What are the possible non‑infectious and atypical causes of persistent right‑lower‑quadrant pain, vomiting, and diarrhea in a young woman with normal CRP and white‑cell count despite courses of trimethoprim‑sulfamethoxazole, amoxicillin, and ciprofloxacin?

Differential Diagnosis of Persistent Right Lower Quadrant Pain with Normal Inflammatory Markers

In a young woman with persistent right lower quadrant pain, vomiting, and diarrhea despite multiple antibiotic courses and consistently normal CRP/WBC, the most likely diagnoses are non-infectious causes including gynecologic pathology (ovarian torsion, ruptured cyst, ectopic pregnancy), early or grumbling appendicitis, inflammatory bowel disease (particularly Crohn's disease), or functional disorders—and immediate CT abdomen/pelvis with IV contrast is the definitive next step.

Critical Clinical Context

The failure to respond to broad-spectrum antibiotics (trimethoprim-sulfamethoxazole, amoxicillin, ciprofloxacin) combined with persistently normal inflammatory markers strongly argues against typical bacterial infection. 1

Key diagnostic pitfall: Fever is absent in approximately 50% of appendicitis cases, and normal WBC/CRP do not exclude appendicitis, particularly in early presentations. 2 Clinical assessment alone misdiagnoses appendicitis in 34-68% of cases. 2

Immediate Diagnostic Algorithm

Step 1: Exclude Pregnancy-Related Emergency

• Obtain quantitative β-hCG immediately before any imaging in a reproductive-age woman to exclude ectopic pregnancy, which can present with right lower quadrant pain and gastrointestinal symptoms. 2

Step 2: Definitive Imaging

• Order CT abdomen and pelvis with IV contrast (no oral contrast needed) as the single most appropriate diagnostic test. 1, 2, 3
• CT achieves 85.7-100% sensitivity and 94.8-100% specificity for appendicitis while simultaneously identifying alternative diagnoses in 23-45% of patients presenting with right lower quadrant pain. 2, 3
• CT identifies gynecologic pathology in approximately 21.6% of cases and gastrointestinal conditions in 46% of alternative diagnoses. 2

Step 3: Alternative Imaging if Radiation Avoidance Desired

• In reproductive-age women where radiation exposure is a concern, start with transvaginal ultrasound (rated "appropriate" by ACR), then proceed to CT if nondiagnostic. 2
• A staged ultrasound-then-CT algorithm achieves 99% sensitivity and 91% specificity for appendicitis. 2

Non-Infectious Differential Diagnoses to Consider

Gynecologic Causes (High Priority in Young Women)

• Ovarian torsion: Can present with intermittent pain, vomiting, and normal inflammatory markers; requires urgent surgical intervention. 3
• Ruptured ovarian cyst or hemorrhagic cyst: May cause peritoneal irritation mimicking appendicitis. 3
• Ectopic pregnancy: Must be excluded first with β-hCG. 2, 3
• Pelvic inflammatory disease: Though typically associated with elevated inflammatory markers, early or atypical presentations may not show leukocytosis. 3

Gastrointestinal Causes

• Early or grumbling appendicitis: May present with normal inflammatory markers initially; CT sensitivity ranges 85.7-100% but early disease may lack classic findings. 2
• Right-sided colonic diverticulitis: Can present with normal inflammatory markers and mimics appendicitis. 2
• Crohn's disease (terminal ileitis): Chronic inflammatory condition that may present with intermittent symptoms and variable inflammatory markers. 1
• Epiploic appendagitis: Self-limited inflammatory condition of colonic fat appendages, often with normal WBC. 4
• Omental infarction: Rare cause of right lower quadrant pain with normal inflammatory markers. 4

Musculoskeletal Causes

• Rectus abdominis muscle tear: Can mimic appendicitis; diagnosed by ultrasound showing loss of linear muscle architecture and decreased echogenicity. 5

Urologic Causes

• Ureteral stone with sterile pyuria: Adjacent inflammatory process (appendicitis or diverticulitis) can cause sterile pyuria without true UTI. 2
• Obtain urinalysis to evaluate for nephrolithiasis or urinary tract pathology. 3

Management Based on CT Findings

If CT Confirms Appendicitis

• Proceed immediately to surgical consultation for appendectomy. 2, 3
• Initiate IV antibiotics at time of diagnosis. 3

If CT Shows Gynecologic Pathology

• Ovarian torsion: Emergency gynecologic surgery required. 3
• Ruptured ovarian cyst: Conservative management or gynecology consultation. 3
• Tubo-ovarian abscess: IV antibiotics and possible drainage. 3

If CT is Negative or Indeterminate

• Clinical reassessment with serial abdominal examinations every 6-12 hours to monitor for evolving peritoneal signs. 2
• Repeat complete blood count to assess for developing leukocytosis. 2
• Consider MRI if high clinical suspicion persists and CT is inconclusive. 2, 3
• Diagnostic laparoscopy if symptoms persist and imaging remains nondiagnostic—this provides both diagnosis and therapeutic intervention. 2, 6

Critical Pitfalls to Avoid

• Do not discharge without establishing clear 24-hour follow-up plan due to measurable false-negative rates in low-risk presentations. 2
• Do not rely on absence of fever or normal WBC to exclude appendicitis—these are absent in approximately 50% of cases. 2
• Do not delay imaging if symptoms persist or worsen during observation period. 2
• Do not assume antibiotic failure equals resistant infection—persistent symptoms despite antibiotics strongly suggest non-infectious etiology. 1

Post-Infectious Considerations

If all imaging and workup are negative, consider post-infectious irritable bowel syndrome, which can develop after acute diarrheal illness and presents with persistent gastrointestinal symptoms despite resolution of infection. 1 However, this remains a diagnosis of exclusion after ruling out structural and inflammatory pathology with CT imaging.