What are the differential diagnoses for a patient who experiences fatigue, low-grade fever, and gastrointestinal (GI) upset, with fever responding to Advil (ibuprofen)?

Differential Diagnoses for Exertion-Related Fatigue, Low-Grade Fever, and GI Upset

The most likely diagnosis is post-infectious irritable bowel syndrome (PI-IBS) triggered by exercise-induced gastrointestinal distress, with the ibuprofen itself contributing to or worsening the GI symptoms rather than simply treating an underlying infection. 1, 2

Primary Differential Considerations

Exercise-Induced Gastrointestinal Syndrome with NSAID-Aggravated Injury

• Ibuprofen directly causes gastrointestinal injury during exercise, increasing intestinal permeability 3-5 fold and inducing gut barrier dysfunction, particularly during physical exertion 1
• The temporal pattern (GI upset 1-2 days after ibuprofen use) strongly suggests NSAID-induced mucosal injury rather than infection 1
• Exercise itself reduces splanchnic blood flow, and NSAIDs compound this by inhibiting protective prostaglandins, creating a "double hit" to the intestinal mucosa 1
• The "fever" may represent exercise-induced hyperthermia or low-grade inflammatory response to intestinal barrier dysfunction rather than true infection 1

Post-Infectious IBS (PI-IBS)

• Up to 27% of patients develop persistent bowel symptoms after gastroenteritis even with completely healed mucosa, with fatigue being a prominent feature 2
• Residual low-grade inflammation with increased mast cells persists without visible mucosal damage, which could explain recurrent low-grade fever 2
• Psychological stress from physical exertion can trigger symptoms through the brain-gut axis, particularly in those with prior GI infections 2
• Small intestinal bacterial overgrowth (SIBO) occurs in up to 30% of PI-IBS patients and causes bloating, pain, and diarrhea 2

NSAID Hypersensitivity Reaction (Delayed Type)

• Delayed hypersensitivity reactions to NSAIDs occur >6 hours after dosing and can manifest days to weeks after initiation 1
• Prodromal symptoms of severe reactions include fever and mucosal involvement, though GI symptoms alone are more common 1, 3
• Ibuprofen is among the most common NSAIDs associated with delayed reactions and can cause drug-induced interstitial nephritis, pneumonitis, or aseptic meningitis 1

Occult Infection with NSAID Masking

• The French ANSM issued warnings about NSAID use masking serious bacterial infections, particularly in patients with infectious diseases 4
• Ibuprofen's antipyretic effect may temporarily suppress fever from an underlying infection without treating the source, leading to delayed diagnosis 1, 5
• Bacterial infections (particularly streptococcal pharyngitis, enteric fever, or traveler's diarrhea) can present with fatigue, low-grade fever, and GI symptoms 1

Critical Diagnostic Workup

Immediate Assessment

• Measure fecal calprotectin: <100 μg/g suggests functional disorder (IBS), >250 μg/g indicates inflammatory process requiring endoscopy 6
• Check C-reactive protein (CRP): elevated in true infection or IBD, normal in IBS and exercise-induced symptoms 6
• Complete blood count with differential: eosinophilia suggests parasitic infection or drug reaction 1
• Comprehensive metabolic panel: assess for hepatic or renal injury from NSAIDs 1

Specialized Testing if Initial Workup Abnormal

• Glucose or lactulose hydrogen breath testing for SIBO if bloating and diarrhea predominate (sensitivity 20-93%) 2
• Stool culture and ova/parasites if travel history or persistent diarrhea 1
• Serum C4 and FGF19 levels for bile acid diarrhea if available 2

Red Flags Requiring Urgent Evaluation

• Weight loss, nocturnal symptoms, rectal bleeding, or high-volume diarrhea suggest IBD rather than functional disorder 6
• Persistent fever >3 days despite NSAID cessation indicates true infection requiring antimicrobial therapy 1
• Jaundice, dark urine, or right upper quadrant pain suggests NSAID-induced hepatotoxicity 1

Management Algorithm

Step 1: Immediate NSAID Cessation

• Discontinue ibuprofen immediately as it aggravates exercise-induced intestinal injury and should be discouraged in those with persistent GI symptoms 1
• Switch to acetaminophen for fever/pain control, which is chemically distinct and does not cause COX-1 mediated GI injury 3
• Avoid all NSAIDs including aspirin, which increases intestinal permeability 1

Step 2: Symptom-Directed Therapy

• For diarrhea-predominant symptoms: Rifaximin 550 mg three times daily for 14 days (can repeat up to two additional cycles) 2
• For abdominal pain: Antispasmodics, gabapentin/pregabalin, or low-dose tricyclic antidepressants 2
• For constipation: Polyethylene glycol or stimulant laxatives 2
• Low FODMAP diet as first-line dietary therapy with attention to nutritional adequacy 2

Step 3: Address Exercise-Related Factors

• Avoid high-fiber foods on days of intense physical activity 1
• Prevent dehydration by starting exercise well-hydrated 1
• Ingest carbohydrates with sufficient water or use lower concentration drinks to prevent high gastric osmolality 1
• Practice nutrition strategies during training to improve gut tolerance 1

Step 4: Psychological Component

• Cognitive behavioral therapy, hypnotherapy, or mindfulness therapy address brain-gut axis dysfunction and have demonstrated efficacy 2
• Screen for anxiety and depression, which are both consequences and perpetuating factors in functional GI disorders 2
• Stress reduction techniques as psychological stress can directly elevate intestinal inflammatory markers 2

Common Pitfalls to Avoid

• Do not continue NSAIDs for "fever" without confirming true infection, as exercise-induced hyperthermia and low-grade inflammation from gut barrier dysfunction can mimic fever 1
• Do not pursue endoscopy unless fecal calprotectin >250 μg/g or alarm features develop (weight loss, bleeding, nocturnal symptoms) 2, 6
• Do not use opiates for pain management as they worsen functional GI symptoms and increase complications 2
• Do not ignore the temporal relationship between ibuprofen use and GI symptoms—the 1-2 day delay is classic for NSAID-induced mucosal injury 1
• Do not assume all "fever" requires antibiotics—many cases represent exercise-induced hyperthermia or inflammatory responses that resolve with NSAID cessation and supportive care 1, 5