What is the differential diagnosis for a patient presenting with fever, headache, and epigastric pain?

Differential Diagnosis of Fever, Headache, and Epigastric Pain

Immediately Rule Out Life-Threatening Conditions

Obtain an ECG within 10 minutes and serial troponins at 0 and 6 hours to exclude myocardial infarction, which presents atypically with epigastric pain in women, diabetics, and elderly patients with mortality rates of 10-20% if missed 1, 2.

Critical Emergency Diagnoses

• Perforated peptic ulcer presents with sudden severe epigastric pain becoming generalized, accompanied by fever, abdominal rigidity, and absent bowel sounds, with 30% mortality if treatment is delayed 1, 2. CT with IV contrast shows extraluminal gas in 97% of cases 1.

• Acute pancreatitis characteristically presents with epigastric pain radiating to the back, diagnosed by serum amylase ≥4x normal or lipase ≥2x normal with 80-90% sensitivity 1, 2.

• Mycotic aneurysm of the abdominal aorta presents with the triad of fever, pain, and pulsatile abdominal mass in 70% of cases, though this classic presentation is actually uncommon 3. Back pain occurs in 65-90% of cases 3.

Infectious Causes Requiring Immediate Consideration

Enteric Fever (Typhoid/Paratyphoid)

After excluding malaria in travelers, enteric fever is the most common serious tropical disease requiring treatment, particularly from Asia 3. The incubation period is 7-18 days (range 3-60 days) 3.

• Characterized by fever with headache, lethargy, malaise, and abdominal pain, followed by hepatosplenomegaly 3.
• Diarrhea is uncommon despite gastrointestinal portal of entry 3.
• Blood cultures are 80% sensitive in the first week 3.
• If clinically unstable, treat empirically with ceftriaxone 3.

Yellow Fever

Yellow fever presents with sudden onset of high fever (up to 104°F), severe headache, generalized myalgias, anorexia, nausea, vomiting, and dizziness 3. In 15% of cases, illness recurs within 48 hours with fever, nausea, vomiting, epigastric pain, jaundice, and renal insufficiency 3. Consider in patients with travel to endemic areas (South America, sub-Saharan Africa) 3.

Rickettsial Infections

Rickettsia conorii (Mediterranean spotted fever) can present with fever, headache, and epigastric pain, potentially progressing to hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation 4. Ehrlichiosis presents with fever, headache, malaise, and myalgia, with gastrointestinal symptoms including epigastric pain 3.

Leptospirosis and Dengue

Both can present with fever, headache, and epigastric pain 5. Dengue is diagnosed by PCR (days 1-8 post symptom onset) or IgM (>5 days) 3. Leptospirosis requires extended blood cultures and serology 3. Coinfection is possible and requires high clinical suspicion in endemic areas 5.

Malaria

Malaria must be excluded in all patients with fever returning from the tropics 3. Most patients present with fever, headache, myalgia, arthralgia, and malaise 3. Roughly half are afebrile on presentation despite fever history 3. Minimum incubation period is 6 days 3.

Non-Infectious Gastrointestinal Causes

Peptic Ulcer Disease and Gastritis

Peptic ulcer disease has an incidence of 0.1-0.3% with complications in 2-10% of cases 1, 2. CT findings include gastric or duodenal wall thickening, mucosal hyperenhancement, fat stranding, and focal outpouching from ulcerations 1.

Gastric Cancer

Gastric adenocarcinoma has only 32% 5-year survival and is now the most common cause of gastric outlet obstruction in adults 1. CT findings concerning for malignancy include ulcer with nodular adjacent mucosa, mass effect, or irregular radiating folds 1.

Functional Dyspepsia

Accounts for 80% of epigastric symptoms in the community but typically lacks fever 1. Rome IV criteria require symptom onset at least 6 months prior with symptoms active within past 3 months 1.

Diagnostic Algorithm

Step 1: Vital Signs and Physical Examination

• Check for tachycardia ≥110 bpm, fever ≥38°C, or hypotension predicting perforation, anastomotic leak, or sepsis 1.
• Examine for peritoneal signs (rigidity, rebound tenderness, absent bowel sounds) indicating perforation requiring immediate surgical consultation 1.
• Obtain ECG within 10 minutes 1, 2.

Step 2: Travel and Exposure History

Document locations visited, dates of travel, dates of symptom onset, and risk activities on all laboratory request forms 3. Consider:

• Enteric fever if travel to South/Southeast Asia within past 60 days 3
• Yellow fever if travel to endemic areas with 3-6 day incubation 3
• Malaria if any tropical travel, especially sub-Saharan Africa 3
• Rickettsial disease if tick exposure 3, 4

Step 3: Initial Laboratory Testing

• Cardiac troponins at 0 and 6 hours 1, 2
• Serum amylase or lipase to exclude pancreatitis 1
• Blood cultures (up to 80% sensitive for enteric fever in first week) 3
• Malaria thick and thin smears (three sets over 24-48 hours if initial negative) 3
• Full blood count, liver function tests 3
• Dengue PCR if days 1-8 post symptom onset, or IgM if >5 days 3

Step 4: Imaging

CT abdomen and pelvis with IV contrast is the gold standard when diagnosis is unclear, identifying pancreatitis, perforation, vascular emergencies, and mycotic aneurysms 3, 1. Use neutral oral contrast (water or dilute barium) when gastric disease is suspected 1.

Step 5: Empiric Treatment Considerations

• If enteric fever suspected and clinically unstable: ceftriaxone empirically 3
• If peptic ulcer disease suspected without alarm features: high-dose PPI (omeprazole 20-40 mg once daily) with 80-90% healing rates 1
• If rickettsial infection suspected: doxycycline 3
• Avoid NSAIDs as they worsen peptic ulcer disease and bleeding risk 1

Critical Pitfalls to Avoid

• Never dismiss cardiac causes regardless of age or "atypical" presentation 1, 2. Serial troponins are mandatory 1, 2.
• Do not delay imaging in patients with peritoneal signs, as perforated ulcer mortality increases significantly with delayed diagnosis 1, 2.
• Never rely on a single troponin measurement—obtain serial measurements at 0 and 6 hours 1, 2.
• Document adequate travel history on all laboratory request forms or correct tests will not be performed 3.
• In elderly patients with fever and abdominal pain, laboratory tests may be normal despite serious infection 3.