Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening mucocutaneous reactions. There is an ongoing controversy regarding the use of systemic corticosteroids and intravenous immunoglobulin (IVIG) in SJS/TEN and their utility in HIV-infected patients.
The objective was to assess the outcome of a combination of intensive supportive care with oral corticosteroids in SJS and a combination of systemic steroids and IVIG for 3 consecutive days in HIV-infected patients with TEN. In addition, we assessed management in a general dermatology ward without implementing wound debridement.
This was a retrospective cohort study of 36 HIV-infected adults with SJS/TEN admitted to a tertiary dermatology unit between 1st January 2010 and 31st July 2011. Standard-of-care protocols included identification and elimination of the possible causative drug, meticulous wound care without debridement, initiation of oral prednisone (1 mg/kg/day) on admission for 3 consecutive days, and the addition of IVIG (1 g/kg/day) for 3 consecutive days to those with TEN.
Of the 36 patients in the study, 32 were female. Nevirapine was the commonest drug implicated. A diagnosis of tuberculosis did not increase the case fatality rate. Complications included infections, anaemia, drug-induced hepatitis, ocular involvement, renal impairment, deep vein thrombosis, respiratory distress, Leucopenia, gastritis and hypernatremia. The overall survival rate was 97%.
HIV-infected SJS and TEN patients were treated in a tertiary dermatology ward with a treatment plan of skin care, and a combination of systemic corticosteroids and IVIG respectively had a survival rate of 97%.
Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening mucocutaneous reactions characterised by epithelial sloughing and systemic symptoms.
In South Africa, there are no published data on the incidence of SJS and TEN. With the current HIV epidemic and increased use of HIV treatment in South Africa, the number of patients with SJS/TEN has increased.
Other factors that contribute to mortality included lymphopenia, neutropenia and hypernatremia, as well as low-serum haemoglobin and hypoalbuminemia.
The use of systemic corticosteroids in the treatment of SJS/TEN is controversial.
The study was undertaken at the Greys Hospital Department of Dermatology, a tertiary referral centre in Pietermaritzburg, KwaZulu-Natal, South Africa. It is a 530-bed tertiary hospital, serving 3.5 million people in the western part of KwaZulu-Natal.
The clinical records of all 39 participants with SJS/TEN admitted to a general dermatology ward from 01 January 2010 until July 2011 were retrospectively reviewed. Three patients were HIV-negative and were thus excluded from the study. All participants were of black African descent.
Participants who presented with organ failure and fulfilled intensive care admission criteria were referred to the intensive care unit where they were co-managed with critical care specialists and the dermatology team.
The review of patient’s clinical records during admission, weekly after discharge for the first month and then monthly for the following 3 months were recorded. Demographics, SCORTEN score, drug history, CD4 count, comorbidities and complications were documented from the records.
SCORTEN (SCORe of toxic epidermal necrosis) is a score used to assess severity and predict mortality in patients with SJS/TEN. It uses seven criteria (
SCORTEN score.
SCORTEN score | Mortality rate (%) | Criteria |
---|---|---|
1 | 3.2 | Age > 40 years |
2 | 12.1 | Heart rate > 120 bpm |
3 | 35.8 | BSA > 10% |
4 | 58.3 | Serum urea > 10 mmol/L |
≥ 5 | 90.0 | Serum bicarbonate < 20 mmol/L |
- | - | Serum glucose > 14 mmol/L |
- | - | Cancer or haematological malignancies |
BSA, body surface area; bpm, beats per minute.
Criteria used to determine drug causality were timing of the skin lesions after the administration of the drugs (temporality), increase of drug dose, previous history of drug reactions and if the drug reaction occurred when the drug was restarted, criteria noted in the Naranjo scale.
The standard-of-care protocols included identifying and eliminating the possible causative drug, initiating oral prednisone (1 mg/kg/day) on admission for 3 consecutive days, and adding IVIG (1 g/kg) for 3 consecutive days to participants with TEN (
Biochemical assessments on admission included a full blood count, glucose level, and renal and liver function tests. Vital signs were registered every 4 h, and plasma glucose was monitored every 12 h. A screen for sepsis was done when clinically indicated. Fluid depletion and electrolyte abnormalities were corrected, nutritional support was guided by the dietician and pain management was optimised. Oral mucosal care included glycothymol irrigation every 6 h, removal of haemorrhagic crusting and the application of a mixture of prednisolone, remicaine, nystatin and sucralfate (8:8:8:1 formulation) to the lips and oral mucosa. Genital mucosa was treated with daily potassium permanganate sitz baths and lubricated with petroleum jelly (Vaseline ®) to prevent adhesions. Pain was controlled with Tramadol hydrochloride 50 mg – 100 mg 6 hourly and paracetamol 1 g 6 hourly. Pethidine was used to alleviate the pain while dressing the wounds. Cutaneous lesions were managed by strict barrier protection nursing and meticulous wound care without debridement using nanocrystalline silver dressings (Acticoat®). Antibiotics were not used prophylactically unless there was a clinical indication. Expert opinion was sought from the ophthalmologists on admission and instructions were carried out as per the ophthalmologist care plan. Their management plan entailed the use of a topical steroid (Maxitrol®), lubricants and glass rodding to prevent adhesions. Obstetricians and physicians were consulted when indicated.
Data were analysed using Stata 13.0 SE (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). Descriptive statistics included means (standard deviations) for continuous variables and frequencies (
Ethical approval was obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee (reference number BE417/14).
Of the 36 patients in the study, 32 (88.9%) were women. Eleven had SJS, 13 had SJS/TEN overlap and 12 had TEN. The number of days of hospitalisation increased exponentially along the spectrum of the disease (
Demographics of 36 HIV-infected patients presenting with Stevens–Johnson syndrome–toxic epidermal necrolysis.
Variable | Total ( |
SJS ( |
SJS/TEN ( |
TEN ( |
||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
% | s.d. | Mean | % | s.d. | Mean | % | s.d. | Mean | % | s.d. | Mean | |||||
< 40 years | 30 | 83.3 | - | - | 10 | 27.8 | - | - | 10 | 27.8 | - | - | 10 | 27.8 | - | - |
> 40 years | 6 | 16.7 | - | - | 1 | 2.8 | - | - | 3 | 8.3 | - | - | 2 | 5.6 | - | - |
Male | - | - | 7.6 | 34.3 | - | - | - | 34.3 | - | - | - | - | - | - | - | - |
Female | - | - | 10.4 | 32.4 | - | - | - | 27.1 | - | - | - | 34.8 | - | - | - | 33 |
Male | 4 | 11.1 | - | - | 4 | 11.1 | - | - | 0 | - | - | - | 0 | - | - | - |
Female | 32 | 88.9 | - | - | 7 | 19.4 | - | - | 13 | 36.1 | - | - | 12 | 33.3 | - | - |
Length of hospital stay (Mean s.d.) no. days | - | - | 11.2 | 15.1 | - | - | 2.4 | 5.8 | - | - | 6.9 | 13.0 | - | - | 11.3 | 25.8 |
Y | 16 | 50 | - | - | 5 | 31.3 | - | - | 5 | 31.3 | - | - | 6 | 37.5 | - | - |
N | 16 | 50 | - | - | 2 | 12.5 | - | - | 8 | 50 | - | - | 6 | 37.5 | - | - |
SJS, Stevens–Johnson syndrome; TEN, Toxic epidermal necrolysis; SJS, TEN overlap; Y, yes; N, no; Regimen 1: NVP, nevirapine; 3TC, lamivudine; D4T, stavudine; TMP/SMX, trimethoprim/sulfamethoxazole; TB, tuberculosis; N/A, not applicable.
Sixteen (50.0%) women in the study were pregnant. The mean (s.d.) CD4 cell count in the pregnant women was 267.2 (60.6) cells/mm3. A significant number of pregnant women (93.8%) developed SJS/TEN secondary to nevirapine, while one was due to isoniazid prophylaxis. The pregnant women presented at a mean (s.d.) of 29.13 (3.76) weeks gestation. Five (31.25%) of the women delivered prematurely as a result of foetal distress, and all five of these patients had TEN. One of the deliveries was a stillbirth at 34 weeks’ gestation. The other four infants were healthy and showed no signs of any drug reaction.
CD4 cell counts were available for all the patients but one (
CD4, SCORTEN, drugs implicated, co-morbidities and mortality of 36 HIV-infected patients presenting with Stevens–Johnson syndrome–toxic epidermal necrolysis.
Variable | Total ( |
SJS ( |
SJS/TEN ( |
TEN ( |
||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
% | Mean | s.d. | % | Mean | s.d. | % | Mean | s.d. | % | Mean | s.d. | |||||
- | - | 236.8 | 146.8 | - | - | 216.3 | 109.2 | - | - | 270.5 | 194.8 | - | - | 217.4 | 115.5 | |
0-1 | 11 | 30.5 | - | - | 11 | 30.5 | - | - | 0 | - | - | - | 0 | - | - | - |
2 | 12 | 33.3 | - | - | 0 | - | - | - | 8 | 22.2 | - | - | 4 | 11.1 | - | - |
3 | 9 | 25.0 | - | - | 0 | - | - | - | 4 | 11.1 | - | - | 5 | 13.9 | - | - |
4 | 3 | 8.3 | - | - | 0 | - | - | - | 1 | 2.8 | - | - | 2 | 5.6 | - | - |
5 | 1 | 2.8 | - | - | 0 | - | - | - | 0 | - | - | - | 1 | 2.8 | - | - |
NVP alone | 15 | 41.7 | - | - | 7 | 19.4 | - | - | 3 | 8.3 | - | - | 5 | 13.9 | - | - |
NVP, D4T, 3TC/TMP/SMX | 6 | 16.7 | - | - | 1 | 2.8 | - | - | 2 | 5.6 | - | - | 3 | 8.3 | - | - |
NVP, D4T, 3TC/Rifafour | 2 | 5.6 | - | - | 1 | 2.8 | - | - | 0 | - | - | - | 1 | 2.8 | - | - |
NVP, D4T, 3TC/INH | 1 | 2.8 | - | - | 0 | - | - | - | 1 | 2.8 | - | - | 0 | - | - | - |
NVP, D4T, 3TC/INH/TMP/SMX | 1 | 2.8 | - | - | 0 | - | - | - | 1 | 2.8 | - | - | 0 | - | - | - |
TMP/SMX | 2 | 5.6 | - | - | 1 | 2.8 | - | - | 1 | 2.8 | - | - | 0 | - | - | - |
TMP/SMX + phenytoin | 1 | 2.8 | - | - | 0 | - | - | - | 0 | - | - | - | 1 | 2.8 | - | - |
TMP/SMX + Rifafour | 3 | 8.3 | - | - | 0 | - | - | - | 1 | 2.8 | - | - | 2 | 5.6 | - | - |
Rifafour | 3 | 8.3 | - | - | 1 | 2.8 | - | - | 2 | 5.6 | - | - | 0 | - | - | - |
Phenytoin | 1 | 2.8 | - | - | 0 | - | - | - | 0 | - | - | - | 1 | 2.8 | - | - |
Fluconazole | 1 | 2.8 | - | - | 0 | - | - | - | 1 | 2.8 | - | - | 0 | - | - | - |
TB | 8 | 22.2 | - | - | 2 | 5.6 | - | - | 3 | 8.3 | - | - | 3 | 8.3 | - | - |
Hypertension | 2 | 5.6 | - | - | 0 | - | - | - | 1 | 2.8 | - | - | 1 | 2.8 | - | - |
Epilepsy | 2 | 5.6 | - | - | 0 | - | - | - | 1 | 2.8 | - | - | 1 | 2.8 | - | - |
1 | 2.8 | - | - | 0 | - | - | - | 0 | - | - | 1 | 2.8 | - | - |
The mean (s.d.) CD4 cell count and confidence interval noted in patients with complications were 236.8 (186.4–287.2) cells/mm3. There was no statistical difference across all complications. Thus, the complications seen in the patients with SJS/TEN were not influenced by the CD4 cell counts and hence the level of immunosuppression in the sample.
The average SCORTEN scores for SJS, SJS-TEN overlap and TEN were 1, 2 and 3, respectively. There was a significant difference in the median SCORTEN score by drug reaction type
Comorbidities included hypertension, tuberculosis and epilepsy (
The most common drugs implicated were nevirapine (69.4%), anti-tuberculosis medication (16.7%) and trimethoprim/sulfamethoxazole (8.3%). Other drugs included phenytoin (2.8%) and fluconazole (2.8%) (
Thirty-two of the study patients had associated complications such as anaemia, drug-induced hepatitis, ocular involvement, renal impairment, deep vein thrombosis, respiratory distress, lichen planus, Leucopenia, gastritis and hypernatremia. The number of complications noted increased along the continuum of the drug reactions with seven complications noted in SJS patients, 19 in SJS-TEN overlap syndrome and 27 noted in the patients with TEN (
Complications correlated to the various drug reactions.
Complications | SJS |
SJS-TEN overlap |
TEN |
Total |
||||
---|---|---|---|---|---|---|---|---|
% | % | % | % | |||||
Infection | 1 | 2.8 | 4 | 11.1 | 5 | 13.9 | 10 | 27.8 |
Anaemia | 3 | 8.3 | 5 | 13.9 | 8 | 22.2 | 16 | 44.4 |
Drug-induced hepatitis | 2 | 5.6 | 4 | 11.1 | 3 | 8.3 | 9 | 25 |
Deep vein thrombosis | 0 | - | 0 | - | 2 | 5.6 | 2 | 5.6 |
Lichen planus | 0 | - | 1 | 2.8 | 0 | - | 1 | 2.8 |
Ocular | 1 | 2.8 | 4 | 11.1 | 3 | 8.3 | 8 | 22.2 |
Renal impairment | 0 | - | 1 | 2.8 | 2 | 5.6 | 3 | 8.3 |
Hypernatraemia | 0 | - | 0 | - | 1 | 2.8 | 1 | 2.8 |
Leucopenia | 0 | - | 0 | - | 1 | 2.8 | 1 | 2.8 |
Acute respiratory distress syndrome | 0 | - | 0 | - | 1 | 2.8 | 1 | 2.8 |
Gastritis and esophageal ulceration | 0 | - | 0 | - | 1 | 2.8 | 1 | 2.8 |
- | - | - |
SJS, Stevens–Johnson syndrome; TEN, Toxic epidermal necrolysis; SJS-TEN overlap.
Profile of the 10 patients with infection, organisms isolated and SCORTEN score.
Drug reaction | CD4 (cells/mm3) | Infection | Organism | Comorbidity | SCORTEN score | Length of hospital stay (days) |
---|---|---|---|---|---|---|
TEN | 268 | Skin infection | TB | 2 | 20 | |
TEN | 302 | Pneumonia | MRSA (ET tube) | - | 4 | 35 |
SJS/TEN | 179 | Genital ulcers | Herpes simplex | 28 weeks pregnant | 2 | 15 |
SJS/TEN | 226 | UTI | 29 weeks pregnant | 2 | 9 | |
TEN | 247 | Skin infection | 34 weeks pregnant | 3 | 20 | |
SJS | 0 | PV discharge Genital warts | Candidiasis HPV | 30 weeks pregnant | 1 | 4 |
TEN | 437 | Skin infection | - | 2 | 24 | |
SJS/TEN | 10 | Lower respiratory tract infection | - | 3 | 18 | |
TEN | 185 | Pneumonia | 32 weeks pregnant | 4 | Died on day 4 post admission | |
SJS-TEN | 237 | Bartholin abscess | 29 weeks | 2 | 18 |
SJS, Stevens–Johnsons Syndrome; TEN, Toxic Epidermal Necrolysis; SJS-TEN overlap; MRSA, methicillin resistant staphylococcus aureus; ET tube, endotracheal tube; UTI, urinary tract infection;
There was one death in our study representing a case fatality rate of 2.8%. The patient was pregnant (34 weeks gestation)and was admitted with TEN secondary to nevirapine. She had a CD4 count of 185 cells/mm3 and a SCORTEN score of 4 which predicted a poor outcome (expected mortality rate of 58.3%). She experienced preterm labour 2 days after admission and gave birth to a stillborn male. She died 4 days after admission. She presented with poor prognostic factors: SCORTEN score of 4 (tachycardia, BSA involvement of 40% acidosis and elevated urea, as well as hypernatremia and
This retrospective cohort study has shown that the use of systemic corticosteroids together with IVIGs for the treatment of SJS/TENS in HIV-infected patients resulted in a 97.2% survival rate compared to the previous report, which has a mortality rate of 30.0%.
The use of systemic corticosteroids in SJS/TEN has been an issue of debate for many years, and its use in HIV-infected patients remains highly controversial as it is thought to cause further immunosuppression.
Those opposing the use of systemic steroids argue that systemic steroids impair the immune system and increase the risk of infections.
The rationale for the use of systemic steroids in SJS/TEN is mainly due to anti-inflammatory and anti-apoptotic effects.
Studies that have opposed the use of systemic corticosteroids are of the view that systemic corticosteroids are associated with a high rate of sepsis, poor wound healing, prolonged hospital stay and a higher mortality rate.
Studies have shown that IVIG arrests disease progression and reduces the time of skin healing.
Recent studies have shown that a combination of corticosteroids and IVIG arrested disease progression, and decreased hospitalisation and mortality in patients with SJS/TEN more than the use of corticosteroids as monotherapy.
Local studies oppose the use of systemic steroids and immunoglobulins in patients with SJS/TEN. Kannenberg et al. conducted a study in which 78.9% of the patients were HIV-infected. All patients in the study received extensive supportive care. There was a mortality rate of 29.8% in the HIV-infected patients and 6.0% in the non-infected patients. The prognostic indicators noted were HIV -tuberculosis co-infection, sepsis and BSA > 40.0%.
Many view TEN and major burns as similar entities based on BSA involvement, and hence the general principles of management should be the same.
None of the patients in this cohort had wound debridement, and this is supported by a number of studies.
Infection is the leading cause of death in patients with SJS/TEN and maybe as high as 40% in tertiary centres.
Ocular lesions are the most common and devastating complications in SJS/TEN (20% – 79% of patients).
In our study, the high female-to-male ratio may be due to the use of nevirapine which is implicated as the cause of SJS/TEN. It was prescribed in pregnant women (who accounted for 44.4% of the study sample) as part of the HIV treatment guidelines at the time of the study.
The three drugs most implicated included nevirapine, trimethoprim/sulfamethoxazole and anti-tuberculosis medication – mainly isoniazid and rifampicin. Risk factors for nevirapine-induced SJS/TEN include female gender, baseline CD4 counts > 250 cells/mm3 in women and > 400 cells/mm3 in men, history of drug allergy, low body weight, high nevirapine serum levels and certain human lymphocyte antigen types.
Pregnancy was not a risk factor for developing a drug reaction in our patient profile. This is contrary to what has been suggested in the literature.
SCORTEN score directly correlated to the severity of the drug reaction. There was no significant correlation between the CD4 cell count and SCORTEN score, the severity of the drug reaction and the various complications. This could be explained by the fact that CD8 cytotoxic T cells are the main cells resulting in keratinocyte apoptosis.
Marks et al. noted that drug reactions to anti-tuberculosis therapy occurred in 13.0% of the non-HIV-infected patients and 27.0% of the HIV-infected patients.
The limitations of this study are the retrospective study design and the small sample of patients. Future recommendations would be for larger randomised controlled studies to confirm the role of short course systemic corticosteroids in the management of HIV-associated SJS/TENS.
This retrospective study has shown that an intensive skin care regimen in combination with systemic corticosteroids and/or IVIG in HIV-infected SJS and TEN patients, respectively, treated in a tertiary dermatology ward resulted in a 97.2% survival rate. Short course (3 days) systemic steroids were not associated with significant mortality in this HIV-infected cohort. A randomised controlled study is needed to confirm the results of this study.
Sincere appreciation to Ms P. Jika in preparation of this manuscript and to Dr Peer for reviewing the manuscript.
The authors have declared that no competing interests exist.
A.V.C., N.C.D., H.D and C.A. equally contributed to the writing and research is this article.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Data sharing is not applicable to this article as no new data were created or analysed in this study.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.