GeneralizedLocalizedErythemaI_2024_James Lyons.pdf

Generalized Erythema & Localized Erythema I Dr. James Lyons Associate Dean of Medical Education Professor of Pathology & Family Medicine  Objectives Define exanthem, enanthem, erosion, and ulceration Describe key features of drug reactions includin...

Generalized Erythema & Localized Erythema I Dr. James Lyons Associate Dean of Medical Education Professor of Pathology & Family Medicine  Objectives Define exanthem, enanthem, erosion, and ulceration Describe key features of drug reactions including general principles and immediate versus delayed reactions Describe key features including etiology, clinical course, and management/treatment of exanthematous drug eruptions, fixed drug eruptions, and drug-induced hypersensitivity syndrome (DIHS) Describe key features including etiology/microbiology, epidemiology, pathophysiology, clinical presentation, diagnosis, histologic findings, and treatment of the following diseases which have associated viral exanthems: rubeola (measles), rubella, roseola Describe general principles and etiologies of toxic erythema  Definitions § Exanthem A rash that appears abruptly and affects several areas of the skin simultaneously Greek origin “exanthema” which means “a breaking out” § Enanthem An eruption upon a mucous membrane  Erosion vs. Ulceration Erosion – Focal area of loss of part or all of the epidermis – The term excoriation is a term that is often used to describe an erosion caused by scratching (UpToDate), excoriations often have a linear shape Ulceration/Ulcer – Focal area of loss of all of the epidermis and at least part of the dermis – Excoriation -> Loss of epidermis and at least part of the dermis due to scratching or exogenous injury (visualDx) Erosion Erosion Ulceration Ulceration Generalized & Localized Erythema Topics 1. Drug Reactions 2. Viral Exanthems 3. Toxic Erythema 4. Connective Tissue Disease 5. Cellulitis/Erysipelas 6. Abscess/Furuncle/Carbuncle  Drug Reactions 1. General Principles 2. Immediate vs. Delayed Reactions 3. Types of Drug Reactions  General Principles § It is always prudent to consider drugs as the cause of a skin reaction § Most cutaneous drug reactions are inflammatory, generalized, and symmetric § Diagnosis is established by their clinical features, including morphology and timing § Histology (skin biopsy) can be helpful § Be sure to document the drug reaction in the patient’s chart with the medication and description of the reaction  Immediate vs. Delayed Reactions § Drug-induced skin reactions can be classified according to timing: Immediate reactions: occur less than 1 hour of the last administered dose Urticaria, angioedema, anaphylaxis* Delayed reactions: occurring after one hour, but usually more than 6 hrs and occasionally weeks to months after the start of administration Exanthematous eruptions Fixed drug eruption Systemic reactions (DIHS, SJS, TEN) Vasculitis (may also be systemic)*  Types of Drug Reactions § Most common and important types of adverse drug reactions Exanthematous Fixed drug eruption Drug-induced hypersensitivity syndrome (DIHS), also called Drug-related eosinophilia with systemic symptoms (DRESS) Epidermal necrolysis: Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN)  Exanthematous Drug Eruption § Exanthematous eruptions are the most common of all cutaneous drug eruptions (~90%) § Limited to the skin § Lesions initially appear on the trunk and spread to the extremities in a symmetric fashion (centrifugal spread) § Predominantly erythematous macules and papules § Pruritus and mild fever may be present § Skin lesions usually appear more than 2 days after the drug has been started, often around days 7-10 Examples of Exanthematous Drug Eruptions  Clinical Course and Treatment § Resolve in a few days to a week after the medication is stopped § Can continue the medication if the eruption is not too severe and the medication cannot be substituted § Resolves without sequelae (though extensive scaling/desquamation can occur) § Treatment consists of topical steroids, oral antihistamines, and reassurance  A complete drug history includes the following: § Remember the seven “I’s”: – Instilled (eye drops, ear drops) – Inhaled (steroids, beta adrenergic) – Ingested (capsules, tablets, syrup) – Inserted (suppositories) – Injected (IM, IV) – Incognito (herbs, non- traditional medicine, homeopathic, vitamins, over-the-counter) – Intermittent (patients may not reveal medications they take on an intermittent basis unless specifically asked)  Drug Timeline § The most important data in determining if a rash is medication-related is its timing § By preparing a drug timeline, you can find likely medication causes § Start with the onset of the rash as Day 0, and work backwards and forwards § For exanthematous drug eruptions, the initiation of the medication is often 7-10 days before the rash For repeat exposures, it may be much shorter  Example of a Drug Timeline -21 -14 -10 -7 -3 Day 0 +3 +7 Albuterol Morphine Hydromorphone Lisinopril Vancomycin Day 0 = when rash first appeared  Risk Factors for Drug Reactions § Female § Prior history of drug reaction § Recurrent drug exposure Repeated courses of therapy with the same drugs or related drugs are associated with higher rates of adverse drug reactions § HLA type SJS/TEN caused by allopurinol shows a strong association with HLA- B 5801 in Han Chinese people § Certain disease states Reactions to aminopenicillins occur more commonly in patients with Epstein Barr virus (EBV) infection HIV-positive patients have high rates of dermatologic reactions to sulfonamides and other drugs https://pubmed.ncbi.nlm.nih.gov/26104483/  Fixed Drug Eruption (FDE) § Fixed Drug Eruption is an adverse drug reaction characterized by the formation of a solitary erythematous patch or plaque that will recur at the same site with re-exposure to the drug This distinguishing feature is why it’s called “fixed” § Commonly involved drugs include: phenolphthalein (laxatives) barbiturates tetracyclines NSAIDs metronidazole salicylates sulfonamides food coloring (yellow)  FDE Morphology § Often affects the mouth, genitalia, face, and acral areas § In previously sensitized individual, lesions may occur from 30 minutes to 8 hours after ingesting the drug § Early lesions are sharply demarcated erythematous macules § Lesions become edematous, forming a plaque, which may evolve to become a bulla and then an erosion § Healed lesions are dark brown with violet hue § Commonly solitary and can become large § May be multiple with random distribution  Examples of FDE FDE with bulla arising from a plaque on the arm FDE to acetaminophen FDE to doxycycline  FDE Treatment § Lesions resolve days to few weeks after the drug is discontinued § Non-eroded lesions can be treated with a potent topical glucocorticoid ointment § Eroded cutaneous lesions can be treated with an antimicrobial ointment and a dressing until the site is reepithelialized § Address pain, especially for mucosal lesions § Oral corticosteroids may occasionally used for extensive symptomatic lesions  Drug-Induced Hypersensitivity Syndrome (DIHS) § Also known as Drug Reaction with Eosinophilia and Systemic Symptoms - DRESS § Skin eruption with systemic symptoms (e.g. fever) and internal organ involvement (e.g. liver, kidney, heart) § Typical signs and symptoms: macular exanthem, erythematous centrofacial swelling, fever, malaise, lymphadenopathy, and involvement of other organs (liver, kidneys) § >70% of patients have an eosinophilia  DIHS: Clinical Course § Signs and symptoms typically begin in the 3rd week (range 1 to 12 weeks) after start of the medication or after increasing the dose This distinguishes DIHS from exanthematous drug eruption, which appears in 7-10 days § Signs and symptoms may persist and recur for many weeks even after cessation of drug treatment § Fatality rate may be up to 10% Medications implicated in DIHS: Allopurinol Anticonvulsants – Phenytoin Antibiotics – Carbamazepine – Sulfonamide – Lamotrigine – Penicillin NSAIDs – Minocycline – Sulindac – Metronidazole – Diclofenac Anti-TB Drugs – Meloxicam – Isoniazid Anti-HIV Drugs – Abacavir  Approach to the Patient with Suspected DIHS § How severe is the reaction? What organ systems are involved? Thorough skin exam Order CBC, LFTs, BUN, creatinine (bone marrow, liver and kidney are common targets) § Which drug is responsible? Review clinical history Examine the medical records to see if there is an apparent temporal relationship between the symptoms and administration of specific drugs For each suspect drug, consider the likelihood of it causing the type of reaction in question  Approach to the Patient with Suspected DIHS Stop (or substitute) all suspect medications and discontinue non-essential medications  DIHS Treatment § Consult dermatology § Stop suspect medication(s) § If not severe, can use topical steroids and systemic antihistamines § If severe, start systemic steroids (prednisone 1mg/kg/day) and very gradually taper Steroids are indicated for lungs involvement (dyspnea and/or abnormal chest radiograph and/or hypoxemia), nephritis (creatinine >1.5 times the basal level and/or proteinuria and/or hematuria) or impending organ failure (e.g. liver, heart)  Viral Exanthems § Commonly described as “morbilliform” which means “composed of erythematous macules and papules that resemble a measles rash.” § Viral exanthems can be difficult to distinguish from a drug eruption. However, viral exanthems are more common in children, and drug eruptions tend to be more common in adults. A thorough history will aid in the diagnosis.  Morbilliform Rash Viral Exanthem (due to measles) Drug Rash  Classic Childhood Exanthems Historically, there were six childhood exanthems whose etiologies are now well-defined: NUMBER NAME ETIOLOGY First Disease Measles (Rubeola) Measles virus Second Disease Scarlet Fever Streptococcus pyogenes Third Disease Rubella Rubella virus No longer accepted as a Fourth Disease Duke’s Disease distinct disorder Fifth Disease Erythema Infectiosum Parvovirus B19 Sixth Disease Roseola Infantum HHV-6 and HHV-7  Classic Childhood Viral Exanthems NAME EXANTHEM & ENANTHEM Measles (Rubeola) Erythematous macules and papules begin on the face and spread cephalocaudally and centrifugally, Koplik spots. Rubella Pruritic, pink to red macules and papules which begin on (German measles) the face and spread to neck, trunk and extremities over 24hrs, Forchheimer’s sign. Erythema Infectiosum Begins with bright red cheeks and as the facial rash fades over 1-4 days, a symmetric, erythematous, reticular eruption appears on the trunk and extremities. Roseola Infantum Pink macules and papules surrounded by white halos. (Exanthem subitum) Begins on trunk, spreads to neck and proximal extremities.  Rubeola (Measles) § Measles is a viral disease § Spread by respiratory droplets § Droplets can be generated from the source person during coughing, sneezing, talking § Incubation period tends to be 8-12 days from exposure to onset of symptoms § Patients are contagious from 1-2 days before onset of symptoms (3-5 days before the rash) to 4 days after appearance of the rash § Immunocompromised patients can be contagious for the duration of the illness  Measles Epidemiology § Most common in children 3-5 years old § Incidence of measles has decreased substantially where measles vaccination has been instituted § Most cases of measles in the United States are imported with spread to unvaccinated individuals § Measles is still common in many developing countries (parts of Africa and Asia) and outbreaks repeatedly occur in communities who do not accept vaccinations (e.g. religious community in Netherlands) § 207,500 deaths worldwide in 2019 § 128,000 deaths worldwide in 2021  Measles: Clinical Presentation § Prodrome: Fever, Malaise, Conjunctivitis, Cough, Coryza*, Koplik spots § Exanthem: Erythematous macules and papules begin on the face and spread cephalocaudally and centrifugally (by the 3rd day, the whole body is involved). Macules and papules may coalesce into patches and plaques § Recovery: Clinical improvement begins within 2 days of appearance of the rash. The rash tends to fade after 3-4 days and will last around 6-7 days. *Coryza: “head cold” with nasal congestion, rhinorrhea, sore throat Erythematous papules and plaques Erythematous macules and patches From: Chapter 192. Measles (Rubeola) Harrison's Principles of Internal Medicine, 18e, 2012 Date of download: 5/2/2014 Copyright © 2012 McGraw-Hill Medical. All rights reserved. From: Chapter 192. Exanthematous Viral Diseases Fitzpatrick's Dermatology in General Medicine, 8e, 2012 Legend: Toddler with classic morbilliform exanthem of measles. Date of download: 5/2/2014 Copyright © 2012 McGraw-Hill Medical. All rights reserved.  Koplik Spots § Pathognomonic for measles—are small, bluish-white papules which may have an erythematous border and may ulcerate § Located in mouth, often on the buccal mucosa opposite the upper molars. § These spots contain giant cells and viral antigens and appear slightly before the rash. Koplik Spots  Diagnosis § Measles is a distinct clinical syndrome with the presence of high fever, Koplik spots, characteristic conjunctivitis, upper respiratory symptoms, and typical exanthem. § All cases of suspected measles should be serologically confirmed and reported immediately to the local or state health department without waiting for results of diagnostic tests. § Testing includes: Serology: Anti-measles IgM and IgG, isolation of measles virus or identification of measles RNA Histologic evaluation of skin lesions or respiratory secretions may show syncytial keratinocytic giant cells  Management § Uncomplicated measles is self-limiting, lasting 10 to 12 days § Treatment in the majority of cases is supportive (antipyretics, fluids) § Malnutrition, immunosuppression, poor health, and inadequate supportive care can worsen the prognosis in any patient. In developing nations, measles is a major cause of infant mortality § Vitamin A supplementation has shown to be of benefit in the treatment of measles § Some experts favor use of ribavirin for treatment of measles pneumonia in patients