Immunologically Mediated Drug Reactions

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  IgE-dependent drug reactions (formerly type I, Gell–Coombs classification): urticaria, angioedema, and anaphylaxis.

  
  
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  Cytotoxic drug-induced reactions (antibody against a fixed antigen; formerly type II): petechiae secondary to drug-induced thrombocytopenia.

  
  
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  Immune complex-dependent drug reactions (formerly type III): vasculitis, serum sickness, and certain types of urticaria.

  
  
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  Delayed-type, cell-mediated drug reactions (activation of CD4 ⁺ and CD8 ⁺ T cells; formerly type IV) : exanthematous, fixed, and lichenoid drug eruptions, as well as Stevens–Johnson syndrome (SJS) and TEN. This group has been further subdivided into the following:

  
  
  
  
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    Th1 immune reaction (IVa): monocytes are preferentially recruited and activated by IFN-γ, leading to CD8 ⁺ T-cell activation and a proinflammatory response (TNF, IL-12)

    
    
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    Th2 immune reaction (IVb): eosinophils are preferentially recruited and activated in part by IL-4, -5, -13 and eotaxin, as in DRESS

    
    
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    Cytotoxic immune reaction (IVc): involves CD4 ⁺ and CD8 ⁺ T cells with release of perforin and granzyme B and/or Fas–FasL interactions, as in SJS/TEN (see Fig. 20.6 )

    
    
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    Neutrophil and T-cell-based immune reaction (IVd): mediated via chemokines (e.g. CXCL8) and cytokines (e.g. GM-CSF), as in acute generalized exanthematous pustulosis (AGEP)

  
  

Non-immunologic Mechanisms (see Table 21.3 )

Overdose

The clinical manifestations of a drug overdose are predictable and represent an exaggeration of the medication’s pharmacologic actions. It may occur as a consequence of a prescribing error, deliberate excess by the patient, or altered absorption, metabolism or excretion. An example of the latter is methotrexate toxicity in elderly patients with reduced renal function ( Fig. 21.1 ).

Methotrexate toxicity.

Increased serum levels of methotrexate secondary to decreased renal excretion can lead to epidermal necrosis. A Large erosions and areas of epidermal necrosis with a shellac-like appearance in a patient with rheumatoid arthritis. B Epidermal necrosis limited to psoriatic plaques.

A, Courtesy, Kalman Watsky, MD.

Idiosyncratic With a Possible Immunologic Mechanism (see Table 21.3 )

The pathophysiology of drug-induced skin reactions such as exanthematous drug eruptions, DRESS, AGEP and TEN, as well as the increased susceptibility of HIV-infected patients, may be partially explained by an interplay between immune mechanisms and genetic predisposition (e.g. slow versus rapid acetylators).

Urticaria, Angioedema, and Anaphylaxis

In urticaria, there is vasodilation and transient edema within the dermis whereas in angioedema, the edema is present in deep dermal, subcutaneous, and submucosal tissues. Although several different mechanisms may be responsible, dramatic outbreaks of acute urticaria usually represent an immediate hypersensitivity reaction mediated by IgE antibodies, especially when the urticaria is associated with angioedema and/or anaphylaxis. Clinically, “anaphylactoid” reactions may mimic IgE-induced histamine release, but are secondary to a non-immunologic liberation of histamine and/or other mediators of inflammation.

Urticaria (see Ch. 18 for details)

Urticaria presents as transient, often pruritic, erythematous and edematous papules and plaques that may appear anywhere on the body, including the palms, soles, and scalp. Lesions can vary significantly in size and number and may assume a figurate configuration ( Fig. 21.2 ). The primary effector cell is the cutaneous mast cell which releases histamine and other inflammatory mediators (see Fig. 18.4 ) .

Urticaria secondary to penicillin.

Several of the lesions have a figurate appearance.

Although drugs are thought to be responsible for <10% of all cases of urticaria, they are more often associated with acute rather than chronic urticaria. That said, patients with chronic urticaria should avoid acetylsalicylic acid (ASA; aspirin), as well as other NSAIDs, as they can lead to an exacerbation.

In IgE-mediated urticaria, lesions typically appear within minutes to less than an hour after drug administration, especially when there has been prior sensitization. Both immunologic assays, such as radio­allergosorbent tests (RAST) that detect specific IgE antibodies, and skin tests (prick tests) can prove useful in confirming the diagnosis. However, the number of drugs for which there are commercially available assays is limited, consisting primarily of penicillin, aminopenicillin, cephalosporin, and insulin. Of course, prick tests should be performed under appropriate medical supervision due to the risk of an anaphylactic reaction. It should also be noted that in some series, only 10–20% of patients who reported a history of penicillin allergy were truly allergic when assessed by skin testing.

Drugs that most frequently produce immunologically-based urticaria are antibiotics, especially penicillins and cephalosporins, and less often, sulfonamides and minocycline. As the use of monoclonal antibodies for neoplastic and inflammatory diseases increases, so will cases of urticaria (and vasculitis; see below) due to these exogenous proteins (see Ch. 128 ).

In anaphylactoid reactions, vasodilation results from the liberation of large amounts of histamine, bradykinin, and/or leukotrienes. Acetylsalicylic acid is the classic example of a drug that induces an anaphylactoid reaction and it does so via cyclooxygenase inhibition and subsequent accumulation of leukotrienes. The majority of urticarial reactions to radiocontrast media are also non-immunologic ( Table 21.8 ), as are many, but not all, reactions to NSAIDs (e.g. ibuprofen, naproxen). Allergic reactions to latex in gloves or medical devices can induce local or generalized urticaria, especially in the case of direct contact with mucosal surfaces (see Chs 16 & 18 ).

Table 21.8

Adverse reactions to radiocontrast media.

ADVERSE REACTIONS TO RADIOCONTRAST MEDIA

Iodinated

Immediate (<1 hour) Urticaria (usually non-immunologic), angioedema Anaphylactoid reaction Delayed (1 hour to 1 week) Morbilliform eruption Acute generalized exanthematous pustulosis (AGEP) Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) Iododerma (also >1 week)

Gadolinium

Urticaria, erythema (rare) Anaphylactoid reactions, anaphylaxis (rare) Nephrogenic systemic fibrosis (in the setting of renal insufficiency; see Ch. 43 )

 

The most important step in the treatment of drug-induced urticaria is withdrawal of the causative agent. Treatment consists primarily of H ₁ antihistamines. Additional therapeutic options are discussed in Chapter 18 as is the differential diagnosis which includes the immune complex-mediated disorders urticarial vasculitis and serum sickness.

Exanthematous Drug Eruptions

The primary underlying pathomechanisms are most likely immunologic, complex, and cell-mediated. Several mechanisms have been proposed (see above) in which the drug or drug-peptide hapten presented by dendritic cells to T lymphocytes can either bind covalently or non-covalently to MHC molecules . CD4 ⁺ and CD8 ⁺ T cells that strongly express perforin and granzyme are then recruited and their cytotoxic activity leads to death of keratinocytes.

Overall, most drug classes can induce an exanthematous eruption in ~1% of treated patients. Higher risk medications (>3% of treated patients develop an eruption) include aminopenicillins, allopurinol, sulfonamides, cephalosporins, and aromatic anticonvulsants. Certain viral infections are also known to increase the incidence of drug reactions. Depending upon the series, the frequency of aminopenicillin-induced exanthematous eruptions in patients with infectious mononucleosis ranges from 33% to 100% (see Ch. 80 ). One theory is that reactive drug metabolites disturb the balance between cytotoxic and regulatory immune responses, leading to a cytotoxic reaction that targets virally infected keratinocytes.

A morbilliform eruption classically begins 7 to 14 days after the initial drug administration, but appears earlier in the case of rechallenge. Symmetrically distributed erythematous macules, papules and/or urticarial lesions initially appear on the trunk and upper extremities; over time they can become confluent ( Fig. 21.3A ). The eruption is typically more polymorphous than a viral exanthem. Sometimes, due to dependency, the lesions on the distal lower extremities become petechial or purpuric ( Fig. 21.3B ). Mucous membranes are usually spared but pruritus and a low-grade fever are often present. There may also be annular plaques ( Fig. 21.3C ) or atypical “target” lesions, leading to a misdiagnosis of erythema multiforme. Once the offending drug is discontinued, the eruption gradually resolves over one to two weeks, without complications and/or sequelae. However, for 1 to 3 days immediately following discontinuation of the responsible medication, an increase in extent and intensity may be observed.

Morbilliform (exanthematous) drug eruptions.

A Erythematous papules and urticarial lesions with confluence on the midback induced by amoxillin. B Due to dependency, lesions on the distal lower extremities can become petechial or purpuric. C Pink papules and annular lesions on the forehead due to phenobarbital.

Signs and symptoms that point to the possibility of a more severe drug-induced eruption (see Table 21.1 ) include edema of the face, pustules, vesicles, dusky or painful lesions, skin fragility, mucous membrane involvement, and marked peripheral blood eosinophilia. Histopathologically, nonspecific findings are typically seen in morbilliform drug eruptions, i.e. a mild superficial perivascular and interstitial lymphocytic infiltrate that may contain eosinophils (up to 70% of cases) in addition to interface changes .

The major entity in the differential diagnosis of a morbilliform drug eruption is a viral exanthem (e.g. Epstein–Barr virus [EBV], enterovirus, adenovirus, early HIV infection, human herpesvirus type 6 [HHV-6]; see Fig. 81.2 ). Peripheral blood eosinophilia and a polymorphous appearance point to a drug eruption, and in the absence of definitive evidence, drug eruptions are favored in adults whereas viral exanthems are favored in children. Occasionally, there is a viral infection that enhances the risk of developing a drug eruption (see above) . Toxic shock syndromes, scarlet fever, acute GVHD, Kawasaki disease, and SCARs should be excluded on the basis of associated clinical features ( Fig. 21.4 ).

Approach to the differential diagnosis of an exanthematous drug reaction.

With a few exceptions (e.g., pityriasis rosea, drug-induced autoimmune bullous disorders), patients with these entities may be febrile. Entities in italics occur primarily in children. Toxic shock syndrome can be staphylococcal or streptococcal (see Ch. 74 ). Drug-induced autoimmune bullous disorders: bullous pemphigoid or linear IgA bullous dermatosis > drug-induced pemphigus. AGEP, acute generalized exanthematous pustulosis; CMV, cytomegalovirus; DIHS, drug-induced hypersensitivity syndrome; DRESS, drug reaction with eosinophilia and systemic symptoms; EBV, Epstein-Barr virus; EM, erythema multiforme; GVHD, graft versus host disease; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

Treatment is largely supportive. Topical antipruritics and corticosteroids may help to alleviate pruritus. Discontinuing the offending agent is the first therapeutic intervention. “Treating through”, i.e. continuing the drug despite the cutaneous eruption, can be considered when the suspected drug is of paramount importance for the patient and there is no satisfactory substitute drug. Usually, the eruption will disappear, but a few patients may experience progressive worsening, leading to erythroderma. Desensitization may be considered in HIV-infected patients who require sulfonamides.

Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)

Although the precise pathogenesis of DRESS is still not fully understood, several underlying mechanisms have been proposed, including a specific alteration in the metabolism of particular drugs. For example, genetic polymorphisms that affect detoxification of anticonvulsants and sulfonamides have been identified in patients recovering from DRESS . For aromatic anticonvulsants, the inability to detoxify toxic arene oxide metabolites is probably a key factor and would provide an explanation for the cross-reactivity between phenytoin, carbamazepine, and phenobarbital which has been well documented, both in vivo and in vitro .

Immune mechanisms have also been implicated based upon several observations including the requirement for sensitization, positive skin tests for the culprit drug in some patients, and a shorter time-to-onset upon rechallenge . Notably, distinct HLA alleles have been associated with a significantly increased risk of developing drug-specific DRESS (see Table 21.4 ) . In addition, IL-5 plays a role in the generation of eosinophilia and drug-specific T cells, activated in the skin and internal organs, serve to mediate the disorder.

Also implicated in the pathogenesis of DRESS is reactivation of human herpes viruses, primarily HHV-6 and HHV-7, but also CMV and EBV . In patients with DRESS, transmission of HHV-6 to skin-infiltrating CD4 ⁺ T cells (and subsequent replication) was found to require recruitment of HHV6 ⁺ peripheral monomyeloid cells to damaged skin . A study of 40 patients with DRESS noted reactivation of EBV, HHV-6, or HHV-7 in 76% of patients; activated circulating CD8 ⁺ T cells with cutaneous homing markers secreted large amounts of TNF-α and IFN-γ, especially in those with the most severe visceral involvement . In patients’ EBV-transformed B cells, culprit drugs triggered the production of EBV .

Clinically, DRESS develops 2 to 6 weeks after drug initiation, i.e. later than most other immunologically mediated skin reactions. With re-exposure, there can be a shorter time to onset. Fever and a cutaneous eruption are the most common symptoms, seen in 85% and 75% of patients, respectively . Cutaneous involvement usually begins as a morbilliform eruption ( Fig. 21.5A ), which later becomes edematous, often with a follicular accentuation. Less common manifestations include vesicles ( Fig. 21.5B ), follicular or non-follicular pustules (~20% of patients), erythroderma, and purpuric lesions. The face, upper trunk, and extremities are usually the initial sites of involvement. Edema of the face is a frequent finding and is a hallmark of DRESS whereas mucosal involvement, if present, is mild.

Drug reaction with eosinophilia and systemic symptoms (DRESS) due to carbamazepine.

A Exanthematous eruption with confluence on the thighs. B Edema and vesiculation on the forearm.

Courtesy, Alicia Little, MD.

Internal manifestations include lymphadenopathy and hepatic involvement (~80% of patients); rarely, the latter may become life-threatening (see Tables 21.9 and 21.10 ). Patients may develop interstitial nephritis, myocarditis, interstitial pneumonitis, myositis, thyroiditis, and even infiltration of the brain by eosinophils. The cutaneous and visceral involvement may persist for several weeks or months after drug withdrawal, and additional sites of involvement (e.g. cardiac, thyroid) may develop weeks or months later, including following a taper of corticosteroids. Overall mortality due to DRESS ranges from 2 to 10% .

Histopathologically, various inflammatory patterns can be seen, including eczematous, interface dermatitis, AGEP-like, and erythema multiforme-like. Prominent peripheral blood eosinophilia is common and is a very characteristic feature. It is often accompanied by mononucleosis-like atypical lymphocytosis. Elevation of hepatic enzymes can be a worrisome finding and requires serial evaluation. Thyroid and cardiac dysfunction (as detected by an ECG and echocardiogram) may develop as delayed complications and patients should therefore undergo longitudinal evaluation ( Table 21.11 ).

The differential diagnosis includes other cutaneous drug eruptions, acute viral infections, hypereosinophilic syndrome, lymphoma, and pseudolymphoma . Involvement of multiple internal organs differentiates DRESS from the more common morbilliform eruptions. In addition to the most common etiologies – the aromatic anticonvulsants (phenobarbital, carbamazepine and phenytoin), lamotrigine (especially when coadministered with valproic acid), and sulfonamides – minocycline, allopurinol, and dapsone may also induce this syndrome, as well as drugs used to treat HIV infection, e.g. abacavir ( Table 21.12 ).

Table 21.12

Drugs associated with drug reaction with eosinophilia and systemic symptoms syndrome (DRESS).

Most commonly associated drugs are in bold . NSAIDs, nonsteroidal anti-inflammatory drugs.

DRUGS ASSOCIATED WITH DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS SYNDROME (DRESS)
Drug category	Specific drugs
Anticonvulsants	Carbamazepine, lamotrigine * , phenobarbital, phenytoin , oxcarbazepine, zonisamide > valproic acid
Antimicrobials	Ampicillin, cefotaxime, dapsone , ethambutol, isoniazid, linezolid, metronidazole, minocycline , pyrazinamide, quinine, rifampin, sulfasalazine (salazosulfapyridine), streptomycin, trimethoprim–sulfamethoxazole , teicoplanin, vancomycin
Antiretrovirals	Abacavir , nevirapine , zalcitabine
Antidepressants	Bupropion, fluoxetine
Antihypertensives	Amlodipine, captopril
NSAIDs	Celecoxib, ibuprofen
Miscellaneous	Allopurinol ** , a zathioprine , imatinib, mexiletine, ranitidine, ziprasidone

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