What is the diagnosis for a 15-year-old male with rapid weight gain, generalized rash, edema, irritability, and fever, presenting with hyperthermia (elevated body temperature) and potential acute kidney injury?

Diagnosis: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome vs. Systemic-Onset Juvenile Idiopathic Arthritis (Still's Disease)

The most likely diagnosis in this 15-year-old male with rapid weight gain (edema), generalized rash, fever, and irritability is DRESS syndrome if he has recent medication exposure, or systemic-onset juvenile idiopathic arthritis (Still's disease) if no drug exposure is identified.

Immediate Diagnostic Priorities

Critical First Steps

• Obtain a detailed medication history immediately - DRESS syndrome has a mean lag time of 21 days (median 8 days) after drug initiation, and fever can take 1-7 days to resolve after discontinuing the offending agent 1
• Assess for life-threatening conditions requiring immediate intervention - petechial or purpuric rash patterns demand urgent evaluation for Rocky Mountain Spotted Fever or meningococcemia 2
• Examine rash characteristics and distribution - salmon-colored evanescent rash on trunk suggests Still's disease, while diffuse morbilliform rash with facial edema suggests DRESS syndrome 3, 4

Essential Laboratory Workup

• Complete blood count with differential - look for eosinophilia (DRESS), neutrophilic leukocytosis (Still's disease), or leukopenia (drug reaction, viral infection) 5, 3, 4
• Comprehensive metabolic panel with liver function tests - elevated transaminases occur in both DRESS syndrome and Still's disease 3, 4, 6
• Inflammatory markers - markedly elevated ESR and CRP support Still's disease diagnosis 3
• Serum ferritin, IL-18, and/or S100 proteins - extremely elevated ferritin supports Still's disease 3
• Urinalysis and urine culture (catheterized specimen) - to evaluate for acute kidney injury and rule out urinary tract infection 5
• Blood cultures before any antibiotics - to exclude bacterial infection 5, 2

Differential Diagnosis Framework

DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)

Key features:

• Facial edema with diffuse erythematous rash 4
• Eosinophilia and eosinophiluria 4
• Acute renal insufficiency 4
• Elevated liver transaminases 4, 6
• Fever typically 101-103°F 4
• Rash and eosinophilia are uncommon in simple drug fever, making DRESS more likely if present 1

Common offending agents: Antibiotics (especially beta-lactams, vancomycin), anticonvulsants, allopurinol 4, 6

Systemic-Onset Juvenile Idiopathic Arthritis (Still's Disease)

Key features per 2024 EULAR/PReS guidelines:

• Daily high-spiking fever ≥39°C (102.2°F) for at least 7 days 3
• Salmon-colored evanescent rash, preferentially on trunk 3
• Arthritis/arthralgia (though arthritis is NOT mandatory for diagnosis) 3
• Markedly elevated inflammatory markers (ESR, CRP) 3
• Extremely elevated ferritin, IL-18, or S100 proteins 3
• Neutrophilic leukocytosis and thrombocytosis 3

Critical pitfall: Do not delay diagnosis while waiting for arthritis to develop - this leads to unnecessary and potentially deleterious diagnostic delays 3

Other Considerations to Exclude

Acute HIV seroconversion:

• Fever, rash, pharyngitis, lymphadenopathy, oral ulcers 7
• Leukopenia and thrombocytopenia 7
• Initial HIV serology is usually negative; diagnosis requires HIV RNA viral load or DNA PCR 7
• Consider if history of unprotected sexual activity 7

Atypical measles:

• Can present with severe symptoms in adolescents despite prior immunization 8
• Requires serologic confirmation 8

Kawasaki Disease:

• Requires fever ≥5 days plus 4 of 5 criteria: bilateral conjunctival injection, oral mucosal changes, polymorphous rash, extremity changes, cervical lymphadenopathy ≥1.5 cm 5
• Urgent echocardiography needed if suspected 5
• This patient's presentation does NOT fit Kawasaki disease - the salmon-colored rash is characteristic of Still's disease, not Kawasaki 3

Staphylococcal toxic shock:

• Sustained low diastolic blood pressure unresponsive to fluids 9
• Look for occult abscess (pilonidal, perirectal) 9

Management Algorithm

If DRESS Syndrome is Suspected:

1. Immediately discontinue all potentially offending medications 1, 4
2. Initiate high-dose intravenous corticosteroids - this led to rapid improvement in documented cases 4
3. Provide aggressive supportive care - IV fluids, monitor renal function, manage hypotension if present 4
4. Monitor for clinical deterioration - DRESS can present as life-threatening multiorgan failure 4

If Still's Disease is Suspected:

1. Apply Yamaguchi criteria for classification - validated with high sensitivity, does not require arthritis 3
2. Exclude alternative diagnoses - malignancies, infectious diseases, other immune-mediated diseases must be carefully ruled out 3
3. Monitor for macrophage activation syndrome (MAS) - a life-threatening complication that can occur at onset, during treatment, or in remission 3
4. Initiate appropriate immunosuppressive therapy per rheumatology consultation 3

Red Flags Requiring Immediate Hospitalization:

• Petechial or purpuric rash pattern 2
• Rash involving palms and soles 2
• Hypotension or signs of shock 2, 4
• Progressive clinical deterioration 2
• Altered mental status 2
• Thrombocytopenia 2

Critical Clinical Pearls

Weight gain represents fluid retention (edema), not true weight gain - this indicates systemic inflammation with capillary leak or renal involvement 4

Irritability in adolescents with fever and rash warrants careful neurologic assessment - consider central nervous system involvement, especially if altered mental status develops 1, 2

The 2-pound weight gain over 6 days (approximately 1 kg) represents significant fluid accumulation - this degree of edema suggests either drug-induced hypersensitivity with capillary leak or systemic inflammatory disease 4

Do not assume viral infection explains all findings - the presence of one viral infection does not preclude coexisting bacterial infection or drug reaction 5, 6