http://www.drmalpani.

com/articles/tuberculosis-and-infertility

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 its 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, its 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 cant 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 doesnt 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, its 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 doesnt 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 its 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 its 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 !