“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!