What is the appropriate evaluation and management for an adult presenting with a stiff neck, markedly elevated serum ferritin (~880 µg/L) and high‑sensitivity C‑reactive protein (~7 mg/L)?

Evaluation and Management of Stiff Neck with Elevated Ferritin and CRP

In an adult presenting with stiff neck, ferritin ~880 µg/L, and high-sensitivity CRP ~7 mg/L, the priority is to rule out bacterial meningitis immediately with lumbar puncture, then systematically evaluate for adult-onset Still's disease, occult infection, malignancy, and inflammatory conditions—because this constellation can represent life-threatening disease requiring urgent intervention.

Immediate Life-Threatening Considerations

Bacterial Meningitis Evaluation

• Perform lumbar puncture urgently if no contraindications exist (papilledema, focal neurologic deficits, coagulopathy, or overlying skin infection). 1
• CRP ~7 mg/L is moderately elevated but not sufficiently high to exclude bacterial meningitis; in one study, bacterial meningitis presented with CRP 21.7 mg/dL, while aseptic meningitis showed CRP 0.2 mg/dL (median). 1
• Stiff neck (nuchal rigidity) is a cardinal sign of meningeal irritation and mandates CSF analysis to differentiate bacterial from aseptic causes. 1
• If bacterial meningitis is confirmed, initiate empiric antibiotics immediately (ceftriaxone 2 g IV q12h + vancomycin 15–20 mg/kg IV q8–12h, with dexamethasone 10 mg IV q6h if pneumococcal meningitis suspected).

Adult-Onset Still's Disease (AOSD)

• Ferritin 880 µg/L is below the typical AOSD threshold (usually 4,000–30,000 ng/mL, occasionally up to 250,000 ng/mL), making AOSD less likely but not excluded. 2
• If ferritin rises above 4,000–5,000 ng/mL with persistent fever, measure glycosylated ferritin fraction; values <20% have 93% specificity for AOSD when combined with 5-fold ferritin elevation. 2, 3
• AOSD classically presents with quotidian fever (daily spiking fever), salmon-pink evanescent rash, arthralgia/arthritis, and sore throat. 2
• Serum ferritin correlates with disease activity in AOSD and often normalizes with remission. 2

Hemophagocytic Lymphohistiocytosis (HLH) / Macrophage Activation Syndrome (MAS)

• Consider HLH/MAS if ferritin >5,000 ng/mL with cytopenias, fever, and multiorgan dysfunction. 3
• Screen for splenomegaly, elevated triglycerides, low fibrinogen, and elevated soluble IL-2 receptor. 4
• HLH/MAS can present with markedly elevated ferritin (often >10,000 µg/L) and requires urgent hematology consultation. 4

Systematic Diagnostic Algorithm

Step 1: Rule Out Infection

• Blood cultures × 2 sets before antibiotics to identify bacteremia or endocarditis. 3
• Chest X-ray to exclude pneumonia as a source of systemic inflammation. 3
• Urinalysis and urine culture to rule out pyelonephritis or complicated UTI. 3
• Consider HIV, hepatitis B/C, and tuberculosis screening if risk factors present, as chronic infections elevate ferritin. 3

Step 2: Evaluate for Malignancy

• Malignancy is the most common cause of ferritin >1,000 µg/L in tertiary-care settings (153/627 cases in one series). 5
• Order complete blood count with differential to assess for leukemia, lymphoma, or myelodysplastic syndrome. 3
• Peripheral blood smear to identify abnormal cells (blasts, atypical lymphocytes). 3
• Lactate dehydrogenase (LDH) is often elevated in hematologic malignancies and tissue necrosis. 3
• CT chest/abdomen/pelvis if solid tumor suspected (lung, renal, hepatocellular carcinoma). 3

Step 3: Assess for Inflammatory/Rheumatologic Disease

• Erythrocyte sedimentation rate (ESR) to complement CRP; both are elevated in inflammatory conditions. 3
• Antinuclear antibody (ANA), rheumatoid factor (RF) to screen for systemic lupus erythematosus or rheumatoid arthritis. 3
• Anti-neutrophil cytoplasmic antibody (ANCA) if vasculitis suspected; serum ferritin is a superior biomarker for disease activity in ANCA-associated vasculitis compared to CRP. 6
• Complement levels (C3, C4) may be low in active lupus or cryoglobulinemic vasculitis. 3

Step 4: Liver Disease Evaluation

• Comprehensive metabolic panel (AST, ALT, alkaline phosphatase, bilirubin, albumin) to assess hepatocellular injury. 2, 3
• Abdominal ultrasound to evaluate for hepatomegaly, fatty liver, or cirrhosis. 3
• Liver disease (alcoholic, viral hepatitis, NAFLD) is a common cause of hyperferritinemia. 3

Step 5: Iron Overload Assessment

• Transferrin saturation (TS) is the single most important test to determine if iron overload is present. 3
• If TS ≥45%, suspect primary iron overload and proceed with HFE genetic testing for C282Y and H63D mutations. 3
• If TS <45%, iron overload is unlikely; ferritin elevation is secondary to inflammation, liver disease, or malignancy. 3
• Ferritin 880 µg/L with TS <45% strongly suggests secondary hyperferritinemia rather than hereditary hemochromatosis. 3

Interpretation of Current Laboratory Values

Ferritin 880 µg/L

• Ferritin is an acute-phase reactant that rises during inflammation, infection, liver disease, and malignancy independent of iron stores. 3
• Ferritin <1,000 µg/L has a 94% negative predictive value for advanced liver fibrosis in hemochromatosis patients. 3
• Common causes of ferritin 880 µg/L include chronic alcohol consumption, inflammation, cell necrosis, tumors, and NAFLD/metabolic syndrome (>90% of cases). 3

High-Sensitivity CRP 7.19 mg/L

• CRP ~7 mg/L indicates moderate systemic inflammation but is nonspecific. 3
• In bacterial meningitis, CRP is typically much higher (21.7 mg/dL in one case), while aseptic meningitis shows CRP 0.2 mg/dL (median). 1
• CRP elevation combined with ferritin 880 µg/L is strongly suggestive of secondary hyperferritinemia from inflammation or metabolic causes. 3

Management Strategy

If Bacterial Meningitis Confirmed

• Continue empiric antibiotics (adjust based on CSF culture and sensitivities). 1
• Dexamethasone 10 mg IV q6h for 4 days if pneumococcal meningitis. 1
• Monitor for complications (cerebral edema, seizures, hydrocephalus). 1

If AOSD Suspected (Ferritin Rising >4,000 ng/mL)

• Measure glycosylated ferritin fraction; <20% is 93% specific for AOSD. 2, 3
• Initiate high-dose corticosteroids (prednisone 1 mg/kg/day or methylprednisolone 1 g IV daily × 3 days). 2
• Consider IL-1 inhibitors (anakinra) or IL-6 inhibitors (tocilizumab) if steroid-refractory. 2

If HLH/MAS Suspected (Ferritin >5,000 ng/mL)

• Urgent hematology/oncology consultation for HLH-2004 diagnostic criteria evaluation. 4
• Consider rabbit anti-thymocyte globulin (ATG) if steroids and cyclosporine fail. 4

If Secondary Hyperferritinemia (TS <45%)

• Treat the underlying condition (e.g., weight loss for NAFLD, antibiotics for infection, chemotherapy for malignancy). 3
• Do not initiate phlebotomy or iron chelation unless TS ≥45% confirms iron overload. 3

Critical Pitfalls to Avoid

• Never assume stiff neck is benign without ruling out bacterial meningitis via lumbar puncture. 1
• Do not diagnose iron overload based on ferritin alone; transferrin saturation ≥45% is required. 3
• Do not overlook AOSD if ferritin continues rising or exceeds 4,000–5,000 ng/mL with persistent fever; measure glycosylated ferritin fraction. 2, 3
• Do not miss HLH/MAS if ferritin >5,000 ng/mL with cytopenias, fever, and multiorgan dysfunction; this is a medical emergency. 3, 4
• Do not delay malignancy screening in patients ≥50 years or with alarm symptoms (weight loss, night sweats, lymphadenopathy). 5