Drug Allergy and Desensitisation — Written Clinical Reasoning

SAQ 1 — Penicillin allergy label complicating syphilis in pregnancy (20 marks, 30 minutes)

Model answer

Diagnosis and risk stratification (5 marks) [1]

This patient has secondary syphilis in pregnancy (rash and positive syphilis serology) with a penicillin allergy label of uncertain significance. Benzathine penicillin is the only recommended treatment for syphilis in pregnancy and is the only treatment proven to prevent congenital syphilis and its sequelae (stillbirth, hydrops fetalis, neonatal death, deafness, dental and skeletal anomalies). The allergy label therefore has high clinical stakes — it cannot be ignored, but it also cannot be assumed to be true. [1]

The first step is a structured allergy history to establish: the culprit drug (was it truly penicillin?), the timing of the reaction relative to dosing (immediate within minutes to one hour suggests IgE; delayed after days suggests T-cell), the clinical features (urticaria and anaphylaxis suggest IgE; a maculopapular rash suggests T-cell; SJS, TEN or DRESS are absolute contraindications), the age at the reaction (childhood rashes are often viral exanthems mislabelled as allergy), and the time elapsed since the reaction (IgE allergy wanes over years in most patients). [1]

This patient's history — a childhood rash of uncertain nature, decades ago, with no features of anaphylaxis — places her at low to moderate risk. Only 10 to 20 per cent of penicillin allergy labels represent true allergy on testing [1]. The goal is to refine the label and, if possible, delabel so she can receive the drug of choice.

Immediate and definitive management (7 marks) [1]

1. Risk-stratify the label. Given the low-moderate risk and non-severe history, the approach is penicillin skin testing with the major determinant (penicilloyl-polylysine, Pre-Pen) and the minor determinant mixture, followed by an oral amoxicillin challenge if the skin test is negative. A negative skin test has a negative predictive value above 95 per cent for IgE allergy [1].
2. If skin testing and challenge are negative, delabel and give benzathine penicillin G 1.8 million units intramuscularly as a single dose for early syphilis, or weekly for three doses for late latent syphilis. Document the delabeling across the medical record, the electronic medication system and the general practitioner.
3. If skin testing is positive, or if the history is more concerning, desensitise. Penicillin desensitisation in pregnancy is justified because untreated syphilis causes congenital syphilis, and the procedure carries less risk than the disease. Desensitisation is performed with graded oral or intravenous penicillin in a monitored setting (resuscitation equipment, intravenous access, physician present), reaching the therapeutic dose over hours.
4. Never re-expose if the history indicates SJS, TEN or DRESS — these are absolute lifelong contraindications. In that case, seek an alternative (doxycycline is not recommended in pregnancy; desensitisation would not be offered).

Principles of desensitisation (4 marks) [1]

Desensitisation induces a temporary state of clinical unresponsiveness by graded administration of escalating drug doses. The mechanism involves transient mast cell and basophil unresponsiveness (mediator depletion, reduced IgE-Fc receptor signalling) and induction of regulatory T cells. The clinical correlate is that the state is temporary and dose-dependent. [1]

The critical rule is the 48-hour rule: tolerance is lost if the drug is withheld for more than approximately 48 hours. For syphilis, this means that if the patient is on a multi-dose regimen and a dose is delayed, a repeat full desensitisation is required. Each subsequent course of the drug requires re-desensitisation. [1]

In the Castells series of 413 desensitisations for chemotherapy, 94 per cent of reactions during the procedure were mild or absent, and the procedure was completed in the vast majority [4]. Severe reactions are rare and the procedure can be paused, treated and resumed at a lower dose.

Communication and follow-up (4 marks) [1]

• Explain to the patient the distinction between a true allergy and a label that may have been incorrect, and the safety of a supervised challenge. The relief of a removed label, and the avoidance of lifelong broad-spectrum antibiotic exposure, is a direct patient benefit.
• Counsel on the temporary nature of desensitisation tolerance if desensitisation is required — it does not cure the allergy, and re-exposure after a gap requires re-desensitisation.
• Document the refined allergy status across the obstetric, microbiology, pharmacy and general practice records. A removed or refined label that is not communicated will be re-applied by the next clinician.
• Address the pregnancy-specific concerns: the risk of untreated syphilis to the fetus (congenital syphilis, stillbirth), the safety of penicillin in pregnancy (penicillin is pregnancy category A), and the Jarisch-Herxheimer reaction that may occur after treatment (fever, uterine contractions, fetal distress — monitor after the dose). [1]

SAQ 2 — DRESS and the severe cutaneous adverse reactions (10 marks, 20 minutes)

Question

A 54-year-old man started carbamazepine six weeks ago for new-onset focal seizures. He now presents with fever to 39 degrees Celsius, a diffuse maculopapular rash, facial swelling, cervical lymphadenopathy and jaundice. Full blood count shows eosinophils 2.1 times 10 to the ninth per litre and atypical lymphocytes. ALT is 420 units per litre. Outline the diagnosis, the confirmatory scoring system, the immediate management, and the absolute contraindication that follows. [1]

Model answer

Diagnosis (2 marks) [1]

This patient has DRESS (drug reaction with eosinophilia and systemic symptoms), also called drug-induced hypersensitivity syndrome (DIHS). The diagnosis is established by the classic features: onset 2 to 8 weeks after a new drug (carbamazepine is a leading culprit), fever, diffuse maculopapular rash, facial oedema, lymphadenopathy, eosinophilia (above 1.5 times 10 to the ninth per litre), atypical lymphocytes, and systemic involvement — here, hepatitis with ALT 420. The differential includes viral exanthem, acute autoimmune hepatitis and serum sickness, but the drug history and the constellation of features make DRESS the leading diagnosis. [1]

Confirmatory scoring (2 marks) [1]

The RegiSCAR scoring system classifies DRESS as no, possible, probable or definite based on the presence and combination of: fever, rash, lymphadenopathy, organ involvement (hepatitis, interstitial nephritis, interstitial pneumonitis, myocarditis), eosinophilia, and atypical lymphocytes [2]. This patient scores highly — fever, rash, lymphadenopathy, hepatitis, eosinophilia and atypical lymphocytes — placing him in the probable or definite category. Human herpesvirus 6 serology may show reactivation, which supports the diagnosis.

Immediate management (4 marks) [1]

1. Stop carbamazepine immediately and avoid all structurally related anticonvulsants (oxcarbazepine, eslicarbazepine share the aromatic ring and cross-react; phenytoin and lamotrigine also carry risk of cross-reactivity through the aromatic anticonvulsant syndrome).
2. Systemic glucocorticoids for the organ involvement (hepatitis) — oral prednisolone 1 mg per kg daily, or intravenous methylprednisolone 0.5 to 1 mg per kg daily in severe disease. Taper slowly over weeks to months because relapse is common with early taper.
3. Supportive care — monitor liver function, renal function and full blood count; assess for other organ involvement (echocardiogram if myocarditis suspected, chest imaging if pneumonitis). Ciclosporin is used for severe or steroid-refractory cases.
4. Switch the anticonvulsant to a non-aromatic agent (levetiracetam, sodium valproate, topiramate) for ongoing seizure control, in consultation with neurology. [1]

Absolute contraindication (2 marks) [1]

Carbamazepine and the structurally related aromatic anticonvulsants are absolutely contraindicated for life — re-exposure causes a more rapid and severe recurrence of DRESS and may be fatal. This contraindication must be documented prominently in the medical record, communicated to the patient and to all future prescribers, and the patient should carry an alert card. Desensitisation is never offered after DRESS. The same principle applies to Stevens-Johnson syndrome and toxic epidermal necrolysis, for which SCORTEN predicts mortality [3] and re-exposure is absolutely contraindicated.