**8. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Drug-induced Hypersensitivity Syndrome (DIHS)**

This DRESS is a life-threatening drug hypersensitivity reaction that can manifest with fever, cutaneous eruptions, and internal organ involvement [30]. Though the disease has a 10% mortality risk, it involves more than 50% of body surface area with skin lesions showing infiltrative papules and plaques with purpuric changes. This may be associated with other clinical features such as facial edema, desquamation during the resolution stage, and mucosal lesion involving the mouth and lips most commonly. Systemic symptoms depend on the organ involved. Eosinophilia (66–95%) is the most common hematological abnormality noted followed by atypical lymphocytosis (27–67%), lymphadenopathy (54%), and the liver is the most common internal organ involved followed by kidney, lung, and heart. The onset of skin reactions is usually observed after 3–8 weeks of the start of suspect drugs. The drugs implicated in such drug reactions are anti-convulsants, anti-infectious agents (anti-tuberculosis, antibiotics, and antiviral agents), sulfonamides, and uric acid-lowering medications. Usually, DRESS lasts for more than 15 days with prolonged courses with flare-ups observed after Human Herpes Virus type 6 reactivation. The immunopathology blamed here is the antiviral and anti-drug immune responses contribute to the disease presentations but the exact interaction is still unclear. Sequelae of this disease could be fulminant type 1 diabetes mellitus, thyroid disorders, autoimmune diseases, or permanent renal dysfunction that needs dialysis [31].

## **9. Acute generalized exanthematous pustulosis (AGEP)**

The clinical characteristics of Acute Generalized Exanthematous Pustulosis (AGEP) are typical with multiple sterile, non-follicular pustules on oedematous erythema mostly on major skin folds. It may be associated with facial edema, blisters, or atypical target lesions. Mucosal lesions are rare and mild. There may be fever and leukocytosis associated with cutaneous eruptions. Systemic involvement is rare (<20%) but may affect the liver followed by the kidney, lung, and bone marrow. The culprit drugs that are strongly associated with these reactions are pristinamycin, ampicillin/amoxicillin, quinilones, hydroxychloroquine, anti-infective sulfonamides, terbinafine, and diltiazem based on multinational case–control EuroSCAR study. The duration between drug intake and occurrence of skin eruption may take a median duration of 1 day in the case of antibiotics and 11 days for other medications. AGEP

*Perspective Chapter: Drug-Induced Severe Cutaneous Adverse Reactions, Diagnostics... DOI: http://dx.doi.org/10.5772/intechopen.108651*

resolves without any sequelae and has a good prognosis as well [32]. The diagnostic criteria for Acute Generalized Exanthematous Pustulosis (AGEP) are as follows [33, 34] – 1) Acute pustular eruption 2) Fever >38 degrees Celsius 3) Neutrophilia with or without eosinophilia 4) Sub corneal or intradermal pustules on biopsy 5) Spontaneous resolution in less than 15 days.

### **10. Diagnostic tests for cutaneous drug hypersensitivity**

Drug associated cutaneous hypersensitivity reaction requires an adequate clinical and physical examination approach with an evaluation of historical details. In addition to clinical history and examination, the diagnostic test will help to confirm the diagnosis of SCARs. Also, it will help us to determine if the initial reaction is IgE or non-IgE mediated. A diagnostic test can be classified into In Vitro tests and In Vivo tests.

*In Vitro Tests:* The quantification of various chemokines (histamine, tryptase, leukotrienes) from a different sample such as peripheral blood, nasal or bronchial secretions, urine sample serves as useful means to differentiate between the immediate and delayed types of hypersensitivity reactions (For details, refer **Table 5**). The Allergen challenge test may be formed to see the difference in the level of chemical mediators from the baseline levels. In case of acute anaphylactic reactions, the test can serially measure serum total tryptase levels, at 1 and 6 hours but is not completely reliable as normal levels may be detected in fatal cases of anaphylaxis. Even plasma histamine levels drop after 1 hour of anaphylactic symptoms making this test not reliable. Moreover, these test kits are expensive.

*In Vivo Tests*: Many skin tests are available as useful tools in the diagnosis of IgEmediated allergy. A skin prick test (SPT) is positive if the mean wheal diameter is≥3 mm after 15 to 20 minutes (associated with a flare response) compared to the negative control. Similarly, the intradermal test (IDT) is positive when meaning wheal diameter is ≥3 mm compared to the baseline diameter for the negative control after 15 to 20 minutes of the intradermal administration of allergen (0.02 to 0.05 ml). Though IDT is more sensitive than the skin prick test, there is still a higher risk of irritation, false positive reaction, and IgE-dependent anaphylactic reactions. The observation for immediate hypersensitivity reaction usually appears in 15 to 20 minutes while 24 to 72 hours' evaluation is required for non-immediate (late) reactions. Patch tests are used for the diagnosis of delayed hypersensitivity drug reactions. In these tests, a patch embedded with the suspected allergen is fixed on the back of the patient for 1 to 2 days and the result is read after 1 day and/or after 2 to 3 days. A photo-patch test is a modified patch test used to diagnose suspected photoallergic or phototoxic reactions. This patch is removed after a day and a skin area of almost 10 J/cm2 is irradiated with ultraviolet A light and the results are read on days 2, 3, and 4. The use of non-irritating skin test concentrations is recommended for SPT, IDT, and patch tests. In very rare cases, a skin biopsy may be helpful in differential diagnoses of skin conditions with typical histological patterns. For instance, connective tissue disease is characterized by interface dermatitis with epidermal atrophy, focal parakeratosis, dermal mucinosis, and fibrinoid deposition in the dermis [35, 36]. Drug provocation (challenge) tests (DPTs) are performed using suspected agents and objectively reproduce the patient's symptoms and signs of hypersensitivity. However, the positive test does not confirm an immune-mediated reaction. For DPTs, the drug is given using slow, incremental dose escalations at fixed time intervals and observing for the presence or absence of an objective reaction under the strict supervision of trained clinicians/nurses with


#### **Table 5.**

*The following table provides information about the in-vitro tests.*

well-equipped resuscitative tools. The DPT can help to exclude drug hypersensitivity when the history is nonsuggestive or the symptoms nonspecific. To definitively diagnose drug allergy when the clinical history is suggestive but allergological tests are negative, inconclusive, or unavailable. Specific contraindications to DPT include pregnancy; comorbidities in which DPT may provoke the medical situation beyond the ability to control it (e.g., acute infections; uncontrolled asthma; or underlying cardiac, hepatic, or renal diseases); immunobullous drug eruptions; and cases in which the initial reaction was a severe cutaneous and/or systemic reaction (e.g., SJS and TEN). The risks and benefits of any DPT must be explained to the patient and informed consent obtained. Short-acting antihistamines (e.g., chlorpheniramine or hydroxyzine) should be stopped for 3 days and long-acting antihistamines (e.g., cetirizine, loratadine, or fexofenadine) for 7 days before performing any DPT. Patients should also be fasted overnight and carefully observed at all times during the DPT for symptoms or signs of

an adverse reaction. Resuscitation equipment should be available at all times, and staff should be trained in the management of acute anaphylaxis [37].
