What is the differential diagnosis for a 16-year-old patient with a recent history of fever, subsequent development of a non-painful, non-itchy rash, and negative tests for Coronavirus Disease 2019 (COVID-19), influenza (flu), and a negative chest X-ray?

Differential Diagnosis for a 16-Year-Old with Post-Febrile Non-Painful, Non-Itchy Rash

The most critical diagnosis to exclude in this adolescent is Multisystem Inflammatory Syndrome in Children (MIS-C), which presents with fever followed by a non-pruritic rash 2-6 weeks after SARS-CoV-2 exposure, even with negative acute COVID-19 testing. 1

Immediate Priority: Rule Out Life-Threatening Conditions

Multisystem Inflammatory Syndrome in Children (MIS-C)

• MIS-C occurs 2-6 weeks after peak COVID-19 incidence and can present with negative acute COVID-19 PCR testing but positive serology 1
• The rash is typically polymorphic, maculopapular, or petechial (not vesicular) and non-pruritic 1
• Critical screening labs needed immediately: CBC with differential, CMP, ESR, CRP, troponin, BNP, and SARS-CoV-2 serology (IgG, IgM, IgA) 1
• Red flags requiring urgent evaluation: gastrointestinal symptoms (diarrhea, abdominal pain, vomiting), conjunctivitis without exudate, oral mucosal changes (red/cracked lips, strawberry tongue), or any cardiac symptoms 1
• High-risk laboratory findings: platelet count <150,000/µL, absolute lymphocyte count <1,000/µL, ESR >240 mm/hour, elevated troponin or BNP, sodium <135 mmol/L 1, 2

Bacterial Sepsis/Meningococcemia

• Petechial or purpuric rash with fever requires immediate blood cultures and empiric antibiotics 3
• Even with defervescence, bacterial causes can present with delayed rash 1

Viral Exanthems (Most Common in This Age Group)

Other Respiratory Viral Infections

• Parainfluenza, adenovirus, respiratory syncytial virus, or metapneumovirus can present with fever followed by maculopapular rash 1
• These viruses present with similar clinical features to COVID-19/influenza but were not tested in this patient 1

Enteroviral Infections

• Common in adolescents, presenting with fever followed by maculopapular rash 3-5 days later 3
• Typically self-limited with non-specific systemic symptoms 3

Epstein-Barr Virus (EBV)/Infectious Mononucleosis

• Classic presentation: fever, fatigue, pharyngitis followed by maculopapular rash 3
• Rash may appear spontaneously or after antibiotic administration 3

Parvovirus B19 (Fifth Disease)

• "Slapped cheek" appearance followed by lacy reticular rash on trunk/extremities 3
• Fever typically resolves before rash appears 3

Atypical Bacterial Infections

Mycoplasma pneumoniae

• Classic presentation in adolescents: fever, headache, arthralgias, progressive cough, with possible maculopapular rash 4
• Chest X-ray may show reticular shadows despite negative initial imaging 1
• Mycoplasma-specific IgM testing is diagnostic 1
• Can cause Stevens-Johnson syndrome as severe dermatological complication 4

Scarlet Fever (Group A Streptococcus)

• Sandpaper-textured erythematous rash with fever, sore throat 3
• Requires throat culture and rapid strep testing 3

Drug Reaction

Drug-Induced Exanthem

• Maculopapular rash appearing 7-14 days after medication initiation 3
• Review any medications started in the week before fever onset, including over-the-counter medications 3

COVID-19 Related Manifestations

Direct COVID-19 Cutaneous Manifestations

• Maculopapular rash occurs in COVID-19 patients and may be the initial or only manifestation 5, 6
• Rash patterns include maculopapular (most common), urticarial, vesicular, chilblain-like, livedoid, and petechial lesions 5
• False-negative COVID-19 PCR testing is common (sensitivity 60-78%), especially with timing relative to symptom onset 7
• Consider repeat COVID-19 PCR and serology testing 7

Recommended Diagnostic Workup

Tier 1 - Immediate Labs

• CBC with differential, CMP, ESR, CRP 1, 2
• SARS-CoV-2 serology (IgG, IgM, IgA) - critical since acute PCR was negative 1, 7
• Blood cultures if patient appears ill 3
• Troponin and BNP if any cardiac symptoms or MIS-C concern 1

Tier 2 - Based on Initial Results

• Mycoplasma pneumoniae IgM if respiratory symptoms present 1, 4
• EBV serology (VCA IgM/IgG, heterophile antibody) if pharyngitis/fatigue 3
• Respiratory viral panel for parainfluenza, adenovirus, RSV, metapneumovirus 1
• Parvovirus B19 IgM if characteristic rash pattern 3
• Throat culture/rapid strep if pharyngitis present 3

Critical Pitfall to Avoid

Do not dismiss this as a benign viral exanthem without excluding MIS-C, as this condition can rapidly progress to myocardial dysfunction, shock, and coronary artery aneurysms despite initially mild presentation. 1 The negative acute COVID-19 test does not exclude MIS-C, which typically occurs weeks after initial infection when PCR is negative but serology is positive 1