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TB ( tuberculosis ) and infertility

Tuberculosis (TB) is still rampant in India; and TB of the genital tract used to be the commonest cause of tubal infertility in the past. Today, TB has become much less common, because of improved socioeconomic conditions. However, it is often misdiagnosed in infertile women, leading to a lot of heartbreak and distress.

Let's start with some basics. First of all, remember that tuberculosis is an infectious disease which is caused by the tubercle bacillus. There is a difference between an infection with the tubercle bacillus and the TB disease. In India, most of us have been exposed to the tubercle bacillus. This is either because of exposure to patients who have TB; or because of vaccination with the BCG vaccine ( which is often given routinely to babies in India). This exposure helps us to become immune to TB and to fight the infection, because it allows us to produce protective anti-TB antibodies which help us to fight off the bacillus in the body.

How does TB cause infertility ? It does so only when it infects the genital tract . This is called genital TB. While the initial exposure to the tubercle bacillus is through the lungs ( because the bacillus is inhaled), most of us can fight off the infection, as a result of which it remains silent in the body, causing no harm. However, sometimes these latent bacilli can get reactivated, and then spread throughout the body through the blood stream. They can then get deposited in any part of the body, causing a TB infection of that part. It is only when it lodges and infects the genital tract, that TB can cause infertility . In the man it causes tuberculous epididymo-orchitis, blocking the passage, as a result of which the man becomes azoospermic ( no sperm enter the semen because the tract is blocked). In the woman, it cause tuberculous endomteritis ( infection of the uterus) and salpingitis ( infection of the tubes). This infection can often be silent, and may not cause any symptoms or signs at all !

Genital TB is always hard to diagnose, because of the fact that it is a silent invader of the genital tract. The only reliable way of making a diagnosis is by actually culturing the tubercle bacillus from tissue sampled from the genital tract. Since it's nearly impossible to take tissue from the fallopian tubes, in practice this means that the diagnosis is usually made by finding tubercle bacilli in the endometrial tissue, obtained by uterine curettage.

While a curettage is an easy procedure to perform, actually growing the bacillus in the lab , even in women with frank genital TB can be very hard, because this is a very temperamental bacillus, which grow very slowly in the microbiology lab. This is why few doctors try to grow the bacillus any more, and depend upon indirect evidence to cinch the diagnosis. The most reliable method is by making a histological diagnosis of tubercles. These are the typical lesions seen in tissue infected with the bacillus, and are usually diagnostic of the infection.

This is why it is so important that the doctor actually biopsy suspicion lesions ( tubercles) seen on laparoscopy to confirm that they are really because of tuberculosis ! Unfortunately, many gynecologists do not do this, and end up treating patients purely on their "gut feeling" !

Once the histologic diagnosis of TB endometritis has been made, then treatment with antiTB medicine must be started to prevent further progression of the disease. However, all patients with TB endometritis also have infection of the fallopian tubes; and the damage caused to the tubes ( TB salpingitis) is irreversible. These patients will have irreversible tubal infertility, and the only treatment option available for them would be IVF. In the past some doctors would try to do surgery to repair the tubes, but this is futile surgery, because the tubes never work properly once they have been infected. Tubes which have been severely damaged may form a hydrosalpinx, and may need to be removed surgically, prior to IVF, if they are very large.

However, often the diagnosis of TB can be hard to confirm. Often patients present with a diagnosis of blocked tubes, and while the doctor may suspect the tubes have been blocked because of a TB salpingitis in the past, because the infection has burnt itself out, it's not possible to confirm the diagnosis. This is why some doctors empirically start treatment with antiTB medicine, based on their clinical suspicion. Unfortunately, what this means is that many patients who never actually had TB are mis-diagnosed as having TB, and subjected to 9 months of wasteful medical therapy - which just wastes time and money. Interestingly, once anti-TB has been started, it is no longer possible to confirm a diagnosis of TB, as the antiTB medications kill the bacilli. It is important to prevent this unnecessary overdiagnosis and overtreatment by insisting on proof before starting antiTB treatment.

In order to improve the ability of the doctor to make a diagnosis of TB , many laboratory tests have been introduced to help detect the presence of the tubercle bacillus. One of the most promising tests was the PCR - polymerase chain reaction. This test can pick up even minute quantities of DNA, and it was hoped that if the lab could pick up the presence of DNA sequences unique to the tubercle bacillus, this would help to make a unequivocal diagnosis of TB infection. Unfortunately, this test has proven to be too unreliable. Because it is very expensive, it has not been validated in the fertile population, as a result of which there are too many false positives - in fact, in some labs, over 50% of the samples sent to them test positive for PCR for TB ! This obviously means the test is unreliable, but doctors continue doing it, without understanding its limitations and pitfalls - and patients are unnecessarily subjected to the trauma of 9 months of useless treatment !

One of the other popular tests for detecting "silent TB" uses 'reproductive molecular immunology' techniques for PAMP ( pathogen-associated molecular pattern ) for immunopathological evaluation.

This is quite a mouthful - and because most gynecologists do not know how to interpret the test results, they blindly go ahead and "treat" the patient with antiTB drugs when the test comes back as positive ( even though the test results have no clinical significance .)

So why do gynecologists continue to do these tests ? For one thing, it's easy to order these tests - and it's very profitable for them to do so ! Also, most gynecologists are not infertility specialists so they are quite happy to "start treatment" with medicines ( since this is something which is within their area of competence). Finally, no expert is willing to get up and explain to them why these tests are useless. Because of the peer pressure, when one gynecologist sees another doctor advise these tests, they start doing so blindly. The herd mentality can be a very powerful influence !

The other group of tests which is very popularly misused to make the diagnosis of TB are the blood tests which test for the presence of antiTB antibodies - both IgG and IgM. Firstly, remember that these tests are not picking up the presence of the TB bacillus - they are only testing for the presence of antibodies ( produced by the immune system to protect the body !) against the TB bacillus. As most Indians have been exposed to the TB bacillus, it is hardly surprising that many have the presence of antiTB antibodies, and often test positive. Doctors often believe that this is proof of TB infection, and promptly start treatment ! However, these tests are so unreliable, that the Government of India has banned their use! If your doctor advises you to get these tests, find another doctor!

The Mantoux ( tuberculin) skin test is equally unreliable. It tests merely for the presence of immunity against TB - and can be similarly misinterpreted. Similarly, the TB Quantiferon Gold test is unreliable and has been discarded by good doctors.

Tuberculosis is endemic in India , and it’s a disease which can affect practically any organ system , including the lung , bones, brain and the reproductive tract. While it's easy to "suspect" TB, it’s also extremely hard to confirm the diagnosis of tuberculosis in the lab, because it's very difficult to grow the TB bacillus in vitro.

In the past few years, it seems that practically every other infertile woman in India seems to be diagnosed as having genital tuberculosis, based on a positive endometrial TB PCR ( polymerase chain reaction) test result. The problem is that very few of them actually have tuberculosis , because the vast majority of these results are false positives. Let me explain where all these false positives come from.

Tuberculosis is a notoriously difficult diagnosis to confirm because it's very hard to grow mycobacteria in the lab. Tuberculosis is an infectious diseases , and the only way to make a definitive diagnosis of an infection is by actually growing the organism ( which is responsible  for the infection ) in the laboratory. Thus , if a patient has pneumococcal pneumonia , you can’t make the diagnosis by looking at a chest x-ray - you need to grow the pneumococci in the lab , in a petri dish. This is exactly the same principle we use in order to make a diagnosis tuberculosis , and these are called Koch's postulates. However, because mycobacterium grows very slowly in the lab, instead of insisting on a bacteriological diagnosis, even a histological diagnosis which shows tubercles or granuolomas is considered to be acceptable. In the past, to make a definitive diagnosis of genital TB , a positive mycobacterium culture or the presence of tubercles in the histopathology report ( from an endometrial biopsy  ) was required. However, what has started to happen is when doctors "clinically suspect" tuberculosis ( for example, when the endometrium remains thin, or the patient has failed multiple IVF cycles) , they send the endometrial tissue for all kinds of tests to confirm their clinical suspicion. One of the most popular tests is a PCR( polymerase chain reaction)  test for mycobacterium tuberculosis.


What is PCR ?

PCR is, in principle, a simple and rapid test for use in the detection of Mycobacterium tuberculosis because it amplifies a DNA sequence which is unique to mycobacteria. Now if the test is positive , this means that mycobacterial DNA is present in the endometrium. Isn't it then obvious that if the TB PCR is positive , this means the patient has endometrial TB  which requires treatment ? Extremely logical , but very flawed. Let's see why by starting from first principles.

Interpreting a positive PCR results

What does a positive PCR mean ? It does NOT mean the patient has genital TB ! All it tells us that a few molecules of mycobacterial DNA was found in the sample processed in the lab.

It does not provide us with any information about -
The type of mycobacteria, because the DNA sequence which is being amplified is not specific only to M tuberculosis - it is found in many other other mycobacterial species as well.
Whether the mycobacteria are alive or dead?
Where the mycobacteria came from ? ( the clinical tissue ; or as a contaminant from the OT or the lab)
How many mycobacteria are present
Most importantly, it does not provide any information on the clinical importance of the finding. Is the mycobacteria a contaminant?  or a pathogen?

More about mycobacteria

When most doctors think about mycobacteria, they refer to Mycobacterium tuberculosis which causes the disease tuberculosis ( TB) ; or , less commonly, Mycobacterium leprae which causes leprosy. However, the reality is that Mycobacteria are a diverse group of rod-shaped bacteria that include more than 100 different species. The others, which are far commoner, are called  Nontuberculous mycobacteria (NTM), environmental mycobacteria, atypical mycobacteria  and mycobacteria other than tuberculosis (MOTT). They live in the soil and water throughout the world. Because they are protected by their waxy lipid-rich cell wall, mycobacteria are resistant to disinfectants. This is why they are ubiquitous inhabitants of the hospital environment ; and frequent contaminants in hospital settings, where they are often found in the water supply and even in the solutions in which the endometrial biopsy is sent to the lab for PCR testing). The TB PCR test is highly flawed, because the DNA sequence which the PCR amplifies is common to both the mycobacterium tuberculosis as well as the other species of mycobacetria.

The problem with false positives

Since these mycobacetria are so common, when the laboratory finds a positive PCR reaction , it doesn’t know whether the mycobacterial DNA is coming from the patient or from the slide on which that sample was sent.  When a specimen is reported as being PCR positive, it is important to discriminate between true infection and contamination. The molecular cross-reaction between the ubiquitous non-pathogenic environmental mycobacteria ( which are harmless colonisers) and M tuberculosis is what creates the diagnostic dilemma. Since they have a similar DNA structure, the presence of either will provide a positive result in a PCR test. The PCR test is quite a dumb test - it's not able to determine which type of mycobacteria is providing a positive signal ! Sadly, most gynecologists and pathologists are completely clueless about the prevalence of environmental mycobacteria; and when the TB PCR test result comes back as positive, their knee jerk reaction is to assume that the patient has genital TB ( when in reality, the result is much more likely to be a false positive, because of contamination). Because environmental mycobacteria are so prevalent ( they are found practically everywhere - even in the water in the lab which is used to clean the instruments !), the chances of the PCR test being positive because of contamination by environmental bacteria is much higher than because the patient actually has genital TB !


Why doctors get fooled

Since the DNA PCR test is not specific only for mycobacterium tuberculosis,  it’s very easy for the doctor to get fooled.  Once the test is reported as positive , the doctor is happy that their clinical suspicion has been confirmed ; and the patient is happy that the doctor has finally found out why the endometrium is thin; or why the IVF cycles have failed . She is quite happy to take the anti TB treatment so that finally she can have a baby ! While a  few patients may get pregnant after starting the antiTB medicines, this doesn't mean that there was a cause and effect relationship between the treatment and the pregnancy. The tragedy is that often the PCR result was a false positive , and that she doesn’t have TB of the endometrium. She has been unnecessarily exposed to nine months of toxic drugs , which can damage her liver or kidneys ; and end up consuming a lot of time , during which her ovarian reserve and fertility will go down. This is why it’s so important that the diagnosis of endometrial tuberculosis should not be made based on the TB PCR reaction.

Unfortunately most gynecologists are not aware about the bacteriology of
mycobacteria . They get fooled by a positive PCR report. They fail to realize that a positive PCR report is very non specific , and in fact it’s because so sensitive that it gives rise to so many false positives,  which mislead both doctors and patients. Patients should insist that if the doctor suspects tuberculosis , they should establish the diagnosis either by histological examination; or by demonstrating the tubercle bacillus in the lab . The good news is there are lots of extremely effective new culture techniques to grow the bacillus, which are far better than the old techniques. And if neither the culture nor the histology shows a positive report , than treating the patient just because she has a thin endometrium with a positive PCR is not acceptable medical practice.

Environmental mycobacteria have always been around, so why wasn't this a problem in the past ? This is because modern PCR is so sensitive !  In the past, it was not easy to grow mycobacteria, which meant that even if a few contaminants were present in the specimen, these would fail to grow. However, PCR is  super-sensitive, and will pick up the presence of even a few molecules of mycobacterial DNA.

With a positive TB PCR, the odds are that a positive result ( in an asymptomatic patient) means that there is something wrong with the test, not with the patient . In fact, I think we should coin a new term for these mycobacteria which have created so much iatrogenic harm - Non pathogenic Ubiquitous Mycobacteria - NUM !

In summary, the diagnosis of TB of the genital tract remains notoriously difficult to make. Most patients are misdiagnosed as having TB when in fact they don't, and many are treated for no good rhyme or reason !If your gynecologist diagnoses you as having genital TB based on these unreliable tests, then please do NOT start anti-TB medicines. Please insist on getting a second opinion from a physician, preferably once who is a TB specialist !

While TB damages the fallopian tubes irreparably, it also damages the endometrium. In most women, if the diagnosis is made quickly and the infection treated promptly, the uterus heals well, partly because the old uterine lining is shed every month in the menstrual period, and a new one ( which is healthy) regenerates. However, in severe cases, the TB endometritis does not heal, and leads to scarring and severe fibrosis and adhesions. These patients usually have scanty menses - and in some of them, the periods may stop completely, because the uterine lining has been burnt out. They have severe Asherman's syndrome ( intrauterine adhesions); and this can be diagnosed by doing a hysteroscopy. Unfortunately, there is no effective treatment for this, as endometrial tissue after TB can become very avascular, and the only option for these unfortunate women is either surrogacy or adoption.

Has your doctor put you on anti TB therapy just because your TB PCR results are positive ? Please send me your medical details by filling in the form at www.drmalpani.com/free-second-opinion so that I can guide you better !

 
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