What is the differential diagnosis and recommended work‑up for a patient presenting with loose stools, low‑grade fever, anorexia, nausea, and bone pain?

Differential Diagnosis and Work-Up for Loose Stools, Low-Grade Fever, Anorexia, Nausea, and Bone Pain

The combination of gastrointestinal symptoms with bone pain requires urgent evaluation for hematologic malignancy, particularly leukemia, which can present with these exact symptoms and carries significant mortality if diagnosis is delayed. 1

Critical Red Flags Present in This Case

The constellation of symptoms presented represents alarm features that mandate immediate comprehensive work-up rather than empiric treatment:

• Bone pain with gastrointestinal symptoms is highly concerning for leukemic infiltration, as GI manifestations occur in up to 25% of leukemia patients 1
• Systemic symptoms (fever, anorexia) combined with diarrhea indicate inflammatory or malignant process rather than functional disorder 2, 3
• Loss of appetite with nausea occurs consistently during acute and chronic pathophysiological processes including malignancy and can be cytokine-mediated 4

Primary Differential Diagnoses

Hematologic Malignancy (Highest Priority)

• Acute or chronic leukemia presents with GI symptoms (diarrhea, nausea), fever, anorexia, and bone pain from marrow infiltration 1
• Leukemic infiltration affects stomach, ileum, and proximal colon most commonly, causing hemorrhagic or infiltrative lesions 1
• Neutropenic enterocolitis can develop with fever, abdominal pain, and diarrhea in leukemia patients 1

Inflammatory Bowel Disease

• Fatigue occurs in 50% at diagnosis and persists in 40-72% during remission 2
• Chronic loose stools lasting >4 weeks with systemic symptoms including fever 2
• Can present with extraintestinal manifestations including arthralgias 2

Infectious Etiologies

• Bacterial diarrhea presents acutely with fever, visible blood, and systemic symptoms 3
• Parasitic infections cause persistent diarrhea with fatigue and weight loss 2
• CMV enteritis in immunocompromised patients presents with nausea, vomiting, diarrhea, fever, abdominal pain, and prolonged anorexia 5

Systemic Amyloidosis

• Presents with intractable nausea, vomiting, diarrhea, weight loss, and multisystem involvement 6
• Can cause malabsorptive and protein-losing enteropathy 6

Immediate Diagnostic Work-Up

First-Line Laboratory Studies (Obtain Immediately)

Complete blood count with differential is the single most critical test:

• Identifies anemia, leukopenia, or thrombocytopenia suggesting hematologic malignancy 1, 7, 8
• Anemia occurs in one-third of patients with bone marrow pathology 7
• Leukopenia with bone pain strongly suggests leukemia 1

Additional baseline laboratories:

• Erythrocyte sedimentation rate (ESR) - elevated in inflammatory conditions, malignancy 5
• Comprehensive metabolic panel including liver function tests and albumin 5
• Serum protein electrophoresis with immunofixation if amyloidosis suspected 6

Stool Studies

Single diarrheal stool specimen for:

• Bacterial culture (Salmonella, Shigella, Campylobacter, Yersinia) if fever and systemic symptoms present 3
• Ova and parasites examination for persistent diarrhea 5, 2
• Fecal calprotectin to distinguish inflammatory from non-inflammatory diarrhea 2
• Clostridium difficile testing if recent antibiotic exposure 5, 9
• Occult blood testing 5

Imaging Studies

Computed tomography of abdomen/pelvis with contrast:

• Evaluates for bowel wall thickening in neutropenic enterocolitis 1
• Identifies organomegaly (spleen, liver, lymph nodes) suggesting leukemic infiltration 1
• Assesses for complications including perforation or peritonitis 1

Urgent Hematology Referral Indications

Immediate hematology consultation if CBC reveals:

• Cytopenias (anemia, leukopenia, thrombocytopenia) 1, 7
• Abnormal white blood cell differential with blasts 1
• Pancytopenia with bone pain 1

Bone marrow biopsy indicated for:

• Unexplained cytopenias with systemic symptoms 1, 7
• Suspected hematologic malignancy 1, 6

Gastroenterology Evaluation

Colonoscopy with biopsies is mandatory if:

• Blood in stool, unintentional weight loss, or nocturnal diarrhea present 2, 9
• Fecal calprotectin elevated suggesting inflammatory process 2
• Age >45 years due to increased neoplasia risk 9
• Biopsies required even if mucosa appears normal to diagnose microscopic colitis 9

Upper endoscopy with duodenal biopsies if:

• Malabsorption suspected (hypoalbuminemia, weight loss) 9
• Persistent nausea and vomiting 6

Critical Pitfalls to Avoid

• Do NOT assume functional bowel disorder without excluding organic causes, as Rome IV criteria have only 52-74% specificity 2
• Do NOT delay hematologic work-up when bone pain accompanies GI symptoms - this combination suggests systemic disease 1
• Do NOT use empiric antibiotics in immunocompetent patients with bloody diarrhea while awaiting results 3
• Do NOT miss anemia and iron deficiency, which independently contribute to fatigue and may indicate underlying malignancy 2
• Do NOT overlook immunocompromised status requiring broader differential including opportunistic infections 5, 9

Algorithmic Approach

1. Obtain CBC with differential immediately - if abnormal, pursue hematologic malignancy work-up urgently 1, 7
2. If CBC normal, proceed with inflammatory markers (ESR, fecal calprotectin) and stool studies 5, 2, 3
3. If inflammatory markers elevated, pursue endoscopic evaluation for IBD 2, 9
4. If infectious work-up negative and symptoms persist >14 days, test for parasites and consider endoscopy 2, 9
5. If bone pain persists with negative initial work-up, obtain imaging and consider bone marrow biopsy regardless of CBC results 1