INTRAVENOUS IMMUNOGLOBULIN THERAPY

IN CHILDREN WITH SJS-TEN

Report of three cases

Presented by:
Kadek Ayu Atrie S, dr.

Consultants:
Prof. dr. Ariyanto Harsono, Sp. A (K)
Dr. dr. Anang Endaryanto, Sp. A (K)
dr. Zahrah Hikmah, Sp A (K)
dr. Azwin Mengindra K, Sp A (K)

Department of Child Health

Faculty of Medicine Airlangga University
Dr. Soetomo Hospital Surabaya
2017

1
INTRODUCTION
StevensJohnson syndrome (SJS) and toxic epidermal necrolysis
(TEN) are one of the most severe mucocutaneous reactions, characterized
by extensive necrosis and detachment of epidermis. Both conditions are
now considered variants of the same hypersensitivity disorder, with
epidermal detachment of less than 10% body surface area considered as
SJS, more than 30% as TEN and between 10 and 30% as SJS/TEN.1
In majority of limited pediatric studies, drugs were implicated as the
most common cause of SJS/TEN, followed by viral and bacterial infection.2
The incidence of SJS and TEN is rare, with an estimate of 1.5 to two cases
per million per year in the general population. Mortality rates in SJS have
been reported at about 5% and sepsis is the main cause of death, but TEN
may be fatal in up to 3050% of cases.3
There is no gold standard for SJS management. The first line of
treatment is immediate withdrawal of the medication.The patients should be
admitted to the burn unit or intensive care unit for supportive care.4
Literature of specific treatment in children is scant and controversial. The
most commonly studied therapy by far is the use of intravenous
immunoglobulins (IVIG), followed by corticosteroid treatment.3
IVIG have shown promising results because it inhibits Fas-mediated
apoptosis in sensitive cell lines by blocking Fas receptors. Most studies
have shown that, when used at a dose of 24 g/kg within the first 4 days of
onset of skin eruptions, patients appear to have a shorter time to cessation
of disease progression and complete re-epithelisation, and also have trend
towards a better survival rate. On the contrary, a few studies did not show
any benefit on mortality rates.5 Several studies have reported a decreased
mortality in patients with SJS-TEN treated with intravenous immunoglobulin.
The purpose of this paper is to report IVIG therapy in 3 cases of
children with SJS/TEN.

2
CASE REPORT-1
A, a 7 years old male, was referred to the emergency department Dr.
Soetomo Hospital from a private hospital on July 11th, 2016 with chief
complaint skin blister spread all over the body. He suffered from skin blister
in the last 4 days before admission, with a split lip and red eyes. This
complaint begins with fever, cough and colds since 4 before admission. His
mother bought Pimtrakol in a drugstore without prescription and several
hours after taking the medicine, he developed red rash on his body. He was
brought to primary health care and treated with salicylic talk.

Figure 1
There is skin blister spread all over the body

The boy was born at term by a midwife with birth weight 3000 grams.
He cried spontaneously after birth. There was no history of cyanosis and
jaundice after birth. His mother was healthy during pregnancy without
history of consuming alcohol, narcotics or other drugs. The patients
nutritional history were breastfed until 6 month-old, formula since 5 months,
rice cereal since 5 months, fruit puree since 6 months, biscuits since 7

3
months, steam rice since 7 months, and egg since 7 months. Nowadays he
eats 3 meals a day and drinks milk once a day. The history of immunizations
of the patient were Hepatitis B, BCG, Polio 1, 2, 3, 4, DPT 1, 2, 3 and
Measles.
He and his family had no history of allergy and adverse drug
reactions previously. Since he was 5 years-old his mother always give
pimtakrol syrup (Paracetamol, Gliceryl guaiacolat, Ephedrine,
Chlorpheniramin maleate) whenever he ill and he never complaint any
reaction.
The physical examination in the emergency room revealed a weak
and alert boy. He had a regular heart rate of 98 bpm, respiratory rate of 22
tpm, axillary temperature of 36.5oC and peripheral saturation of 99%. Head
and neck examinations revealed no anemia and no dyspnea, no icterus, no
cyanosis, and no lymph node enlargement. Nose, throat and mouth
examinations were normal. Chest was symmetrical and no retraction.
Cardiovascular examination revealed neither murmur nor gallop. Pulmonary
examination was vesicular, no rales or wheezing in the both side of lungs.
Abdomen was flat, no enlargements of the liver or spleen, and no palpable
mass were noted. Extremities were dry and warm with capillary refill time <
2 seconds. Central nervous system examinations revealed no abnormality.
Status dermatologist found hyperpigmented macule with diameters
5-7 cm. Bulla found in some region with positive nickolsky's sign. There was
hemorrhagic crust in oral mucous. Genitalia and anal region revealed
mucous erosion. Status ophthalmology from both eyelids: edema, spasm,
crust, excoriation. From conjunctiva on both eyes: hyperemia,
symblepharon. From cornea on both eyes: hazy. Over all lesion was 29%
body surface area (head 6%, body 13%, upper extremity 4%, lower
extremity 5%, and genital 1%).
The anthropometric measurements showed a good nutritional status.
Weight 18 kg, height 104 cm, head circumference 53 cm, IBW 19 kg, %IBW
94, H/A 4.6 years, BMI 15.7, BMI percentiles was P50.

4
Figure 2. Head Circumference of the patient according to Nellhaus Chart
Patient was normal head circumference
Source: Nellhaus G. Head circumference from birth to eighteen years. Practical
composite international and interracial graphs. Pediatrics. 1968;41:106-14.

A B
A

Figure 3. (A) The Body Mass Index of the patient is normal

(B) Patient was normal Body Mass Index, but the was stunted
Source: CDC Growth Chart, 2000

5
 Laboratory examination on July 11th, 2016 revealed hemoglobin level
12.1 g/dL, white blood cells 4.53x103/L, platelets 245x103/L, BUN 6
mg/dL, serum creatinin 0.46 mg/dL, albumin 3.47 g/dL, ALT 40 U/L, ALP 18
U/L, sodium 131 mmol/L, potassium 4.7 mmol/L, chloride 102 mmol/L, and
calcium 8.1 mg/dL. Chest radiography on July 12th, 2016 revealed normal.
Based on history, physical examination, laboratory and radiology
findings the diagnosis was Steven Johnson SyndromeToxic Epidermal
Necrolysis (SJSTEN). The patient was admitted to the isolation room and
planned for consultation to nutritional and metabolic disease,
gastroenterology, dermato-venereology, opthalmology and dentistry
department. The treatment was stop all drug which suspected as the cause,
gentamycin injection 100 mg once daily, omeprazole injection 8 mg twice a
day, dexamethasone injection 0.8 mg three times a day, oral hygiene,
preservative-free artificial tear, tobroson eye drop 6 times a day 1 drop on
each eye, and eyelid hygiene.
On the 2rd day of admission, patient still suffered from fever, cough,
pain in the mouth and eyes, and pain during urinating. On the skin were
found hyperpigmented macules, bulla at lower extremity, epidermolisis at
back, and pain on the ulcer. Eyelid are edema, spasm, crust, and
excoriation. Conjunctiva are hyperemia and had symblepharon. The cornea
was hazy. On the mouth was found hemorrhage crust, genital area were
edema and had erosion, and in region anal was found hemorrhagic crust.
The IVIG was started at 0,5 mg/kgbw (~10 mg twice per day) followed by
other treatment such as gentamycin injection 100 mg once daily,
omeprazole injection 8 mg twice a day, dexamethasone injection 0.8 mg
three times a day, oral hygiene, preservative-free artificial tear, tobroson
eye drop 6 times a day 1 drop on each eye, and eyelid hygiene.
On the 4th day of admission, no fever and cough, but still suffered with
pain in the mouth, in the eyes, and during urinating. His skin still had
hyperpigmented macules, bulla at lower extremity but not spreading and
most of the bullae already heal, he still had epidermolysis on his back, and
still suffered pain on the ulcer. Eyelid are not edema, still spasm, crust, and

6
excoriation. Conjunctiva were still hyperemia and had symblepharon. The
cornea was hazy. On the mouth was no hemorrhagic crust, genital area was
not edema but still had erosion, anal area was no hemorrhagic crust. IVIG
10 mg twice per day was stopped and continued other treatment
(gentamycin 100 mg intravenous once daily, omeprazole injection 8 mg
twice a day, dexamethasone injection 0.8 mg three times a day, oral
hygiene, preservative-free artificial tear, tobroson eye drop 6 times a day 1
drop on both eyes, eyelid hygiene).
On the 6th day of admission, patient had no fever, no cough, no pain
of the mouth, no pain of the eyes, and no pain during urinating. His skin still
had hyperpigmented macules, bullae at lower extremity but not spreading
and most of the bullae already heal, epidermolysis at back are heal and no
pain on the ulcer. Palpebra not edema, spasm decreased, no crust, and
excoriation. Conjunctiva is not hyperemia and no symblepharon. Cornea
was still hazy. On the mouth was no hemorrhagic crust, on the genital area
not edema anymore and erosion heal, and on anal area was no
hemorrhagic crust. From blood and feces culture on July 12th, 2016 revealed
sterile. Urine culture revealed Staphylococcus hominis, sensitive to
gentamycin, ampicilin-sulbactam, oxacillin, tetrasiclin, clindamycin,
erithromysin, moxifloxacin, nitrofurantoin, meropenem, daptomycin, and
resistance to ampicillin, chloramphenicol, fosfomycin. Swab bulla on July
18th, 2016 revealed Staphylococcus haemolyticus and sensitive to antibiotic
daptomicyn and fosfomicyn. The treatment was continued (gentamycin 100
mg intravenous once daily, dexamethasone injection 0.8 mg three times a
day, oral hygiene, preservative-free artificial tear, tobroson eye drop 6 times
a day 1 drop on both eyes, eyelid hygiene).
He was discharged on July 19th, 2016 with no fever, no cough, no
pain of the mouth, no pain of the eyes, and no pain during urinating. His skin
still had hyperpigmented macules, bullae at lower extremity but not
spreading and most of the bullae already heal, epidermolysis at back are
heal and no pain on the ulcer. Eyelid not edema, spasm decreased, no
crust, and excoriation. Conjunctiva is not hyperemia and no symblepharon.

7
Cornea was still hazy. On the mouth was no hemorrhagic crust, on the
genital area not edema anymore and erosion heal, and on anal area was
no hemorrhagic crust. He was scheduled for visiting allergic immunology
disease outpatient clinic for further follow up.

A B

Figure 4. (A) There is skin blister spread all over the body, before getting IVIG therapy.
(B) There is skin blister spread all over the body, after getting IVIG therapy.

8
CASE REPORT-2
D, a 6 years 5 months old male, was referred to emergency
department Dr. Soetomo Hospital from Ahmad Dahlan Hospital, Pare in
November 5th, 2016 with chief complaint sloughing of epidermis, high fever
and skin blister after administration of fever and cough drug. Patient had
cough and fever in the last 7 days before admission and his mother gave
him Ibuprofen. On October 31th, 2016 he was still fever and black spots
appeared on his abdomen. Her mother took him to the clinic and the
physician gave him compound medicine. His mother took him back to the
clinic and after 5 days with no change in his condition, he was referred to
Dr. Soetomo hospital.

Figure 5. There is skin blister spread all over the body

The patient was born at term by a midwife with birth weight 2700
grams. He cried spontaneously after birth with no history of cyanosis and
jaundice after birth. His mother was healthy during pregnancy without
history of consuming alcohol, narcotics or drugs. Nutritional history was,
breastfed until age 24-month-old, rice cereal since 3 months, steam rice
since 8 months, rice since 12 months. Nowadays he eats 3 meals a day and
drinks milk once a day. The history of immunizations of the patient were
Hepatitis B, BCG, Polio 1, 2, 3, 4, DPT 1, 2, 3 and Measles.

9
 He and his family had no history of allergy and adverse drug
reactions previously. Ibuprofen was given whenever he ill and he never
complaint any reaction.
The physical examination in the emergency room revealed a weak
with alert boy. He had a regular heart rate of 112 bpm, respiratory rate of 26
tpm, axillary temperature of 38.7oC, and peripheral saturation of 99%. Head
and neck examinations revealed no anemia, no dyspnea, no icterus, no
cyanosis, or lymph node enlargement were observed. Nose, throat and
mouth examinations were normal. Chest was symmetric and no retraction.
Cardiovascular examination revealed neither murmur nor gallop. Pulmonary
examination was vesicular, with rales and no wheezing in the both side of
lungs. Abdomen was flat, no enlargements of the liver or spleen and no
palpable mass. Extremities were dry and warm with capillary refill time < 2
seconds. Central nervous system examinations revealed no abnormality.
Status dermatologist revealed morbilliform, hyperpigmented
macules. On labium oris region was found hemorrhagic crust. The orbitalis
region was difficult to evaluate because he can't opened his eyes. On
palmar plantar manus and pedis dextra et sinistra was found erythematous
macules with clear boundaries and morbilliform lesions. Over all lession was
29% body surface area (head 7%, body 13%, upper extremity 4%, lower
extremity 4%, and genital 1%).
The anthropometric measurements showed a good nutritional status.
Weight 17 kg, height 104 cm, head circumference 53 cm, IBW 19 kg,
%IBW100, H/A 4.6 years, BMI 15.7, percentiles BMI P50.

10
Figure 6. Head Circumference of the patient according to Nellhaus Chart
Patient was normal head circumference
Source: Nellhaus G. Head circumference from birth to eighteen years. Practical composite
international and interracial graphs. Pediatrics. 1968;41:106-14.

A B

Figure 7. (A) The Body Mass Index of the patient is normal

(B) Patient was normal Body Mass Index, but the was stunted
Source: CDC Growth Chart, 2000

11
 Laboratory examination on November 5th, 2016 revealed a
hemoglobin level was 9.5 g/dL, white blood cells was 4.3x10 3/L, platelets
was 507x103/L, BUN 9 mg/dL, serum creatinin 0.46 mg/dL, albumin 3.3
g/dL, ALT 137 U/L, ALP 149 U/L, sodium 138 mmol/L, potassium 4.1
mmol/L, chloride 102.4 mmol/L, and calcium 8.2 mg/dL. Chest radiography
on November 5th, 2016 revealed pneumonia. Blood, urine and feces culture
on November 7th, 2016 revealed sterile. Swab skin on November 7th, 2016
revealed Streptococcus constellatus and sensitive with antibiotic
gentamicyn, resistance ampicyllin, penicyllin G, cotrimoxazole,
chloramphenicol, erytromycin, and clindamycine.
Based on history, physical examination, laboratory and radiology
findings the diagnosis was Steven-Johnson Syndrome (SJS)-Toxic
Epidermal Necrolysis (TEN) and Pneumonia. The patient was planned for
consultation to respirology, nutritional and metabolic disease,
gastroenterology, dermato-venerology, opthalmology, and dentistry
department. The treatment was discontinued drug which is suspected as
the cause, dexamethasone injection 5 mg four times a day (~1
mg/kgbw/day), cetirizine 5 mg once times a day, NaCl compress for
hemorrhagic crust in the mouth, sodium fusidat 2% cream for erosion,
gargarisma khan oral gargle 3 times a day, levofloxacin eye drop 6 times a
day 1 drop on each eye, cenfresh eye drop monodose 4 times a day 1 drop
on each eye, and ocuflam eye drop 4 times a day 1 drop on each eye.
On the 4th day of admission, patient still suffered from fever, cough,
and pain in the eyes. On labium oris region was found hemorrhagic crust.
The orbitalis region was difficult to evaluate because he can't opened his
eyes. On palmar plantar manus and pedis dextra et sinistra was found
erythematous macules and morbilliform lesions. Patient were consulted to
respirology division and was diagnosed as Community Acquired
Pneumonia and was given antibiotic gentamycin four 5 days. The therapy
was gentamycin injection120 mg once times a day, IVIG 7.5 gr/day for 3
days (~ 0.375 mg/kgbw/time), stopped the dexamethasone injection,
cetirizine 5 mg once times a day, NaCl compress for hemorrhagic crust in

12
the mouth, sodium fucidat 2% cream for erosion, gargarisma khan oral
gargle 3 times a day, levofloxacin eye drop 6 times a day 1 drop on each
eye, cenfresh eye drop monodose 4 times a day 1 drop on each eye, and
ocuflam eye drop 4 times a day 1 drop on each eye.
On the 6th day of admission, patient had no fever, no cough, skin
started to dry and flaky. The treatment were continued with gentamycin
injection 120 mg once times a day, cetirizine 5 mg once times a day, IVIG
~ 0.375 mg/kgBB/time (last day), NaCl compress for hemorrhagic crust in
the mouth, sodium fusidat 2% cream for erosion, gargarisma khan oral
gargle 3 times a day, Levofloxacin eye drop 6 times a day 1 drop on each
eye, cenfresh eye drop monodose 4 times a day 1 drop on each eye, and
ocuflam eye drop 4 times a day 1 drop on each eye. Respirology division
planned to do chest radiography evaluation after 5 days of antibiotic and
chest radiography on November 11th, 2016 revealed normal.
On the 13th day of admission, patient had no fever and cough, the
skin was peeling off entirely, and the eyes has been relieved. Laboratory
examination on November 18th, 2016 revealed a hemoglobin level 9.5 g/dL,
white blood cells 8.9x103/L, platelets 696x103/L, BUN 9 mg/dL, serum
creatinin 0.58 mg/dL, albumin 3.2 g/dL, ALT 27 U/L, ALP 53 U/L, sodium
132 mmol/L, potassium 4.9 mmol/L, chloride 93 mmol/L, and calcium 8.2
mg/dL. The treatment was stopped gentamycin injection and continued
other treatment (cetirizine 5 mg once times a day, application of NaCl
compress for hemorrhagic crust in the mouth, sodium fusidat 2% cream for
erosion, gargarisma khan oral gargle 3 times a day, Levofloxacin eye drop
6 times a day 1 drop on each eye, cenfresh eye drop monodose 4 times a
day 1 drop on each eye, and ocuflam eye drop 4 times a day 1 drop on each
eye).
He was discharged on November 21th, 2016 with no fever, no cough,
the skin was peeling off entirely (leave multiple hypopigmentation macules),
and the eyes has been relieved. He was scheduled for visiting allergic
immunology disease outpatient clinic for further follow up.

13
 A B

Figure 8. (A) There is skin blister spread all over the body, before getting IVIG therapy.
(B) There is skin blister spread all over the body, after getting IVIG therapy.

14
CASE REPORT-3
DV, a 10 years old female, was referred to emergency department at
Dr. Soetomo Hospital from Perkebunan Hospital in January 9th, 2017 with
chief complaint bullae in the skin and decreased consciousness. Patient
suffered from fever and seizure in the last 9 days before admission. Her
mother took her to a doctor and was given Valproic acid and Phenytoin.
From the past history, she got phenytoin for epilepsy but the family stopped
the drug before the patient was cured. Six days before admission she
suffered from fever and itchy in her body and then her mother gave her
Dumin and Amoxan syrup. On January 7th 2017 the rash appeared on the
skin. In the night, bulla spread, she got seizure, and her consciousness
decreased. Her mother took her to the Perkebunan hospital in Jember and
since no improvement in her condition, she was referred to Dr. Soetomo
Hospital.

A B

Figure 9. (A)There is skin blister spread in the body. (B) There is bulla spread at back.

15
 The girl was born at term by cesarean section with birth weight 3000
grams. She cried spontaneously after birth. There was no history of
cyanosis and jaundice after birth. His mother was healthy during pregnancy
without history of consuming alcohol, narcotics or drugs. The nutritional
history was: breastfed until 24-month-old, rice cereal since 3 months, steam
rice since 8 months, rice since 12 months. Nowadays she eats 3 meals a
day and drinks milk once a day. The history of immunizations of the patient
were Hepatitis B, BCG, Polio 1, 2, 3, 4, DPT 1, 2, 3 and Measles. No history
of allergy on patient and her family.
The physical examination in the emergency room revealed a weak
girl with GCS status X15. The body weight was 31 kg and length 140 cm.
He had a regular heart rate of 130 bpm, respiratory rate of 30 tpm, axillary
temperature of 38.5oC, and peripheral saturation of 99%. Head and neck
examinations revealed no anemia, no dyspnea, no icterus, no cyanosis, and
no lymph node enlargement were observed. Nose, throat and mouth
examinations were normal. Chest was symmetric and subcostal retraction
were noted. Cardiovascular examination revealed neither murmur nor
gallop. Pulmonary examination revealed vesicular with rales in the both side
of lungs but no wheezing was heard. Abdomen was flat, no enlargements
of the liver or spleen and no palpable mass were noted. Extremities were
dry and warm with capillary refill time < 2 seconds.
Status dermatologist from generalized region was hyperpigmented
macules, bulla, erosion, and epidermolysis. On labium oris region was found
hemorrhagic crust. Orbitalis region was difficult to evaluate because she
couldn't open her eyes. Over all lesion was 35% body surface area (head
6%, body 13%, upper extremity 5%, lower extremity 10%, and genital 1%).
The anthropometric measurements showed a good nutritional status.
Weight 31 kg, height 140 cm, head circumference 55 cm, IBW 33 kg, %IBW
93, H/A 10.5 years, BMI 15.8, percentiles BMI P25-50.

16
Figure 10. Head Circumference Chart
Patient was normal head circumference
Source: Nellhaus G. Head circumference from birth to eighteen years. Practical
composite international and interracial graphs. Pediatrics. 1968;41:106-14

Figure 11. (A) The Body Mass Index of the patient is normal
(B) Patient was normal Body Mass Index
Source: CDC Growth Chart, 2000

17
 Laboratory examination on January 9th, 2017 revealed a hemoglobin level was
9.9 g/dL, white blood cells was 3.5x103/L, platelets was 68x103/L, BUN 9 mg/dL,
serum creatinine 0.6 mg/dL, albumin 3.3 g/dL, ALT 303 U/L, ALP 86 U/L, sodium 129
mmol/L, potassium 4.6 mmol/L, chloride 101 mmol/L, and CRP 20.2 mg/l.
Based on history, physical examination, laboratory and radiology findings the
diagnosis was Toxic epidermal necrolysis + epilepsy + encephalopathy + sepsis. The
patient was planned for consultation to respirology, neurology, nutrition and metabolic
disease, tropic infection, dermatovenerology, ophthalmology and stopped the drug
which is suspected as the cause. She was treated with O2 mask 6 lpm, partial
parenteral nutrition, dexamethasone injection 5 mg for three times a day (~0.5
mg/kgBB/day), gentamicin injection 155mg once times a day, IVIG 18,6 gr for 3 days
(~0.6g/kgbw/day), paracetamol 300mg for three times a day, NaCl 0,9% compress for
hemorrhagic crust on the lips, chloramphenicol eye drop 6 times a day 1 drop for both
eyes.
On the 2rd day of admission, patient's consciousness still decreased, she still
had fever, bullae full on her body, and difficulty to open her eyes. Patient was moved
to isolation room on bona. The therapy was continued.
On the 3rd day of admission, patient's consciousness still decreased, she still
had fever, bullae full on her body, difficulty to open her eyes, nausea, and vomiting.
We plan blood culture, urine culture, feces culture, and head CT Scan. Laboratory
examination on January11th, 2016 revealed hemoglobin level 8.8 g/dL, white blood
cells 2.5x103/L, platelets 61x103/L, PTT 13,2 second, APTT 50.6 second, BUN 13
mg/dL, creatinin serum 0.5 mg/dL, albumin 2.8 g/dL, ALT 501 U/L, ALP 122 U/L,
sodium 139 mmol/L, potassium 3.9 mmol/L, chloride 102 mmol/L, calcium 6.4mmol/L,
CRP 24.2 mg/l, negative IgG and IgM anti dengue, serum iron 13, TIBC 101, Feritin >
1200. From BGA revealed pH7.35, pCO2 20 mmHg, pO2 83mmHg, HCO3 11mmol/L,
TCO2 11.6 mmol/L, BE -14.6 mmol/L, SO2 96%, %FiO2 21. Head CT Scan revealed
Subarachnoid cyst, chest radiography revealed normal. Urinalysis revealed rbc 107,
wbc 9.1, Ec 17.9, cast 0.54, bact 205, specific gravity 1.02, pH 7, leucocyte (-), nitrit (-
), protein (+), glucose (-), keton (-), urobilinogen >131, bilirubin (-), clarity clear,
erythrocyte +3. Urine and swab bulla culture on January11th, 2016 revealed sterile.
She was treated with O2 mask 6 lpm, total parenteral nutrition, dexamethasone
injection 5 mg for three times a day (~0.5 mg/kgBB/day), gentamicin injection 155mg

18
once times a day, IVIG 18,6 gr for 3 days (~0.6g/kgbw/day), paracetamol 300mg for
three times a day, NaCl 0,9% compress for hemorrhagic crust on the lips,
chloramphenicol eye drop 6 times a day 1 drop for both eyes.
On the 6th day of admission, patient's consciousness still decreased, she still
had fever, dyspnea, and agitated, but 25% of bulla already resolved. Gentamycin and
dexamethasone injection were stopped, continued the treatment with cetirizine 5 mg
once times a day, IVIG 18,6 gr (~0.6g/kgbb/day) (last day), started claritomycin 250
mg twice a day, omeprazole injection 30 mg twice a day, NaCl compress for crust in
mouth, sodium fusidate cream 2% for erosion, gargarisma khan oral gargle 3 times a
day, levofloxacin eye drop 6 times a day 1 drop for each eye, cenfresh eye drop
monodose 4 times a day 1 drop for each eye, and ocuflam eye drop 4 times a day 1
drop for each eye.
On the 7th day of admission, patient's consciousness still decreased, she still
had fever, dyspnea, and agitated, and had diarrhea > 10 times/day. From laboratory
examination revealed K 5.3, Na 125, Cl 88, Alb 22.4, BUN 7, creatinine 0.59, ALT 134,
AST 156, GDA 177, calcium 7, Hb 8.2, HCT 25.1, Leucocytes 3.200, platelate 96.000.
From BGA: pH 7.21, pCO2 56, pO2 50, TCO2 24.1, BE -5.5, SpO2 25%, AaDO2 229,
FiO2 45%, HCO3 22.4. From stool analysis revealed FOB (-), brown, mushy
consistency, blood (-), mucus (-), erythrocyte 2-4/lp, leucocyte 0-2/lp, worm egg (-),
larva (-), amoeba (-), cyst (-), yeast cell (-). Blood culture revealed Staphylococcus
hemolitycans. The treatment was continued, corrected the serum electrolyte
imbalance, and delayed albumin transfusion due to risk of allergy. Based on blood
culture result, tropic infection division suggest to stop Gentamycin and change it with
cloxacillin injection 750mg four times a day.
On the 8th day of admission, patient's consciousness still decreased, she still
had fever, dyspnea, and agitated, and had diarrhea > 10 times/day. From laboratory
result on January 17th, 2017 revealed hemoglobin level 6.4 g/dL, white blood cells
1.5x103/L, platelets 60x103/L, sodium 134 mmol/L, potassium 4.2 mmol/L, chloride
93 mmol/L, Calcium 6.2 mmol/L, BGA: pH7.07, pCO2 48 mmHg, pO2 93 mmHg, HCO3
13.9 mmol/L, TCO2 15.4 mmol/L, BE -16.2 mmol/L, SO2 93%, %FiO2 21. The treatmen
was continued, started total parenteral nutrition, albumin transfusion, FFP transfusion,
and WE transfusion.

19
 Patient died on the 9th day of admission due to septic shock. She desaturated,
decreased of consciousness, fever, gasping, agitated, bleed from mouth and nose.
She was intubated and got active PPV. The other treatment was continued. Cardiac
arrest happened at 12.30, the patient was resuscitated, got adrenalin pump, and
dopamin~5mcg.kg/sec but unfortunately patient died.

20
21
DISCUSSION
The 1st case was diagnosed with SJS-TEN because, based on physical
examination, total involvement of body surface area was 29% (6% on head,13% on
body, 4% on upper extremity, 5% on lower extremity, and 1% on genital area). The
2nd also diagnosed with SJS-TEN with total involvement of body surface area was 29%
(7% on head,13% on body, 4% on upper extremity, 4% on lower extremity, and 1%
on genital area). The 3rd case was diagnosed with TEN because, based on physical
examination, total involvement of body surface area was 35% (6% on head, 13% on
body, 5% on upper extremity, 10% on lower extremity, and 1% on genital area).
Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are
acute onset, life threatening mucocutaneous disease. SJS and TEN are an immune
mediated hypersensitivity reaction occurring after exposure to certain medications and
are believed to be part of the same disease spectrum.6 Based on percentage of Body
Surface Area (BSA) involved, patients are classified into three groups. SJS has less
than 10 percent BSA involved, SJS- TEN overlap has 10-30 percent BSA involved and
term TEN is used when more than 30 percent BSA is involved. The percentage of
body surface area involved is an important prognostic factor in SJS/TEN syndrome.6,7

Figure 12.
Representation of SJS, SJS-TEN overlap and TEN 8

22
Figure 13. Percentage of Body Surface Area in assessment of Burns9

In our case series, all of our cases had fever, hyperpigmented macule with
boarder lines, bulla and epidermolysis in some region, generalized erythematous, and
hemorrhagic crust.
Clinical manifestations in children overlap with clinical presentation in adults.10
SJS/TEN is an acute inflammatory disease, characterised by fever, malaise,
cutaneous and mucosal lesions, commonly preceded by prodromal symptoms lasting
17 days. The prodromal period is characterised by nonspecific symptoms, such as
malaise, fever, ocular pruritus and dysphagia. Erythema, erosions, scabs and
pseudomembranes gradually develop in the oral, genital and ocular mucous
membranes. Inflammation and soreness of the mouth and genitalia is frequent, and
usually precedes the skin lesions by a few days.3 Skin lesions vary in severity,
presenting as red macules and papules that sometimes coalesce to a generalized
erythematous rash with atypical targetoid lesions, and progress to vesicles, bullae and
extended skin necrosis that detaches in large sheets. When the leading cutaneous
finding is erythema, the Nikolsky sign may guide the diagnosis, although it is not
exclusive of SJS/TEN. Nikolsky sign is defined as an epidermal detachment that
appears when applying a tangential pressure on erythematous, non-blistering skin.11
In our cases, all the patient had a history of drug intake prior to the onset of
reaction, this first patient was treated with pimtrakol, ibuprofen for the second patient,
and valproic acid and phenytoin for third patient.

23
 Drugs are an important cause of SJS-TEN but infections or a combination of
infections and drugs has also been implicated.2,12 Drugs at high risk of causing
SJS/TEN are allopurinol, antibacterial sulfonamides, aromatic anticonvulsants, and
oxicam NSAID's.6 In a majority of paediatric studies, drug were implicated as the most
common cause of SJS-TEN, followed infection.13,3
The pathologic mechanism that induced skin damage in SJS/TEN are
incompletely understood. Early studies of immunophenotpe of lymphocyte detected in
blister fluid of SJS/TEN lesion suggested a cell-mediated cytotoxic reaction against
keratinocytes leading to a massive apoptosis.14 Subsequent studies demonstrated
that cytotoxic T-cell are drug specific and directed against the native form of the drug
rather than against a reactive metabolite.15 Drug can stimulate the immune system by
directly binding to the major histocompatibility complex (MHC) I and T-cell receptor.
This result in the clonal expansion of a population of a drug specific cytotoxic T-Cell
that kill keratinocytes directly and indirectly through the recruitment of other cells that
release soluble death mediators, including granulysin.14,15
In our case for three patients we give IVIG, the first and second patient are
success (two days after gave of IVIG had started to dry skin) but unfortunately the third
patient is die because she came with poor condition (sepsis). In our case for three
patients we give IVIG, the first and second patient are success (two days after gave
of IVIG had started to dry skin) but unfortunately the third patient is die because she
came with poor condition (sepsis).
In our cases, the three patients were given IVIG. The first and second patient
were successfully treated (two days after IVIG, the skin started to dry), but
unfortunately the third patient died because she had poorer condition (sepsis).
Management of patients with SJS or TEN requires three measures: removal of
the offending drug, particularly drugs known to be high-risk; supportive measures and
active interventions. Early diagnosis of the disease, recognition of the causal agent
and the immediate withdrawal of the drug are the most important actions, as the
course of the disease is often rapid and fatal. 11,16 The supportive care includes fluid
and electrolyte management, wound and ocular care, nutritional support, prevention
and treatment of secondary infections.6
As soon as the diagnosis of SJS or TEN has been established, the severity and
prognosis of the disease should be determined so as to define the appropriate medical
24
setting for further management. Systemic steroids were the standard treatment until
the early 1990s, although no benefit has been proven in controlled trials. In the
absence of strong evidence of efficacy, and due to the confusion resulting from the
numerous steroid treatment regimens reported (treatment of short versus long
duration, various dose regimens), their use has become increasingly disputed. In
France and Germany concluded that corticosteroids did not show a significant effect
on mortality in comparison with supportive care only.17 Corticosteroids have been used
in the management of TEN for over 30 years, but their use is much debated and
controversial. They may appear to have the theoretical beneficial anti-inflammatory,
immunosuppressive, and antiapoptotic effects but treatment with systemic steroids for
more than 48 hours has been associated with higher rate of infection, longer
hospitalization, and increased mortality especially in severe exfoliating cases. Also,
incidence of TEN is reported to be higher in patients already on high-dose
corticosteroids for preexisting diseases. Because of the diverse nature of pre-referral
corticosteroid treatment, the general consensus is to routinely wean and/or stop the
corticosteroids on admission.2

Figure 14. Immunomodulatory actions of intravenous immunoglobulin. Intravenous immuno- globulin

(IVIG), may for the purposes of understanding, be thought of as four separate components: (1) actions
mediated by the variable regions F(ab)2, (2) actions of Fc region on a range of Fc receptors (FcR), (3)
actions mediated by complement binding within the Fc fragment and (4) immunomodulatory substances
other than antibody in the IVIG preparations. It should be remembered that not all the potential
mechanisms of action fit perfectly into the groupings and that several mechanisms may act concurrently
(TCR, T cell receptor; ADCC, antibody dependent cellular cytotoxicity; DC, dendritic cell). 18
Sorce: Jolles S, Sewell WAC, Misbah SA. Clinical uses of intravenous immunoglobulin. Br Soc Immunol
2005;142:111.

25
 The concomitant administration of corticosteroids or immunosuppressive
agents remains controversial. IVIG has also been applied in a few children with
SJS/TEN, and two non-controlled studies suggest a possible benefit.17 IVIG is a
useful and safe therapy for children with SJS/TEN. Rapid and consistent recovery
ensued in every patient following use of IVIG, and there were no deaths.19

Figure 15. Fas-mediated keratinocyte apoptosis in TEN and potential mechanism of inhibition by IVIG.
(A) Normal epidermis and (B) Toxic Epidermal Necrolysis: induction of keratinocyte FasL expression
and interaction with Fas at the cell surface, leading to keratinocyte apoptosis (C) epidermis during
TEN treated by IVIG: predicted inhibition of keratinocyte apoptosis by blockade of Fas by anti-Fas Ab
in IVIG.
Source: French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal
necrolysis and Stevens Johnson syndrome: Our current understanding. Int Immunopharmacol
2006;6:5439

Although, the pathophysiology of SJS is unknown, one of hypothesis is that

keratinocyte apoptosis induced by interaction of Fas (CD95) with its natural ligand Fas
ligand (FasL).20 Enhancing re epithelization and skin healing. it has been shown that
IVIG is an inhibitor of the Fas-Fas ligand mediated apoptosis keratinocyte. This is the

26
purported basis for its use in the treatment of Toxic Epidermal Necrolysis, Steven
Johnson's syndrome, severe drug rashes as well as in situations where there ie
destructive necrosis of the epidermis. 21
Therapeutic usage of IVIGs is associated in most cases with a low incidence of
side effects according to WHO criteria. IVIGs are basically considered as a safe and
efficacious therapeutic option but it is still associated with some adverse effects. They
are divided into two groups minor and severe side effects. Side effects are transient
and often appear during the infusion or up to 72 h following the infusion. It is
characterized by headache, nausea, fever, vomiting, cough, malaise, muscle, join and
abdominal pain, flushing, urticarial lesions, and variations in heart rate and blood
pressure. These reactions are probably due to aggregated immunoglobulin molecules
that cause the complement system activation, antigen-antibody, contaminants, or
stabilizers reactions. Premedication with systemic steroids, antihistamines
(diphenhydramine 50 mg), and nonsteroidal anti-inflammatory drugs (acetaminophen
650mg) can minimize or prevent them. Leukopenia, neutropenia, and monocytopenia
are also seen in IVIGs therapy, however in most of cases those side effects appear to
be self-limited and do not lead to increased susceptibility to infection. 22
However, in paediatric patients with SJS/TEN, IVIG seems to be a useful and
safe therapy.23,5 Reviewed 28 previous reports in which IVIG was used in paediatric
patients with SJS/TEN and discussed their experience in 7 children with SJS. They
concluded that IVIG (0.5-1.0 g/kg/day for 3 days) was a useful and safe therapy for
children with SJS/TEN5,20
Treatment of SJS-TEN with intravenous immunoglobulin (IVIG) has been
reported in several studies with equivocal results. IVIG consists of mainly IgG (IgG3,
IgG4) antibodies as well as variable amounts of proteins; IgA, IgE, and IgM Ab,
albumin, salt and sugar content. The mechanism of action of IVIG in most autoimmune
diseases remains unclear; however various mechanisms have been proposed. IVIGs
have an immunomodulatory activity based on biological processes that are implicated
in innate or acquired immune response.22,21 The other postulated mechanisms for IVIG
success include attenuation of complement mediated damage, anti-inflammatory
cytokine induction, neutralization of microbial toxins, and selective downregulation of
B- and T-cell function.2,24
As a consequence of the discovery of the anti-Fas potential of pooled human
intravenous immunoglobulins (IVIG) in vitro, IVIG have been tested for the treatment
27
of SJS-TEN, and their effect reported in different non-controlled studies. To date,
numerous case reports and 12 non-controlled clinical studies containing 10 or more
patients have analyzed the therapeutic effect of IVIG in SJS-TEN. All except one
study, confirm the known excellent tolerability and a low toxic potential of IVIG when
used with appropriate precaution in patients with potential risk factors (renal
insufficiency, cardiac insufficiency, IgA deficiency, thromboembolic risk). To determine
if a dose response relationship exists, Trent et al. analyzed the published literature
between 1992 and 2006, selected all studies performed in adults in which the dose of
IVIG administered was reported for each patient, excluded cases appearing as
duplicates in separate publications where possible, and performed a multivariate
logistic regression analysis to evaluate mortality and total IVIG dose after controlling
for age and affected body surface area.17

28
SUMMARY

The three cases of Steven Johnson Syndrome-Toxic Epidermal Necrolysis has

been reported. Steven Johnson Syndrome-Toxic Epidermal Necrolysis is a true
dermatological critical condition that affect also children and requires the contribution
of multidisciplinary teams. Any drug can be the causative agent, over anticonvulsants
and antibiotics, and infectious origin should always be considered. Patients should
rapidly be admitted to specialized unit and discontinuation of offending drug is
mandatory. Optimal supportive care and management of denuded skin areas are still
the mainstay of treatment and the only action that has demonstrated to affect survival
rate. The use of specific therapies is still controversial, but several studies have
suggested that the use of IVIG may reduce mortality and morbidity. Fortunately,
compared with adults, the disease in children is milder and has lower mortality rate.

29
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