Non-Invasive Investigations for Genital Tuberculosis

1. Immunological Tests (Screening)

a) Mantoux Test (Tuberculin Skin Test / TST)

• Intradermal injection of 5 tuberculin units (PPD); read at 48-72 hours
• Induration interpretation:
  • ≥5 mm: HIV positive, recent close TB contact, chest X-ray showing old healed TB
  • ≥10 mm: Other risk groups (healthcare workers, immigrants from endemic areas, etc.)
  • ≥15 mm: All others with no known risk factors
• Limitations: Does NOT distinguish active disease from latent TB or prior BCG vaccination; high false-positive rate in endemic areas like India
• A positive Mantoux alone cannot diagnose genital TB but supports further workup

b) Interferon-Gamma Release Assays (IGRAs) - QuantiFERON-TB Gold / T-SPOT.TB

• Blood test measuring IFN-gamma release from sensitized T-cells after stimulation with TB antigens (ESAT-6, CFP-10)
• More specific than TST - not affected by BCG vaccination
• Like Mantoux, cannot distinguish active from latent disease
• WHO recommends TST or IGRA for latent TB screening in high-risk populations
• A positive IGRA in an infertile woman from an endemic area raises suspicion for FGTB

2. Radiological / Imaging Investigations

a) Chest X-Ray

• First-line, cheapest, and most accessible non-invasive investigation
• Up to 20% of genitourinary TB cases have concurrent pulmonary TB
• Findings: upper lobe fibrosis, calcified Ghon focus, pleural effusion, miliary pattern, hilar lymphadenopathy
• A normal CXR does NOT rule out genital TB

b) Hysterosalpingography (HSG)

• Technically semi-invasive (transcervical dye injection) but non-surgical
• Most informative radiological test for female GTB
• Classic HSG findings in genital TB:
  • Rigid, pipestem tubes - loss of normal tortuosity
  • "Golf-club" appearance of fallopian tube
  • "Beaded" or "corrugated" tubes - nodular irregularity
  • Corkscrew or tortuous tubes
  • Tubal obstruction (cornual or ampullary)
  • Hydrosalpinx - distended blocked tube
  • T-shaped uterine cavity - synechiae causing Asherman's syndrome
  • "Rosette" pattern at the cornua
  • Calcification in tubes or adnexa in chronic disease
  • Peritubal adhesions with loculation of contrast
• Note: Findings can overlap with PID, post-surgical adhesions, and other causes of tubal disease

c) Ultrasonography (USG) - Transvaginal (TVS) / Transabdominal

• Non-invasive, widely available
• Findings suggestive of GTB:
  • Hydrosalpinx / pyosalpinx
  • Tubo-ovarian masses or abscess
  • Endometrial irregularity or synechiae (Asherman's pattern)
  • Free fluid in pouch of Douglas
  • Omental thickening and ascites (peritoneal involvement)
  • Calcifications in adnexa
• USG alone is non-specific; cannot confirm TB histologically

d) HyCoSy (Hysterosalpingo Contrast Sonography)

• Ultrasound-based tubal patency assessment using contrast
• Can identify tubal blockage similarly to HSG, without radiation
• Increasingly used as an alternative to HSG in infertility workup

e) CT Scan / MRI Pelvis

• CT: better for calcifications, lymphadenopathy, peritoneal thickening, complex masses
• MRI: superior soft-tissue resolution; can show endometrial irregularity, pyosalpinx signal characteristics, adhesions
• Both are adjunctive - used when USG is inconclusive or for surgical planning

3. Microbiological / Molecular Tests on Non-Invasive Samples

a) Menstrual Blood - The Most Important Non-Invasive Sample

• Menstrual blood is a non-invasive source of endometrial cells and secretions that can be tested for MTB
• Sample collected on days 1-2 of menstruation (maximum bacterial shedding from endometrial granulomas)
• Tests performed on menstrual blood:
  • AFB smear and culture - low sensitivity but non-invasive
  • PCR / NAAT - most useful; especially hsp65 nested PCR and multiplex PCR
  • Studies show menstrual blood PCR sensitivity of 72-90% with specificity 83-86% vs. endometrial biopsy as reference
  • Paine et al. (2018) showed multiplex PCR from menstrual blood is a non-invasive, cost-effective approach to reduce diagnostic dilemma
• Optimal timing: within 12 hours of onset of menses (maximum endometrial granuloma development)

b) Urine AFB Culture and PCR (for Male / Urogenital TB)

• In male genital TB (epididymo-orchitis, prostatic TB), first-void early morning urine x 3-5 samples on consecutive days
• Sensitivity: 10-90% depending on collection protocol
• PCR/NAATs on urine: faster results (1-2 days) vs. 4-8 weeks for LJ culture
• GeneXpert MTB/RIF: also detects rifampicin resistance simultaneously

c) GeneXpert MTB/RIF (on non-invasive samples)

• Cartridge-based automated NAAT; results in ~2 hours
• Can be run on menstrual blood or urine
• High specificity (~100%) but variable sensitivity (11-50% on endometrial samples)
• A positive result is confirmatory; a negative does not rule out GTB

d) Nucleic Acid Amplification Tests (NAATs)

• General category includes PCR, IS6110-based assays, nested PCR, TB-LAMP
• IS6110 insertion sequence-based PCR: best sensitivity for MTB
• TB-LAMP (Loop-mediated isothermal amplification): sensitivity 66%, specificity 93% on endometrial biopsy; data on menstrual blood limited
• NAATs have high specificity and PPV - a positive test in a high pre-test probability patient is confirmatory; a negative test does NOT rule out GTB

4. Blood Tests (Supplementary)

5. Cervical / Vaginal Swabs

• Routine swabs are generally low yield for MTB but can exclude other STIs (Chlamydia, gonorrhoea, BV) that mimic GTB
• Cervical PCR for MTB has been studied but sensitivity is low given paucibacillary nature

Summary Table - Non-Invasive Investigations

Key Points to Remember

1. No single non-invasive test is sufficient - diagnosis requires combining multiple findings (the "Composite Reference Standard" approach)
2. Menstrual blood PCR is the single most useful non-invasive molecular investigation
3. HSG is the most informative non-invasive imaging test for female genital TB
4. TST/IGRA positive + consistent HSG findings + raised ESR + excluding other causes = strong presumptive diagnosis
5. A negative test never rules out GTB given its paucibacillary nature
6. The gold standard remains endometrial biopsy for histopathology + culture + GeneXpert (invasive)

• Campbell-Walsh-Wein Urology, Chapter 60 (Genitourinary Tuberculosis), pp. 1713-1721
• Sharma JB et al. (2021) - Recent Advances in Diagnosis and Management of FGTB, JOGI India (PMID: 34483510)
• Tjahyadi D et al. (2022) - Female Genital Tuberculosis: Clinical Presentation, Current Diagnosis and Treatment, Infect Dis Obstet Gynecol (PMID: 36438172)
• Aggarwal A et al. (2022) - Imaging Spectrum of Female Genital Tuberculosis, Curr Probl Diagn Radiol (PMID: 34304946)