Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Abstract

Early diagnosis and prognosis monitoring for Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN) still remain a challenge. This study aims to explore any cytokine/chemokine with prognostic potential in Stevens-Johnson syndrome/TEN. Through screening a panel of 28 serological factors, IL-6, IL-8, IL-15, tumor necrosis factor-α, and granulysin were upregulated in patients with Stevens-Johnson syndrome/TEN and selected for the further validation in total 155 patients with Stevens-Johnson syndrome/TEN, including 77 from Taiwan and 78 from the Registry of Severe Cutaneous Adverse Reactions. Among these factors evaluated, the levels of IL-15 (r = 0.401; P < 0.001) and granulysin (r = 0.223; P = 0.026) were significantly correlated with the disease severity in 112 samples after excluding patients with insufficient data to calculate the score of TEN. In addition, IL-15 was also associated with mortality (P = 0.002; odds ratio, 1.09; 95% confidence interval, 1.03-1.14; P = 0.001; adjusted odds ratio, 1.10; 95% confidence interval, 1.04-1.16). Consistent results were obtained after the exclusion of Taiwanese patients with sepsis to rule out possible confounders. Moreover, IL-15 was shown to enhance cytotoxicity of cultured natural killer cells and blister cells from patients with TEN. Our findings highlight a usefulness of IL-15 in prognosis monitoring and therapeutic intervention of this devastating condition.

Acute generalized exanthematous pustulosis and epidermal necrolysis differ in innate cytokine patterns

“…As was previously shown, 1,4 we confirmed the extent of skin detachment and IL-15 level as markers of prognosis in SJS and TEN.…”

“…2,3 Increased levels of granulysin and interleukin-15 (IL-15) were found significantly correlated with severity and mortality. 4 In contrast, in AGEP, which has a better prognosis, circulating Th17 cells are involved in recruiting neutrophils that mediate inflammation. 3 Innate immune cytokines are key to driving inflammation and engaging the adaptive immunity.…”

Case of toxic epidermal necrolysis in immunocompromised patient possibly due to Streptococcus pneumoniae serotype uncovered by vaccine

“…3 In drug-induced TEN cases, IL-8 levels in the serum ranged 7-2458 pg/mL, and those in bullae ranged 101-40 000 pg/mL, and were more than 90 000 pg/mL in one case; this concentration was not related to disease severity. 1 In OPSI cases, serum IL-8 concentration was approximately 1000 pg/mL, 4 which was similar to our case. On the other hand, in our OPSI-induced TEN case, the IL-8 in bullae showed a more than 200-times higher concentration compared with the average of drug-induced TEN cases, suggesting that the destruction of keratinocytes may be more severe in infection-induced TEN.…”

Altered levels of complement components associated with non-immediate drug hypersensitivity reactions

“…Unfortunately, to date, the complex pathogeneses of most niDHR remain largely unknown. They are generally considered delayed hypersensitivity reactions in which drug-specific T-cells play a vital role in the diverse clinical manifestations (Chung et al 2008;Su et al 2017). CD4 þ T-cells are responsible for the immune disorders associated with MPE, in which T-helper type-1 (T H 1) cells and their related secreted cytokines are predominant (Kokuba et al 1999;Fernandez et al 2008).…”

“…In contrast, in SJS and TEN, activated CD8 þ T-cells and NK cells kill keratinocytes by secreting a large amount of nonspecific 15 kDa granulysin in blister fluids (Chung et al 2008). Other studies have reported that tumor necrosis factor (TNF)-a, interferon (IFN)-c, and interleukin (IL)-15 also contribute to the massive keratinocyte death seen in SJS and TEN (Viard-Leveugle et al 2013;Su et al 2017). Thus, niDHR including SJS and TEN are considered to be T-cell-mediated non-immediate hypersensitivity reactions.…”