases linked to COVID-19, especially in cases of severe illness, while lymphopenia is still common.¹¹ In contrast to traditional viral lymphocytosis, COVID-19-specific reactive lymphocytes were recognised by automated convolutional neural networks as activated effector memory CD4+/CD8+ T cells¹⁰

Also, there are possible connections of increased lymphocytosis due to co-infection of COVID-19 with additional viruses. Although there is currently little evidence, co-infections with viruses such as cytomegalovirus (CMV) or Epstein-Barr virus (EBV) may cause lymphocytosis. Higher procalcitonin levels are linked to bacterial co-infections, which are more commonly reported and can account for up to 50% of fatal COVID-19 cases.^12,13 Nonetheless, co-infected patients frequently have lower lymphocyte counts, indicating that viral co-infections might be a unique mechanism that needs more research.¹³

Diagnostic challenges of atypical lymphocytes in covid-19 

Diagnostic difficulties arise from the morphological overlap between COVID-19 atypical lymphocytes and those found in haematologic malignancies and other viral infections. For example, cells with nucleoli and plasmacytoid lymphocytes can resemble blast cells, which raises the possibility of acute leukaemias or lymphomas. Similarly, when the clinical context is limited, their similarity to reactive lymphocytes (atypical lymphocytes) in EBV or cytomegalovirus (CMV) infections can make differential diagnosis more difficult.¹⁰

Additionally, these atypical lymphocytes are frequently flagged by haematology analysers as aberrant or blast-like cells, which leads to peripheral blood smear reviews to differentiate between reactive and malignant cells. This is crucial because misunderstandings can result in inappropriate treatments or needless invasive procedures. To prevent misdiagnosis, careful morphological evaluation, immunophenotyping, and clinical correlation are therefore crucial.^10,14

Interpretations and clinical implications of lymphocytosis in covid-19

Instead of lymphocytosis, lymphopenia (low lymphocyte count) is commonly acknowledged as a powerful prognostic indicator linked to severe illness and increased mortality in COVID-19. Patients with lymphopenia at admission are more likely to need intensive care, experience organ failure, including acute kidney injury, and have a higher chance of dying, according to numerous studies. One retrospective cohort, for instance, discovered that lymphocytopenia was associated with worse clinical outcomes and 3.4 times higher odds of intensive care unit (ICU) admission.¹⁵ According to a different study, recovery was linked to normalising lymphocyte counts, while fatal outcomes were linked to lymphocyte percentages below 5% within two weeks of symptom onset.¹⁶

On the other hand, lymphocytosis in COVID-19 is less frequent, and because of insufficient available data, its prognostic significance is still unknown. According to some reports, patients with lymphopenia typically recover more quickly than those with higher or normal lymphocyte counts.¹⁷ Interpretation is made more difficult by the fact that lymphocytosis can also happen in particular situations, such as co-infections or haematologic disorders. Overall, lymphopenia continues to be the primary predictor of poor outcomes in COVID-19, and lymphocytosis has not been proven to be a reliable indicator of prognosis.

Summary

While lymphocytosis in COVID-19 is less common and its prognostic role is not well defined, careful interpretation in the clinical context is essential. During a COVID-19 illness, tracking lymphocyte counts offers important insights into the course of the illness and treatment choices. Persistent lymphopenia frequently indicates deteriorating health and can lead to intensive immunomodulatory or supportive care. On the other hand, the appearance of reactive or atypical lymphocytes, occasionally coupled with lymphocytosis, could be a sign of immune activation and possible stages of recovery.

Atypical lymphocyte patterns, however, may make clinical interpretation more difficult. For example, COVID-19 or its treatments may worsen lymphocytosis in patients with underlying haematologic disorders, impacting management choices like modifying immunosuppressive therapy. Furthermore, antimicrobial stewardship and diagnostic workup can be guided by the understanding that lymphocytosis may indicate secondary complications or co-infections.