39.2 Non-Infectious Rashes: Urticaria, Drug Eruptions & Erythema Multiforme

ABFM Family Medicine Certification Study Guide Exam

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1 Chapter 1: Exam Structure, Blueprint & Clinical Decision-Making

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2 Chapter 2: Healthcare Systems, Practice Management & Quality

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3 Chapter 3: Ethics, Law, Biostatistics & Health Equity

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4 Chapter 4: Lifestyle Counseling & Behavior Change

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6 Chapter 6: Routine Adult Immunizations

6.1 ACIP Adult Respiratory Vaccines: Influenza, COVID-19, RSV & Pneumococcal 6.2 ACIP Adult Non-Respiratory Vaccines: Tdap, Shingrix, HPV & Hep B 6.3 Immunizations in Special Populations: Pregnancy, Asplenia & Immunocompromise

7 Chapter 7: Pediatric Health Maintenance & Surveillance

7.1 Newborn Examination & Early Postnatal Care 7.2 Well-Child Care, Developmental Surveillance & Milestones 7.3 Pediatric & Adolescent Screening: Vision, Hearing, Anemia & Lead 7.4 Pediatric Oral Health, Dental Screening & Fluoride

8 Chapter 8: Behavioral Health & Safety Screening

8.1 Primary Care Depression, Anxiety & Behavioral Health Screening 8.2 Domestic Violence, Intimate Partner Violence & Firearm Safety 8.3 Occupational Health & Recreational Safety Counseling

9 Chapter 9: Adult Preventive Screening: Cardiovascular & Metabolic

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10 Chapter 10: Adult Cancer Screening: Breast & Gynecologic

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11 Chapter 11: Adult Cancer Screening: Colorectal, Lung & Prostate

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12 Chapter 12: Sexual Health, Infectious Disease Screening & Contraception

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13 Chapter 13: Reproductive Life Planning, Lactation & Preoperative Care

13.1 Preconception Planning & Comprehensive Contraception Management 13.2 Lactation Support & Breastfeeding Counseling 13.3 Preoperative Medical Evaluation & Pre-Participation Sports Exam

14 Chapter 14: Emergent Cardiovascular Conditions

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15 Chapter 15: Cardiac Arrhythmias, Heart Failure & Hypertensive Crises

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16 Chapter 16: Vascular & Thromboembolic Emergencies

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17 Chapter 17: Neurologic Emergencies: Stroke & Altered Consciousness

17.1 Acute Ischemic Stroke & Intracranial Hemorrhage 17.2 Syncope Evaluation & Status Epilepticus 17.3 Acute Delirium, Encephalopathy & Severe Confusion

18 Chapter 18: Neurologic Trauma & Acute Cranial Emergencies

18.1 Concussion, Moderate-to-Severe TBI & Intracranial Injury 18.2 Thunderclap & Acute Severe Secondary Headaches 18.3 Acute Ophthalmologic Emergencies

19 Chapter 19: Acute Abdominal, Pelvic & Gastrointestinal Emergencies

19.1 Acute Abdominal & Pelvic Pain Triage 19.2 Upper & Lower Gastrointestinal Bleeding 19.3 Acute Hepatic Failure, Cholangitis & Severe Jaundice

20 Chapter 20: Acute Pulmonary & Airway Emergencies

20.1 Acute Hypoxic Respiratory Failure & ARDS 20.2 Severe Community-Acquired Pneumonia & Empyema 20.3 Acute Severe Epistaxis & Airway Obstruction

21 Chapter 21: Acute Traumatic Injuries & Wound Care

21.1 Major Trauma Resuscitation & Initial Assessment 21.2 Burn Assessment, Inhalation Injury & Resuscitation 21.3 Laceration Management, Complex Wounds & Animal Bites

22 Chapter 22: Acute Orthopedic & Musculoskeletal Emergencies

22.1 Acute Ambulatory Fractures & Initial Splinting 22.2 Compartment Syndrome & Major Orthopedic Trauma 22.3 Septic Arthritis & Acute Microcrystalline Crises

23 Chapter 23: Severe Infections, Sepsis & Systemic Emergencies

23.1 Sepsis, Septic Shock & Initial Fluid Resuscitation 23.2 Necrotizing Soft Tissue Infections & Severe CNS Infections 23.3 Anaphylaxis Diagnosis, Epinephrine Dosing & Airway Protection

24 Chapter 24: Metabolic, Endocrine & Electrolyte Emergencies

24.1 Diabetic Ketoacidosis & Hyperosmolar Hyperglycemic State 24.2 Critical Electrolyte Emergencies: Dyskalemias & Dysnatremias 24.3 Severe Calcium Abnormalities & Acute Adrenal Crisis

25 Chapter 25: Hematologic, Urologic & Dental Emergencies

25.1 Severe Symptomatic Anemias & Coagulopathic Emergencies 25.2 Testicular Torsion, Priapism & Acute Urinary Retention 25.3 Urgent Odontogenic Infections & Dental Trauma

26 Chapter 26: Psychiatric, Behavioral & Obstetric/Gynecologic Emergencies

26.1 Suicidal Ideation, Acute Agitation & Behavioral Emergencies 26.2 Acute Physical & Sexual Assault Care 26.3 Life-Threatening Vaginal Bleeding & Ectopic Pregnancy 26.4 Environmental Heat Stroke & Severe Hypothermia

27 Chapter 27: Acute Head, Neck & Neurologic Symptoms

27.1 Primary Acute Headaches: Migraine, Tension & Cluster 27.2 Concussion & Minor Closed Head Injury Evaluation 27.3 Transient Ischemic Attack Evaluation & ABCD2 Risk Scoring

28 Chapter 28: Acute Cranial Nerves, Hearing & Sensory Symptoms

28.1 Peripheral Neuropathies: Bell's Palsy, Carpal Tunnel & Radiculopathy 28.2 Acute Tinnitus, Sudden Sensorineural Hearing Loss & Cerumen Impaction 28.3 Acute Dizziness, Benign Paroxysmal Positional Vertigo & Vestibular Neuritis

29 Chapter 29: Acute Upper Respiratory Tract Infections

29.1 Acute Viral Rhinosinusitis vs. Bacterial Rhinosinusitis 29.2 Acute Pharyngitis: Group A Streptococcus & Centor Criteria 29.3 Acute Otitis Media, Otitis Externa & Serous Effusion

30 Chapter 30: Acute Lower Respiratory Infections & Cough

30.1 Influenza, COVID-19 & Viral Respiratory Syndromes 30.2 Acute Bronchitis & Lower Respiratory Tract Infections 30.3 Ambulatory Community-Acquired Pneumonia

31 Chapter 31: Allergic, Nasal & Non-Infectious Pulmonary Conditions

31.1 Allergic Rhinitis & Acute Non-Anaphylactic Allergic Reactions 31.2 Acute Dyspnea in Ambulatory Care 31.3 Interstitial Lung Diseases & Sarcoidosis Presentation

32 Chapter 32: Acute Chest, Cardiac & Vascular Symptoms

32.1 Palpitations Evaluation & Arrhythmia Triage in Primary Care 32.2 Deep Vein Thrombosis & Superficial Thrombophlebitis 32.3 Ambulatory Hypotension & Orthostasis Evaluation

33 Chapter 33: Acute Upper Gastrointestinal Conditions

33.1 Peptic Ulcer Disease & Gastritis 33.2 Dysphagia, Esophagitis & Acute Esophageal Disorders 33.3 Acute Nausea, Vomiting & Foodborne Illness

34 Chapter 34: Acute Lower Gastrointestinal Conditions

34.1 Acute Infectious Diarrhea & Gastroenteritis 34.2 Acute Constipation & Functional Bowel Changes 34.3 Ano-Rectal Disorders: Hemorrhoids, Fissures, Abscesses & Pruritus Ani

35 Chapter 35: Inflammatory, Functional & Malabsorptive GI Disorders

35.1 Acute Flares of Inflammatory Bowel Disease 35.2 Irritable Bowel Syndrome: Diagnosis, Subtyping & Management 35.3 Celiac Disease & Malabsorption Syndromes

36 Chapter 36: Acute Abdominal, Hepatic & Biliary Disorders

36.1 Ambulatory Abdominal & Pelvic Pain Triage 36.2 Acute Cholecystitis, Biliary Colic & Pancreatitis 36.3 Acute Liver Injury & Viral Hepatitis

37 Chapter 37: Acute Abdominal Wall, Hernias & Dental Conditions

37.1 Abdominal Wall, Inguinal & Ventral Hernias 37.2 Acute Dental Pain, Odontogenic Abscess & Aphthous Ulcers 37.3 Acute Edema: Unilateral vs. Bilateral Diagnostic Evaluation

38 Chapter 38: Acute Infectious Dermatoses

38.1 Bacterial Skin Infections: Impetigo, Cellulitis & Cutaneous Abscesses 38.2 Fungal Skin Infections: Tinea Corporis, Cruris, Pedis & Onychomycosis 38.3 Viral Cutaneous Infections: Herpes Simplex, Zoster & Molluscum Contagiosum

39 Chapter 39: Inflammatory, Allergic & Autoimmune Dermatoses

39.1 Atopic Dermatitis, Contact Dermatitis & Eczematous Flares 39.2 Non-Infectious Rashes: Urticaria, Drug Eruptions & Erythema Multiforme 39.3 Cutaneous Malignancies & Premalignant Lesions: AK, BCC, SCC & Melanoma

40 Chapter 40: Acute Shoulder, Elbow & Upper Extremity Injuries

40.1 Rotator Cuff Pathology, Tendinopathy & Shoulder Impingement 40.2 Lateral & Medial Epicondylitis, Olecranon Bursitis & Elbow Sprains 40.3 Wrist & Hand Soft-Tissue Injuries: De Quervain, TFCC & Finger Sprains

41 Chapter 41: Acute Knee, Ankle & Lower Extremity Injuries

41.1 Meniscal Tears, Ligamentous Knee Injuries & Patellofemoral Pain 41.2 Ankle Sprains, Ottawa Ankle Rules & Achilles Tendinopathy 41.3 Plantar Fasciitis, Shin Splints & Overuse Syndromes

42 Chapter 42: Acute Ambulatory Fractures & Dislocations

42.1 Distal Radius, Scaphoid & Common Upper Extremity Fractures 42.2 Metatarsal, Clavicle & Common Lower Extremity Fractures 42.3 Joint Dislocation Management: Nursemaid's Elbow & Shoulder Subluxation

43 Chapter 43: Acute Axial Musculoskeletal Pain & Falls

43.1 Acute Low Back Pain: Red Flags, Strain & Disc Herniation 43.2 Acute Cervical Strain, Whiplash & Axial Neck Pain 43.3 Evaluation of Falls in Ambulatory & Older Patients

44 Chapter 44: Acute Inflammatory Arthropathies & Generalized Pain

44.1 Acute Inflammatory Arthritis & Spondyloarthropathies 44.2 Myalgias, Rhabdomyolysis & Post-Viral Pain Syndromes 44.3 Acute Non-Headache Pain Management Strategies

45 Chapter 45: Acute Renal, Urinary & Genitourinary Conditions

45.1 Uncomplicated UTI, Pyelonephritis & Acute Urethritis 45.2 Hematuria Workup & Glomerulonephritis 45.3 Nephrolithiasis & Acute Urinary Tract Obstruction

46 Chapter 46: Acute Male Genitourinary & Prostatic Conditions

46.1 Acute Prostatitis, Epididymitis & Orchitis 46.2 Acute Scrotal Pain: Torsion vs Appendage, BPH & Male Genital Emergencies 46.3 Acute Urinary Retention & Incontinence Evaluation

47 Chapter 47: Acute Women's Health & Early Pregnancy Care

47.1 Early Pregnancy Diagnosis, Dating & Initial Complications 47.2 Abnormal Uterine Bleeding & Acute Menstrual Disorders 47.3 Premenstrual Syndrome & Premenstrual Dysphoric Disorder

48 Chapter 48: Breast Disorders, STIs & Pediatric Elimination

48.1 Palpable Breast Mass, Mastitis & Nipple Discharge 48.2 Sexually Transmitted Infections: Diagnosis, Staging & CDC Guidelines 48.3 Pediatric Enuresis & Encopresis

49 Chapter 49: Systemic Signs, Metabolic Dysregulation & Miscellaneous Infections

49.1 Acute Fever, Sepsis Screening & FUO in Primary Care 49.2 Acute Hyperglycemia & Symptomatic Hypoglycemia 49.3 Electrolyte Abnormalities: Mild-to-Moderate Disturbances 49.4 Vector-Borne, Tick-Borne & Rickettsial Illnesses

50 Chapter 50: Chronic Cardiovascular Diseases: Hypertension & Ischemia

50.1 Essential Hypertension Management: 2025 AHA/ACC Guideline & JNC Strategies 50.2 Chronic Coronary Artery Disease & Post-MI Secondary Prevention 50.3 Chronic Heart Failure: HFrEF, HFpEF & Quadruple GDMT

51 Chapter 51: Chronic Vascular, Valvular & Dyslipidemic Diseases

51.1 Peripheral Arterial Disease & Claudication 51.2 Chronic Valvular Heart Disease & Murmur Evaluation 51.3 Lipid Disorders & ASCVD Risk-Based Statin Therapy

52 Chapter 52: Chronic Respiratory Diseases: Asthma & COPD

52.1 Chronic Asthma Management: GINA Stepwise SMART Therapy 52.2 Chronic Obstructive Pulmonary Disease: GOLD Recommendations 52.3 Solitary Pulmonary Nodule Evaluation & Fleischner Society Criteria

53 Chapter 53: Chronic Metabolic Diseases: Diabetes Mellitus

53.1 Type 2 Diabetes Management: ADA Pharmacotherapy Algorithms 53.2 Type 1 Diabetes: Basal-Bolus Insulin, CGMs & Diabetic Complications 53.3 Diabetic Microvascular & Macrovascular Disease Surveillance

54 Chapter 54: Obesity, Nutrition & Metabolic Bone Diseases

54.1 Medical & Behavioral Management of Obesity & Incretin Mimetics 54.2 Osteoporosis & Metabolic Bone Disease: DEXA, FRAX & Antiresorptives 54.3 Nutritional Deficiencies: Vitamin D, B12, Iron & Malnutrition

55 Chapter 55: Chronic Endocrine Disorders

55.1 Primary & Subclinical Hypothyroidism, Hyperthyroidism & Nodules 55.2 Adrenal Disorders: Addison's Disease & Cushing's Syndrome 55.3 Hypercalcemia, Hyperparathyroidism & Pituitary Disorders

56 Chapter 56: Chronic Kidney Disease & Venous Disorders

56.1 Chronic Kidney Disease: KDIGO Staging & Renoprotective Therapy 56.2 Chronic Venous Insufficiency, Stasis Dermatitis & Lymphedema 56.3 Chronic Electrolyte & Acid-Base Management in CKD

57 Chapter 57: Chronic Gastrointestinal & Hepatic Diseases

57.1 Gastroesophageal Reflux Disease, Barrett's Esophagus & Dyspepsia 57.2 Chronic Liver Disease: MASLD/NAFLD, Cirrhosis & Portal Hypertension 57.3 Viral Hepatitis B & C: Long-Term Monitoring & DAA Therapy

58 Chapter 58: Colorectal Surveillance & Chronic Pancreaticobiliary Care

58.1 Post-Polypectomy Colorectal Polyp Surveillance Guidelines 58.2 Chronic Pancreatitis & Exocrine Pancreatic Insufficiency 58.3 Chronic Nausea, Gastroparesis & Functional GI Disorders

59 Chapter 59: Chronic Musculoskeletal & Rheumatologic Disorders

59.1 Osteoarthritis: Hip, Knee & Hand Management 59.2 Spinal Conditions: Spinal Stenosis, Spondylolisthesis & Compression Fractures 59.3 Chronic Myopathies & Fibromyalgia Syndrome

60 Chapter 60: Chronic Neurologic & Neurodegenerative Disorders

60.1 Dementia: Alzheimer's, Vascular & Lewy Body Disease 60.2 Parkinson's Disease & Essential Tremor 60.3 Epilepsy: Chronic Antiseizure Medications & Post-Stroke Care

61 Chapter 61: Chronic Peripheral Nerves, Pain & Sensory Disorders

61.1 Diabetic & Chronic Peripheral Neuropathies 61.2 Chronic Pain Syndromes & Chronic Daily Headaches 61.3 Chronic Tinnitus, Presbycusis & Persistent Dizziness

62 Chapter 62: Chronic Psychiatric Disorders

62.1 Major Depressive Disorder & Generalized Anxiety Disorder 62.2 Bipolar Disorder: Maintenance Pharmacotherapy & Lithium Monitoring 62.3 Adult & Pediatric Attention-Deficit/Hyperactivity Disorder

63 Chapter 63: Chronic Behavioral Health & Neurodevelopmental Conditions

63.1 Chronic Behavioral Conditions: PTSD, OCD & Somatization 63.2 Autism Spectrum Disorder & Intellectual Disabilities 63.3 Eating Disorders: Anorexia Nervosa, Bulimia & Binge Eating

64 Chapter 64: Chronic Substance Use Disorders & Tobacco Cessation

64.1 Alcohol Use Disorder: Pharmacotherapy & Relapse Prevention 64.2 Opioid & Stimulant Use Disorders: MOUD & Harm Reduction 64.3 Longitudinal Tobacco Cessation Pharmacotherapy

65 Chapter 65: Chronic Dermatologic Conditions

65.1 Acne Vulgaris, Rosacea & Seborrheic Dermatitis 65.2 Chronic Plaque Psoriasis & Biologic Therapies 65.3 Chronic Eczema, Hidradenitis Suppurativa & Cutaneous Lupus

66 Chapter 66: Chronic Reproductive, Infectious & Geriatric Special Care

66.1 Chronic Menstrual Disorders, Infertility & Sexual Dysfunction 66.2 Menopause Management & Hormone Replacement Therapy 66.3 Chronic HIV Infection Management & Primary Care Integration 66.4 Gender-Affirming Primary Care & Hormone Therapy 66.5 Advance Care Planning, Palliative Care & End-of-Life Symptom Control

67 Chapter 67: Continuity Care: Sleep, Fatigue, Cancer, Pregnancy & the Adult Preventive Visit

67.1 Chronic Insomnia & Obstructive Sleep Apnea 67.2 Chronic Malaise, Fatigue & ME/CFS 67.3 Primary Care During Cancer Treatment & Survivorship 67.4 Routine Prenatal Care & Longitudinal Pregnancy Management 67.5 The Periodic Adult Health Examination & Medicare Annual Wellness Visit

39.2 Non-Infectious Rashes: Urticaria, Drug Eruptions & Erythema Multiforme

Key Takeaways Explain This Topic AI

Acute urticaria (<6 weeks) is most commonly triggered by viral infections in children and adverse drug reactions or foods in adults; individual urticarial wheals are intensely pruritic, edematous plaques with central pallor that characteristically appear, evolve, and completely resolve within 24 hours without residual scarring or pigmentary change.

First-line therapy for urticaria is a second-generation non-sedating H1-antihistamine (e.g., cetirizine, fexofenadine, or loratadine); in recalcitrant cases, guidelines recommend titrating the second-generation H1-antihistamine up to 4 times the standard daily dose before adding second-line agents (H2-blockers, montelukast) or omalizumab (anti-IgE).

Exanthematous (morbilliform) drug eruption is the most common adverse cutaneous drug reaction (90%), occurring 7-14 days after starting a new medication (antibiotics, anticonvulsants); it presents with symmetric, blanching macules/papules on the trunk and limbs without facial edema, mucosal involvement, fever, or organ dysfunction, resolving spontaneously upon drug withdrawal.

DRESS/DIHS is a life-threatening delayed hypersensitivity reaction (2-8 weeks post-drug exposure) characterized by severe morbilliform rash with prominent facial/periorbital edema, marked eosinophilia (>1,500/mcL or >10%), atypical lymphocytosis, and visceral organ involvement (acute hepatitis in >70%, interstitial nephritis); treatment requires immediate culprit drug cessation and a prolonged oral corticosteroid taper over 8-12 weeks.

SJS (<10% BSA detachment) and TEN (>30% BSA detachment) are cytotoxic T-cell/granulysin-mediated dermatologic emergencies featuring dusky targetoid purpuric macules, flaccid bullae, full-thickness epidermal necrosis with a positive Nikolsky sign, and painful mucosal erosions in >90%; Erythema Multiforme (EM) is primarily triggered by infections (HSV-1 in >70%, Mycoplasma) and features true three-zoned target lesions with minimal to no epidermal detachment (<10%).

Last updated: September 2026

Pathophysiology of Urticaria & Mast Cell Activation

Urticaria (hives) is characterized by the sudden appearance of intensely pruritic wheals, angioedema, or both. It affects up to 20% of the population at some point during their lifetime. URTICARIA PATHOPHYSIOLOGY

• Immunologic Triggers Non-Immunologic Triggers
• (IgE-Mediated, Autoantibodies) (Opiates, Radiocontrast, NSAIDs)
• │ │
• ▼ ▼
• ┌─────────────────────────────────────────────────────────┐
• │ DERMAL MAST CELL DEGRANULATION │
• │ • Preformed Mediators: Histamine, Tryptase │
• │ • De Novo Lipids: Leukotrienes (LTC4, LTD4), PGD2, PAF │
• │ • Cytokines: TNF-alpha, IL-4, IL-5 │
• └─────────────────────────────────────────────────────────┘
• │
• ┌─────────────────────┴─────────────────────┐
• ▼ ▼
• Post-Capillary Venular Dilation Sensory C-Fiber Stimulation
• & Increased Vascular Permeability • Unmyelinated C-nerve fibers
• Transudation of fluid into dermis • Intense Pruritus
• LOCALIZED DERMAL EDEMA (WHEAL) • Axon reflex flare (erythema)
• Cellular Mechanisms

Superficial Dermal Edema : Mast cell degranulation in the papillary and reticular dermis releases histamine, which binds to endothelial H1 receptors , stimulating nitric oxide and prostacyclin production. This causes marked arteriolar vasodilation and post-capillary venular gap formation, permitting plasma extravasation into the extracellular space to form a circumscribed wheal .

Sensory Nerve Activation : Histamine acts on local unmyelinated C-type sensory nerve endings, transmitting intense pruritus to the central nervous system and stimulating local substance P and CGRP release, producing the surrounding axon reflex erythematous flare.

Angioedema : When mast cell activation or vasoactive mediator release occurs in the deeper reticular dermis, subcutaneous tissue, or submucosal layers , it manifests as angioedema —a non-pitting, poorly demarcated swelling that is frequently painful or burning rather than pruritic.

Acute vs. Chronic Urticaria & Diagnostic Red Flags

Urticaria is chronologically classified into acute and chronic forms based on an arbitrary cutoff of 6 weeks .

1. Acute Urticaria (<6 Weeks)

Etiology : Most cases are self-limited and resolve within days to a few weeks.

Infections (>80% of pediatric cases) : Acute viral upper respiratory infections, enteroviruses, Epstein-Barr virus, adenovirus, and rotavirus;

Adverse Drug Reactions : IgE-mediated (beta-lactams) or direct non-IgE mast cell degranulation (opiates, vancomycin, radiocontrast media) or COX-1 inhibition altering arachidonic acid shunting to cysteinyl leukotrienes (aspirin, NSAIDs);

Food Allergies : IgE-mediated reactions to peanuts, tree nuts, shellfish, milk, eggs, or soy (onset occurs within 30 to 120 minutes of ingestion);

Hymenoptera Stings : Bee, wasp, or fire ant envenomation.

Laboratory Evaluation : Extensive laboratory testing or routine allergy panels are strictly not recommended for uncomplicated acute urticaria, as testing yields high false-positive rates and does not alter clinical management.

2. Chronic Urticaria (>=6 Weeks)

Subtypes :

Chronic Spontaneous Urticaria (CSU, >80%) : Hives occurring most days of the week for >=6 weeks without an identifiable physical trigger. Up to 40% to 50% have an autoimmune pathogenesis driven by circulating IgG autoantibodies directed against the alpha subunit of the high-affinity IgE receptor ( anti-Fc-epsilon-RI-alpha ) or against IgE itself ( anti-IgE ), cross-linking receptors and triggering continuous mast cell degranulation. CSU is strongly associated with autoimmune thyroid disease (Hashimoto thyroiditis with anti-TPO antibodies).

Chronic Inducible Urticaria (CIndU, <20%) : Provoked by specific physical stimuli: symptomatic dermographism (stroking the skin), cold urticaria (ice cube test), cholinergic urticaria (elevated core body temperature from exercise or hot showers; pinpoint wheals), delayed pressure urticaria, solar urticaria, or vibratory angioedema.

Recommended Basic Workup for CSU : Complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), and thyroid-stimulating hormone (TSH) with anti-thyroperoxidase (anti-TPO) antibodies. Routine extensive food allergy panels, ANA, or total IgE are non-contributory.

The Cardinal Rules of Urticaria & Board Red Flags

The 24-Hour Evanescence Rule : Individual urticarial wheals are characteristically transient and migratory ! An individual wheal arises rapidly, peaks within hours, and completely resolves within 24 hours (usually 2 to 12 hours) without leaving behind any residual bruising, petechiae, scaling, or post-inflammatory hyperpigmentation, while new lesions may appear elsewhere.

Warning

RED FLAG: URTICARIAL VASCULITIS If an individual hive remains fixed in the exact same anatomic location for longer than 24 to 48 hours , causes burning, tenderness, or stinging rather than itching , and resolves leaving behind residual purpura, ecchymosis, or hyperpigmentation , this is NOT simple urticaria! This presentation indicates urticarial vasculitis (a leukocytoclastic vasculitis of post-capillary venules associated with SLE, Sjögren syndrome, or hypocomplementemia). A skin punch biopsy is mandatory for definitive histologic diagnosis.

Stepwise Management of Urticaria: The 4-Fold Antihistamine Rule

International guidelines (EAACI/GA²LEN/EDF/WAO) dictate a clear, stepwise pharmacotherapeutic algorithm for managing acute and chronic urticaria. STEPWISE URTICARIA MANAGEMENT

• STEP 1: Second-Generation H1-Antihistamine at Standard Licensed Dose
• (Cetirizine 10 mg, Fexofenadine 180 mg, Loratadine 10 mg, Desloratadine 5 mg)
• │
• ▼ Uncontrolled after 2-4 weeks (or severe)

STEP 2: UPTITRATION OF SECOND-GENERATION H1-ANTIHISTAMINE UP TO 4X DOSE!

• (e.g., Cetirizine 20 mg BID OR Fexofenadine 180 mg BID)
• The Gold Standard Second Step (superior efficacy, excellent safety)
• │
• ▼ Uncontrolled after 2-4 weeks at 4x dose
• STEP 3: Add-On Biologic Therapy (Omalizumab) or Secondary Agents
• Omalizumab (Anti-IgE) 300 mg Subcutaneously every 4 weeks (First-Line Add-on)
• Adjuncts: H2-Blocker (Famotidine 20 mg BID), Montelukast 10 mg daily
• │
• ▼ Refractory to Omalizumab
• STEP 4: Cyclosporine A (3 to 5 mg/kg/day) in specialized care
• Step 1: Second-Generation H1-Antihistamines (First-Line)

Rationale : Modern second-generation H1-antihistamines (cetirizine 10 mg daily, levocetirizine 5 mg daily, fexofenadine 180 mg daily, loratadine 10 mg daily, desloratadine 5 mg daily) are non-sedating inverse agonists that selectively stabilize inactive H1 receptors.

Avoid First-Generation Antihistamines as First-Line : First-generation agents (diphenhydramine, hydroxyzine, chlorpheniramine) cross the blood-brain barrier, causing profound daytime sedation, impaired psychomotor skills, rapid-eye-movement (REM) sleep architecture disruption, and potent anticholinergic toxicity (urinary retention, dry mouth, blurred vision, confusion in older adults). They are relegated to optional short-term bedtime use for intractable nocturnal pruritus.

Step 2: The 4-Fold Dose Escalation Rule

If urticaria symptoms persist after 2 to 4 weeks (or sooner in patients with severe daily hives), guidelines strongly recommend escalating the dose of the second-generation H1-antihistamine up to four times the standard licensed dose (e.g., cetirizine 20 mg twice daily, or fexofenadine 180 mg twice daily) before switching classes.

High-dose second-generation antihistamines achieve greater H1-receptor occupancy without causing significant sedation or organ toxicity.

Step 3: Add-On Therapies & Biologics

Omalizumab : A humanized recombinant monoclonal antibody that binds free circulating IgE, downregulating Fc-epsilon-RI receptors on mast cells and basophils. Administered at 300 mg subcutaneously every 4 weeks , it clears hives in up to 70% to 80% of antihistamine-refractory CSU patients.

Secondary Oral Adjuncts : H2-receptor antagonists ( Famotidine 20 mg twice daily ) block the 15% of cutaneous vascular H2 receptors; Leukotriene receptor antagonists ( Montelukast 10 mg daily ) provide benefit in NSAID-sensitive or angioedema-predominant urticaria.

Systemic Corticosteroids in Urticaria: Strict Practice Parameters

Rescue Therapy Only : Oral corticosteroids (prednisone 40 to 50 mg daily for adults, 1 mg/kg/day for children) should be restricted to a short rescue burst of 3 to 5 days for severe acute flares or debilitating angioedema. No taper is necessary for courses <=5 days.

Strict Rule for Chronic Urticaria : Systemic corticosteroids are strictly contraindicated for long-term maintenance in chronic spontaneous urticaria due to unacceptable cumulative toxicity (osteoporosis, diabetes, hypertension, adrenal suppression) and severe rebound exacerbation upon withdrawal.

Adverse Cutaneous Drug Reactions: Benign Morbilliform Eruptions

Adverse cutaneous drug reactions occur in 1% to 3% of hospitalized patients and up to 2% of outpatient prescriptions. Accurately distinguishing benign exanthems from severe cutaneous adverse reactions (SCARs) is a critical board competency.

Exanthematous (Morbilliform) Drug Eruption

Epidemiology : The most common adverse cutaneous drug reaction, accounting for >90% of cases .

Pathophysiology : Delayed Type IV cell-mediated hypersensitivity reaction driven by drug-specific CD4+ and CD8+ T cells reacting to haptenated peptides presented by MHC molecules.

Onset Timing : Typically develops 7 to 14 days after starting a new medication ; on re-exposure, the eruption appears much faster (within 24 to 48 hours).

High-Risk Culprit Drugs : Beta-lactam antibiotics (penicillins, aminopenicillins, cephalosporins), sulfonamides (TMP-SMX), anticonvulsants (carbamazepine, phenytoin), allopurinol, and NSAIDs.

Clinical Morphology & Distribution :

Symmetrical, widely distributed, bright pink-to-red macules and small papules (measuring 2 to 5 mm) that frequently coalesce into larger reticular plaques;

Begins centrally on the trunk and upper extremities, spreading symmetrically and centrifugally down to the lower extremities;

Important Sparing : Spares the face, mucous membranes, palms, and soles ;

Moderate to severe pruritus is common, but skin pain or tenderness is absent.

Strict Absence of Systemic Toxicity : Patients are afebrile , hemodynamically stable, with zero facial edema , zero mucosal erosions , and normal hematologic, hepatic, and renal laboratory parameters.

Management :

Promptly identify and discontinue the culprit medication ;

Supportive therapy: Medium-potency topical corticosteroids (triamcinolone acetonide 0.1% cream) for pruritus, oral second-generation antihistamines, and cool baths;

Natural history: The exanthem peaks over several days, turns a dusky brownish-red, and fades over 7 to 14 days, often resolving with fine, powdery superficial desquamation.

Severe Cutaneous Adverse Reactions (SCARs): DRESS / DIHS Syndrome

Severe Cutaneous Adverse Reactions (SCARs) encompass life-threatening, T-cell-mediated drug reactions with high morbidity and mortality: DRESS, SJS, and TEN.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS / DIHS)

Synonym : Drug-Induced Hypersensitivity Syndrome (DIHS).

Latency Period : Characteristically delayed onset of 2 to 8 weeks (average 3 to 4 weeks) after drug exposure. This long latency often causes clinicians and patients to overlook the offending medication!

Culprit Medications :

Aromatic Anticonvulsants : Carbamazepine, phenytoin, phenobarbital, lamotrigine;

Allopurinol : Especially in patients with underlying renal insufficiency or carrying the HLA-B*5801 allele (common in Han Chinese, Korean, and African ancestry);

• Sulfonamides : Sulfasalazine, dapsone, trimethoprim-sulfamethoxazole;
• Antibiotics : Minocycline, vancomycin;

Antiretrovirals : Abacavir (HLA-B*5701), nevirapine.

Pathogenesis : Complex interplay of genetic pharmacogenomic susceptibility (specific HLA alleles), defective drug detoxification pathways, drug-specific T-cell hyperactivation, and reactivation of latent human herpesviruses (especially HHV-6 , HHV-7, Epstein-Barr virus [EBV], and CMV).

The Classic Diagnostic Triad of DRESS

Severe Cutaneous Eruption & Facial Edema :

Begins as an extensive morbilliform exanthem involving >50% BSA that rapidly progresses into an indurated, edematous, infiltrated erythroderma or exfoliative dermatitis;

Hallmark Clinical Sign : Prominent facial and periorbital edema (present in >70% to 80% of patients) , creating a distinctive puffy, distorted facial appearance.

Hematologic Abnormalities :

Marked Peripheral Eosinophilia : Absolute eosinophil count >=1,500/mcL (or >10% of differential) ;

Atypical Lymphocytosis : Mononucleosis-like reactive atypical lymphocytes on peripheral blood smear in >30%.

Multiorgan Visceral Involvement (>=1 Internal Organ) :

Liver (Most Common, >75%) : Acute drug-induced hepatitis with marked transaminitis (ALT/AST >2 to 10x upper limit of normal), hyperbilirubinemia, and fulminant hepatic failure (the primary cause of death in DRESS);

Kidneys (10-30%) : Acute interstitial nephritis with elevated serum creatinine, microscopic hematuria, and proteinuria (predominates with allopurinol exposure);

Lungs (10%) : Interstitial pneumonitis causing cough, dyspnea, and hypoxemia;

Heart : Acute eosinophilic myocarditis (can present weeks after onset, requiring baseline troponin and ECG monitoring).

Clinical Management of DRESS

Immediate Culprit Drug Withdrawal : Prompt discontinuation is the most vital determinant of survival.

Systemic Corticosteroids (First-Line) : High-dose Oral Prednisone 1.0 mg/kg/day (or IV methylprednisolone for severe visceral involvement). Corticosteroids suppress T-cell hyperactivity and halt visceral organ necrosis.

The 8- to 12-Week Taper Rule : Corticosteroids must be tapered very slowly over a minimum of 8 to 12 weeks ! Premature or rapid dose reduction triggers severe, catastrophic inflammatory rebounds and recurrent organ failure.

Long-Term Monitoring : Patients are at high risk of developing delayed autoimmune endocrinopathies (autoimmune Hashimoto thyroiditis, Graves disease, Type 1 diabetes) months to years later, requiring long-term TSH and glycemic surveillance.

Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN)

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent severity variants of the same life-threatening, acute cytotoxic T-cell-mediated mucocutaneous necrolysis syndrome. SJS / TEN EPIDERMAL DETACHMENT SPECTRUM

• [ STEVENS-JOHNSON SYNDROME ] ───────> <10% Body Surface Area Detachment
• Mortality: ~5% to 10%

• [ SJS / TEN OVERLAP ] ──────────────> 10% to 30% Body Surface Area Detachment
• Mortality: ~15% to 30%

• [ TOXIC EPIDERMAL NECROLYSIS ] ─────> >30% Body Surface Area Detachment
• Mortality: >30% to 50%
• Pathophysiology

Cytotoxic Keratinocyte Apoptosis : Drug-specific HLA-restricted CD8+ cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells infiltrate the dermoepidermal junction.

Mediators of Death : Massive release of granulysin (a cytotoxic protein that directly lyses keratinocytes and acts as the master mediator of epidermal necrolysis), perforin/granzyme B, and soluble Fas ligand (FasL) binding to Fas (CD95) receptors. This induces apoptosis of the entire epidermal cell layer, resulting in full-thickness dermal-epidermal separation and massive fluid loss.

Latency : Onset occurs 1 to 3 weeks (7 to 21 days) after drug initiation.

Major Culprit Drugs : Allopurinol (HLA-B 5801), Carbamazepine (HLA-B 1502), Phenytoin, Lamotrigine, Sulfonamide antibiotics (TMP-SMX), Nevirapine, and Oxicam NSAIDs (meloxicam, piroxicam).

Clinical Presentation & Hallmark Signs

Prodrome : High fever (>39°C / 102.2°F), severe malaise, sore throat, cough, stinging eyes, and arthralgias occurring 1 to 3 days prior to the rash.

Cutaneous Eruption :

Initial lesions: Ill-defined, dusky, purpuric, targetoid atypical macules (irregular dark purpuric centers without concentric rings) originating symmetrically on the pre-sternal chest and face, rapidly coalescing across the trunk and extremities;

Lesions become exquisitely tender to light palpation ("skin pain out of proportion to exam" is an early hallmark sign);

Coalescent dusky areas develop flaccid, fluid-filled bullae that rupture, leaving sheets of denuded, weeping, bleeding dermis resembling severe second-degree thermal burns.

Pathognomonic Physical Examination Signs :

Positive Nikolsky Sign : Application of gentle, lateral shearing pressure with a finger to normal-appearing perilesional skin results in dislodgement and peeling of the epidermis;

Positive Asboe-Hansen Sign (Bulla Spread Sign) : Gentle downward vertical pressure on the center of an intact flaccid bulla causes lateral extension and dissection of the blister fluid beneath adjacent intact epidermis.

Severe Mucosal Involvement (>90% of Cases) :

Severe, excruciating inflammation involving two or more mucosal surfaces :

Oral Mucosa : Hemorrhagic crusting of the lips, extensive denuded stomatitis, severe odynophagia preventing oral intake;

Ocular Mucosa (>80%) : Severe bilateral purulent conjunctivitis, pseudomembrane formation, corneal erosions, and symblepharon (adhesion of palpebral conjunctiva to bulbar conjunctiva); without urgent treatment, leads to cicatricial ectropion, corneal ulceration, and permanent blindness;

Urogenital Mucosa : Severe erosive urethritis (causing acute urinary retention), vulvovaginal ulcerations, and late vaginal canal stenosis;

Respiratory Epithelium : Tracheobronchial mucosal sloughing causing acute respiratory distress syndrome (ARDS) requiring mechanical ventilation.

• SCORTEN Mortality Prediction & Burn Center Transfer Criteria
• The SCORTEN Prognostic Score

SCORTEN is a validated, illness-severity score calculated within the first 24 to 48 hours of hospital admission to predict in-hospital mortality in SJS/TEN. One point is scored for each of the following 7 independent clinical variables:

• Age >= 40 years ;
• Presence of Malignancy (hematologic or solid tumor);
• Tachycardia >= 120 beats/min ;
• Initial Epidermal Detachment >= 10% BSA ;
• Serum Blood Urea Nitrogen (BUN) > 28 mg/dL (>10 mmol/L) ;
• Serum Glucose > 252 mg/dL (>14 mmol/L) ;

Serum Bicarbonate < 20 mEq/L .

• SCORTEN Score Predicted In-Hospital Mortality
• 0 - 1 3.2%
• 2 12.1%
• 3 35.3%
• 4 58.3%
• >= 5 >90.0%
• Emergent Management & Burn Center Transfer

Immediate Cessation of Culprit Drug : Prompt drug removal reduces mortality by approximately 30% per day of early withdrawal.

Emergent Transfer to a Burn Center or Surgical ICU : Patients with SJS/TEN overlap (>10% BSA detachment) or TEN (>30% BSA) must be transferred immediately to a specialized Burn Center or specialized ICU. Outcomes in burn units are vastly superior due to specialized reverse isolation, dedicated nursing, advanced non-adherent wound dressings, and infection control.

Supportive Critical Care :

Fluid and Electrolyte Resuscitation : Administer warmed isotonic intravenous crystalloids (titrated to maintain urine output 0.5-1.0 mL/kg/h); fluid requirements are approximately 2/3 of standard thermal burn Parkland formulas because capillary permeability is lower than in thermal injury;

Environmental Temperature : Maintain ambient room temperature at 30°C to 32°C to prevent hypothermia from extensive transcutaneous heat loss;

Wound Care : Strict avoidance of aggressive surgical debridement! Preserve the detached epidermal roof as a biologic dressing, covering denuded areas with non-adherent silicone or impregnated petrolatum dressings;

Immediate Ophthalmology Consultation : Daily bedside ophthalmologic examination, aggressive preservative-free lubrication, topical antibiotics, lysis of conjunctival symblepharon adhesions with glass rods, and early amniotic membrane transplantation within the first 7 to 10 days to preserve corneal architecture and prevent blindness.

Systemic Immunomodulatory Therapies : High-dose IVIG (blocking Fas-FasL interactions), Cyclosporine A (inhibiting cytotoxic T-cell activation), or Anti-TNF biologics (Etanercept). Systemic corticosteroids remain controversial in established TEN due to increased sepsis risk.

Erythema Multiforme: Herpes Simplex Association & Iris Target Lesions

Erythema Multiforme (EM) is an acute, immune-mediated, self-limited mucocutaneous condition characterized by distinctive "target" (iris) lesions. Historically conflated with SJS, EM is now recognized as an entirely distinct clinicopathologic disease.

Etiology: Infectious Dominance

Infections Account for >90% of Cases :

Herpes Simplex Virus (HSV-1 and HSV-2) is the primary trigger in >70% of cases of recurrent and acute EM ;

Mycoplasma pneumoniae is the second most common infectious trigger (particularly in children and young adults, often causing prominent mucosal disease termed MIRM: Mycoplasma-induced rash and mucositis );

Other infections: EBV, Histoplasma capsulatum, parapoxvirus.

Medications Trigger <10% of Cases : Unlike SJS/TEN, medications are an uncommon cause of true erythema multiforme.

Pathognomonic Target (Iris) Lesions

True individual target lesions are symmetric, regular, round, well-demarcated, and measure <3 cm in diameter , displaying three distinct concentric zones :

Central Dusky / Purpuric Zone : A dark red, purpuric, or necrotic center, often topped by a small vesicle or crust;

Intermediate Pale Edematous Ring : A raised, pale, edematous middle ring;

Outer Erythematous Border : A sharp, bright red, flat peripheral inflammatory halo.

Anatomical Distribution : Striking acral and extensor predilection : dorsum of the hands, palms, extensor forearms, elbows, soles of the feet, and face, arranged symmetrically. TRUE THREE-ZONED TARGET LESION (IRIS)

• (●) Outer Erythematous Halo
• ( ) Intermediate Pale Edematous Ring
• ( • ) Central Dusky / Purpuric Core
• Classification: EM Minor vs. EM Major

Erythema Multiforme Minor : Typical acral target lesions without mucosal involvement (or mild involvement of a single mucosal surface, usually the lips). Absence of systemic fever or prostration. Resolves spontaneously over 2 to 4 weeks.

Erythema Multiforme Major : Targetoid cutaneous lesions accompanied by severe mucosal involvement of two or more surfaces (oral, ocular, genital) and constitutional symptoms (fever, arthralgias).

Distinguishing EM Major from SJS :

In EM Major, cutaneous lesions are true three-zoned target lesions located predominantly on the acral extremities ;

In SJS, cutaneous lesions are flat, atypical, two-zoned dusky purpuric macules centered on the trunk and face ;

Epidermal Detachment : In EM Major, epidermal detachment is absent or <10% BSA , and there is no generalized epidermal sheet necrolysis .

Management of Erythema Multiforme

Symptomatic Relief : Mid- to high-potency topical corticosteroids for pruritic skin lesions; oral antihistamines; topical anesthetic/antiseptic mouthwashes (viscous lidocaine, diphenhydramine, aluminum hydroxide) for oral stomatitis.

Treating the Infectious Trigger : Oral acyclovir or valacyclovir does not alter the course of an established HSV-induced EM flare, but early antiviral therapy is indicated if active HSV lesions are present. Macrolide antibiotics (azithromycin) are indicated for Mycoplasma pneumoniae .

Suppressive Antiviral Prophylaxis for Recurrent EM : For patients with frequent, debilitating recurrences of HSV-associated EM (>=2 to 4 episodes per year), continuous daily oral suppressive antiviral therapy ( Valacyclovir 500 mg to 1,000 mg daily or Acyclovir 400 mg twice daily) for 6 to 12 months provides highly effective suppression.

Loading diagram... Algorithmic Differentiation of Cutaneous Drug Reactions and Rash Red Flags