The relationship between COVID-19 and Mononucleosis (Mono) has been a topic of growing public interest since the start of the pandemic. COVID-19 is a respiratory disease that can affect multiple organ systems, while Mono is a common infectious illness known for causing fever and extreme fatigue. The question of whether one can cause the other, or if they are otherwise connected, stems from the noticeable overlap in the symptoms people experience with both infections. Exploring this connection requires a look at the distinct biological agents responsible for each disease and the complex way the body’s immune system responds to both.
The Distinct Viral Causes of COVID-19 and Mononucleosis
COVID-19 and Mononucleosis are fundamentally different diseases caused by two distinct types of viruses. COVID-19 is caused by SARS-CoV-2, a member of the coronavirus family. This virus primarily targets the respiratory system, though its effects are systemic due to its interaction with the Angiotensin-Converting Enzyme 2 (ACE2) receptor found on many cells throughout the body.
In contrast, Mononucleosis is overwhelmingly caused by the Epstein-Barr Virus (EBV), a member of the herpesvirus family. EBV primarily infects B cells and epithelial cells. The acute phase of Mono is marked by a robust immune response.
The genetic and structural differences between SARS-CoV-2 and EBV establish that COVID-19 cannot directly cause Mononucleosis. The two viruses belong to completely different families, making the direct conversion biologically impossible. The connection between the two conditions is one of complex interaction within the host immune system, not direct causation.
Why Symptoms Are Often Confused
The initial confusion between COVID-19 and Mononucleosis arises because many of the symptoms of the acute phases of both illnesses overlap significantly. Both infections frequently present with nonspecific, flu-like symptoms, including high fever, severe sore throat, body aches, and persistent fatigue.
Both viruses are also known to trigger immune responses that involve the lymphatic system. Acute Mononucleosis is characterized by swollen lymph glands in the neck, armpits, and groin, alongside possible inflammation of the spleen or liver. While less pronounced than in Mono, COVID-19 can also cause generalized lymphadenopathy, or swollen lymph nodes, especially in more severe cases.
The shared symptom profile means that a definitive diagnosis cannot rely on symptoms alone and requires specific laboratory testing. A positive test for SARS-CoV-2 confirms COVID-19, while a Monospot test or serological markers like EBV-specific IgM antibodies are necessary to diagnose acute Mononucleosis or EBV reactivation.
COVID-19 and EBV Reactivation
The most significant link between the two conditions is the ability of SARS-CoV-2 infection to trigger the reactivation of latent EBV. The Epstein-Barr Virus is carried in a dormant state by over 90% of the world’s adult population, residing silently within B cells. In this latent state, the immune system, particularly specialized CD8+ T cells, keeps the virus in check through constant surveillance.
A major systemic stress, such as a severe COVID-19 infection, can disrupt this delicate balance of immune control. SARS-CoV-2 infection is known to cause significant immune dysregulation, including widespread inflammation and T-cell exhaustion. This systemic immune stress temporarily compromises the surveillance mechanism required to suppress EBV.
When immune control falters, EBV can switch from its latent phase to a lytic, or active, phase, allowing the virus to replicate. Studies have shown that EBV reactivation is measurably elevated in people with COVID-19 compared to those who are COVID-negative. This reactivation is indicated by the presence of lytic EBV markers, such as viral capsid antigen (VCA) IgM, in the blood.
The incidence of EBV reactivation has been reported to be particularly high in patients with severe COVID-19, including those requiring intensive care. This suggests a connection between the intensity of the SARS-CoV-2-induced immune response and the likelihood of the herpesvirus re-emerging. Furthermore, the reactivation of EBV may contribute to a worsening of COVID-19 symptoms or an increased length of hospitalization.
Comparing Long-Term Post-Viral Fatigue Syndromes
Both COVID-19 and Mononucleosis can lead to prolonged health issues known as post-viral syndromes, characterized by persistent symptoms long after the initial infection clears. For COVID-19, this is known as Long COVID, or Post-Acute Sequelae of COVID-19 (PASC). Common persistent symptoms include debilitating fatigue, cognitive dysfunction often called “brain fog,” and post-exertional malaise (PEM), where symptoms worsen significantly after minimal physical or mental effort.
Similarly, a subset of individuals who have acute Mononucleosis develop Post-Mononucleosis Syndrome, which is also characterized by lasting, profound fatigue and cognitive issues. This post-EBV condition shares a substantial symptomatic overlap with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
The symptoms resulting from EBV reactivation following a COVID-19 infection often closely mirror the symptoms of Long COVID. Researchers have found markers of EBV reactivation in a significant percentage of patients experiencing Long COVID fatigue and other chronic symptoms.
This symptomatic mimicry makes it challenging for clinicians to determine if the chronic fatigue is a direct result of the SARS-CoV-2 infection itself, or if it is primarily driven by the inflammation and immune response triggered by the reactivated EBV. The potential role of EBV reactivation in driving some Long COVID manifestations is a significant area of ongoing research.