Drug Eruptions

Cutaneous reactions are the most frequently occurring adverse reactions to drugs.  These reactions can range from mild (two-thirds of cases) to life-threatening (one-third of cases) in the hospital setting.  Distinguishing a mild versus a life-threatening reaction is challenging, yet critical in the management of drug allergies.  Cutaneous manifestations are frequently the earliest signs of a systemic drug allergy and can provide information on the severity and prognosis of an allergic reaction. Numerous risk factors predispose patients to severe cutaneous drug reactions, including immunosuppression (especially infection with human immunodeficiency virus) or mononucleosis, female gender, number of drugs being taken, and elderly age.
Cutaneous reactions are considered severe when they result in serious skin compromise or involve multiple organs.  Severe cutaneous adverse reactions (SCARs) include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS).  Recently, the SCARs definition was reclassified to include acute generalized exanthematous pustulosis (AGEP).  Due to the evolving definition, the true incidence of SCARs is difficult to ascertain.  However, in one study conducted in Singapore in 2002, analysis of an inpatient network-based electronic drug allergy notification system showed that in over 90,000 admissions, 210 drug allergy cases were verified by an allergist.  Cutaneous manifestations were the most common clinical presentation (96%) with SCARs occurring in 5% of patients.  The most common causative drugs were antimicrobials and anti-epileptic drugs. 

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
SJS and TEN are severe reactions commonly triggered by medications.  They are chiefly distinguished by the severity and percentage of body surface involvement.  Blistering and skin loss between 1 and 10% of the body surface area (BSA) is known as SJS, whereas skin detachment greater than 30% is known as TEN.  SJS/TEN overlap syndrome describes patients with involvement of greater than 10 percent but less than 30% BSA. SJS was first described in the 1920s as an acute mucocutaneous syndrome characterized by severe purulent conjunctivitis, severe stomatitis with extensive mucosal necrosis, and purpuric macules and was thought to have an infectious etiology at the time.  First reported in the 1950s,TEN was believed to be triggered by drugs as reports accumulated. 
In absolute numbers, SJS and TEN are rare diseases with the incidence of severe exfoliative skin reactions estimated at 1 to 7 cases per million person-years for SJS and 0.4 to 1.5 cases per million person-years for TEN. In children, TEN affects both genders equally.  In adults, women are more frequently affected by a ratio of 3:2.  Additionally, the elderly seem to be at increased risk of developing TEN. Patients with HIV infection have been reported to be at three times increased risk for SJS/TEN. The reasons for this susceptibility are not fully understood, although exposure to multiple medications (including sulfonamide antibiotics), “slow acetylation” status, immune dysregulation, and the presence of concomitant infections may contribute.  There is support for genetic susceptibility as well, for instance, an increased incidence of HLA-B12 has been seen in pathogenesis studies of TEN.  Certain drugs show a genetic predisposition to cause SJS or TEN in association with certain alleles.  Allopurinol and HLA-B*580 in the Han Chinese population as well as HLA-B*150 and carbamazepine have been reported in the same population. In patients with HIV, the annual incidence of TEN is 1000-fold higher than in the general population, with approximately 1 case per thousand patient years. The estimated mortality from SJS is 10%, SJS/TEN overlap 30%, and TEN is almost 50%.
There are differing opinions about the degree to which SJS and TEN overlap with severe erythema multiforme (EM), a condition with similar presentation that is commonly associated with infections, particularly herpes simplex virus and mycoplasma pneumonia. EM, the least severe of the disorders, is characterized by targetoid, edematous papules and/or plaques In EM, less than 10% of cases are drug-induced and patients typically present with a prodrome of flu-like symptoms prior to the skin eruption which classically affects the hands, feet, and limbs.  Characteristic EM lesions can be erythematous macules or wheals and are usually 1 to 2 cm in diameter.  They are usually darker in the center and paler peripherally; sometimes larger lesions exhibit concentric rings, or so-called target lesions.  There is often some systemic disturbance including fever, malaise, and organ dysfunction.  It has been hypothesized that SJS and TEN are varying degrees of the same process, different in the extent of involvement.  However, unifying this concept has not been universally accepted as some cite subtle histologic differences between EM and SJS or TEN.
The pathogenesis of SJS and TEN is not completely understood, but the etiology is hypothesized to be immune-mediated.  Various groups contend that the ligand FasL and the cognate receptor, Fas, permit signaling that triggers the apoptosis of keratinocytes. Gene expression analysis of blister fluid from patients with SJS and TEN has also recently identified secretory granulysin protein, a key molecule responsible for the induction of keratinocyte death.

The majority of SJS and TEN cases are caused by drug exposure.  Anti-gout agents (allopurinol), antibiotics (sulfonamides>>penicillins>cephalosporins), antipsychotics and anti-eplileptics (carbamazepine, dilantin, lamotrigine, and phenobarbital), and analgesics or NSAIDs (piroxicam). A survey of TEN in children identified similar drugs to those in adults, additionally implicating acetaminophen. However, pediatric infections with Mycoplasma pneumonia and herpes virus, rather than drug ingestion, represent a greater proportion of pediatric cases of SJS.
SJS/TEN typically presents 1 to 3 weeks after the administration of the responsible drug.  Clinically, both SJS and TEN present similarly.  The initial prodromic symptoms can be nonspecific; however, symptoms can include fever, stinging eyes, and discomfort when swallowing.  TEN often displays temperatures that are higher that SJS, often exceeding 39°C. Within days, early sites of cutaneous involvement typically occur on the presternal trunk, face, and palms and soles.  Skin lesions manifest as generalized macules with purpuric centers which progress to large confluent blisters with subsequent epidermal detachment. A positive Nikolsky sign may be elicited in which light lateral pressure applied with the index finger results in the detachment of the full-thickness epidermis.  Erythema and erosions of the buccal, genital, or ocular mucosa occurs in greater than 90% of patients, and occasionally the respiratory or gastrointestinal tracts are affected at the same time.  In the following three to five days, separation of the epidermis advances leading to large denuded areas associated with extreme pain, bleeding, massive fluid loss, hypothermia, and infection.
SJS, TEN, and SJS/TEN overlap syndrome are clinical diagnoses supported by compatible histologic findings.  Currently, there are no universally-accepted diagnostic criteria and histologic findings are neither specific nor diagnostic.  Despite these limitations, the diagnosis of SJS or TEN would be appropriate in a patient with a history of antecedent drug exposure or illness, a prodrome of acute onset-febrile illness with malaise, diffuse erythema which progresses to vesicles or bullae, or necrosis with sloughing of the epidermis.  Rapid supportive evidence of SJS or TEN should be obtained by submitting a frozen section of the already peeling layer of skin, which can help the clinician institute treatment as soon as possible.  The histology of skin lesions commonly reveals a subepidermal bullae with full thickness necrosis of the epidermis.  Histopathologic analysis of the skin biopsy is critical in ruling out other diagnoses such as autoimmune blistering diseases, bullous fixed drug eruptions, AGEP, and, although uncommon in adults, staphylococcal scalded skin syndrome. Extent of skin involvement is a major prognostic factor and when evaluating BSA coverage, only necrotic skin which is already detached should be included in the evaluation. Various appropriate cultures should be performed on blood, wounds, and mucosal lesions to evaluate for the presence of staphylococcal species, in particular.  In children, serologies for Mycoplasma pneumoniae infection should also be sought out.

As soon as the diagnosis of SJS or TEN has been established, the severity, prognosis, and management plan can be determined via the severity-of-illness score for TEN. Experts advocate admission to an intensive care unit, when the score is 2.  Once the SCORTEN reaches 3 the predicted mortality is 35%.
Garcia-Doval and colleagues demonstrated better prognosis with early withdrawal of the causative agent, and exposure to agents with long half-lives carried higher mortality. Oplatek et al showed that early referral to a specialized ICU, along with supportive care, correlated with increased survival rates.
Patients with SJS or TEN are at high risk of infection which can enter through the compromised skin barrier.  Sepsis remains a prominent cause of mortality, however, prophylactic systemic antibiotics are not employed by the majority of burn units.  Topical antibiotics are commonly used such as silver nitrate and newer silver-imbued nanocrystalline gauze materials. Supportive care is comparable to that in those with severe burns, focusing on correcting hypovolemia, electrolyte imbalance, renal insufficiency, and sepsis.  Daily wound care and nutritional/hydrational support most commonly takes place in an intensive care setting.  A dermatologic consult is warranted for cutaneous care.  For the face and sera, isotonic sterile sodium chloride solution should be used to wash sites, an antibiotic ointment should be applied to orificies, and silicone dressings are used to covered denuded areas.  An ocular examination by an opthomologist should be carried out regularly as well.
The use of systemic corticosteroids in SJS/TEN remains controversial. Theoretically, glucocorticoids increase the risk of sepsis, increase protein catabolism, and decrease the rate of epithelialization.  Studies have found that administration of systemic glucocorticoids was associated with increased morbidity and mortality, particularly if patients had TEN and received glucocorticoids for prolonged periods of time. As a consequence of the discovery of the anti-Fas potential of pooled human intravenous immunoglobulins (IVIG) in vitro, IVIG ( 1g/kg/day for three consecutive days) has been tested for the treatment of TEN.  To date the majority of studies confirm the mortality benefit, excellent tolerability, and low toxic potential of IVIG.  However, caution should be exercised in those with renal or cardiac insufficiency and thromboembolic risk.  Use of IVIG is contraindicated in those with IgA antibodies or IgA deficiency. In one phase II trial, although not statistically significant, cyclosporine was administered orally (3 mg/kg/d for 10days) and resulted in no deaths, whereas the prognostic score predicted 2.75 deaths amongst the 29 patients with either SJS, SJS/TEN, or TEN included in the trial. Other anti-inflammatory therapies, like tumor necrosis factor-alpha (TNF-α) antagonists, have been published in case reports, however the published data is insufficient to draw a conclusion on the therapeutic potential of TNF-α antagonists in TEN.
Re-challenge with culprit drugs is not recommended in the patient with SJS/TEN; however, the current focus of allergy testing lies more on ex vivo/in vitro tests such as the lymphocyte transformation test (LTT) which measures the proliferation of T cells to a drug in vitro by generating T-lymphocyte cell lines and clones.  Pichler and Tilch report a sensitivity of 60 to 70% for those allergic to beta-lactam antibiotics in the classic exanthematic drug rash. However, the sensitivity of LTT is still very low in SJS/TEN.  To improve the sensitivity in SJS and TEN, LTT should be done within one week after onset of the disease to get the highest sensitivity.

Studies have shown TEN to commonly produce sequelae including hypo- and hyperpigmentation (63%), nail dystrophies (38%), and ocular complications. Chronic ophthalmic complications occur more frequently in patients with initial ocular involvement, but loss of vision secondary to corneal inflammation also occurs in those without initial infection of the eye and is considered to be the most severe long-term complication in SJS/TEN survivors. Long-term mucosal complications including xerostomia or keratoconjunctivitis have also been reported in small clinical studies.
Hematologic abnormalities, particularly anemia and lymphopenia, are common in TEN.  Eosinophilia is unusual despite the strong association of TEN with drug ingestion.  Neutropenia is noted in approximately one third of patients and correlates with poor prognosis.  Glucocorticoids can cause demarginalization and mobilization of neutrophils in the circulation, giving a falsely elevated white blood count. This must be considered in patients who received these agents prior to testing, as this may obscure neutropenia.
The time course of SJS/TEN from prodrome to hospital discharge in the absence of significant complications is typically two to four weeks.  Reepithelialization may begin after several days and typically requires two to three weeks.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
DRESS is a severe and potentially fatal adverse drug reaction characterized by fever, skin eruption, hematologic abnormalities (prominent eosinophilia or atypical lymphoctytes), and multi-organ involvement which may affect the liver, kidneys, heart and/or lungs. Also known as the drug-induced hypersensitivity syndrome, DRESS has other noteworthy features including a delayed onset, usually two to six weeks after initiation of drug therapy, and the possible persistence or aggravation of symptoms despite the discontinuation of the culprit drug.
The estimated incidence of this syndrome ranges from 1 in 1000 to 1 in 10,000 drug exposures. The incidence may be higher in African-Americans and patients from the Caribbean.  DRESS is considered to be a Gell and Coombs type IV reaction.  Type IV drug reactions involve the activation of T cells and in some cases other cell types (macrophages, eosinophils, or neutrophils).  Clinically, those reactions involving T cells have prominent cutaneous findings, because the skin is a repository for T cells. Many cutaneous T cells are primed memory-effector cells, which react rapidly if immunogenic agents penetrate the skin barrier or diffuse into the skin from the circulation.
In Type IV reactions, onset of clinical presentation is usually delayed by at least 48 to 72 hours and sometimes by days to weeks following exposure to culprit drug. Upon re-challenge with the suspect drug, symptoms can appear within 24 hours.  Onset of symptoms depends partly upon the number of T cells activated by the drug.  These responses are polyclonal in nature, and symptoms appear rapidly if the drug stimulates a large number of different T cell clones.  In contrast, a drug that activates just a few clones may not cause clinical symptoms until these T cells have proliferated for a longer period of time, such as weeks. In DRESS, patients may suddenly develop signs and symptoms of a fulminant immune reaction.  This reaction results from uncontrolled expansion of oligoclonal T cells that have been massively stimulated by the culprit drug, reminiscent of superantigen-like stimulation.
Detection of herpes viruses has been recently proposed as a diagnostic marker of DRESS. Herpes viruses have been shown to reactivate in a certain order with the cascade of reactivation initiated by Epstein Barr virus (EBV), human herpes virus-6 (HHV-6), HHV-7, and then cytomegalovirus (CMV). In one study, HHV-6 was detected via PCR in 6 of 7 patients with DRESS. It has been hypothesized that certain drugs have intrinsic properties to induce an immunosuppression that reactivates herpesviruses.  Subsequent anti-viral T cells activation leads to a cross-reaction with drug antigens, and, as a consequence, DRESS develops.  Although this could suggest a key role for the viral infection in the development of an immunologic reaction, it could just represent non-specific activation of an ubiquitous virus.
Clinically, this hypersensitivity syndrome develops two to six weeks after the culprit drug is initiated, which is of later onset compared to most other immunologically mediated skin reactions.  Fever and a morbilliform eruption are the most common symptoms, seen in 85% and 75% of cases respectively.  The face, upper trunk, and extremities are usual sites of involvement.  Vesicles, tense bullae, pustules, erythroderma and purpuric lesions can also be seen.  In one study by Chen et al involving DRESS subjects close to half of all patients were reported to have lesions involving at least one mucosal area, always affecting the oral mucosa. The liver is the most common visceral organ involved with a fulminant hepatitis being the major cause of death in this syndrome.  Myocarditis, interstitial pneumonitis, interstitial nephritis, thyroiditis, and infiltration of the brain may be observed.  Cutaneous and visceral symptoms can last for weeks even after drug withdrawal.  For this reason, liver function tests should be conducted periodically after drug withdrawal. On skin biopsy, specimens showed various degrees of basal vacuolization, dyskeratosis, lymphocyte exocytosis, dermal edema, and superficial perivascular inflammation, resulting in a pathologic diagnosis of EM. Because thyroiditis has been reported to develop in a small subset of patients, thyroid stimulating hormone levels should also be measured and repeated after 2–3 months.

Anticonvulsants (phenytoin, phenobarbital, carbamazepine) are the most common causes of DRESS.  Other drugs such as lamotrigine, valproic acid, allopurinol, NSAIDs, and minocycline have also been associated with this clinical entity. Certain medications may cause inflammation affecting a specific organs. For example, anticonvulsant-induced DRESS frequently involves hepatitis, allopurinol can cause nephritis, and abacavir can cause pneumonitis. Some DRESS reactions occur more frequently in those with certain HLA types, a phenomenon also seen in SJS/TEN. For instance, DRESS secondary to allopurinol is associated with HLA-B*5801.
DRESS can be difficult to distinguish from serum sickness or vasculitis on clinical grounds.  The diverse presentations and varied organ involvement highlight the need for a set of diagnostic criteria that are easily applicable in the clinical setting.  The RegiSCAR group has suggested a series of criteria in which hospitalized patients with a drug rash must have at least three of four systemic features (fever, lymphadenopathy, internal organ involvement, hematological abnormalities).  To qualify for a diagnosis of DRESS, abnormalities must include either eosinophilia or atypical lymphocytes as well as changes reflective of hepatic or renal dysfunction.
Systemic steroid therapy is the first line for DRESS, starting with a moderate dose followed by a gradual taper.  Topical steroids can be utilized for skin manifestations.  It is not uncommon for the reaction to flare up again with abrupt discontinuation of steroid therapy. Cross-sensitivity among phenytoin, cabamazepine, and phenobarbital has been reported in 40 to 80% of patients with anticonvulsant hypersensitivity syndrome.  Therefore, afflicted patients should not be treated with any aromatic anticonvulsants and should inform family members that they too may be at a higher risk for severe adverse reactions to these medications, since susceptibility is believed to be partially genetic.

Acute Generalized Exanthematous Pustulosis (AGEP)
AGEP is characterized by fever above 38°C and a cutaneous eruption with nonfollicular sterile pustules on an edematous erythematous background.  The interval between drug administration and onset of eruption can vary from 24 hours to three weeks.  A long interval probably indicates primary sensitization and the shorter interval may be related to an unintentional re-exposure. Neutrophil counts are elevated and there is usually no visceral involvement.  Spontaneous healing typically occurs in 10-15 days.  Similarly to TEN/SJS and DRESS, AGEP is considered to be a type IV drug reaction involving the activation of T cells. 
The eruption begins on the face or intertriginous area and disseminates within a few hours.  Subcorneal aseptic pustules are characteristic and easily recognized.  Edema of the face also may occur along with targetoid skin lesions, purpura, and vesicles.  Mild, non-erosive lesions occur in the mouth and tongue in about 20% of cases. Occasionally the pustules coalesce to produce extensive superficial detachment and a positive Nikolsky sign which may be confused with TEN. The syndrome is generally self-limited, resolving spontaneously in approximately two weeks, although fatalities are reported in about 5% of cases.
The clinical presentation of AGEP is very similar to that of acute pustular psoriasis (PP).  However, in PP, the initial stage is less acute, the fever is lower, and the duration of eruption is usually longer than three weeks.  A history of plaque psoriasis on the palms and soles is frequent in those with disseminated PP.  AGEP also occurs in those with psoriasis, perhaps more frequently than expected by chance.  Nevertheless, skin pathology can help to differentiate the two pustular eruptions.  While both entities are characterized by subcorneal spongiform pustules, AGEP is characterized by edema in the superficial dermis, vasculitis, exocytosis of eosinophils, and single-cell necrosis of keratinocytes, while psoriasiform hyperplasia is suggestive of PP.  The acute onset of AGEP in association with a recent intake of pharmaceuticals is the cornerstone of its identification.
Antibiotics are thought to play a role in 80% of AGEP cases with penicillins and macrolides being the most common offenders.  A large, multinational case-control study also found quinolones, hydroxychloroquine, terbinafine, and diltiazem to be highly associated with AGEP.  Additional drugs with weaker associations include glucocorticoids, NSAIDs, and antiepileptics. Infection is a less common cause of AGEP.  However, reports of viruses such as enterovirus, parvovirus B19, adenovirus, EBV, CMV, and hepatitis B, have been implicated in causing AGEP.  AGEP usually spontaneously regresses upon removal of the culprit drug.  Topical steroids, antipyretics, and emollients are usually required to assist with the healing process.

Serum Sickness & Serum Sickness-Like Reactions
While not an official part of the SCAR definition, serum sickness and serum sickness-like reactions (SSLRs) are integral members of the family of emergent drug eruptions as afflicted patients can appear severely ill during this self-limited disease.  In 1905, von Pirquet and Schick provided the first detailed description of serum sickness in humans.  Eight to 12 days after subcutaneous injections of horse serum was injected in children who were being treated with serum containing diphtheria antitoxin, a clinical syndrome characterized by fever, lymphadenopathy, cutaneous eruptions, and arthralgias was reported to occur   Proteinuria without evidence of glomerulonepthritis, was also observed.  A delay was noted between the administration of the horse serum and the development of symptoms.  The delay was shortened if the serum was re-administered.
Serum sickness is the prototypic example of Gell and Coombs type III or immune complex mediated hypersensitivity reaction.  The reaction requires the presence of antibodies directed against an antigen which subsequently form immune complexes.  These complexes are normally cleared by the mononuclear phagocyte system; however, if this system is not functioning well or becomes saturated, excess immune complexes deposit in tissues or directly develop within involved tissues.  Immune complexes react with the Fc IgG receptors on neutrophils, mast cells, and phagocytes and trigger an inflammatory response releasing cytokines, histamine, and other inflammatory mediators (activating the complement cascade). Resolution of illness occurs when the antigen is completely cleared from the serum;.  Recurrence can develop more rapidly if a previously immunized patient becomes re-exposed to the culprit antigen.  The subsequent amnestic IgG response to a recall antigen initiates a more acute, severe response within 12 to 36 hours.
In contrast, SSLRs are defined by the presence of fever, urticaria, and arthralgias occurring one to three weeks after drug initiation. Other findings such as lymphadenopathy and eosinophilia may also be present; however, immune complexes, hypocomplementemia, vasculitis, and renal involvement are absent. Drugs, particularly antibiotics, are the leading cause of SSLRs.  Penicillin, amoxicillin, cefaclor, and trimethoprim-sulfamethoxazole are most commonly implicated, although many drugs have been associated with these reactions.  In children, SSLRs are about 15-fold more likely with cefaclor than with other cephalosporins or amoxicillin. In one study of children under the age of five, cefaclor-associated SSLRs were reported to occur in 0.2 percent with about 50% of these patients requiring hospitalization.[80]  SSLRs also occur following infections (especially streptococcal and some viral infections) and a variety of vaccines.
Historically, serum sickness has been described following the administration of anti-toxin or anti-venom.  More recently, serum sickness has been reported in patients receiving biologic immunotherapy with agents such as anti-thymocyte globulin, infliximab, and rituximab.  Risk factors for serum sickness include increasing dose and duration, nature of the heterologous protein, and age less than 16 years old. 
The cutaneous manifestations of serum sickness are variable.  Almost all develop a pruritic rash, which is often the earliest clinical feature.  The rash often starts in the region around the injection site if a drug was administered locally by intramuscular or subcutaneous injection.  Skin changes may be prominent at the lateral aspect of the feet and the hands, at the junction of the sole and side of the foot, or at the border between the palm and dorsal skin of the fingers or hands.  Mucus membranes are spared.  Virtually all patients develop fever which usually peaks 38.5ºC, and arthrlagias appear in approximately two thirds of patients with metacapophalangeal joints, knees, wrists, and ankles most commonly involved.
Neutropenia, mild thrombocytopenia, and eosinophlia can be present, and mild proteinuria occurs in about 50% of patients. During severe episodes, complement measurements including C3, C4, and total hemolytic complement are depressed reflecting complement consumption.  Histologically, mild perivascular infiltrates consisting of lymphocytes and histiocytes in the absence of vessel necrosis are observed in skin biopsies of those who develop serum sickness from equine antithymocyte globulin.
Diagnosis of serum sickness and SSLRs is made clinically after exposure to a potential offending agent.  Complete blood count with differential, urinalysis, serum chemistries, and complement studies often aid diagnosis.  Skin biopsies are rarely used in confirmation of diagnosis as findings are variable.  The differential diagnosis in patients of any age includes viral exanthems, urticarial vasculitis, acute rheumatic fever, and disseminated gonococcemia or meningococcemia. 
Randomized controlled trial data concerning the treatment of serum sickness or SSLRs is lacking; however, one published retrospective chart review of the management of children with SSLRs caused by cefaclor showed that discontinuation of the culprit drug in combination with antihistamines and glucocorticoids to provide the most symptomatic relief.