Drug allergy differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

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Overview

True drug allergy needs to be differentiated from other reactions caused by drugs, such as pseudoallergic reactions and drug induced autoimmune like reactions. Drug allergy also needs to be differentiated from other conditions and reactions that present similarly to drug allergy.

Differentiating Drug Allergy from Other Diseases

Pseudoallergic Reactions

There are reactions called pseudoallergic reactions which, are in the category of adverse drug reactions. Although they mimic drug allergies, immunologic mechanisms have not been demonstrated as an underlying cause. There are also reactions called non-immunologic hypersensitivity reactions for which immunologic mechanisms of reactions have also not been demonstrated.

Some pseudoallergic reactions occur as a result of direct activation of immune cells and inflammatory cells, so the final steps of pathogenesis are the same and the clinical features are similar. Despite the similarities, the diagnosis, prognosis and future prevention are different.

Non-immunologic anaphylaxis can also occur. All types of anaphylaxis are life-threatening. The term “anaphylactoid reaction” often used for non-immunologic anaphylaxis can sometimes be interpreted as less severe, although this is not true. Some patients who show marked dermographism, have profound mast cell instability, which is thought associated with pseudoallergic reactions.

Some agents commonly implicated in pseudoallergic reactions are;

• NSAIDS
• Vancomycin
• Local anesthetics
• Radiocontrast agents
• Opiates
• Chemotherapeutics
• Monoclonal antibodies and other biologic therapies used in cancer treatment

Auto-immune Like Syndromes Caused by Drugs

Lupus like syndromes can be caused by the following medications;

• Penicillamine
• Procainamide
• Phenytoin
• Isoniazid
• Sulfasalazine
• Amiodarone
• Minocycline

A pemphigus like syndrome can be caused by penicillamine

IgA bullous dermatitis can be caused by:

• Vancomycin
• Ceftriaxone
• Ciprofloxacin
• Metronidazole

IgE Mediated Drug Allergies

Certain IgE mediated conditions need to be differentiated from IgE mediated drug allergies (angioedema, urticaria, anaphylaxis, bronschospasm) ;

• Insect bites and stings
• Carcinoid syndrome
• Asthma
• Food allergy
• Latex allergy
• Scombroid fish poisoning
• Mastocytosis
• Infection (EBV, gastrointestinal parasites, hepatitis A, hepatitis B, and hepatitis C

Non-IgE Mediated Drug Allergies

Certain non-IgE mediated conditions need to be differentiated from non-IgE mediated allergic reactions (exanthema, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-johnson syndrome (SJS), toxic epidermal necrolysis (TEN).

• Kawasaki disease
• Still's disease
• Acute graft-versus-host disease
• Psoriasis
• Insect bites/ stings
• Streptococcal infection
• Viral infection

Differentiating drug allergy from other rashes

Drug allergy should be differentiated from other diseases causing papulosquamous or erythmatosquamous rash. The differentilas include:

Disease	Rash Characteristics	Signs and Symptoms	Associated Conditions	Images
Cutaneous T cell lymphoma/Mycosis fungoides	Premycotic phase: A scaly, red rash in areas of the body that usually are not exposed to the sun. This rash does not cause symptoms and may last for months or years. Patch phase: Thin, erythematous, eczema-like rash. Plaque phase: Small raised bumps (papules) or hardened lesions on the skin, which may be erythematous. Tumor phase: Tumors form on the skin. Infection secondary to ulcers.	Epidermal atrophy or poikiloderma Generalized itching (pruritus) Pain in the affected area of the skin Insomnia Red (erythematous) patches scattered over the skin of the trunk and the extremities Tumor-like lobulated outgrowths form on the skin in the latter phase of the disease Weight loss Lymphadenopathy Malaise and fatigue Anemia May progress to Sezary syndrome (skin involvement plus hematogenous dissemination)	Sezary syndrome
Pityriasis rosea	Pink or salmon in color, which may be scaly; referred to as "herald patch" Oval shape Long axis oriented along the cleavage lines Distributed on the trunk and proximal extremities Squamous marginal collarette and a “fir-tree” or “Christmas tree” distribution on posterior trunk Secondary to viral infections Resolves spontaneously after 6-8 weeks	Preceded by a prodrome of: Sore throat Gastrointestinal disturbance Fever Arthralgia	Infection by any of the following: HHV-6 HHV-7 HHV-8
Pityriasis lichenoides chronica	Recurrent lesions are usually less evenly scattered than in cases of psoriasis Brownish red or orange-brown in color Lesions are capped by a single detachable, opaque, mica-like scale Often leave hypopigmented macules	High fever Malaise Myalgias Paraesthesia Pruritus	Infection by any of the following: Epstein-Barr virus (EBV) Toxoplasma gondii Human immunodeficiency virus (HIV)
Nummular dermatitis	Multiple coin-shaped eczematous lesions Commonly affecting the extremities (lower>upper) and trunk May ooze fluid and become dry and crusty	Often appears after a skin injury, such as a burn, abrasion (from friction), or insect bite Lesions commonly relapse after occasional remission or may persist for long periods Pruritus	Associated with: Dry skin Emotional stress Allergens (rubber chemicals, formaldehyde, neomycin, chrome, mercury, and nickel) Staphylococcus infection Seasonal variation Alcohol Drugs Atopy
Secondary syphilis	Round, coppery, red colored lesions on palms and soles Papules with collarette of scales	Fever Generalized lymphadenopathy Sore throat Patchy hair loss Headache Weight loss Myalgia Fatigue	Associated with: Condylomata lata Corona verinata Positive VDRL test
Bowen’s disease	Erythematous, small, scaly plaque, which enlarges erratically over time Scale is usually yellow or white and it is easily detachable without any bleeding Well-defined margins	Pruritus Pain Bleeding lesions	Associated with: Erythroplasia of Queyrat (Bowen's disease of the penis) Squamous cell carcinoma Solar radiation and ultraviolet (UV) exposure Radiotherapy Immunosuppression Arsenic exposure Human papilloma virus (HPV) type 16 Merkel cell polyomavirus Sjögren’s syndrome
Exanthematous pustulosis	Numerous small, primarily non-follicular, sterile pustules, arising within large areas of edematous erythema	Fever Leukocytosis Intracorneal, subcorneal, and/or intraepidermal pustules with papillary dermal edema containing neutrophils and eosinophils	Associated with: Antibiotics (penicillins, sulfonamides, tetracyclines) Carbamazepine Calcium channel blockers (Diltiazem) Hydroxychloroquine
Hypertrophic lichen planus	Classically involves shin and ankles and is characterized by hyperkeratotic plaques and nodules covered by a scale Lesions may transform into hyperkeratotic thickened, elevated, purplish or reddish plaques and nodules	Chronic pruritus Scaling May be asymptomatic	Associated with Hepatitis C virus infection
Sneddon–Wilkinson disease	Flaccid pustules that are often generalized and have a tendency to involve the flexural areas Annular configuration	Pruritus May be asymptomatic	Associated with: Monoclonal gammopathy, usually an IgA paraproteinemia Crohn's disease Osteomyelitis Adalimumab
Small plaque parapsoriasis	Erythematous plaques with fine scaly surface May present with elongated, finger-like patches Symmetrical distribution on the flanks Known as digitate dermatosis	Lesions may be asymptomatic May be mildly pruritic May fade or disappear after sun exposure during the summer season, but typically recur during the winter	May progress to mycosis fungoides
Intertrigo	Red and fleshy looking lesion in skin folds Itching Oozing May be sore	Pruritus Musty odor	Associated with: Infections (Fungal, bacterial, viral) Allergies Diabetes Obesity
Langerhans cell histiocytosis	Scaling and crusting of scalp	Pathological fractures Visceromegaly (hepatomegaly, spleenomegaly) Chronic cough Dyspnea Lymphadenopathy	Associated with: Diabetes insipidus Pancytopenia
Tinea manuum/pedum/capitis	Scaling, flaking, and sometimes blistering of the affected areas Hair loss with a black dot on scalp in case of tinea capitis	Pruritus KOH preparation of the lesions confirms fungal infection	Associated with: Diabetes Immunosupression Intimate contact with infected person May lead to asthma exacerbation
Seborrheic dermatitis	Papulosquamous, scaly, flaky, itchy, and red rash found particularly at sebaceous gland-rich areas of the body	Pruritus	Associated with: AIDS Stress Fungal infection Fatigue Sleep deprivation Change of season Parkinson's disease Biotin deficiency

References

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