Can the influenza (flu) vaccine cause elevated Carbohydrate Antigen 19-9 (CA-19-9) levels?

Can the Flu Shot Cause Elevated CA-19-9 Levels?

Yes, the influenza vaccine can cause elevated CA-19-9 levels, though this is not a commonly recognized or well-documented phenomenon in standard guidelines. Based on emerging evidence, vaccination-related inflammatory responses may transiently elevate CA-19-9, similar to other benign inflammatory conditions.

Evidence for Vaccine-Related CA-19-9 Elevation

The most relevant evidence comes from a 2024 case report documenting significantly elevated CA-19-9 levels (>12,000 U/mL) following COVID-19 vaccination, which resolved without malignancy 1. While this specific case involved COVID-19 vaccination rather than influenza vaccination, the mechanism—vaccine-induced inflammatory response—is biologically plausible for any vaccine that triggers immune activation 1.

The key principle is that CA-19-9 is not tumor-specific and can be elevated by any inflammatory condition affecting the hepatobiliary system or pancreas 2, 3.

Known Benign Causes of CA-19-9 Elevation

CA-19-9 elevation occurs in multiple non-malignant conditions that share inflammatory mechanisms potentially triggered by vaccination:

• Inflammatory hepatobiliary conditions including cholangitis and choledocholithiasis can elevate CA-19-9 2
• Pancreatitis (acute and chronic) and autoimmune pancreatitis are well-documented causes 2, 1
• Severe hepatic injury from any cause can elevate CA-19-9 2
• Inflammatory bowel disease is associated with elevated levels 2
• Biliary obstruction causes false-positive results in 10-60% of cases 4, 5

Clinical Approach to Post-Vaccination CA-19-9 Elevation

If CA-19-9 is elevated after influenza vaccination, follow this algorithm:

1. Assess timing and clinical context:

• Document the temporal relationship between vaccination and CA-19-9 measurement 1
• Evaluate for symptoms suggesting malignancy (weight loss, jaundice, abdominal pain) 2
• Common vaccine side effects include injection site pain, fatigue, myalgia, headache, and fever—all reflecting inflammatory responses 4

2. Check for biliary obstruction first:

• Obtain abdominal ultrasound as first-line imaging 2, 6
• Check liver function tests (alkaline phosphatase, bilirubin, GGT) which correlate with CA-19-9 in benign disease 6

3. Interpret CA-19-9 levels in context:

• Values <100 U/mL are less specific and more likely benign 2
• Values >100 U/mL have 75% sensitivity and 80% specificity for cholangiocarcinoma in high-risk patients (PSC), but this threshold is not absolute 2, 6
• CA-19-9 levels correlate with bilirubin levels, and cholestasis induces false-positive results 5

4. Consider observation with repeat testing:

• If imaging is negative and clinical suspicion for malignancy is low, repeat CA-19-9 after 4-8 weeks 1
• Vaccine-related elevations should normalize as the inflammatory response resolves 1

5. Pursue advanced imaging only if indicated:

• MRI with MRCP is optimal for suspected cholangiocarcinoma or persistent elevation 2, 6
• Persistently elevated CA-19-9 after resolution of any inflammatory process strongly suggests malignancy 2

Critical Limitations of CA-19-9 Testing

• 5-10% of the population is Lewis antigen-negative and cannot produce CA-19-9, making testing ineffective in these individuals 2, 7, 5
• CA-19-9 should never be used alone for diagnosis without confirmatory imaging or biopsy 2, 7
• CA-19-9 is not recommended as a screening test in asymptomatic individuals 7, 5
• Small tumors may not cause CA-19-9 elevation 7, 6

Common Pitfalls to Avoid

• Do not assume malignancy based solely on elevated CA-19-9, especially in the post-vaccination period when inflammatory responses are expected 2, 1
• Do not order CA-19-9 as a screening test in asymptomatic patients, even after vaccination 7
• Always correlate CA-19-9 with imaging findings and clinical presentation 2, 3
• Recognize that vaccine-induced transient adenopathy and inflammatory responses are normal and may theoretically affect tumor markers 4

The evidence suggests that while not specifically documented for influenza vaccination in guidelines, the biological plausibility for vaccine-related CA-19-9 elevation exists based on inflammatory mechanisms 1. Clinical judgment should prioritize imaging and clinical context over isolated tumor marker elevations in the post-vaccination period 2, 3.