Toxic epidermal necrolysis: lessons from three fatal cases
Marko Demenj
1
, Vesna Reljić
1,2
, Emilija Manojlović Gačić
2,3
, Maja Vilotijević
1
, Dubravka Živanović
1,2 ✉
1
Dermatology Clinic, University Clinical Center of Serbia, Belgrade, Serbia. 
2
Dermatology Department, Faculty of Medicine, University of Belgrade, 
Belgrade, Serbia. 
3
Institute of Pathology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
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2025;34:139-144
doi: 10.15570/actaapa.2025.27
Introduction
Toxic epidermal necrolysis (TEN) represents the most severe form 
of adverse cutaneous reaction within the spectrum that includes 
Stevens–Johnson syndrome (SJS), SJS/TEN overlap, and TEN. 
These conditions are distinguished by the percentage of skin de-
tachment: less than 10% for SJS, between 10% and 30% for SJS/
TEN overlap, and more than 30% for TEN (1). The most common 
triggers of TEN are various medications, particularly anticonvul-
sants, non-steroidal anti-inflammatory drugs (NSAIDs), and anti-
biotics (2).
TEN typically starts with prodromal symptoms resembling a fe-
brile illness, occurring 1 to 21 days prior to the appearance of skin 
and mucosal lesions (1). The evaluation of patients diagnosed with 
TEN includes the use of the Severity-of-Illness Score for Toxic Epi-
dermal Necrolysis (SCORTEN) scale, assessing clinical and labora-
tory risk factors to predict mortality. The mortality rate varies from 
3.2% with one risk factor to over 90% with five or more risk factors 
(1).
We present a series of patients diagnosed with or treated for 
TEN at our center, all of whom had fatal outcomes. We discuss dif-
ferential diagnoses, associated comorbidities, and complications 
that may have contributed to poor outcomes, supported by data 
from current research.
Methods
Data were collected from the electronic medical records of pa-
tients hospitalized at the women’s department of the Belgrade 
Dermatology Clinic from 2016 to 2021. Information was collected 
on the clinical presentation, comorbidities, medical treatment, 
laboratory findings, and histopathological results. Three patients 
with unique clinical features were identified.
Results
Case 1
A 42-year-old and otherwise healthy female patient presented 
with high fever and cough that began 3 days prior, along with 
erythema and erosions on the conjunctiva, genitalia, and minor 
intraoral lesions, with sparse atypical targetoid lesions on her 
hands involving 5% of the body surface area (BSA), raising sus-
picion of mycoplasma-induced rash and mucositis (MIRM; Figs. 
1a, 1b). Empirical treatment with azithromycin and low-dose cor-
ticosteroids was initiated; however, 1 day later, the lesions spread 
to the oral mucosa, and skin lesions covered 60% of her BSA (Figs. 
1c, 1d). Conjointly, a negative serology test for Mycoplasma pneu-
moniae and the history of ibuprofen use prompted a diagnosis 
of TEN with a SCORTEN 2. Intravenous immunoglobulin (IVIg) 
treatment was started, but the patient soon developed decreased 
oxygen saturation, requiring respiratory support. She was trans-
ferred to urgent care and developed sepsis, ultimately succumb-
ing to septic shock 1 week after admission.
Case 2
A 50-year-old patient was transferred from a secondary medical 
center due to TEN, affecting 80% of her BSA, with confluent ery -
thema and 40% denuded skin, as well as oral and genital erosions 
(Figs. 2a, 2b). She was on ventilatory support and unresponsive. 
The condition began 9 days prior with a high fever, and she had
Abstract
Introduction: Toxic epidermal necrolysis (TEN) is a severe cutaneous adverse reaction triggered by various classes of drugs. Clini-
cal manifestations include prodromal symptoms resembling a febrile illness, followed by skin and mucosal lesions. This study 
presents a series of fatal TEN cases, with a focus on factors that may have influenced mortality, including differential diagnoses, 
associated comorbidities, treatment choices, and complications of TEN.
Methods: Data were collected from electronic medical records of patients hospitalized at a dermatology clinic.
Results: Case 1 involved TEN in a 42-year-old female, initially misdiagnosed as mycoplasma-induced rash and mucositis (MIRM), 
who succumbed to sepsis. Case 2, a 50-year-old female with 80% of her body surface area affected, saw low-dose IVIg treatment 
prove ineffective, leading to multiorgan failure. Case 3 involved allopurinol-induced TEN in a 53-year-old with Balkan endemic ne-
phropathy, resulting in fatal renal failure.
Conclusions: The cases presented highlight potential challenges in differentiating TEN from MIRM in the early stages of TEN. High-
dose IVIg is generally recommended, whereas the effectiveness of low-dose IVIg is inconsistent, and it proved insufficient in the 
case presented, potentially due to the presence of multiple comorbidities. Preexisting conditions such as renal disease signifi-
cantly influence fatal outcomes in TEN patients.
Keywords: Balkan endemic nephropathy, cutaneous adverse reactions, low-dose IVIG, mycoplasma-induced rash and mucositis, 
toxic epidermal necrolysis
Acta Dermatovenerologica 
Alpina, Pannonica et Adriatica
Acta Dermatovenerol APA
Received: 6 June 2025 | Returned for modification: 16 August 2025 | Accepted: 20 August 2025
✉ Corresponding author: dubravkazivanovic@yahoo.com

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Acta Dermatovenerol APA | 2025;34:139-144 M. Demenj et al.
been taking over-the-counter NSAIDs while her skin lesions de-
veloped. Four days after symptom onset, she was diagnosed with 
TEN and treated with high-dose corticosteroids and low-dose IVIg 
(0.07 g/kg/day for 5 days), without improvement. Upon admission 
to our center, we started treatment with high-dose corticosteroids 
and IVIg (1 g/kg/day). Despite this, her condition deteriorated, and 
she was transferred to the urgent care unit for multiorgan failure, 
where the fatal outcome ensued.
Case 3
A 53-year-old patient presented with severe erythema, bullae, and 
erosions covering 50% of her BSA and a SCORTEN 5. Her history 
included Balkan endemic nephropathy (BEN) and stage IV chron-
ic renal insufficiency. Two weeks before developing TEN, she was 
prescribed allopurinol. A fever emerged 10 days after starting al-
lopurinol, followed by mucosal and skin lesions. Initially treated 
with low-dose corticosteroids at a regional medical center, her 
condition worsened. At our center, she received high-dose corti-
costeroids and IVIg therapy (1 g/kg/day for 3 days), which initi-
ated epithelization (Figs. 2c, 2d). However, 4 days after admission 
to our center, her renal function deteriorated, requiring hemodial-
ysis. Severe renal damage led to transfer to the nephrology clinic, 
where she ultimately succumbed to renal failure. Key characteris-
tics of the three cases are summarized in Table 1.
Discussion
The differential diagnoses of TEN are extensive, encompass-
ing a variety of conditions including infections (staphylococcal 
scalded skin syndrome, toxic shock syndrome, purpura fulmi-
nans, coxsackievirus-induced severe mucocutaneous disease, 
chikungunya fever), immune-mediated conditions (lupus erythe-
matosus, pemphigus vulgaris, paraneoplastic pemphigus, lichen 
planus pemphigoides, graft-versus-host disease, inflammatory 
epidermolysis bullosa acquisita), other drug-induced skin reac-
tions (acute generalized exanthematous pustulosis, generalized 
bullous fixed drug eruption, drug reaction with eosinophilia and 
systemic symptoms, toxic erythema of chemotherapy), metabolic 
conditions such as pseudoporphyria, and (thermal/chemical) 
burns (3–14). A potential challenge in diagnosis lies in differen-
tiating the SJS/TEN spectrum from MIRM, especially during the 
Figure 1 | (a, b) Patient 1 on the day of admission, displaying involvement of the lips, conjunctiva, and acral sites; (c) 1 day after admission, progression of skin 
lesions with involvement of trunk is seen; (d) 2 days after admission, extensive skin involvement with multiple targetoid and confluent lesions as well as bullae 
is seen.

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Acta Dermatovenerol APA | 2025;34:139-144 Atypical features in TEN
early phases of the disease, when they may exhibit overlapping 
clinical features. As established by Canavan et al. in 2015, MIRM 
and SJS are distinct entities with different etiologies, presenta-
tions, and outcomes (15). However, both MIRM and SJS/TEN are 
Figure 2 | (a, b) Patient 2, previously treated with very low-dose intravenous immunoglobulins for 5 days, presenting with extensive skin erythema, bullae, and 
areas of skin detachment, unresponsive and on ventilatory support at admission to our center; (c, d) patient 3, with significant re-epithelization of skin lesions, 
but worsening renal disease unresponsive to the therapy provided.
Table 1 | Primary demographic, clinical, and laboratory data for toxic epidermal necrolysis (TEN) patients.
Patient 1 Patient 2 Patient 3
Age (years) 42 50 53
Sex Female Female Female
Comorbidities None Hypertension, chronic renal 
insufficiency, chronic 
obstructive pulmonary disease
Balkan endemic nephropathy, 
chronic renal insufficiency grade 
4, hypertension
Symptom onset before admission 3 days 9 days 6 days
Probable culprit drug Ibuprofen Penicillin and ibuprofen Allopurinol
Skin lesion localization at admission Oral, conjunctival, genital 
mucosa, upper extremities
Oral, conjunctival, genital 
mucosa, diffuse skin involvement
Oral and conjunctival mucosa, 
trunk, extremities
BSA at admission 5% 80% 50%
SCORTEN at admission 2/7 6/7 5/7
Histologically proven disease Yes Yes Yes
Treatment received IVIg (2 g/kg over 5 days), 
methylprednisolone pulse 
therapy (1,000 mg over 3 days)
IVIg (0.07 g/kg/day over 5 days), 
methylprednisolone pulse 
therapy (500 mg over 3 days)
IVIg (2 g/kg over 5 days), 
dexamethasone pulse therapy 
(100 mg over 3 days*)
Complications leading to fatal 
outcome
Respiratory failure, acute renal 
insufficiency, sepsis
Hypotensive shock Sepsis
*Prior to admission to our center, the patient received 25 mg of dexamethasone over 2 days, followed by 100 mg of dexamethasone over 3 days at our center.
SCORTEN = Severity-of-Illness Score for Toxic Epidermal Necrolysis, BSA = body surface area, IVIg = intravenous immunoglobulins.

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mucocutaneous eruptions characterized by prominent mucosal 
involvement. In their early stages, both can present with fever and 
painful mucositis, and the cutaneous lesions in MIRM can resem-
ble those seen in SJS/TEN. This similarity led early classifications 
to often label M. pneumoniae–associated eruptions under desig-
nations such as SJS or erythema multiforme (15, 16). Case 1 in our 
series initially raised suspicion of MIRM given the involvement 
of three different mucosal sites, sparse atypical target lesions 
on the skin, absence of widespread detachment, and prodromal 
symptoms of fever and cough. Our case parallels a case report of 
a 3-year-old patient initially diagnosed with atypical SJS that was 
later confirmed to have MIRM due to positive M. pneumoniae se-
rology, and a 36-year-old woman, whose condition was initially 
considered SJS before being diagnosed as MIRM (17, 18). Key dis-
tinctions between MIRM and TEN are shown in Table 2.
Regarding TEN treatment, high-level evidence suggests that cy-
closporine, corticosteroids, and IVIg combination therapy, as well 
as etanercept, are efficacious. However, conclusions are mixed 
for corticosteroid monotherapy, and thalidomide use is associ-
ated with high mortality (19–30). A significant area of debate con-
cerns the optimal dosage of IVIg. European guidelines for treat-
ing TEN indicated that high-dose IVIg (≥ 2 g/kg) was associated 
with significantly lower mortality than low-dose IVIg (< 2 g/kg,  
p = 0.022), with a strong inverse correlation between IVIg dosage 
and standardized mortality rate, suggesting that dosages of ≥ 2 g/
kg significantly decreased mortality (31). However, evidence re-
garding optimal IVIg dosage is inconsistent. A recent meta-anal-
ysis found a significantly lower mortality rate in adult patients 
treated with high-dose IVIg (18.9%) compared to low-dose (50%), 
but this was not significant when adjusted for confounding fac-
tors such as age, total BSA, and time to treatment. Furthermore, 
another systematic review and network meta-analysis found no 
differences in efficacy based on IVIg treatment dose (≥ 3 g/kg or < 
3g/kg) (23, 29). Our Case 2 provides additional information on the 
therapeutic effect of low-dose IVIg. The patient received a cumu-
lative low dose of IVIg (0.35 g/kg over 5 consecutive days, or 0.07 
g/kg/day) in conjunction with high doses of corticosteroids. It is 
important to note that this low-dose IVIg therapy was adminis-
tered at a referring secondary medical center prior to transfer to 
our facility. This treatment occurred in early 2016, which predates 
the 2016 European guidelines recommending high-dose IVIg for 
TEN, reflecting the local protocols and prevailing clinical evi-
dence. Unfortunately, this treatment was ineffective because the 
patient’s skin detachment progressed from an initial 30% to 80% 
of BSA. This patient represents one of the rare cases in the litera-
ture for whom such low doses of IVIg were utilized. The hypoth-
esis for low-dose IVIg efficacy centers on its ability to block the 
Fas-FasL pathway (implicated in TEN pathogenesis and thought 
to be dosage independent), but this intervention did not yield an 
adequate response in our patient. This lack of response was pre-
sumably due to the presence of multiple comorbidities, including 
uncontrolled hypertension, stage II chronic renal insufficiency, 
and chronic obstructive pulmonary disease, a profile similar to 
that of a patient with a fatal outcome in another study (32). De-
spite the outcome in Case 2, evidence for the effectiveness of 
low-dose IVIg in certain TEN cases exists, relying on prospective 
cohort studies and case reports. A prospective comparative study 
involving 36 (adult and pediatric) patients demonstrated that low-
dose IVIg (0.2–0.5 g/kg, divided over 3 days) combined with sys-
temic steroids effectively halted disease progression compared to 
steroid therapy alone (32). Similarly, an open uncontrolled study 
in 10 pediatric patients found that low doses of IVIg (0.05–0.1 g/
kg per day for 5 days) halted disease progression and facilitated 
rapid re-epithelialization (33). A case report also described an ex-
cellent outcome in a patient with TEN treated with a combination 
of systemic steroids and low-dose IVIg (1.2 g/kg) over 3 days (34).
Factors affecting outcome in SJS and TEN are traditionally incor-
porated into validated scores that predict mortality. The SCORTEN 
scale is the most widely recognized, proving beneficial in predict-
ing mortality when the score exceeds 2 within the first 24 hours 
(35). In addition, the new Clinical Risk Score for TEN (CRISTEN) 
score has been developed, focusing exclusively on clinical aspects 
for prognosis determination (36). The specific clinical risk factors 
that constitute this score are presented in Table 3. Beyond these 
scores, a recent meta-analysis highlights other factors highly rel-
evant to adverse outcomes, including the general presence of co-
morbidities, longer time to hospitalization, preexisting renal dis-
ease, diabetes mellitus, involvement of the respiratory tract, and 
Table 2 | Key differences between mycoplasma-induced rash and mucositis (MIRM) and toxic epidermal necrolysis (TEN).
MIRM TEN
Primary cause Mycoplasma pneumoniae infection Drug-triggered disease
Age Primarily young patients Most frequently in adults
Cutaneous involvement Sparse or absent; detachment typically < 10% of BSA; 
extensive detachment extremely rare
Widespread epidermal necrosis and sloughing; > 30% of 
body surface area
Mucosal involvement
Prominent and nearly universal (oral 94%, ocular 82%, 
urogenital 63%); major cause of morbidity
Universal; two or more mucosal surfaces involved in up to 
80% of cases
Lesion morphology Vesiculobullous (77%), targetoid (48%), atypical targets, 
or macules; true targets are rare; lesions often in acral 
distribution or on extremities
Erythematous macules or atypical target lesions on the trunk 
that progress to confluent areas of erythema with dusky 
centers, flaccid blisters with a positive Nikolsky sign, and 
sheets of denuded epidermis
Disease course Generally milder with excellent prognosis; infrequent 
long-term sequelae
More severe than MIRM; associated with significant 
morbidity
Mortality rate Very low; fatalities likely due to pulmonary complications 
in pre-antibiotic era
Associated with significant mortality
BSA = body surface area.
Table 3 | Clinical Risk Score for TEN (CRISTEN) to predict mortality in patients 
with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in 
early stages based on clinical information (36).
Risk factors Points assigned
Patient age ≥ 65 years 1
≥ 10% of body surface area (BSA) involved 1
Use of antibiotics as culprit drugs 1
Prior systemic corticosteroid therapy before onset 1
Damage affecting ocular, buccal, and genital mucosa 1
Underlying condition: renal impairment 1
Underlying condition: diabetes (under treatment) 1
Underlying condition: cardiovascular disease 1
Underlying condition: malignant neoplasm 1
Underlying condition: bacterial infection 1
Each of the 10 clinical risk factors identified contributes one point to the to-
tal score, which then correlates to a predicted probability of mortality ranging 
from 0% (0 points) to 100% (8 or more points).

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the development of sepsis (37). Further cohort studies have identi- 
fied additional potential risk factors for mortality, such as fever, 
hypertension, presentation with vesicles and bullae, utilization 
of plasmapheresis, urinary microscopic abnormalities, visceral 
organ involvement, HIV infection, a high neutrophil-to-lympho-
cyte ratio, cutaneous lesions preceding mucosal lesions, female 
sex, inborn errors of urea cycle metabolism, chronic obstructive 
pulmonary disease, lower hemoglobin, and higher platelet count 
(2, 35, 38–48). The identification of preexisting renal disease as a 
significant risk factor is particularly pertinent for Case 3, which 
involved the rare occurrence of TEN in a patient with BEN. BEN is 
a chronic tubulointerstitial disease primarily found in the Balkan 
Peninsula, which over time leads to end-stage renal disease in 
nearly all individuals affected (48). This case represents a unique 
intersection of TEN with BEN, which is especially important given 
that approximately 100,000 individuals are at risk for BEN, with 
about 25,000 already affected by the disease (49).
Conclusions
In summary, the cases presented highlight several key points: 
there are possible difficulties in differentiating the SJS/TEN spec -
trum and MIRM due to overlapping clinical features in early dis-
ease phases, the cases provide additional information on the 
therapeutic effect of low-dose IVIg in combination with systemic 
corticosteroids for TEN treatment, and they underscore the poten-
tial for severe kidney complications among individuals with BEN 
that develop TEN.
Funding
DZ was partially supported by the Ministry of Education, Sci-
ence, and Technological Development through grant no. 451-03-
66/2024-03/200110.

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