Exploring the Possible Link between Stevens-Johnson Syndrome and COVID-19

As the number of COVID cases continues to rise globally, there has been a concerning increase in medical conditions that were once considered rare.

One such condition is Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN). These conditions are characterized by a potentially life-threatening mucocutaneous delayed hypersensitivity reaction.

While SJS/TEN is commonly associated with certain medications, it can also be triggered by infections. In recent times, there have been suggestions of a potential association between SJS/TEN and COVID or its vaccines. This article presents the largest case series of SJS/TEN associated with COVID or vaccination, providing insights into possible immunological pathways connecting COVID and the development of SJS/TEN.

Understanding SJS/TEN Pathophysiology

SJS/TEN is believed to be triggered by a T-cell mediated response. Although the exact mechanism remains unclear, two major pathways have been proposed: the granule-mediated exocytosis pathway and the Fas-Fas ligand apoptosis cascade. In the granule-mediated pathway, cytotoxic T cells and natural killer cells release perforin, granulysin, and granzyme B, which lead to damage of keratinocytes.

On the other hand, the Fas-Fas ligand pathway involves the secretion of Fas ligand by lymphocytes, which binds to Fas death receptors on keratinocytes, resulting in their apoptosis.

Understanding COVID Pathophysiology

COVID is caused by the SARS-CoV-2 virus, which primarily targets the ACE-2 receptors on pulmonary epithelial cells. This interaction leads to a conformational change in the epithelial cell membrane, facilitating viral penetration. Subsequently, the virus hijacks the cell’s endoplasmic reticulum for replication. Newly formed viral particles are transported to the cell membrane via Golgi vesicles and released through exocytosis.

The Rising Cases of SJS/TEN and COVID

The first case of COVID in Australia was diagnosed in January 2020. By the end of that year, the country had reported approximately 28,500 cases, with 4,928 cases in the state of New South Wales. In 2022, the state saw a relatively low number of cases compared to global standards, with 182,576 new cases reported. However, a rapid rise in cases began in January 2022.

During the first six months of 2022, 7,627,874 new cases were reported, although it is believed that these numbers are likely underreported due to asymptomatic cases and limited testing.

Studies have shown that approximately 40.5% of COVID-positive cases globally are asymptomatic. Vaccination rates also saw a significant increase during this period.

The Association between SJS/TEN and COVID/Vaccination

In the six-month period corresponding to the rise in COVID cases and vaccinations, 14 cases of SJS/TEN were observed, marking a seven-fold increase compared to the incidence prior to the pandemic. However, establishing causality between SJS/TEN and COVID or the vaccine is challenging due to confounding factors such as concomitant medications known to trigger the disease. Nevertheless, the sharp increase in SJS/TEN cases is concerning.

Potential Theories for the Increase in SJS/TEN Cases

There are three theories proposed to explain the sudden rise in SJS/TEN cases during the COVID pandemic:

1. Virus-Induced: It is possible that the SARS-CoV-2 virus directly binds to receptors that trigger a T-cell mediated response, subsequently leading to SJS/TEN. Similar associations have been observed with other viruses such as herpes simplex virus, Epstein-Barr virus (EBV), cytomegalovirus, and influenza. These viruses’ proteins bind to the major histocompatibility complex (MHC) class I on antigen-presenting cells, triggering the activation of cytotoxic T cells. Several cases of SJS/TEN following COVID infection have been reported, with an average onset time of 3 weeks from diagnosis.
2. Vaccine-Induced: Like drugs, vaccines may also directly bind to receptors, triggering SJS/TEN. Recent studies have shown that the ChAdOx1 nCoV-19 adenoviral vector vaccine induces a T helper type 1 cell response, leading to the clonal expansion of cytotoxic T cells. This immune response can also induce the release of perforin, granulysin, and granzyme B, causing keratinocyte apoptosis seen in SJS/TEN. The time peak for this T-cell response aligns with the reported cases, with eight case reports linking SJS/TEN to COVID vaccines.
3. Threshold Lowering: The SARS-CoV-2 virus or vaccine may lower the threshold for a drug to trigger SJS/TEN. It is hypothesized that the virus or vaccine “primes” the immune system, making it more susceptible to developing SJS/TEN when exposed to certain drugs. Infectious mononucleosis caused by EBV has a similar “priming” effect, resulting in drug-induced hypersensitivity reactions when individuals are exposed to specific medications. This hypothesis suggests that the expansion of EBV-specific cytotoxic T cells during infectious mononucleosis may cross-react with certain drugs, leading to a hypersensitivity reaction.

Conclusion

This case series highlights the possible associations between COVID, vaccination, and the development of SJS/TEN. The sharp increase in SJS/TEN cases observed at our institution during the COVID pandemic, along with the concurrent rise in COVID infections and vaccinations, raises concerns.

Three theories are proposed to explain this phenomenon: virus-induced, vaccine-induced, and threshold lowering pathways. Future research should focus on investigating the impact of viruses such as SARS-CoV-2 on immune-mediated diseases like SJS/TEN.

Understanding these associations will be crucial in identifying preventive measures and providing better management for patients affected by these conditions.

reference link: https://www.sciencedirect.com/science/article/pii/S0305417923001286