Female genital tuberculosis: Revisited

Fallopian tubes

Both fallopian tubes are involved in most (>90%) women in FGTB and the involvement can be TB endosalpingitis, exosalpingitis, interstitial TB salpingitis and Salpingitis isthmica nodosa8910111219. In tuberculous endosalpingitis, with the haematogenous route of spread, the infection starts from endosalpinx making tubes swollen, oedematous and irregular with the formation of hydrosalpinx, pyosalpinx, tubo-ovarian masses and dense adhesions8910111219. Endosalpinx may be hyperplastic or oedematous or totally destroyed by disease making women more susceptible to ectopic pregnancy and infertility681223. In tuberculous exosalpingitis, infection starts in the muscularis mucosa of oviducts with hyperaemia, flimsy adhesions and miliary tubercles on the surface of the tubes689101112. Later beading, closed tubes, tubo-ovarian masses, hydrosalpinx, pyosalpinx and the development of synechiae formation occurs89101112.

Hydrosalpinx and the tubal condition can be graded on laparoscopy and laparotomy as per the type of adhesions, patency of tubes, morphology of tubes and fimbrial stricture for prognostication of fertility2425.

Uterus

The endometrium is affected in 50-80 per cent (average 70%) patients through haematogenous, lymphatic or contagious route. Initially, there are no obvious lesions, later ulcers are formed and in advanced stages, distortion of the uterus occurs due to synechiae. The lesions can be focal or multiple ulcers, necrosis or haemorrhagic areas. Destruction of the endometrium may occur with Asherman's syndrome manifesting as secondary amenorrhoea and infertility26. On microscopy, typical caseative epithelioid granulomas, epithelioid cells and specialized Langerhans giant cells may not form due to the shedding of the endometrium during menstruation. The presence of a focal collection of lymphocytes on endometrial biopsies may also indicate FGTB18.

Ovaries

Ovaries are affected in 20-30 per cent patients with adhesions, caseation, adnexal cyst or mass formation with defective ovarian function and reserve and sometimes complete destruction of ovary2728. Sometimes tubo-ovarian cyst can manifest as acute abdomen simulating acute appendicitis and may be diagnosed on laparoscopy or laparotomy29.

Peritoneum

Pelvic and abdominal peritoneum is often involved in abdomino-pelvic TB with multiple tubercles, ascites and abdominal masses simulating ovarian cancer30. Various types of adhesions are formed in the pelvis and abdomen such as perihepatic synechiae (Fitz-Hugh-Curtis syndrome), hanging gall bladder sign and ascending colonic synechiae and frozen pelvis in the abdomino-pelvic TB313233. Ascitic fluid sampling for biochemical analysis (increased adenosine deaminase levels) and peritoneal biopsy may confirm the diagnosis of TB and thus can avoid laparotomy. FGTB and endometriosis may present together in some cases34.

Cervix

The cervix may be involved in about five per cent cases of genital TB usually secondary to tubal or endometrial TB, but may rarely be primary disease transmitted by the partner through infected semen. It manifests as polypoidal growth or ulceration simulating cervical cancer necessitating biopsy and histopathological demonstration of granulomatous inflammation35.

Vagina and vulva

The involvement of vagina and vulva is rare and is usually an extension from endometrium or cervix, or rarely primary due to transmission from an infected semen of the partner. There may be a hypertrophic ulcer or growth on the vulva or vagina requiring biopsy and histopathological demonstration of granuloma and to rule out cancer and other diseases such as syphilis and lymphogranuloma venereum89101136. Rarely, a giant vulval tumour may be formed in FGTB37. Even vesicovaginal and rectovaginal fistulas can rarely occur in FGTB38.

Tubal factors

Tubal factors include unilateral and bilateral tubal blockage, loss of tubal function due to ciliary damage in FGTB, perisalpingitis causing adhesions and tubo-ovarian mass formation, and unilateral or bilateral hydrosalpinx with or without obstruction affecting fertilization and embryonic implantation3940.

Defective ovarian function

Endocrine dysfunction, chronic anovulation, antigonadotropic effect of M. tuberculosis even on an in vitro fertilization (IVF) cycle, poor quality of embryo due to intrinsic oocyte factor defect and decreased production of progesterone (luteal phase defect), implantation failure, lower pregnancy rates and higher abortion rates are observed in FGTB2728.

Uterine (endometrial) factors

Genital TB affects endometrial receptivity leading to defective endometrial markers and vascularization of the endometrium, and endometrial atrophy and synechiae formation26. Defective or failed implantation has also been reported in FGTB41. In FGTB, there is T-helper-1 cell (Th-1) response that leads to implantation failure instead of Th-2 cell response needed for successful implantation of fertilized ovum. Hence, FGTB shifts Th-2 response to Th-I response in endometrium leading to implantation failure. In fact, Dam et al41 observed latent FGTB to be an important cause of repeat IVF failure in Indian setting through poor implantation.

Clinical signs and symptoms of FGTB are depicted in Table I.

Investigations

• (i)

  Blood test: Full blood count may demonstrate anaemia, raised leucocytes and lymphocytes and raised ESR in TB81011. Serological tests are not considered sensitive and specific, hence are banned by the WHO and Government of India.

• (ii)

  X-ray chest (postero-anterior view) may show active pulmonary TB (fibrocavitory disease, infiltrations, mediastinal or hilar lymphadenopathy, miliary TB) or old healed lesions of past TB.

• (iii)

  Mantoux/(Tuberculin) test and interferon gamma release assay (IGRA)43: These have sensitivity of 55 per cent and specificity of 80 per cent and alone cannot be used for diagnosis of FGTB. Positive tests just indicate infection but not disease and negative tests do not rule out infection.

• (iv)

  Blood markers: Cancer antigen 125 (CA 125) is a good tumour marker for ovarian malignancies (normal levels <35 U/ml). However, its levels can be significantly raised in advanced abdominal tuberculosis. Thakur et al44 reported a very high (1255 U/ml) levels of CA 125 in their case of advanced abdominal tuberculosis, which came down to 42 U/ml after one month of ATT (antitubercular treatment). Its levels are only moderately raised usually <200 U/ml in FGTB (as compared to the higher rise in thousands in cancer ovary)1130. However, CA 125 is not a very reliable marker for the diagnosis of FGTB8.

• (v)

  Imaging methods: These are of use only in tubo-ovarian masses. Ultrasonography (USG) may show tubo-ovarain masses with calcification and fluid in the pouch of Douglas5845. It may show thin endometrium, the heterogenous appearance of the endometrium, endometrial fluid, calcification or bands and intrauterine synechiae45. It can demonstrate hydrosalpinges with cog wheel sign and inhomogenous enlarged ovaries with free peritoneal fluid and fixed adnexal masses45.

  Computerized axial tomography (CAT) scan (Fig. 1) may show masses in abdomen and pelvis with ascites, thickened and enhanced peritoneum, with lesions in the abdominal viscera and lymph node46. Magnetic resonance imaging (MRI) has a higher resolution and may show tubo-ovarian masses. Unilateral or bilateral tubo-ovarian masses, hydrosalpinx, adnexal cysts or tuberculous deposits on peritoneum or liver have been reported in our study47. Positron-emission tomography (PET) scan shows unilateral or bilateral tubo-ovarian masses with increased fluorodeoxy glucose (FDG) uptake by TB lesion4849. We observed increased FDG uptake by TB lesions in our study on 17 women of tubercular tubo-ovarian masses (Fig. 2). It also helps in differentiating between carcinoma ovary and abdomino-pelvic TB. Hysterosalpingography (HSG) is contraindicated in FGTB as it can result in flare-up of subclinical infection. However, it is often performed as part of infertility workup in unsuspected cases. It shows the internal architecture of the uterus and tubes and thus helps in the diagnosis of FGTB (Figs 3 and 4). Various HSG findnigs like tobacco pouch, golfclub and maltese cross appearance of tubes and shruken uterine cavity with tubal block have been reported by different authors in FGTB505152.

• (vi)

  Microbiological tests: Endometrial biopsy, curettage or aspirate performed in the luteal phase (day 21) are the most important tests for the diagnosis of genital TB6891011. All efforts should be made to achieve microbiological confirmation. Demonstration of typical caseous granuloma with or without Langerhans giant cells on histopathology is diagnostic of genital TB. Multiple biopsies may increase pick up rate53. WHO approved rapid diagnostic tests (WRDT) are cartridge based nucleic acid amplification test (CBNAAT/ GeneXpert MTB/RIF) and liquid culture by mycobacterial growth indicator tube (MGIT) with phenotypic drug sensitivity testing (DST) or genotypic DST by line probe assay (LPA) are done on endometrial sample sent in saline545556. Polymerase chain reaction (PCR) is a fast, sensitive and specific test to diagnose mycobacterial DNA in endometrial sample by targeting 65 kDa and the mpt 64 gene5758. It has a high sensitivity and can detect 1-10 bacilli per ml5758. However, the false-positive rate of PCR is high. Many researchers have advised against PCR for the rapid detection of TB59. Rana et al60 observed better results of reverse transcriptase-PCR in the detection of FGTB. In our experience, there is high false positivity of PCR and it is recommended not to start antitubercular treatment (ATT) only on positive PCR unless there is evidence of FGTB clinically on examination, or on radiology or endoscopy81161.

  A positive CBNAAT (cartridge based nucleic acid amplification test) result is a useful confirmation, but a negative test does not always rule out TB. The Xpert MTB/RIF is an automated test which can detect purified DNA of M. tuberculosis on the endometrial sample. It can also detect rifampicin resistance and can give report within two hours. Sharma et al62 observed GeneXpert) to have a 33-50 per cent sensitivity, 100 per cent specificity for the diagnosis of FGTB. We also observed 35 per cent sensitivity and 100 per cent specificity in the detection of FGTB with GeneXpert63.

  Loop-mediated isothermal amplification (LAMP) assay has been used on endometrial biopsy64 Sethi et al64 observed high sensitivity of 66.18 per cent for LAMP in contrast to 29.4 per cent for AFB smear, 10.29 per cent for AFB culture, 8.82 per cent for histopathology and 95 per cent for PCR. They also observed a high concordance of 63 per cent between PCR and LAMP.

• (vii)

  Hysteroscopy: It is endoscopic visualization of endometrial cavity and may be normal in the absence of endometrial TB (as the uterus is involved in only about 70% of cases of TB) and in early disease. Usually, there is a pale looking cavity, the presence of tubercles, small white caseous nodules, varying grades of intrauterine synechaie (Fig. 5) and Asherman's syndrome2665. Kumar and Kumar66 observed white caseous nodules as stars shining against the blue background of methylene blue dye in their study of endometrial TB on hysteroscopy at higher magnification. As there is a high-risk of complications and difficulties in performing hysteroscopy in FGTB cases due to the small shrunken cavity, the procedure needs to be performed by expert gynaecologists preferably under laparoscopic guidance67.

• (viii)

  Laparoscopy: A laparoscopy or dye test performed under general anaesthesia is the most reliable modality for the detection of FGTB and abdomino-pelvic TB, particularly affection of oviducts, ovaries and peritoneum. It is often done with hysteroscopy for better results. While performing laparoscopy one has to carefully visualize the whole of the peritoneal cavity (and not only pelvis) by rotating the laparoscope by 360° systematically [ first pelvis for genital organs, then ileocecal region, ascending colon, hepatic flexure, liver, gallbladder, stomach, whole of small bowel, descending colon, omentum (Fig. 6) and whole of peritoneum] to observe various lesions and adhesions of TB and any other coincidental findings8116869.

  Various laparoscopic findings can be as follows: (a) In subacute stage, the findings are congestion, oedema, fluid-filled pockets, miliary tubercles (Fig. 7), white yellow and opaque patches on the uterus, tubes, ovaries and peritoneum; (b) In chronic stages, there may be small swollen tubes with agglutinated fimbriae (nodular salpingitis), varying types of tubal block (fimbrial, mid tubal or cornual block), beading of tubes, hydrosalpinx (Fig. 8) and pyosalpinx caseous nodules can be seen in utero vesical pouch (Fig. 9); (c) We observed alternate constrictions and dilatations of fallopian tubes on injection of methylene blue in FGTB cases (Sharma's blue python sign)70. Fusion of fimbrial ends due to caseous material in a case of FGTB (Sharma's Kissing fallopian tube sign)71 and calcified tubes like a dried tree branch (Sharma's Dried tree branch sign)72 were also observed in FGTB cases; and (d) Varying grades of abdominal and pelvic adhesions (Fig. 6) are common in FGTB. The adhesions are thick and vascular. We have observed a high incidence (48%) of perihepatic synechiae (Fitz-Hugh-Curtis Syndrome) in FGTB cases31. Hanging gall bladder sign due to perihepatic adhesions was also observed in FGTB (Fig. 10)32. Another observation was ascending colonic adhesions at the junction of lower 2/3^rd and upper 1/3^rd of ascending colon in abdomino-pelvic TB33.

  It has been observed that performing laparoscopy in FGTB is difficult and associated with risk such as the inability to see pelvis (10.3%), excessive bleeding (2.3%), and peritonitis (8%), and should be performed by experienced gynaecologists73.

• (ix)

  Combination of tests and diagnostic algorithm: Ultimately, the diagnosis of FGTB is made by meticulous examination and suitable investigations like endometrial sampling, radiology (in tubo-ovarian masses) and the use of hysteroscopy and laparoscopy. An algorithm has been developed for FGTB in INDEX-TB Guidelines, an initiative of Central TB Division, Ministry of Health and Family Welfare, Government of India and the WHO in 2016 for the diagnosis and management of FGTB74. Another Indian team is also working to develop an algorithm suitable for the detection and management of FGTB75. It is mandatory to notify every case diagnosed and treated under NIKSHAY, a web-based notification system maintained by the Ministry of Health and Family Welfare, Government of India (http://nikshay.in).

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Fig. 1

Computed tomography with unilateral tubo-ovarianmass in female genital tuberculosis.

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Fig. 2

Positron emission tomography and computed tomography scan showing unilateral increased FDG uptake in tubo-ovarian masses (arrow).

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Fig. 3

Hysterosalpingography showing bilateral tubal block (arrows).

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Fig. 4

Hysterosalpingography showing left hydrosalpinx with fimbrial block (arrow).

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Fig. 5

Hysteroscopy showing grade II adhesions in female genital tuberculosis being resected.

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Fig. 6

Laparoscopy showing omental adhesions.

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Fig. 7

Laparoscopy showing tubercles on uterus, fallopian tubes and ovaries (arrows).

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Fig. 8

Laparoscopy showing bilateral hydrosalpinxs, tubo-ovarian masses, adhesions and frozen pelvis (arrows).

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Fig. 9

Laparoscopy showing caseous nodules in uterovesical pouch (single arrow) and on anterior abdominal wall (double arrow).

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Fig. 10

Laparoscopy showing Fitz-Hugh-Curtis syndrome (single arrow) and hanging gall bladder sign (double arrow).

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Directly observed treatment short course strategy (DOTS)

The treatment of FGTB is shown in Fig. 11. DOTS is favoured and recommended by the WHO1. Daily treatment is given under direct supervision of a treatment supporter. Four drugs isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) is given for two months (HRZE), followed by H, R and E (HRE) daily for four months (Fig. 11). Thrice-weekly regimen is no longer used.

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Fig. 11

Treatment regimens for female genital tuberculosis (FGTB). ^*Moxifloxacin to be given, if resistance to levofloxacin. Recently, 4 drug fixed dose combination (FDC) HRZE (75, 150, 400, 275) has been introduced. HRZE, isoniazid, rifampicin, pyrazinamide and ethambutol; INH, isoniazid; MDR, multi-drug resistant resistant; IM, intramuscular; O, oral. Source: Refs 13811.

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Non DOTS treatment

Self administered therapy for women not willing to take medicines from the DOTS centre can buy combination kits containing four drugs (HRZE) for two months followed by kit containing three drugs (HRE) for four months.

Treatment of HIV-TB and DRTB

If the patient is both HIV and TB positive, both need to be treated. ATT is started to all patients with drug-sensitive or DR TB and HIV irrespective of CD4 cell count, as early as possible, usually by two weeks of initiation of ATT. In drug-sensitive TB patient on the second-line ART, rifampicin is replaced by rifabutin (150 mg daily)13. Any patient who fails to respond clinically and/ or radiologically despite 2 months of supervised adequate ATT is a presumptive DRTB case and should be offered WRDTs to confirm drug sensitivity. The diagnosis of drug resistant TB is based on the results of WRDT. Drug-resistant [RR/ MDR/ XDR (extensively DR)]. FGTB is treated with reserve drugs for 18-24 months like for pulmonary MDR (Fig. 11).

Adverse effects of drugs

First-line drugs are safe and may have minor side effects but rarely serious side effects like hepatitis. However, reserve drugs are toxic and are to be given for longer duration. Various adverse effects of ATT are shown in Table III.

Surgical treatment

Schaefer12 had advised surgical treatment by removal of the uterus, both tubes and ovaries for persistent disease, tubercles, pyosalpinx, tubo-ovarian mass, non-healing ulcers in MDR TB despite medical treatment12. Besides, surgical treatment in TB is difficult and hazardous with more complications as observed by us in hysteroscopy and laparoscopy, laparotomy and vaginal hysterectomy performed in women with genital tuberculosis67737879. However, limited surgery in the form of drainage of persistent pelvic or tubo-ovarian abscess despite medical treatment can be performed as recommended by the American Thoracic Society80.

Repeat laparoscopy and hysteroscopy after anti-tubercular treatment

Repeat laparoscopy and hysteroscopy can be performed after completion of a full course of ATT for the disappearance of disease. This also helps in prognostication for treatment of infertility. It was observed that after ATT, minor TB lesions disappeared, but major adhesions, frozen pelvis, blocked tubes (advanced disease) persisted with poor prognosis for fertility81. Bahadur et al82 observed significant improvement in grades I and II adhesions only on repeat hysteroscopy after completion of ATT in FGTB patients, but major adhesions (grade III onwards) persisted. We observed the persistence of advanced Asherman's syndrome and adhesions on repeat hysteroscopy in FGTB patients83. Tuboplasty should be avoided in case of FGTB as it does not improve the prognosis for fertility but there is risk of flare-up of TB and further ectopic gestation after ATT101123.

Assisted reproduction in female genital tuberculosis

Despite ATT, results for fertility is low in FGTB patients with conception rate being only 19.2 per cent1742. In vitro fertilization and embryo transfer (IVF-ET) has been found to be useful modality in treating FGTB with blocked tubes but normal endometrium42848586. Parikh et al84 observed 16.6 per cent pregnancy rate per embryo transfer (ET) with in vitro fertilization (IVF) after completion of ATT in patients with normal endometrium. Jindal et al85 found IVF-ET to be the most effective modality in FGTB with pregnancy rate of 17.3 per cent as compared to only 4.3 per cent with tubal surgery. Malik86 observed a pregnancy rate of 38.2 per cent with IVF-ET in 120 women with FGTB after completion of ATT. Another study observed IVF to be a successful modality in FGTB patients87. Chimote et al88 also recommended IVF-ET as a treatment for FGTB cases with blocked tubes but normal endometrium. If the endometrium is destroyed despite ATT but ovaries are normal, gestational surrogacy can be a successful modality in such patients89. Samantha et al89 observed a viable delivery rate of 50 per cent with gestational surrogacy. If ovaries are destroyed, then adoption is advised to the couple891011.

Tuberculosis (TB) and pregnancy

A patient of pulmonary tuberculosis during pregnancy must take full treatment even in the first trimester as all four primary drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) are safe in pregnancy9. Jana et al90 observed increased maternal and perinatal morbidity in pregnancies complicated of pulmonary TB. The same group observed increased maternal and perinatal morbidity in EPTB cases91. However, with adequate treatment and nutrition and care during pregnancy there is no adverse maternal and perinatal outcome in PTB or EPTB92.

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