In a recent study, Australian authors presented the largest case series of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) that may be associated with SARS-CoV-2 infection and anti-SARS-CoV-2 vaccination. In a six-month period, they had 14 cases of SJS/TEN, seven times the incidence before COVID infection and vaccination. They proposed theories that could explain a possible connection between an increased incidence of Stevens Johnson syndrome/toxic epidermal necrolysis and COVID-19 infection and vaccination.
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, the oral cavity and the 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.
SJS/TEN is classified according to its percentage of total body surface area (%TBSA) desquamation. The changes affect less than 10% of the TBSA in Stevens-Johnson syndrome, and more than 30% of the TBSA in toxic epidermal necrolysis. If changes affect between 10 and 30% of the TBSA, it is considered to be SJS/toxic epidermal necrolysis 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. Findings show that 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 Fas-FasL pathway of apoptosis is another theory. The interactions 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, observed the seven-fold increase in SJS/TEN presentations over a six-month period in 2022. In six-month period, they had 14 cases of SJS/TEN, seven times the incidence before COVID.
All fourteen cases were vaccinated against SARS-CoV-2. The authors presented eight of the fourteen cases in this article. Five of these cases were diagnosed with COVID-19 during the preceding month, whereas three of these cases were vaccinated during the same month.
Case 1: A 60-year-old woman was admitted with TEN, which affected 55% of TBSA. She had COVID infection six weeks before the onset. She received allopurinol for the exacerbation of her gout. Previously, she has taken allopurinol with no adverse effect. She was double vaccinated with mRNA vaccine.
Pictures from the original paper by Stanley EA. et al. Burns (2023). doi.org/10.1016/j.burns.2023.06.016. 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 disgnosed with COVID with pneumonitis and received piperacillin/tazobactam. She was double vaccinated with mRNA vaccine.
Case 3: A 54-year-old woman was admitted with TEN, which affected 40% of TBSA. She had COVID with pneumonitis secondary to aspergillus, and received voriconazol four weeks before the onset of TEN. She was double vaccinated with mRNA vaccine.
Case 4: A 26-year-old man was admitted with TEN, which affected 70% of TBSA. He received mRNA vaccine three weeks prior to onset. Due to the vaccine associated symptoms, he took paracetamol and ibuprofen. He used paracetamol and ibuprofen before without any adverse effect. With the previous two doses of a viral vector vaccine, he was triple vaccinated.
Case 5: A 45-year-old man was admitted with TEN, which affected 70% of TBSA. He had COVID infection four weeks prior to onset. He was treated with levetiracetam for seizure prophylaxis. The patient was triple vaccinated with mRNA vaccine.
Case 6: A 53-year-old woman was admitted with TEN, which affected 95% of TBSA. She received a viral vector vaccine three weeks prior to onset. 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.
Case 7: A 47-year-old man was admitted with SJS/TEN overlap, which affected 10% of TBSA. He had COVID infection five weeks before the onset of SJS/TEN overlap, and was treated with amoxicillin. The patient has previously taken amoxicillin without any adverse effect. He was triple vaccinated with mRNA vaccine.
Case 8: A 53-year-old woman was admitted with TEN, which affected 90% of TBSA. She received mRNA 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 mRNA vaccine.
The authors pointed out that the rarity of SJS/TEN makes it difficult to establish a causal link with COVID or the vaccine, particularly in the context of concomitant medications that are known to initiate the disease. They emphasized, however, that the rapid increase in the number of cases since the pandemic outbreak and immunization is alarming. The seven-fold increase in SJS/TEN is correlated with a rise in COVID infection and vaccination rates. In their state (New South Wales, Australia), a rapid rise in cases and in vaccination rates began in January 2022.
The researchers proposed three theories to explain this increase in case number: a virus-induced increase, a vaccine-induced increase, and a threshold lowering pathway. One theory is that SARS-COV-2 may directly bind to receptors that trigger T cell mediated response and subsequently SJS/TEN. Other viruses, such as the herpes simplex virus, Epstein-Barr virus, cytomegalovirus and influenza have already been implicated in the development of SJS/TENS. The second theory proposed that vaccine may directly bind to receptors and initiate SJS/TEN. Eight case reports have been published previously describing SJS/TEN following anti-SARS-CoV-2 vaccination. Four of these cases were associated with mRNA vaccines, three with viral vector vaccines and one with whole virus vaccines.
In the present article, all fourteen patients received anti-SARS-CoV-2 vaccine. One month before the onset of SJS/TENS, three patients were vaccinated, two patients with the mRNA vaccine and one patient with the viral vector vaccine. The third theory is that either the SARS-COV-2 virus or a vaccine may lower 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”.
This is the largest case series exploring a possible association between Stevens Johnson syndrome/toxic epidermal necrolysis and COVID-19 infection and vaccination. The authors suggested that future studies should examine the underlying mechanisms of this immune mediated disease.
This article was published in Burns.
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