Article type : Concise Report

Accepted Article Bronchiolitis Obliterans as long-term sequela of non-drug related Stevens-Johnson

Syndrome and Toxic Epidermal Necrolysis in children

E. Seccombe,1 M. Ardern-Jones,1 W. Walker,2 S. Austin,3 S. Taibjee,3 S. Williams,4 P. Hossain5

and A. Fityan1
1
University Hospital Southampton NHS Foundation Trust, Department of Dermatology,
Southampton, UK
2
University Hospital Southampton NHS Foundation Trust, Paediatric Respiratory
Department, Southampton, UK
3
Dorset County Hospital NHS Foundation Trust, Department of Dermatology, Dorchester,
Dorset, UK
4
University Hospital Southampton NHS Foundation Trust, Department of Paediatrics,
Southampton, UK
5
University Hospital Southampton NHS Foundation Trust, Department of Opthalmology,
Southampton, UK

Corresponding author: Ella Seccombe

E-mail: ellaseccombe@gmail.com

Funding: None

Conflicts of interest: None to declare

Abstract
Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) are characterised by
widespread skin and mucosal necrosis and are infrequently reported in children. Triggers
and long-term sequelae differ to those reported for adult cases. Bronchiolitis obliterans
(BO) is a rarely reported complication but is associated with significant long-term morbidity.

We report 3 paediatric cases of non-drug related SJS (n=1) TEN (n=2) that developed BO. 2
were treated with intravenous immunoglobulin therapy (2 - 2.4g/kg) and all three survived.

BO as a complication of SJS/TEN is rare and there are only 13 previously reported cases in
the literature. It can present 2 weeks to 5 months after SJS/TEN supporting the need for
close follow-up. It is often progressive with some cases requiring lung transplantation. We
discuss our cases and review the literature.

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doi: 10.1111/ced.13969
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 Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, potentially
Accepted Article life-threatening conditions; characterised by widespread skin and mucosal necrosis. The

incidence is lower in children than adults: 5.3 vs 9.3, 0.8 vs 1.9 and 0.4 vs 1.6 cases per

million of SJS, SJS-TEN and TEN respectively in the US1,2. Medication is usually culpable

although infection may be causative particularly in children. To date there are no guidelines

for the management of paediatric SJS/TEN and no international consensus. However,

intravenous immunoglobulin (IVIG) and/or systemic corticosteroids are frequently

reccomended3. Mortality in childhood is reportedly 0% (SJS), 4% (SJS-TEN) and 16% (TEN)1,

with deaths most frequently due to sepsis and organ failure1. However, similarly to adults,

increased mortality is noted with higher degrees of epidermal detachment: 60-70% body

surface area (BSA) involvement reported 37.5% mortality in one study4. Bronchiolitis

obliterans (BO) is a rarely reported complication but when present is associated with

significant long-term morbidity. We report 3 paediatric cases of non-drug related SJS/TEN

that developed bronchiolitis obliterans (BO) and review the literature.

Case 1:

A well 5-year-old boy presented with an erythematous maculopapular rash for 2 days in

association with fever and coryzal symptoms. 95% BSA was involved with 40% epidermal

detachment. Bilateral conjunctival defects and severe oral mucosal ulceration were

apparent early in the disease course. Subsequent development of stridor necessitated

intubation.

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 TEN was confirmed histologically with negative direct immunofluorescence. Bronchoscopy
Accepted Article showed ulceration at the base the endotracheal tube. Pseudomonas aerugionosa was

cultured from bronchoalveolar lavage (BAL) and Adenovirus, Rhinovirus and Enterovirus

from nasopharyngeal aspirate (NPA). Mycoplasma IgG titre was weakly positive.

He received IVIG 2g/kg over 2 days. Skin re-epithelialisation occurred within 3 weeks.

Conjunctival inflammation was severe requiring multiple amniotic membrane transplants

acutely and subsequent pulsed methylprednisolone and mycophenolate mofeil. He is now

awaiting a corneal stem cell transplant.

5 months post-TEN he developed exertional dyspnoea and a non-productive cough.

Spirometry showed a reduced forced expiratory volume in 1 second (FEV1) (29% predicted)

and forced vital capacity of 55% predicted, without reversibility with bronchodilators. High

Resolution (HRCT) confirmed BO with characteristic mosaic perfusion and air trapping on

expiratory films (Figure 1). Treatment with twice-daily high-dose inhaled flixotide, acapella

physiotherapy, azithromycin prophylaxis (200mg daily 3xweek) plus rescue courses of oral

co-amoxiclav for infective exacerbations have ameliorated pulmonary function. After 1

year, FEV1 is 71% predicted.

Case 2:

A 5-year-old boy had a sore throat and fever for 11 days before developing a diffuse

erythematous rash which became bullous over 24 hours. 26% skin detachment was noted,

with prominent oral ulceration and conjunctival injection. TEN was subsequently confirmed

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 histologically. IVIG was commenced (total 2.4g/kg over 3 days). NPA detected adenovirus,
Accepted Article which was the likely infectious trigger. SCORETEN on arrival to PICU was 1.

On discharge (26 days) the skin had re-epithelised. A few weeks after discharge, he

developed exertional dyspnoea. HRCT showed bilateral air trapping and vascular paucity

suggestive of BO. FEV1 and FVC were 48% and 66% predicted respectively without

reversibility. Oral prednisolone 2mg/kg daily did not improve his symptoms. Management

continued with anti-inflammatory strategies: azithromycin 200mg 3xweek prophylaxis and

inhaled corticosteroids alongside regular chest physiotherapy.

Case 3:

A well 14-year-old girl developed cutaneous blistering, severe oral mucosal ulceration and

eye pain 1 week after developing a sore throat and cough. She had multiple targetoid

lesions on the body and at acral sites with 5% epidermal detachment. The clinical diagnosis

of SJS was made. Mycoplasma titre was positive (CFT titre >64). Chest X-Ray was normal.

4 weeks post-SJS she complained of breathlessness on exertion and wheeze. FEV1 was

significantly impaired, 25% predicted without reversibility and HRCT confirmed BO.

Treatment involved 10mg/kg methylprednisolone for 3 days per month for 6 months in

addition to azithromycin, inhaled corticosteroids and physiotherapy. There has been

minimal improvement in FEV1, currently 33% predicted, 6 months after starting treatment.

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 Discussion
Accepted Article BO is an uncommon fibrosing chronic lung disease, which is rarely associated with SJS/TEN

and was not recorded in a recent retrospective review of 36 cases in one centre 5 We

undertook a literature review (MEDLINE database) and identified only 17 cases of BO

occurring in conjunction with SJS/TEN in children and summarised in Table 1 (4 cases in non-

English language journals excluded).

The characteristics of our cases were comparable to other reports. Overall age of onset was

5-14 years and mean time to onset of respiratory symptoms following initial presentation

with SJS/TEN was 5 days to 5 months (Figure 2). There were no risk factors for BO identified

in any case and specifically, no reports of pre-existing lung disease.

These findings highlight the insidious onset of BO following SJS/TEN and the need for close

follow-up. Parents of affected children should be advised to monitor for the development of

breathlessness. Pulmonary function tests typically show varying degrees of obstruction with

a limited response to bronchodilators. HRCT is generally diagnostic, demonstrating mosaic

perfusion, vascular attenuation and central bronchiectasis6.

The pathogenesis of BO is not fully understood but possible pathomechanisms include

bronchial injury from primary blister lesions, secondary lung infection or a type III immune

mechanism6. In immunocompetent children, BO most often develops after a severe lower

respiratory tract infection. Adenovirus is the most commonly documented cause

worldwide7. Adenovirus was isolated from aspirates in two of our patients but was not

documented to have been present in any of the other reports. The relevance of this remains

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 uncertain. In the cases identified, 6/16 were reported to be caused by a drug, suggesting
Accepted Article that infection may have been the initiating factor in the majority (63%) of post SJS/TEN BO

cases.

Small studies have suggested azithromycin may improve FEV1 in BO8. All 3 of our cases

received azithromycin and demonstrated stable or improved lung function. The use of

systemic corticosteroids in the management of BO is contentious, with no data to suggest

that early treatment improves outcomes. No clear benefit was identified in those patients

receiving systemic therapy early in the course of their disease; patient 1 (systemic

corticosteroids, IVIG and MMF) and patient 2 (IVIG), however it is difficult to draw firm

conclusions from such small patient numbers.

Post-TEN BO is often progressive with reports of severe cases requiring lung transplantation

and death. In the reported cases 3/14 required lung transplantation. Mortality appears to

be low in this sub group of SJS/TEN (n=2; 13%, including our cases). However, it is difficult to

be certain that the literature captures late mortality, which might be associated with BO. In

a recent case series of 5 BO patients needing lung transplant, 2 were post-SJS, and none

post-LRTI6. This may suggest a more aggressive disease course in SJS/TEN related BO,

particularly in those triggered by drug exposures.

This series and review highlights a clear association between SJS/TEN and the development

of BO in children. Pulmonary complications may develop many months after the resolution

of the initial presentation. BO is associated with significant morbidity and a mortality rate of

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 13%. A multi-disciplinary approach to both the acute management and follow-up is
Accepted Article therefore recommended in all cases of SJS/TEN in children.

Table 1: Summary of cases of broncholitis obliterans (BO) post-SJS/TEN from the literature and our own series

Authors Age Culprit Timing Outcome

Our case 5 Infection- nd 5 months Some

improvement
Our case 5 Adenovirus 6 weeks Some
improvement
Our case 15 Mycoplasma 4 weeks Minimal
improvement
Sato S. 11 Clarithromycin ns ns
Silva T. 8 ns 4 weeks Night oxygen
required
Wang W. 9 Lamotrigine 1 week No progression
Dogra S. 5 Nimesulide 2 weeks Died after 1
year
Shoji T. 6 Antibiotic -ns 2 weeks Ventilator for 7
months then
lung transplant
Chiu C. 6 ns ns Improved
Chiu C. 6 ns ns Lung transplant
then died
Baktiras A. 8 ns 2 weeks Some
improvement
Baktiras A. 13 ns 5 months Some
improvement
Date H. 13 ns 1 week Successful lung
transplant
Dogra S. 9 Ibuprofen 1 week Improved
Kim M. 10 Anti TB treatment 2 months No progression
Kim M. 6 ns 5 days Some
improvement
Nd, not determined, Ns, not specified

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 Learning points
Accepted Article
• SJS and TEN are triggered by infection more frequently in children than adults
• Bronchiolitis obliterans is an uncommon fibrosing chronic lung disease rarely
associated with SJS/TEN
• Onset is insidious and can be many months after the acute episode of SJS/TEN
demonstrating the need for close follow-up
• There is no clear evidence that early systemic corticosteroids in BO improves
outcomes
• Post-TEN BO is often progressive and severe cases may require lung transplantation
or result in death

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Accepted Article

Figure 1: High Resolution CT (HRCT) confirmed bronchiolitis obliterans with mosaic profusion and air trapping
on expiratory films

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 Figure 2: Graph showing the time from onset of SJS/TEN to the development of pulmonary symptoms, such as
breathlessness and cough, as initial signs of bronchiolitis obliterans
Accepted Article
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