​Kembara Xtra - Medicine -Drugs Cutaneous Reaction

​Kembara Xtra - Medicine -Drugs Cutaneous Reaction 
Introduction 

An unpleasant cutaneous reaction that occurs as a result of the administration of a medication. Rash is the most common manifestation of an adverse drug response, also known as an ADR.
Morbilliform and urticarial eruptions are the most common, accounting for approximately 94% of cutaneous drug reactions. Approximately 2% of cutaneous drug reactions are severe and life-threatening. The severity can range from mild eruptions that resolve within 24 hours after the removal of the inciting agent to severe skin damage with multiorgan involvement.

Epidemiology (Incidence and Prevalence) People of all ages can get it Immunosuppressed people have a greater chance of getting it

In comparison to the general population, those living with AIDS have an 8.7-fold increased risk of developing cutaneous adverse medication responses.
• Increased chance of severe cutaneous and systemic responses in geriatric population; it is unclear if this is due to polypharmacy or a change in the drug's metabolism • Difficult to distinguish from viral exanthems in pediatric patients
Incidence
In hospitalized patients in the United States, the incidence is between 1% and 3%, and it is believed that 1 in 1,000 hospitalized patients have experienced a severe cutaneous reaction.

Causes and effects: etiology and pathophysiology 
ADR can be divided into two categories:
Predictable (category A): dosage dependant, known pharmacologic effect of drug, and potential for drug–drug interaction
Drug intolerance, drug idiosyncrasy related to irregularity in metabolism, drug allergy, and drug pseudoallergy fall under the category of "unpredictable" (type B) reactions.
 
Reactions that are immunologically mediated include: immunoglobulin (Ig) E–mediated reaction (type I hypersensitivity), cytotoxic/IgG/IgM triggered (type II), immune complex reactions (type III), and delayed-type hypersensitivity (type IV) with T cells, eosinophils, neutrophils, and monocytes
There are more than 700 different medicines that have been linked to cutaneous adverse drug reactions.
- Morbilliform, urticarial, and exfoliative erythroderma: penicillins, cephalosporins, sulfonamides, tetracyclines, ibuprofen, naproxen, allopurinol, acetylsalicylic acid, and radiocontrast medium (1)
– Acneiform: over-the-counter pain relievers (OCPs), corticosteroids, iodinated chemicals, hydantoins, and lithium
- Fixed drug eruptions: NSAIDs, sulfonamides, tetracycline, barbiturates, salicylates, OCPs
– Acute generalized exanthematous pustulosis (AGEP):
penicillins, cephalosporins, macrolides, calcium channel
blockers, antimalarials, carbamazepine, acetaminophen,
terbinafine, nystatin, vancomycin
– Drug rash with eosinophilia and systemic symptoms
(DRESS) syndrome: anticonvulsants, sulfonamides,
dapsone, minocycline, allopurinol
– Erythema multiforme/Stevens-Johnson syndrome
(SJS)/toxic epidermal necrolysis (TEN): >100 drugs
reported. Most frequent are sulfonamides, cephalosporins, NSAIDs, barbiturates, hydantoins, anticonvulsants tetracycline, terbinafine, allopurinol.
– Lichenoid: thiazides, nonsteroidal anti-inflammatory drugs (NSAIDs), gold, angiotensin-converting enzyme (ACE) inhibitors, proton pump inhibitors, antimalarials, sildenafil
– Drugs that cause photosensitivity include doxycycline, thiazides, sulfonylureas, quinolones, sulfonamides, and nonsteroidal anti-inflammatory drugs (NSAIDs).
– Vasculitis caused by hypersensitivity: hydralazine, penicillins, cephalosporins, thiazides, gold, sulfonamides, nonsteroidal anti-inflammatory drugs (NSAIDs), and propylthiouracil
– Sweet syndrome (acute febrile neutrophilic dermatosis): sulfa medications, granulocyte colony-stimulating factor (GCSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), diazepam, minocycline, nitrofurantoin, captopril, penicillamine
There is a connection between certain HLA antigens and a greater vulnerability to particular drug eruptions, suggesting that genetics may play a role in this phenomenon.

HLA-B*5801, HLA-B*5701, and HLA-B*1502 have each been associated to allopurinol-induced SJS/TEN, whereas HLA-B*1502 has been linked to carbamazepine-induced SJS/TEN.
The HLA-DQB1*0301 allele was detected in 66% of erythema multiforme patients, compared to only 31% of control subjects
TEN and fixed drug eruptions, respectively, have been associated to HLA class I antigens such HLA-A2, HLA-B12, and HLAB22. TEN is a condition that affects the nervous system.
phenytoin has been associated to certain CYP2C9*3 polymorphisms, which are TEN and SJS risk factors.
Previous adverse medication reaction, polypharmacy, concomitant infection, being immunocompromised, metabolic problems, and particular genetic HLA haplotypes are also risk factors.
GENERAL PREVENTION
Always inquire about previous negative drug reactions from the patient. Be mindful of medications that have a greater incidence of side effects, as well as the potential for drug–drug interactions.

History of the Present Illness Please list any new medications that you have started taking in the past six weeks, including oral, parenteral, and topical treatments, as well as over-the-counter pharmaceuticals, vitamins, and herbal therapies. Think about the possibility of other causes, such as associated acute or chronic urticaria, bacterial infections, viral exanthems, or underlying skin diseases such cutaneous lymphoma.

The Patient's Clinical Examination 
May appear as any one of a variety of distinct forms of volcanic eruptions, including, but not limited to the following:
Morbilliform eruptions (exanthems) are the most common type of cutaneous reaction (75–95%); they are difficult to differentiate from viral exanthems and are frequently the result of antibiotic use. Morbilliform eruptions begin on the trunk as pruritic red macules and papules and then extend symmetrically to the extremities in a confluent fashion, sparing the face, palms, soles, and mucous membranes.
- Onset typically occurs between 7 and 21 days after the first dose of medicine 
Urticaria is characterized by the presence of pruritic, erythematous wheals that can appear anywhere on the body, including the mucous membranes. Lesions can range in size and shape (for example, they can be round, oval, or rhomboid), and their appearance can shift over time.
– Angioedema is a similar symptom that can present itself as an asymmetrical swelling of the soft tissues. This swelling can cause breathing difficulties and could be fatal.
– The individual lesions will typically disappear within twenty-four hours, but more lesions may appear.
Acneiform eruptions are characterized by foliculocentric, monomorphous pustules, and they most commonly appear on the face, trunk, and proximal extremities. However, acneiform eruptions can also appear in locations that are not generally affected by acne vulgaris, such as the forearms and legs.
characterized by the absence of comedones, in contrast to acne vulgaris

Fixed drug eruptions are characterized by a single or a small number of sharply demarcated, round and/or oval erythematous plaques with a dark center that may leave postinflammatory hyperpigmentation. They can occur on the skin or the mucous membranes. Fixed drug eruptions appear shortly after drug exposure and recur in the same location after reexposure. Some patients have a refractory period during which the drug does not activate lesions.
- Typical onset time ranges from thirty minutes to eight hours after drug administration
AGEP is characterized by the rapid appearance of multiple nonfollicular sterile pustules on an erythematous background, which typically involve intertriginous areas; it typically resolves within one to three days after the removal of the drug that caused it, leaving behind a desquamation pattern; and AGEP frequently causes fever and marked leukocytosis with neutrophilia and/or eosinophilia in the blood.
Presentation may include cutaneous eruptions (typically pruritic erythematous papules and patchy erythematous macules), fever, eosinophilia (in most cases but not all), hepatic dysfunction, renal dysfunction, and lymphadenopathy. DRESS syndrome is a drug-induced multiorgan inflammatory response that has the potential to be fatal.
– Onset typically occurs between two and eight weeks following drug exposure. – Symptoms and organ involvement may intensify after the offending agent is stopped, and they may continue for several months.
- Mucosal involvement unusual

 Erythema multiforme is a disorder that is acute, immune-mediated, and mucocutaneous. It is most usually associated with herpes simplex virus (HSV) and other viral/bacterial etiologies (such as Mycoplasma); medication exposure is less likely to be the cause (10% of cases).
– Palpable classic target lesions and/or two-zone atypical target lesions with localized erythema – Most usually distributed in a symmetrical pattern on the extensor surfaces of the acral extremities; may involve the mucus membrane (25–60%)
SJS/TEN - The classification of SJS and TEN, as well as the differentiation between the two, is based on the afflicted body surface area (BSA).
○ SJS: <10% BSA; SJS–TEN overlap: 10–30% BSA; TEN: >30% BSA
- TEN is substantially connected with drug use (>95%), whereas SJS is associated with drug use less strongly (50%)
- Onset can occur anywhere between 4 and 28 days, but can be as late as 8 weeks following the first use of the offending drug: erythematous macules that are truncal and widespread with mucosal involvement, as well as flat unusual two-zone target lesions.
It is possible for confluent areas of bullae, erosions, and necrosis to form, and there is a high potential for infection and sepsis.
- SJS: mortality between 1 and 5%; TEN: mortality between 25 and 35%
Lichenoid eruptions are characterized by the appearance of violaceous, pruritic polygonal papules that are symmetrically distributed, with a preference for sun-exposed areas and extensor surfaces. The time frame of development varies depending on the drug that is the underlying cause.
- Chronic lesions continue to appear weeks or months after medication treatment has been stopped.
Photosensitivity reaction - Phototoxic reactions: typically develop from minutes to hours following exposure to sunshine, manifesting as an extreme sunburn reaction
– Photoallergic reactions: more pruritic than painful; photodistributed sparing scalp, submental, and periorbital areas Hypersensitivity vasculitis: nonblanching petechiae/palpable purpura that most typically occur on lower extremities – Hypersensitivity vasculitis:
- Onset typically occurs between 7 and 21 days after being exposed to the substance
The biopsied tissue reveals that the vessel walls have been inflamed and necrotized.
– Possible but infrequent involvement of the renal, hepatic, pulmonary, gastrointestinal, and central nervous systems Sweet syndrome – Fever; neutrophilia; painful, edematous violaceous papules, plaques, or nodules, with or without pustules/vesicles that cure on their own – Typically observed in younger women, especially after a minor bout of respiratory or gastrointestinal sickness.
erythroderma and other forms of exfoliative dermatitis
— A severe form of end-stage dermatosis that can result from various adverse medication reactions; frequently coupled with systemic signs including fever and chills
– A widespread reddening of the skin that may be accompanied by exfoliation and/or a fine desquamation of large confluent areas – Instability of the patient's hemodynamic status is associated with an increased risk of subsequent infection as well as insensible fluid and temperature loss.

Differential Diagnosis 
The presence of fever, lymphocytosis, and other systemic symptoms may be helpful in reducing the differential diagnosis of viral exanthem.
Primary dermatosis, such as pustular psoriasis: a correlation between drug discontinuation and resolution of the rash may assist clarify the diagnosis; a skin biopsy is beneficial.
Bacterial infection: Cultures of pustules can help differentiate primary infection from acneiform eruptions and AGEP.

Results From the Laboratory 
Initial Tests (lab, imaging)
The findings of the clinical history and physical exam should be used to guide the selection of initial testing. CBC with differential; substantial eosinophilia may be found in patients who have DRESS as well as other drug-induced allergic responses. LFT, urinalysis, and serum creatinine tests are performed to evaluate the involvement of internal organs; a chest x-ray is performed if vasculitis is suspected.

Diagnostic Methods and Other Procedures

 The specific tests to be performed are determined by the possible mechanisms:
– Testing of the skin and intradermal testing, as well as the radioallergosorbent test (RAST) – Testing of the direct and indirect Coombs method, type II
– Type III: erythrocyte sedimentation rate, acute nephritic assay (ANA), cryoglobulin assay, and C-reactive protein assays
- Type IV: lymphocyte proliferation assay and patch testing (investigative)
– Anaphylaxis and other types of nonimmunologic mast and basophil cell reactions: plasma histamine, serum tryptase levels, and 24-hour urine N-methylhistamine
Cultures are helpful in ruling out the possibility of an infectious origin; a skin biopsy, while vague, is helpful in defining the nature of an eruption and ruling out primary skin diseases.
Create a timeline that documents the beginning and ending times of all pharmacological treatments, as well as dosages and the beginning of cutaneous eruption.

Interpretation of the Test Nonspecific histologic findings include superficial epidermal and dermal infiltrates constituted of varying numbers of lymphocytes, neutrophils, and eosinophils. These infiltrates are seen in the superficial layers of the skin.

 SJS/TEN: necrosis of the epidermis that can be partial or full-thickness, with necrotic keratinocytes and vacuolization that leads to a subepidermal blister at the basal membrane zone.

Management 

 Be on the lookout for warning symptoms of an imminent collapse of the cardiovascular system, such as anaphylactic responses, DRESS, SJS/TEN, severe bullous reactions, and generalized erythroderma. Inpatient therapy may be necessary in these cases.
Do not retest with medications that can trigger an allergic reaction such as urticaria, bullae, angioedema, DRESS, anaphylaxis, or erythema multiforme.

Medication Continual withholding of the drug that caused the problem. Symptomatic treatment may be helpful, but for the vast majority of cases, the only treatment that is required is the elimination of the irritant that caused the rash in the first place.
Anaphylaxis or extensive urticaria: epinephrine 0.1 to 0.5 mg (1:1,000 [1 mg/mL] solution) IM in the mid-outer thigh every 5 to 15 minutes. For severe refractory instances, prednisone may be given orally at a rate of 1 mg/kg in decreasing doses.
Acute urticaria (lasting less than six weeks) and chronic urticaria (lasting more than six weeks): antihistamines of the second generation (recommended since they cause less sedation): cetirizine 10 to 20 mg daily, loratadine 10 to 20 mg daily, and fexofenadine 180 mg daily. H2 antagonists: ranitidine 150 mg BID
The treatment for erythema multiforme is often supportive, and it also involves the care of any possible underlying infections.
- Prophylaxis with acyclovir 400 mg BID, valacyclovir 500 mg BID, or famciclovir 250 mg BID "Magic mouthwash" and oral antiseptics are helpful for treating mucosal erosions in patients with recurrent herpes simplex virus infections (HSV). In cases with serious ocular involvement, a consultation with an ophthalmologist may be helpful.
SJS/TEN: Treatment focuses on providing support. If necessary, you should seek the advice of a dermatologist, an ophthalmologist, and a gynecologist. The use of systemic corticosteroids is still highly contentious. Consider administering 2 to 3 g/kg of IVIG for severe illness, despite the fact that few studies have demonstrated any advantages to survival in adults. IVIG and systemic glucocorticoids appear to enhance outcome in juvenile SJS/TEN patients; various success rates have been observed with the use of antitumor necrosis factor- agents, cyclosporine, cyclophosphamide, and plasmapheresis. To reduce the likelihood of developing hypertrophic scars, debridement should be avoided, and detached epidermis should be considered for use as a natural biologic dressing.

 DRESS: immediate removal of the offending medicine and supportive measures; high-potency topical steroids for the rash; systemic steroids in cases of severe organ involvement; appropriate supportive multidisciplinary treatment guided by organ involvement

Continued Patient Observation and Monitoring
Close follow-up is necessary for lesions that are urticarial, bullous, or part of the erythema multiforme spectrum. In some cases, hospitalization may be necessary if there is a suspicion of a life-threatening kind, such as SJS/TEN or DRESS.
Patients who have anaphylaxis or angioedema should be provided with EpiPens for secondary prevention to keep at home, at work, and in the car. Additionally, these patients should be given a Med-Alert bracelet. The patient's medical record should be labeled with the agent and the response.

● Induction of drug tolerance or graded challenge procedures may be required in the event that the patient would eventually require administration of the substance that caused the reaction (for example, an antibiotic).

The majority of cases will resolve themselves once the offending medicine is removed from the patient's system.
In most cases, the eruptions will start to subside a few days after the offending agent has been removed. Morbilliform eruptions can continue to spread distally even after the causative agent has been eliminated, but they eventually clear up.
responses such as anaphylaxis, angioedema, DRESS, SJS/TEN, and bullous responses can have lethal consequences.
The severity-of-illness score for toxic epidermal necrolysis, often known as SCORTEN, is a prognostic grading system that can be used to guide the management of SJS/TEN patients who are hospitalized. It may also be helpful when discussing prognosis.

Complications 
Anaphylaxis, suppression of bone marrow, hepatitis (dapsone, hydantoin), renal failure, psychological trauma, sepsis, and pulmonary and thyroid toxicity are some of the side effects that might occur.

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