Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare, potentially life-threatening, acute hypersensitivity reaction of the skin, and the mucosa of the ocular surface, oral cavity, and genitals. Macules rapidly spread and coalesce, resulting in epidermal blistering, necrosis, and sloughing. The disease is often drug-related, although it may be triggered by infection or vaccination. In this study, Australian authors presented the largest case series of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with COVID-19 or vaccination. During six months, the authors from the state-wide burns unit in New South Wales, which serves as a referral center for SJS/TEN, had 14 cases of SJS/TEN, seven times the incidence before COVID-19 infection and vaccination.
SJS/TEN is classified according to the percentage of total body surface area (TBSA) desquamation. In Stevens-Johnson syndrome, the changes affect less than 10% of the TBSA, in TEN, more than 30% of the TBSA. If changes affect between 10 and 30% of the TBSA, it is considered SJS/TEN overlap.
In severe cases of toxic epidermal necrolysis, large sheets of epithelium slide off the entire body at pressure points, exposing painful and erthythematous skin. Painful oral crusts and erosions, keratoconjuctivitis, and genital problems accompany skin sloughing in up to 90% of cases.
The exact mechanism of SJS/TEN is unknown, but it is speculated that it is triggered through a T-cell-mediated cytotoxic reaction. The implicated pathways are believed to involve a granule-mediated exocytosis or Fas-Fas ligand (FasL) apoptosis cascade. In the granule-mediated pathway, cytotoxic T cells and natural killer cells release perforin, granulysin, and granzyme B, which destroy keratinocytes. The concentration of perforin, granzyme B, and granulysin in blister fluid correlates with the severity of the disease. It has also been found that interleukin-15, which is elevated in patients with SJS/TEN, enhances the production of granylisin. The theory of Fas-FasL pathway apoptosis cascade implies that interaction between Fas (a cell surface receptor that induces apoptosis) and its ligand, particularly a soluble form of FasL released from activated mononuclear cells, results in apoptosis of keratinocytes and blister formation.
About the study
The authors from the state-wide burns unit in New South Wales, Australia, which serves as a referral center for SJS/TEN, reported a seven-fold increase in SJS/TEN presentations over six months in 2022. In six months, they had 14 cases of SJS/TEN, seven times the incidence before COVID-19.
All fourteen cases were vaccinated against SARS-CoV-2. The authors presented eight of the fourteen cases in this article.
Case 1
A 60-year-old woman was admitted with TEN which affected 55% of TBSA. She was infected with SARS-CoV-2 six weeks before the onset of TEN and was double vaccinated with the mRNA COVID-19 vaccine. She received allopurinol for the exacerbation of her gout. She was treated with allopurinol before, with no adverse effects.
Pictures from the original paper by Stanley EA. et al. Burns (2023). Toxic epidermal necrolysis with 55% of total body surface area desquamation (Case 1). Left: desquamation. Right: frozen section demonstrating necrotic keratinocytes, full-thickness epidermal necrosis, and subepidermal bullae.
Case 2
A 78-year-old woman was admitted with TEN, which affected 60% of TBSA. Five weeks before the onset of TEN, she was diagnosed with COVID-19 with pneumonitis and received piperacillin/tazobactam. She was double vaccinated with the mRNA COVID-19 vaccine.
A 54-year-old woman was admitted with TEN, which affected 40% of TBSA. She had COVID with pneumonitis secondary to Aspergillus and received voriconazole four weeks before the onset of TEN. She was double vaccinated with the mRNA vaccine.
A 26-year-old man was admitted with TEN, which affected 70% of TBSA. He received the mRNA COVID-19 vaccine three weeks before the onset of TEN. Due to the vaccine-associated symptoms, he took paracetamol and ibuprofen, he used them before without any adverse effects. She was triple vaccinated with the previous two doses of a viral vector vaccine.
A 45-year-old man was admitted with TEN, which affected 70% of TBSA. He had a COVID-19 infection four weeks before the onset of TEN. He was treated with levetiracetam for seizure prophylaxis. The patient was triple vaccinated with the mRNA vaccine.
A 53-year-old woman was admitted with TEN, which affected 95% of TBSA. She received a viral vector vaccine three weeks before the onset of TEN. The patient was treated with captopril and amlodipine for scleroderma renal crisis. She was quadruple vaccinated with previous doses of viral vector and mRNA vaccines.
A 47-year-old man was admitted with SJS/TEN overlap, which affected 10% of TBSA. He had a COVID-19 infection five weeks before the onset of SJS/TEN overlap and was treated with amoxicillin. The patient has previously taken amoxicillin without any adverse effects. He was triple vaccinated with the mRNA vaccine.
A 53-year-old woman was admitted with TEN, which affected 90% of TBSA. She received the mRNA COVID-19 vaccine four weeks before the onset. The patient was treated with piperacillin/tazobactam for bacterial peritonitis. She has previously taken penicillin with no adverse effects. She was triple vaccinated with the mRNA COVID-19 vaccine.
The authors emphasized that the rarity of SJS/TEN makes it difficult to establish a causal link with COVID-19 or the vaccine, particularly in the context of concomitant medications that are known to initiate SJS/TEN. However, the rapid increase in cases since the pandemic outbreak and immunization is alarming. The seven-fold increase in SJS/TEN, observed in their state (New South Wales, Australia), correlates with a rise in COVID infection and vaccination rates.
The researchers proposed three theories to explain the increased incidence of SJS/TEN: a virus-induced increase, a vaccine-induced increase, and a threshold-lowering pathway. The first assumption is that SARS-COV-2 may directly bind to receptors that trigger T cell-mediated response and SJS/TEN. Other viruses, such as herpes simplex, Epstein-Barr, cytomegalovirus, and influenza have already been implicated in the development of SJS/TENS.
The second theory proposed that vaccines may directly bind to receptors and initiate SJS/TEN. In this article, all fourteen presented patients who developed SJS/TEN were previously vaccinated with COVID-19 vaccines. The third theory suggests that the SARS-COV-2 virus or a vaccine may reduce the threshold for a drug that triggers SJS/TEN. The virus or vaccine could “prime” the immune system for a drug that triggers SJS/TEN, which may not have happened without this “priming”.
Conclusion
This is the largest case series exploring Stevens-Johnson syndrome and TEN associated with COVID-19 infection or vaccination. Future studies should investigate the underlying mechanisms of this immune-mediated disease.
This article was published in Burns.
Journal Reference
Stanley EA. et al. The Seven-Fold Rise in Incidence of Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis: Associations with COVID-19 and the Vaccine. Burns (2023) (Open Access) https://doi.org/10.1016/j.burns.2023.06.016
