Drug reactions with systemic manifestations

Contents

Overview

Drug reactions with systemic involvement extend beyond the skin. They encompass a spectrum of immune-mediated and direct toxicity syndromes affecting multiple organ systems. Delayed reactions are particularly challenging to recognise in critically ill patients receiving multiple agents. Identifying and withdrawing the culprit drug is the cornerstone of management in all cases.

DRESS

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a severe delayed hypersensitivity syndrome, also known as Drug-induced Hypersensitivity Syndrome (DiHS).

Presentation

DRESS typically develops 2–8 weeks after starting the offending drug — a longer latency than most other drug reactions. Features include:

  • Widespread maculopapular rash (often beginning on the face and upper trunk)
  • Fever (commonly >38.5°C)
  • Lymphadenopathy
  • Facial oedema
  • Internal organ involvement: hepatitis (most common), pneumonitis, nephritis, myocarditis, encephalitis
  • Haematological: eosinophilia, atypical lymphocytosis

Mortality is approximately 10%, usually from hepatic failure.

Causative Drugs

Allopurinol is the most common cause in the UK. Other implicated drugs include carbamazepine, phenytoin, lamotrigine, phenobarbitone, sulphonamides, dapsone, and minocycline. A genetic predisposition exists; HLA-B*58:01 is strongly associated with allopurinol-induced DRESS in patients of East Asian and South Asian ancestry.

Diagnosis

The RegiSCAR score is used to classify cases as possible, probable, or definite DRESS. There is no single diagnostic test; diagnosis is clinical, supported by characteristic laboratory findings and HHV-6 reactivation (common in DRESS and may drive organ involvement).

Management

Stop the offending drug immediately. Systemic corticosteroids (prednisolone 0.5–1 mg/kg/day) are used in moderate-to-severe cases, particularly with hepatic or pulmonary involvement, though evidence is observational. Slow tapering over weeks to months is important — rapid withdrawal risks flare. Patients require monitoring for up to 3 months; organ dysfunction may persist or worsen after stopping the drug.

Serum Sickness and Serum Sickness-Like Reaction

Serum sickness is an immune complex (type III) hypersensitivity reaction, classically caused by heterologous serum (equine antivenom, antithymocyte globulin). Immune complexes deposit in vessel walls, activate complement, and cause systemic inflammation.

Serum sickness-like reaction (SSLR) is clinically similar but lacks demonstrable immune complex deposition. It is associated with beta-lactam antibiotics and minocycline.

Features develop 1–3 weeks after exposure: fever, urticarial rash, arthralgias, lymphadenopathy, and occasionally nephritis. Treatment is supportive; antihistamines and NSAIDs relieve symptoms. Corticosteroids are used in severe cases.

Drug-Induced Lupus

Drug-induced lupus (DIL) mimics systemic lupus erythematosus but resolves on discontinuing the causative drug.

Common implicated drugs: hydralazine, procainamide, isoniazid, minocycline, and anti-TNF agents.

Features include arthralgia, myalgia, serositis (pleuritis, pericarditis), and rash. Renal and CNS involvement is uncommon. Serological findings: positive ANA (often anti-histone antibodies, particularly with hydralazine and procainamide), negative anti-dsDNA.

Treatment is stopping the drug. Symptoms typically resolve within weeks. Short courses of NSAIDs or corticosteroids may be used for symptom control.

Drug-Induced Vasculitis

Drug-induced ANCA-associated vasculitis (DIV) typically presents as small-vessel vasculitis with pauci-immune glomerulonephritis, cutaneous vasculitis, and pulmonary haemorrhage.

Implicated drugs include propylthiouracil (PTU), hydralazine, minocycline, allopurinol, and cocaine adulterated with levamisole. Many of these are associated with MPO-ANCA (p-ANCA), and some (particularly PTU and hydralazine) with dual ANCA positivity.

Management: stop the drug. Immunosuppression with corticosteroids and cyclophosphamide is required in severe organ-threatening disease, following the same approach as idiopathic ANCA vasculitis. Renal function should be monitored closely; some patients require renal replacement therapy.

Anaphylaxis

Anaphylaxis is an immediate, IgE-mediated (type I) hypersensitivity reaction causing systemic mast cell and basophil degranulation. It can also occur through non-IgE mechanisms (direct mast cell activation, complement activation).

Common triggers in ICU: beta-lactam antibiotics, neuromuscular blocking agents, latex, iodinated contrast media.

The clinical presentation is rapid: urticaria, angioedema, bronchospasm, hypotension, and cardiovascular collapse. Intubated patients will not manifest the typical cutaneous features, and may present with unexplained cardiovascular instability or high airway pressures.

Management: remove trigger, adrenaline 0.5 mg IM (or IV in cardiac arrest/profound shock), IV fluids, chlorphenamine, hydrocortisone. Refer to allergy services for skin testing and IgE assay after recovery to identify the specific culprit.

Management Principles

The first step in any suspected systemic drug reaction is to identify and stop the offending drug. In patients on multiple agents, a thorough medication review should consider all drugs started in the preceding 8 weeks. The drug most recently introduced is the most likely culprit, but longer-latency reactions (DRESS) implicate drugs started weeks earlier.

All relevant drugs should be documented in the allergy field with the nature of the reaction recorded precisely. Patients should be advised not to re-expose themselves to the implicated drug or close chemical relatives.

Viva Questions

What is DRESS and how does it differ from SJS/TEN?

DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are both severe cutaneous adverse reactions but have distinct mechanisms and presentations. DRESS has a delayed onset of 2–8 weeks, is characterised by internal organ involvement (hepatitis, nephritis, pneumonitis) and haematological abnormalities (eosinophilia, atypical lymphocytes), and is thought to involve T-cell-mediated immune activation with HHV-6 reactivation. The skin rash is typically maculopapular without mucosal involvement or epidermal detachment. SJS/TEN presents earlier (1–3 weeks), is defined by mucosal involvement and epidermal detachment (by definition >10% body surface area in TEN), and carries a higher acute mortality, primarily from fluid loss, sepsis, and multi-organ failure. DRESS does not cause epidermal detachment. The two conditions may overlap, and in rare cases features of both have been reported with the same drug.

How would you manage a patient with suspected drug-induced ANCA vasculitis?

The first priority is to identify and stop the offending drug. In a patient receiving PTU, hydralazine, or minocycline who presents with haematuria, proteinuria, pulmonary haemorrhage, or a vasculitic rash, drug-induced ANCA vasculitis should be considered. ANCA serology (MPO and PR3), urinalysis, renal function, and chest imaging should be obtained. Renal biopsy may be required to assess the degree of renal involvement and guide the intensity of immunosuppression. For severe organ-threatening disease (pulmonary haemorrhage, rapidly progressive glomerulonephritis), high-dose corticosteroids and cyclophosphamide are used, guided by the same protocols as idiopathic ANCA vasculitis. Plasma exchange may be considered in severe pulmonary haemorrhage or renal failure. The prognosis is generally better than for idiopathic disease once the causative drug is stopped, though some renal impairment may persist.

Which drugs commonly cause systemic drug reactions and through what mechanisms?

The mechanisms vary by reaction type. Allopurinol and aromatic anticonvulsants (carbamazepine, phenytoin, lamotrigine) cause DRESS through delayed T-cell activation, often with a genetic predisposition. Hydralazine and procainamide cause drug-induced lupus by impairing complement-mediated clearance of nuclear material and inducing anti-histone antibodies. PTU and hydralazine cause ANCA vasculitis through incompletely understood mechanisms, possibly involving neutrophil activation. Beta-lactam antibiotics cause immediate anaphylaxis via IgE-mediated mechanisms and SSLR through immune complex formation. The varied mechanisms explain the different latencies and clinical phenotypes across these conditions, and underscore the importance of a detailed drug and timing history in any patient with unexplained systemic features.