What are the potential causes and treatment options for a macular papular rash?

Maculopapular Rash: Causes and Treatment

Immediate Life-Threatening Causes to Rule Out First

Begin by excluding severe cutaneous adverse reactions (SCARs) that require immediate drug discontinuation and hospitalization: Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Acute Generalized Exanthematous Pustulosis (AGEP) 1. Look specifically for tiny vesicles or crusts, grey-violaceous or dusky color of lesions, painful or burning skin with fever and malaise, hemorrhagic erosions of mucous membranes, skin detachment, exanthema with pustules, purpura, or facial edema with acute fever ≥38.5°C 1.

Critical Warning Signs

• Mucosal involvement (oral, ocular, genital erosions) indicates SJS/TEN 1
• Progression >50% body surface area with abnormal liver/kidney parameters suggests DRESS 1
• Palms and soles involvement raises concern for Rocky Mountain Spotted Fever (RMSF), secondary syphilis, or meningococcemia 1, 2
• Petechial progression from initial maculopapular rash indicates possible meningococcemia or RMSF 1

Common Infectious Causes

Viral Etiologies

Maculopapular rashes occur with multiple viral infections, distinguished by associated symptoms 1:

• Adenovirus (Pharyngoconjunctival Fever): Fever, pharyngitis with tonsillar exudates, bilateral conjunctivitis, and periauricular lymphadenopathy 3. Self-limited, resolving in 5-14 days 3.
• Human herpesvirus 6 (Roseola): Typically in young children with high fever followed by rash as fever breaks 1
• Parvovirus B19: "Slapped cheek" appearance in children, lacy reticular rash on extremities 1
• Enteroviral infections (Coxsackievirus, Echovirus): Summer/fall seasonality, may have hand-foot-mouth features 1
• Epstein-Barr virus: Associated with pharyngitis, lymphadenopathy, splenomegaly; rash exacerbated by amoxicillin/ampicillin 1

Bacterial Causes

• Rocky Mountain Spotted Fever: High fever, severe headache, myalgias with rapid onset; rash begins on wrists/ankles and spreads centrally, involving palms/soles in 50% of cases late in disease 1. This progresses rapidly to petechial rash and can cause death within 24 hours if untreated 1.
• Secondary syphilis: Involves palms and soles, associated with lymphadenopathy and mucous patches 1, 4
• Leptospirosis: Exposure to contaminated water, conjunctival suffusion 1
• Disseminated gonococcal infection: Migratory polyarthritis with sparse skin lesions 1

Tickborne Rickettsial Diseases

When fever, severe headache, and myalgias accompany maculopapular rash with tick exposure history, obtain complete blood count showing thrombocytopenia, comprehensive metabolic panel showing hyponatremia, and elevated hepatic transaminases 1. Start empiric doxycycline immediately without waiting for confirmatory testing if RMSF is suspected 1.

Drug-Induced Maculopapular Exanthema

Drug reactions are among the most common causes of maculopapular rash 5, 4. The cytokine pattern shows Th1 predominance with CD4 T-lymphocyte involvement 5.

High-Risk Medications

• Antibiotics: Clindamycin 6, neomycin (5-15% sensitization rate) 1, sulfonamides 1
• Anticonvulsants: Phenytoin, barbiturates 1
• Chemotherapy agents: Enzalutamide (appears 3 days after initiation, Grade 2 by CTCAE criteria) 7
• Topical agents: Neomycin causes maculopapular and eczematous eruption on conchal bowl and ear canal 1

Management of Drug-Induced Rash

For Grade 2 reactions (covering <30% body surface area without systemic symptoms): Discontinue the offending drug, administer oral antihistamines, and consider topical corticosteroids 7. For enzalutamide-induced rash specifically, withhold drug for 10-14 days until complete resolution, then reinitiate 7. For severe reactions (Grade 3-4), start prednisone 1-2 mg/kg/day and permanently discontinue the drug 1.

Immune-Mediated and Autoimmune Causes

• Kawasaki disease: Bilateral nonexudative conjunctivitis without discharge, fever >5 days, oral mucosal changes, cervical lymphadenopathy 1, 3
• Still's disease: Salmon-pink evanescent rash, high spiking fevers, arthritis 4
• Sarcoidosis: Papular lesions, hilar lymphadenopathy, systemic involvement 4
• Behçet's disease: Pustular rash, oral/genital ulcers, uveitis 4

Immune Checkpoint Inhibitor-Related Rash

Maculopapular rash occurs in 30-40% of patients on PD-1/PD-L1 inhibitors and 50% on ipilimumab 1. Onset typically within days to weeks, though can be delayed months 1.

Treatment Algorithm by Grade

• Grade 1: Continue immunotherapy, topical corticosteroids as needed 1
• Grade 2: Hold immunotherapy, start oral prednisone 0.5-1 mg/kg/day; if no improvement in 2-3 days, increase to 2 mg/kg/day; resume immunotherapy once resolved to Grade 1 and off corticosteroids 1
• Grade 3: Hold immunotherapy, start prednisone 1-2 mg/kg/day; if no improvement in 2-3 days, add alternative immunosuppressant; discontinue immunotherapy if no improvement in 4-6 weeks 1
• Grade 4: Permanently discontinue immunotherapy, start IV methylprednisolone 1-2 mg/kg/day 1

Add PCP prophylaxis if >3 weeks of immunosuppression expected (>30 mg prednisone daily) and proton pump inhibitor for GI prophylaxis 1.

Topical Treatment for Non-Severe Cases

For minor skin irritations and rashes without systemic involvement: Apply hydrocortisone cream to affected area 3-4 times daily 8. In adults and children ≥2 years, this provides symptomatic relief for eczema, psoriasis, contact dermatitis, insect bites, and seborrheic dermatitis 8. Clean the affected area with mild soap and warm water before application 8.

Critical Diagnostic Pitfalls to Avoid

• Never assume bilateral conjunctivitis with rash is benign viral infection without examining for corneal involvement with fluorescein staining 3
• Do not miss meningococcemia which begins as maculopapular rash and progresses more rapidly to petechial rash than RMSF 1
• Consider sexual abuse in children with gonococcal or chlamydial conjunctivitis 3
• Recognize Koebner phenomenon where drug-induced rashes preferentially involve areas of trauma, including striae distensae, surgical scars, or pressure points 6
• Distinguish urticarial from macular rash: Urticarial lesions are raised, palpable, blanching, and individual wheals last 2-24 hours before moving to different locations; macular rashes are flat, persist longer in the same location, and may evolve through color changes 2