What conditions can cause epididymo‑orchitis with normal inflammatory markers?

Epididymo-Orchitis with Normal Inflammatory Markers: Causes and Clinical Approach

Epididymo-orchitis with normal inflammatory markers most commonly occurs with sexually transmitted infections (particularly Chlamydia trachomatis), viral orchitis (especially mumps), fungal infections in immunocompromised patients, mycobacterial disease (tuberculosis), and early-stage bacterial infection before systemic inflammatory response develops. 1

Primary Infectious Causes

Sexually Transmitted Pathogens

• In men under 35 years, Chlamydia trachomatis and Neisseria gonorrhoeae are the most common causes and frequently present without elevated systemic inflammatory markers. 1 These pathogens cause localized inflammation that may not trigger significant leukocytosis or elevated CRP/ESR, particularly in early or mild cases.

• Sexually transmitted epididymitis is typically accompanied by urethritis, which is often asymptomatic, and diagnosis requires nucleic acid amplification testing (NAAT) rather than relying on inflammatory markers. 1

• Even in older patients, sexually transmitted infections remain a consideration—gonococcal epididymo-orchitis has been documented even in octogenarians with multiple sexual partners. 2

Viral Orchitis

• Mumps virus is the most frequent cause of viral orchitis and typically presents with normal or only mildly elevated inflammatory markers. 1 Diagnosis is made by IgM serology for mumps antibodies or acute and convalescent IgG serology rather than standard inflammatory markers.

• Other viral causes include Coxsackie virus, rubella virus, Epstein-Barr virus, and varicella zoster virus, all of which may present without significant elevation of routine inflammatory markers. 1

Fungal and Mycobacterial Infections

• Systemic fungal diseases (Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis) and Mycobacterium tuberculosis can involve the epididymis or testis, particularly in immunocompromised patients, and often present with normal initial inflammatory markers. 1

• These infections require specific culture media and prolonged incubation, and clinicians must communicate with the laboratory to ensure proper specimen processing. 1

Critical Diagnostic Considerations

Ultrasound Findings Supersede Laboratory Values

• Color Doppler ultrasound has nearly 100% sensitivity for detecting scrotal inflammation through increased blood flow (hyperemia), making it far more reliable than inflammatory markers for diagnosing epididymo-orchitis. 1, 3 The enlarged, hypoechoic epididymis with increased vascularity on Doppler is the hallmark finding.

• Reactive hydrocele and scrotal wall thickening are commonly present on ultrasound even when systemic inflammatory markers remain normal. 1, 3

Distinguishing from Testicular Torsion

• The most critical differential diagnosis is testicular torsion, which also may present with normal inflammatory markers but shows decreased or absent blood flow on Doppler ultrasound—the opposite of epididymo-orchitis. 1, 4, 3 Correlation with clinical data including fever, waxing and waning pain pattern, and urinalysis findings must be integrated, as reperfusion after early ischemia (torsion/detorsion) can mimic the hyperemia of epididymo-orchitis. 1

• If clinical suspicion for torsion remains high despite normal inflammatory markers, immediate urological consultation and surgical exploration should proceed, as testicular viability is compromised if not treated within 6-8 hours. 4

Age-Stratified Approach to Etiology

Men Under 35 Years

• Prioritize testing for Chlamydia trachomatis and Neisseria gonorrhoeae using NAAT on first-void urine or urethral swab, as these sexually transmitted pathogens are the predominant cause and frequently present without elevated inflammatory markers. 1

• Obtain urethral Gram stain to look for >5 polymorphonuclear leukocytes per oil immersion field as evidence of urethritis, even if systemic markers are normal. 1

Men Over 35 Years

• Consider enteric gram-negative organisms (E. coli) and gram-positive pathogens similar to those causing urinary tract infections, though these more commonly elevate inflammatory markers. 1 However, early infection or localized disease may present with normal systemic markers.

• Evaluate for underlying urologic abnormalities including bladder outflow obstruction, benign prostatic hyperplasia, and recent urinary tract instrumentation. 1, 5

Immunocompromised Patients

• In HIV-infected or otherwise immunosuppressed patients, fungi and mycobacteria are more likely causes and may present with minimal systemic inflammatory response. 1 Tissue culture for fungal and mycobacterial pathogens requires specific communication with the laboratory regarding specimen handling.

Common Pitfalls to Avoid

• Do not exclude epididymo-orchitis based solely on normal inflammatory markers—the diagnosis is clinical and sonographic, not laboratory-based. 1, 3 Color Doppler showing increased blood flow is the definitive diagnostic feature.

• Failure to improve within 3 days of empiric antibiotic treatment requires comprehensive reevaluation, including consideration of tumor, abscess, infarction, testicular cancer, tuberculosis, and fungal epididymitis. 1 Swelling and tenderness persisting after antimicrobial therapy completion mandate further investigation.

• Do not rely on urine culture alone in younger men—NAAT testing for Chlamydia and Gonorrhea is essential, as these organisms may not grow on routine urine culture. 1

• In patients with persistent or recurrent symptoms despite appropriate antibiotics, consider chronic epididymitis (>3 months duration), which may have non-infectious etiologies including autoimmune processes or granulomatous disease. 5, 6

Practical Diagnostic Algorithm

1. Obtain scrotal ultrasound with color Doppler immediately—increased blood flow confirms epididymo-orchitis; decreased flow suggests torsion requiring emergency surgery. 1, 3

2. Age-based pathogen testing: Under 35 years, obtain NAAT for Chlamydia and Gonorrhea plus urethral Gram stain; over 35 years, obtain urine culture and consider prostate evaluation. 1

3. If immunocompromised or treatment failure occurs, obtain tissue culture for fungi and mycobacteria with specific laboratory communication regarding specimen handling. 1

4. Initiate empiric antibiotics immediately (ceftriaxone 250 mg IM plus doxycycline 100 mg PO twice daily for 10 days in younger men; fluoroquinolone in older men) without waiting for inflammatory marker elevation. 1

5. Reassess at 48-72 hours—lack of clinical improvement mandates surgical consultation for possible abscess, infarction, or alternative diagnosis. 6