What is the most likely diagnosis and immediate next step for a painful nodule that developed two weeks after an intramuscular injection, without erythema, warmth, fever, fluctuance, or neurologic deficits?

Most Likely Diagnosis and Immediate Management

The most likely diagnosis is a benign post-injection granuloma (sterile inflammatory nodule), and the immediate next step is conservative observation with reassurance, as most lesions resolve spontaneously over 3-6 months without intervention. 1

Clinical Reasoning

The presentation of a painful nodule appearing 2 weeks after intramuscular injection, without signs of infection (no erythema, warmth, fever, or fluctuance), strongly suggests a benign post-injection granuloma rather than an infectious process or severe complication. 1, 2, 3

Key Distinguishing Features

• Timing supports benign etiology: Early implant nodules typically appear 2-4 weeks after injection, which matches this presentation exactly 4
• Absence of infection markers: The lack of erythema, warmth, fever, or fluctuance effectively rules out abscess formation or bacterial infection 5
• Pain alone is common: Pain at the injection site is a well-documented, frequent reaction to intramuscular injections that does not necessarily indicate a serious complication 2, 3

Critical Differential to Exclude: Nicolau Syndrome

While the presentation could theoretically represent early Nicolau syndrome (embolia cutis medicamentosa), several features make this unlikely:

• Nicolau syndrome presents acutely: Symptoms typically begin immediately or within hours of injection with severe pain, followed rapidly by livid discoloration, livedoid dermatitis, and tissue necrosis 6, 7, 8
• This patient lacks the characteristic progression: No mention of immediate severe pain, purplish network discoloration, or skin necrosis at 2 weeks 6, 7
• Nicolau syndrome is rare: It results from unintentional intra-arterial injection causing ischemic necrosis, not a delayed inflammatory response 8

Immediate Management Algorithm

Step 1: Conservative Observation (First-Line)

For nodules <3 cm without infection signs, adopt a watch-and-wait approach without immediate treatment. 1

• Most post-injection nodules resolve gradually over 3-6 months without intervention 1
• Provide patient reassurance that this represents a benign, self-limited inflammatory reaction 1
• Schedule follow-up in 4-6 weeks to assess for resolution or progression 1

Step 2: Symptomatic Relief

• Apply ice to the affected area for symptomatic pain relief 3
• Consider oral NSAIDs (if no contraindications) for pain management 5, 2
• Avoid manipulation or aspiration at this stage, as most lesions resolve spontaneously 1

Step 3: Monitor for Red Flags Requiring Escalation

Reassess immediately if any of the following develop:

• Signs of infection: Erythema, warmth, fever, fluctuance, or purulent drainage would indicate abscess formation requiring drainage and antibiotics 5
• Rapid progression to necrosis: Development of livid discoloration, skin necrosis, or severe worsening pain would suggest Nicolau syndrome requiring urgent surgical consultation and debridement 6, 7, 8
• Nodule enlargement >3 cm or persistence >6 months: Consider biopsy to exclude rare complications like injection granuloma mimicking soft tissue sarcoma 9

Common Pitfalls to Avoid

Pitfall 1: Premature Surgical Intervention

• Do not rush to surgical excision: Foreign body granulomas grow fingerlike into surrounding tissue, making surgery technically difficult and potentially disfiguring 4
• Surgery should be reserved as a last option after failed conservative management 4

Pitfall 2: Misdiagnosing as Infection

• The presence of pain alone does not indicate infection 2, 3
• Nodule or furuncle formation may indicate localized infection, but only if accompanied by warmth, erythema, or systemic signs 3
• Unnecessary antibiotics or drainage of sterile nodules can worsen outcomes 1

Pitfall 3: Overlooking Vaccine-Related Adenopathy

• If this injection was a vaccine (particularly COVID-19 or influenza), regional adenopathy can occur and persist for weeks 5, 9
• Vaccine-related nodules typically manifest within 2-4 days and last 1-2 days to 10 days, though granulomas can persist longer 5, 9

When to Consider Advanced Treatment

If the nodule persists beyond 3-6 months or causes significant functional impairment, consider:

• Intralesional corticosteroid injection: Triamcinolone, betamethasone, or prednisolone injected directly into the lesion in 4-week cycles until resolution 4
• Combination therapy: Corticosteroids combined with 5-fluorouracil to lower the risk of skin atrophy 4
• Biopsy: If diagnostic uncertainty persists or malignancy cannot be excluded clinically 9

Prevention for Future Injections

• Use appropriately sized needles (1-1.5 inches for adult gluteal injections) to ensure true intramuscular delivery 1
• Administer injections in the upper outer quadrant of the gluteus maximus to avoid sciatic nerve injury 1
• Apply the subcutaneous-fat-pinch technique when indicated to confirm proper depth 1
• Rotate injection sites systematically 2