What are the differential diagnoses for a 14-year-old female with enteritis, joint pain, markedly elevated C-Reactive Protein (CRP), and a history of seizure?

Differential Diagnoses for a 14-Year-Old Female with Enteritis, Joint Pain, Markedly Elevated CRP (>300 mg/L), and Seizure

The combination of enteritis, arthritis, extremely elevated CRP (>300 mg/L), and seizure in an adolescent female most urgently suggests Crohn's disease with extraintestinal manifestations, but also requires immediate exclusion of systemic lupus erythematosus (SLE) with CNS involvement, intestinal lymphoma, Whipple disease, and chronic active EBV infection-associated enteritis.

Priority Life-Threatening Differentials Requiring Immediate Workup

Crohn's Disease with Extraintestinal Manifestations

• Crohn's disease presents with enteritis and elevated CRP, and is specifically associated with inflammatory arthritis (enteropathic arthritis). 1
• The markedly elevated CRP (>300 mg/L) is consistent with severe active Crohn's disease, as CRP correlates well with clinical disease activity in Crohn's disease 2
• Seizures can occur as a rare extraintestinal manifestation of inflammatory bowel disease, related to cerebral vasculitis, venous thrombosis, or metabolic derangements 1
• Immediate colonoscopy with biopsy is essential to look for aphthous ulceration, skip lesions, and granulomas 1

Systemic Lupus Erythematosus (SLE) with CNS Lupus

• SLE can present with enteritis (lupus enteritis/mesenteric vasculitis), inflammatory arthritis, markedly elevated inflammatory markers, and neuropsychiatric manifestations including seizures
• Obtain ANA, anti-dsDNA, complement levels (C3, C4), complete blood count looking for cytopenias, and urinalysis for proteinuria/hematuria immediately 3
• This is a medical emergency if CNS lupus is present, requiring urgent immunosuppression

Intestinal Lymphoma

• Intestinal lymphoma presents with enteritis, abdominal pain, fever, weight loss, and can have systemic manifestations including seizures from CNS involvement or metabolic derangements 1
• The extremely elevated CRP (>300 mg/L) is consistent with lymphoproliferative disorders 1
• Obtain CT scan of abdomen/pelvis, capsule endoscopy if safe, PET scan, and urgent hematology consultation 1
• Histology showing monoclonal T-cell population confirms diagnosis 1

Chronic Active EBV Infection-Associated Enteritis (CAEAE)

• CAEAE presents with fever, enteritis with intestinal ulcers, elevated inflammatory markers (WBC and CRP commonly elevated), and can have neurological manifestations 4
• This condition has a 63.6% mortality rate within 6 months and is frequently misdiagnosed as inflammatory bowel disease 4
• Obtain serum EBV DNA load, and ensure intestinal biopsies are tested for EBV-encoded small nuclear RNA (EBER) via in situ hybridization 4
• The average serum EBV DNA load in CAEAE is 6.3 × 10^5 copies/mL 4

Additional Critical Differentials

Whipple Disease

• Whipple disease classically presents with joint inflammation (often preceding GI symptoms), enteritis, and can have CNS manifestations including seizures 1
• Histology shows PAS-positive macrophagic infiltration of the lamina propria 1
• Obtain PCR for Tropheryma whipplei from intestinal biopsy and consider CSF analysis if CNS involvement suspected 1

Autoimmune Enteropathy

• Presents with intractable diarrhea, weight loss, and can have systemic autoimmune features 1
• Histology shows few intraepithelial lymphocytes, lymphoplasmacytic infiltrate, decreased goblet cells, and neutrophilic cryptitis 1
• Test for anti-enterocyte antibodies 1

Tuberculosis (Intestinal TB)

• Can present with enteritis, systemic inflammation with markedly elevated CRP, and CNS involvement (tuberculous meningitis causing seizures) 1
• Obtain interferon-gamma release assay, chest CT, and if ascites present, perform ascitic fluid analysis 1
• Histology shows granulomatous disease 1

Common Variable Immunodeficiency (CVID)

• Presents with recurrent infections, persistent diarrhea, and onset after age 2 years 1
• Measure immunoglobulin levels: IgG <5 g/L plus low IgA or IgM confirms diagnosis 1
• Histology shows absence of plasma cells and polymorphonuclear infiltrate 1

Essential Immediate Workup (Within 24-48 Hours)

Laboratory Testing

• Complete blood count with differential, comprehensive metabolic panel, ESR, blood cultures if febrile 3
• Serum immunoglobulin levels (IgG, IgA, IgM) 1
• ANA, anti-dsDNA, RF, anti-CCP antibodies, complement levels (C3, C4) 1, 3
• EBV serology and EBV DNA load 4
• Interferon-gamma release assay for tuberculosis 1
• HIV antibody test 1
• Fecal calprotectin or lactoferrin 1

Imaging

• CT abdomen/pelvis with contrast to evaluate for intestinal inflammation, lymphadenopathy, masses, or complications 1
• MRI brain with and without contrast to evaluate seizure etiology and rule out CNS vasculitis, lymphoma, or tuberculoma

Endoscopic Evaluation

• Urgent colonoscopy with ileoscopy and multiple biopsies from affected and unaffected areas 1
• Ensure biopsies are sent for routine histology, EBER in situ hybridization, PCR for Tropheryma whipplei, and mycobacterial culture 1, 4

Critical Clinical Pitfalls

Do Not Assume Inflammatory Bowel Disease Without Excluding Mimics

• The combination of extremely elevated CRP (>300 mg/L) with seizures is atypical for uncomplicated IBD and mandates broader differential consideration 2
• CAEAE is frequently misdiagnosed as IBD, leading to delayed diagnosis and high mortality 4

Recognize CRP >300 mg/L Indicates Severe Systemic Inflammation

• CRP >100 mg/L typically indicates bacterial infection or severe inflammatory disease, not simple IBD flare 5
• This level of elevation (>300 mg/L) should prompt consideration of lymphoma, severe infection, or systemic vasculitis 1, 5

Do Not Delay Rheumatology Consultation

• If joint swelling (synovitis) is present or symptoms persist >4 weeks, early rheumatology referral is essential 1
• Seronegative inflammatory arthritis associated with enteritis (enteropathic arthritis) requires specialized evaluation 3

Ensure Adequate Biopsy Sampling and Special Stains

• Standard histology alone may miss CAEAE, Whipple disease, or lymphoma—specifically request EBER in situ hybridization, PAS staining, and T-cell receptor gene rearrangement studies 1, 4

Monitoring Strategy

• Serial CRP measurements every 2-4 weeks to assess trend and response to any interventions 3, 6
• If CRP remains persistently elevated despite clinical improvement, this warrants further investigation for occult infection, malignancy, or ongoing inflammation 3, 6
• In inflammatory bowel disease specifically, normalization of CRP suggests endoscopic improvement, while persistent elevation despite symptomatic remission requires repeat measurement in 3-6 months before invasive testing 6