“I’ve got you under my skin…”
Dr Emily Woolnough
Infectious Diseases Registrar, Alfred Hospital 2015
The Case
20 year old male
Previously well
Multi trauma following high-speed motorbike accident:
Urgent exploratory thoracotomy
Bilateral pneumothoraces – ICCs
C5/C6 pedicle fracture – Aspen collar
Right parafalcine subdural haematoma (conservative management)
Complex pelvic fractures requiring metalware
Right femoral fracture with right SFA damage – Above knee amputation
Distal radius and open hand fractures
Multiple degloving injuries requiring skin grafting
Initial ID Referral
1 month post-admission, after multiple operations
Right above knee amputation stump infection (deep)
Evidence of associated femoral osteomyelitis
Polymicrobial
Antibiotic choice and duration?
Wound swab – right femoral stump site
Intra-operative tissue culture – right femur
Meropenem 1g TDS
Vancomycin (adjusted to levels)
Plan to treat with
meropenem for several
weeks and then change to
ciprofloxacin
Admission One
Infectious Diseases referral
ADMISSION ONE SUMMARY
ID R
efe
rral
Re-admission to Hospital
Development of new fevers whilst at rehabilitation
On meropenem and vancomycin at time
Source not clear – possibly line related
PICC line removed
Switched vancomycin to teicoplanin (?VRE)
Initial improvement and afebrile
First 3 sets blood cultures and PICC tip – no growth
4 days of improvement
Day 8 ICU admission Increasingly more unwell
Becoming increasingly unwell (day 8 – day 12)
Extensive investigation for source of sepsis or non-infective cause
-NAD
Blood cultures – single bottle Staphylococcus epidermidis, single
bottle Staphylococcus haemolyticus
Broadened cover to linezolid, gentamicin and added
fluconazole
Chest x-ray – clear
Required intubation
Day 11
Type I respiratory failure - intubation
Nikolsky sign
Day 12
Widespread bullous
rash with
desquamation
(35% body surface
area involved)
Mucosal involvement
Onset of rash
Onset of rash
Skin biopsy report:
There is a surface layer of hyperkeratosis and parakeratosis
which is partly attached forming a subcorneal vesicle. The
underlying epidermis contains widely-spaced necrotic
keratinocytes, with occasional basal apoptotic bodies.
Eosinophils are not seen. There is no vasculitis.
Conclusion – consistent with drug hypersensitivity rash
Blister fluid:
VZV/HSV PCR - Negative
ADMISSION TWO SUMMARY
Clinical improvement
Extensive investigation
RASH
29 Nov 8 Jan
Drug Exposure
30 Dec 20 Jan
?
Key issues raised by case
1. Making the diagnosis of drug hypersensivity
reaction and assessing severity
2. Determining drug causality
3. Managing underlying infection with limited
drug options – which drug to choose next?
And… these decisions are time critical!
1. Making the diagnosis of drug hypersensitivity reaction and
assessing severity
Stevens-Johnson
Syndrome (SJS)
Toxic Epidermal
Necrolysis
(TEN)
Acute Generalised Exanthematous
Pustulosis
(AGEP)
Drug Reaction with Eosinophilia and
Systemic Symptoms
(DRESS)
Spectrum
Harr, Thomas et al. (2010) Severe Cutaneous Adverse Reactions: Acute Generalized Exanthematous Pustulosis,
Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome Medical Clinics of North America. Volume 94, Issue 4.
727-742
Stevens-Johnson Syndrome/Toxic
Epidermal Necrolysis
- Longer latency
- Mucosal involvement
- More severe
- Full thickness epidermal necrosis
- Bullous changes
Acute Generalised Exanthematous
Pustulosis
- Shorter latency
- Worst in flexural regions
- Less mucosal involvement
- Less organ involvement
Drug Reaction with Eosinophilia and
Systemic Symptoms
- Very long latency
- More severe than AGEP
- Confluent inflammation, not bullous
- Eosinophilia predominant
- More organ involvement
• Retrospective review of 74 cases at Taiwanese hospital
• Examined antibiotics specifically
• Wide variation in latency period 1.44 days – 19.5 days
• Overall mortality rate 21.6% (66% in TEN!)
• Patients had higher mortality than severity score predicted
0.00%
10.00%
20.00%
30.00%
40.00%
Organ Involvement
Percentage
2014;58(10):1377-1385
SJS/SJS-
TEN
34%
TEN
16%
AGEP
16%
DRESS
34%
Established patient-based risk
factors
HLA type - HLA-B*1502
HIV infection
Systemic lupus erythematosis
Malignancy
Concurrent radiotherapy
Wetter, DA & Camilleri MJ. (2010) Clinical, etiologic and histopathological features of Stevens-Johnson syndrome
during an 8-year period at Mayo Clinic. Mayo Clin Proc 85:131
Mittman, N et al. (2012) Incidence of toxic epidermal necrolysis and Stevens-Johnson syndrome in an HIV cohort:
an observational, retrospective case series study. Am J Clin Dermatology 13:49
Pharmacogenomics
in the future??
2013; 133: 1197-1204
• 460 patients included in European
RegiSCAR database
• All-cause mortality assessment
2. Determining drug causality in SCARs
Anticonvulsants
Antibiotics
Antiretrovirals
NSAIDS
Other
Drug Relative Risk (95% CI)
Cotrimoxazole 102 (14-754)
Other sulphonamides 53 (7.0–410)
Carbamazepine 33 (12–95)
Phenytoin 26 (7.8–90)
Tramadol 20 (4.4-93)
Cephalosporins 11.3 (4.7–27)
Allopurinol 11 (7.0–18)
Quinolones 10.7 (3.8–30)
Macrolides 7.5 (3.4–16)
Tetracyclines 5.6 (1.8–18)
Aminopenicillins 4.1 (2.1–8.0)
• European case-control
study 1997-2001
• 379 cases vs 1505
controls
• Clinical photography
and histopathology
• Blinded panel
assessment
• ‘Exposure’ meant taking that drug in the
preceding 7 days
2008; 128(1): 35-44
Carbepenems n=1
Lin, Y et al. (2014) Severe Cutaneous Adverse Reactions Related to Systemic
Antibiotics. Clinical Infectious Diseases. 58(10): 1377-1385
Drugs probably NOT associated with
SCARs
Beta blockers
ACE inhibitors
Calcium channel blockers
Thiazide diuretics
Frusemide
Insulin
Sulphonylureas
Mokenhaupt, M et al. (2008) Stevens-Johnson syndrome and
Toxic Epidermal Necrolysis: assessment of medication risks with emphasis on recently marketed drugs. J Invest Dermatol. 128(1):
35-44
Components of ALDEN algorithm
Time delay from drug intake to index day
Drug present in the body on index day
Prechallenge/rechallenge
Dechallenge
Notoriety of the drug
Possibly caused by another drug
2010; 88(1): 60-68
Complex scoring
system to calculate
probability of
causation
Abe, R. et al. (2009) Granulysin as a marker for early diagnosis of the Stevens-Johnson syndrome. Ann Intern Med. Oct 6;151(7): 514-515
Nickoloff, B. (2008) Saving the skin from drug-induced detachment. Nature Medicine. 14:1311-1313
Specific to drug
Could we detect drug-specific activated T
cells as a method for determining causality?
A number of smaller studies have demonstrated drug-specific T
cells can be isolated in patients with severe cutaneous adverse
reactions:
Rozieres, A et al. (2009) Detection and quantification of drug-specific T
cells in penicillin allergy. Allergy. 64: 534-542
Naisbett, DJ et al. (2003) Characterisation of drug-specific T cells in
lamotrigine hypersensitivity. J Allergy Clin Immunol. 111: 1393-403
Nassif, A et al. (2002) Drug specific cytotoxic T cells in the skin lesions of a
patient with toxic epidermal necrolysis. J Invest Dermatol. 118(4): 728-733
Yawalkar, N et al. (2000) T cells isolated from positive
epicutaneous test reactions to amoxicillin and ceftriaxone are
drug specific and cytotoxic. J Invest Dermatol. 115: 647-652
An area for future development…
3. Managing the underlying infection with limited drug
options
• 5 patients with established delayed drug hypersensitivity
• Enzyme linked immunospot (ELISpot) testing
• Quantitative testing for drug-reactive cytokine-secreting T cells
after remission
• Found these cells present up to 12 years later!
“Patients with severe delayed drug hypersensitivity reactions are potentially prone to react again to the incriminated drug even
years after strict drug avoidance”
2006;117(2): 231-484
What about cross-reactivity?
Often inferred from data on IgE mediated immediate
hypersensitivity
Highest risk when drugs differ by single OH group
Hypothesis – drug hypersensitivity itself predisposes to further
hypersensitivity by ‘priming’ the immune response
•As evidenced by infections increasing risk (EBV, CMV)
•Also more precipitous and severe 2nd reactions
Triggering of T cell activation cascade and
secretion of cytokines with lower affinity
TCR-drug interactions
Thank you to all involved!