Delayed Drug Hypersensitivity

Drug Exanthems

The clinical manifestation of drug exanthems is vast, ranging from common morbilliform rashes to severe cutaneous adverse reactions (SCARs) (eg, Stevens-Johnson syndrome [SJS]/toxic epidermal necrolysis [TEN], drug reaction with eosinophilia and systemic symptoms [DRESS], acute generalized exanthematous pustulosis [AGEP]).

Given the broad range of cutaneous findings, the differential diagnosis includes miliaria, lichen planus, folliculitis, pityriasis rosea, tinea corporis, and mycosis fungoides.

While many drugs can cause exanthems, there are no commercially available laboratory or other diagnostic tests to reliably confirm these adverse reactions.

Management

Management consists of immediate cessation of suspected medications and monitoring for symptom resolution.

For extensive dermatitis or other organ involvement, systemic corticosteroids may be indicated.

Severe Cutaneous Adverse Reactions (SCARs)

Potentially life-threatening, systemic drug-induced hypersensitivity reactions most commonly occur with exposure to anticonvulsants and sulfonamides, although other classes of medications (other antimicrobials, antifungals, allopurinol, NSAIDs, and antidepressants) have been implicated.

Included in these severe delayed drug hypersensitivity reactions are SJS/TEN, DRESS and AGEP.

Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS/TEN)

SJS and TEN comprise a spectrum of disease that are differentiated by the severity of disease.

Drugs and infections are the main etiologies and include anticonvulsants, sulfonamide antibiotics, NSAIDs, and allopurinol, and Mycoplasma pneumoniae and herpes simplex virus.

Allopurinol hypersensitivity is increased with the HLA-B*58:01 allele, the prevalence of which is highest in Han Chinese, Korean, and Thai persons, as well as in African Americans. Testing for the HLA-B*58:01 allele before starting allopurinol is conditionally recommended for these patients. Universal testing for HLA-B*58:01 is not recommended.

Clinical Findings

Symptoms start 4–28 days after initiation of an implicated medication or infection and include fever and influenza-like symptoms that precede the onset of cutaneous involvement by a few days.

Skin lesions begin as painful round purpuric blisters/bullae with two regions (“atypical target” lesions) on the face and trunk and spread to the extremities.

At least 90% of patients have mucosal involvement of the eyes, mouth, or genitalia, or all of the above.

Management

Management involves immediate cessation of the suspected medications and supportive care (eg, fluid replacement, nutrition support and monitoring for infection).

For suspected infection, antibiotics are recommended.

Adjunctive therapies are controversial (eg, intravenous immunoglobulin [IVIG], corticosteroids), while others (eg, cyclosporine, TNF inhibitors) demonstrate promise.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Drug-Induced Hypersensitivity Syndrome (DIHS)

DRESS typically includes eosinophilia, lymphocytosis, and systemic symptoms such as fever and lymph node enlargement, along with rash.

Recent classification of DRESS and DIHS indicates that they likely form a continuum of disease with DIHS representing a more severe form of DRESS with HHV-6.

A limited number of drugs are implicated in induction of DRESS including anticonvulsants, sulfonamide antibiotics (eg, sulfasalazine), allopurinol, minocycline, dapsone, and vancomycin.

Clinical Findings

The onset of DRESS typically occurs 2–6 weeks after drug initiation. DRESS often begins with pruritus and fever soon followed by a maculopapular rash with facial and periorbital edema and lymphadenopathy.

Rash affects the face, trunk, and upper and lower extremities most commonly although the rash tends to generalize into an exfoliative dermatitis or erythroderma.

Mucocutaneous involvement is uncommon.

The most common organ damage in DRESS is hepatitis; however; renal, pulmonary, and cardiac involvement may also occur.

Laboratory abnormalities include leukocytosis with eosinophilia (greater than 1.5 × 109/L), atypical lymphocytosis, elevated hepatic transaminases (> two times above the upper limits of normal) and alkaline phosphatase, and increased serum creatinine, pyuria, and proteinuria (indicative of interstitial nephritis).

The most common skin biopsy findings are a dense, perivascular lymphocytic infiltrate in the papillary dermis with eosinophils and dermal edema.

Management

Management consists of discontinuation of causative medications and initiation of systemic corticosteroids. A dose of 1.0–1.5 mg/kg of oral prednisone is recommended as a starting dose, followed by a gradual taper occurring over 3–6 months after laboratory normalization and stabilization.

Additional supportive therapies include antipyretics for fever, topical steroids for skin lesions, or fluid and electrolyte replacement in the case of more severe exfoliative dermatitis.

Acute Generalized Exanthematous Pustulosis (AGEP)

AGEP is characterized by hundreds of small, pruritic, sterile pustules on an erythematous base distributed mainly on the trunk and intertriginous areas.

The pathogenesis of AGEP results from drug-specific activation of CD4+ and CD8+ T cells that migrate to the dermis and epidermis. At this site in the skin, the CD8+ T cells release cytotoxic perforin/granzyme B as well as engaging Fas on keratinocytes leading to keratinocyte cell death/apoptosis.

Additionally, the production of interferon-γ and granulocyte/macrophage colony stimulating factor increases neutrophil survival allowing for pustule formation.

Clinical Findings

Onset of AGEP occurs within hours to days following the initiation of the culprit drug.

In addition to pustules, mucosal involvement is minimal to none and, if present, is only found in a single site such as the lips or buccal mucosa.

Many patients will have fever and neutrophilia (> 7.5 × 106/mL).

Management

Treatment of AGEP includes cessation of the suspected drug with resolution of symptoms within a few days.

The area of skin involved desquamates as the patient recovers from AGEP.

While uncommon, mortality occurs in < 5% of patients.

Wet dressings and antiseptic solutions applied while the patient has active pustules is recommended while antibiotics should be used only if there is pustular superinfection.

The utility of other treatments such as systemic corticosteroids is unclear.

Other Delayed Drug Hypersensitivity Reactions

Aspirin- and NSAID-Exacerbated Respiratory Disease

Aspirin- and NSAID-exacerbated respiratory disease is caused by aberrant arachidonic acid metabolism.

Clinical Findings

Patients typically have increased airway responsiveness, bronchospasm, rhinorrhea, and nasal congestion.

Chronic rhinosinusitis with nasal polyps and asthma is called “Samter’s triad.”

Ocular, cutaneous, and gastric symptoms may also occur.

Diagnosis is largely based on history and clinical findings.

Management

A positive aspirin challenge can demonstrate NSAID hypersensitivity and may suggest benefit from nasal polypectomy and aspirin desensitization. Long-term aspirin therapy following desensitization has been shown to reduce the need for nasal polypectomy and asthma therapy. Referral to an allergist is appropriate for aspirin desensitization.

Treatment may also include montelukast or inhibition of 5-LOX with zileuton.