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Cervical TB Kills More But Is Rarely Diagnosed- Experts

Out of 5,236 women diagnosed with cervical cancer, at least 3, 211 women die from the disease every year. [Courtesy]

As Kenya joins the globe in creating awareness on cancer of the cervix this month, experts want emphasis put on cervical tuberculosis.

Kenyan researchers say cervical TB should be considered a differential diagnosis for cervical masses. Currently, the majority of patients in the country with cervix TB are treated as cancer of the cervix.

In a study published in the Journal of Obstetrics and Gynecology of East Africa, cervix TB is associated with high level of morbidity and mortality.

"Cervical cancer and tuberculosis remain significant health concerns," states a section of the study published on December 12.

Cervical cancer is the second most common cancer among women in Kenya. Out of 5,236 women diagnosed with cervical cancer, at least 3, 211 women die from the disease every year.

TB of the cervix accounts for 0.1 to 0.65 per cent of all tuberculosis cases.

According to the study, genital TB is documented to commonly affect the upper genital tract.

"Approximately five per cent of upper genital tract TB cases are cervical TB," reads a section of the study.

The study was done by a team of researchers drawn from the Department of Obstetrics and Gynecology and the Department of Human Pathology at the University of Nairobi.

The researchers reveal that patients having cervical TB, are reported to develop cervical lesions that appear as papillary or vegetative growth; exophytic or ulcerative lesions in the cervix.

"Tuberculosis may spread to the cervix hematogenously, lymphatically, or direct extension," adds the study.

Cervical cancer is the second most common cancer among women in Kenya. [Courtesy]

Findings on the study were based on a 37-year-old nulliparous woman who presented to a gynaecological clinic at Kenyatta National Hospital (KNH), having been referred with post-coital bleeding for examination-under-anaesthesia.

The patient had a five-year history of per vaginal bleeding, a condition that was on and off.

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She also had inter-menstrual bleeding that was associated with per vaginal discharge and dyspareunia and post-coital bleeding.

However, she had no history of cervical cancer screening, nor had she been in contact with a TB patient.

At the facility, she underwent speculum examination that revealed a friable cervical mass, and cervical cancer was suspected - she was referred to a gynaecological oncology clinic.

Doctors performed a biopsy of the cervical mass, and made a diagnosis of a cervical mass and pelvic inflammatory disease. She was scheduled for examination under anaesthesia, which revealed normal external genital with normal vaginal walls.

But mass was seen on the cervix involving the entire transformation zone, with a mobile cervix.

"The mass was friable and bled on touch. The mass did not involve the vaginal walls and parametria. The adnexa was free. The uterus was not bulky. The recto-vaginal mucosa was free. An impression of cancer of the cervix stage 1B2 was made," noted doctors during the study.

Further biopsies were taken for histological examination that demonstrated a heavily inflamed endocervical tissue. The examination within the stroma were necrotizing granulomatous inflammations with attendant giant cells of the Langerhans type.

Doctors noted that features presented during examination were consistent with cervical tuberculosis.

After diagnosis, the patient was managed with anti-tuberculous drugs- rifampicin, isoniazid, ethambutol, and pyrazinamide for six months.

One month after being put on treatment, a vaginal examination showed that the cervical mass had petered out.

The patient did not have cervical mass, even with subsequent follow-up.

The upper genital tract organs most affected by tuberculosis are the fallopian tubes at between 95 and 100 per cent. [Courtesy]

In the study, researchers noted that the upper genital tract organs most affected by tuberculosis are the fallopian tubes at between 95 and 100 per cent.

Per percentage of endometrium was ranged 50 to 60, while the ovaries were at 20 to 30 per cent and 0.1 to 0.65 per cent of TB cases.

"Genital tract tuberculosis may present with abdominal pain, constitutional symptoms, menstrual irregularities, and vaginal bleeding. It may mimic malignancies. Making a diagnosis of cervical tuberculosis may be difficult due to its atypical clinical presentation,' said researchers.

Cervical TB may be introduced to a woman by a partner with tuberculous epididymitis or disease in the genitourinary areas.

In addition, it was revealed that cervical TB as a primary infection is rare, but sputum is thought to be a transmission route, if used as a sexual lubricant.

It was explained that hematogenous spread typically affecting the pelvic organs, with the chest as a primary focus has been implicated, while spread to the cervix may be from a lymphatic or direct extension.

The primary lesion may have healed upon presentation.

"Given that 80 per cent of cases occur in the reproductive period, hormone dependence of the infection has been hypothesized,"

In a macroscopical examination, TB of the cervix appears as friable papillary or vegetative masses or hypertrophy of the cervix, which may simulate invasive cervical cancer.

Pap smears, which is gradually adopted by Kenyan women, may provide a tentative diagnosis as granulomas from endometrial lesions may appear in Pap smears.

"A suspicion for tuberculous endometritis should be raised if epithelioid cells are present in smears.

Alternatives To The Traditional Pap Smear Are On The Way. Here's What To Know.

Alternatives to the often dreaded pap smear may be on the horizon for cervical cancer screenings.

Typically, the procedure involves inserting a device called a speculum, which helps open the vaginal canal, in order for a swab to be inserted and brushed against the cervix to collect a cell sample. All this is done while laying back with feet hoisted in stirrups to keep legs spread apart.

For some, pap smears are an uncomfortable but necessary evil when it comes to health screenings. For others, it's an experience bad enough to avoid a doctor's visit, risking not detecting cancer cells early.

But this year, some health care companies are preparing to introduce self-collection options, allowing patients to skip awkward interfaces with healthcare professionals.

"Any step toward expanding screening and access in women's health in a good thing," Dr. Jillian LoPiano, OB-GYN and chief health officer at sexual and reproductive health company Wisp, told CBS News. "Women should keep open lines of communication with their doctors on if these new innovations are appropriate for them as an individual."

Labs are now able to test samples from the vaginal walls, as opposed to from the cervix itself, which has been a key change in making self-collection options possible, according to a report from The New York Times.

In May, the Food and Drug Administration approved primary human papillomavirus self-collection for cervical cancer screening in a health-care setting, allowing for a more convenient and private option — a move the American Cancer Society applauded for expanding access to screening and reducing barriers.

"Despite the benefits of cervical cancer screening, not all women and people with a cervix get screened regularly," Dr. William Dahut, chief scientific officer at the society, said in a news release at the time. "Most cervical cancers are found in people who have never had a cervical cancer screening test or who have not had one recently. That's why adding self-collection in a health-care center as a screening method for this potentially deadly disease can make a huge impact."

Tests included in the self-collection approval included Onclarity HPV, made by Becton, Dickinson and Company, and cobas HPV, made by Roche Molecular Systems.

Availability of these tests can vary depending on several factors, LoPiano said, including local regulations, healthcare infrastructure and the readiness of medical providers to implement new testing methods.

But researchers are looking to take things one step further, seeking approval for at-home self-collection tests.

After reviewing midpoint clinical trial data, for example, the FDA granted company Teal Health priority status when submitting its final study data on the company's "Teal Wand" at-home collection device for FDA review.

While screening at home is already available in other countries, The New York Times reports this method could gain approval in the United States by early next year.

LoPiano said the timeline for widespread availability of these at-home tests can vary based on regulatory approvals, manufacturing and distribution logistics.

"Typically once a test is approved by the FDA or other regulatory bodies, it may take additional time for it to become commercially available to consumers," she said. "It is tough to say when we will see these at-home tests come to market, but with the current pace of innovation we might see some options become available in the next one to two years."

Researchers Develop Four New Regimens To Treat People With Multidrug-resistant TB Meningitis

In a preliminary study with a small number of humans, rabbits and mice, researchers at Johns Hopkins Children's Center say they have developed four new regimens that have the potential to treat and save the lives of people with multidrug-resistant (MDR) tuberculous (TB) meningitis.

While TB meningitis -; which affects the brain and spine -; is extremely rare in the United States, worldwide it is believed to be the deadliest form of TB.

In a report that will be published Aug. 14 in Nature Communications, the investigators present the regimens, mainly composed of antibiotics already approved by the U.S. Food and Drug Administration (FDA) for other uses, or antibiotics currently in clinical trials. Study investigators say the regimens could be readily evaluated in new clinical studies, or used to treat people with MDR-TB meningitis on a case-by-case basis now.

According to the World Health Organization, tuberculosis remains a global public health threat, with the largest number of cases occurring in the Southeast Asian region and Africa, and is a leading killer by a single infectious agent, the tubercle bacillus. There are no FDA-approved antibiotic treatments specifically effective for tuberculous meningitis, although antibiotic treatments developed for TB of the lungs are widely available.

A previous Johns Hopkins Children's Center study led by Sanjay Jain, M.D., senior author of the new study and director of the Johns Hopkins Center for Infection and Inflammation Imaging Research, showed that the FDA-approved regimen of three antibiotics currently used for treating drug-resistant pulmonary TB -; bedaquiline, pretomanid and linezolid (BPaL) -; is not effective in treating TB meningitis, because bedaquiline and linezolid can't efficiently cross the blood-brain barrier -; a network of cells that prevents the entry of germs and toxins into the brain.

The new study used positron emission tomography (PET) scan and CT scan technology on people, rabbits and mice to show how different antibiotics penetrate the brain and other areas of the body, says Jain, who is also a pediatric infectious diseases specialist at Johns Hopkins Children's Center.

For the new experiments, researchers first created a chemically identical and scan-friendly version of the antibiotic pretomanid, and conducted a whole-body study in eight people: six healthy volunteers and two patients newly diagnosed with pulmonary TB. Using PET and CT imaging, researchers measured the antibiotic's penetration into the brain and lung tissue, and found that pretomanid penetrated the brain more than two times better than the lungs of all human subjects. Pretomanid levels in the cerebrospinal fluid (CSF) were also different from those in the brain.

We have found that CSF levels of antibiotics often have no relation to those in the brain."

Xueyi Chen, M.D., one of the study's first authors and pediatric infectious diseases fellow at the Johns Hopkins University School of Medicine

Next, using PET imaging, the researchers tested four different antibiotics (chemically identical and imageable versions) active against MDR-TB -; pretomanid, sutezolid, linezolid and bedaquiline -; and their penetration into the lung and brain tissues in mouse and rabbit models of TB meningitis.

All four antibiotics distributed well in the body, but with significantly different brain and lung tissue penetration. While pretomanid levels were significantly higher in the brain versus lung tissue, sutezolid, linezolid and bedaquiline had at least three times higher levels in lung tissue -; with bedaquiline demonstrating levels almost tenfold higher than in the brain. "Interestingly, pretomanid brain levels were double the amount in the plasma. In contrast, while bedaquiline brain levels were almost one-fifth the plasma levels, the lung levels were double the amount in the plasma. This preferential accumulation of different antibiotics in brain or lung tissues is very important, and explains why certain antibiotics are highly effective in the lungs, but not in the brain and vice versa," says Jain.

Researchers next created computer models that parallel and measure how drugs behave in living systems, so called pharmacokinetics, for pretomanid, sutezolid, linezolid and bedaquiline. Mathematical simulations based on the models were then used to predict which tissue exposures and doses would be necessary to attain therapeutic brain penetration of each antibiotic. Only pretomanid achieved therapeutic brain tissue exposures at the standard human oral dosing. Even at a dose four times the standard human oral dose, bedaquiline brain tissue exposures were predicted to be only one-third of the target levels.

Researchers found that the three pretomanid-based multidrug regimens -; BPa50LZ (bedaquiline, pretomanid, linezolid, pyrazinamide), Pa100LZ (pretomanid, linezolid, pyrazinamide), and Pa50LMxZ , (pretomanid, linezolid, moxifloxacin, pyrazinamide) -; were highly effective in treating TB meningitis in animal models when administered at human equivalent dosing. Each regimen's ability to kill bacteria in the brain was several magnitudes higher than both the standard TB treatment (R10HZ ) and the BPaL regimen (BPa50L ).

Since MDR-TB strains can also be resistant to pyrazinamide, researchers developed a fourth regimen, one without pyrazinamide: Pa100SMx (pretomanid, sutezolid, moxifloxacin). They found it was as effective as the first-line standard TB treatment, and 10 times better in reducing the bacterial burden in the brain than the BPaL regimen.

Investigators cautioned that their experiments were limited by the small quantities of the imageable version of antibiotics used per subject. However, several studies support that dosing with small quantities of a drug are a reliable predictor of a drug's bodily distribution.

Along with Jain and Chen, the study authors from Johns Hopkins include Oscar Nino-Meza, Mona Sarhan, Medha Byeonghoon Jeon, Elizabeth Tucker, Maunank Shah and Laurence Carroll. Other authors are Bhavatharini Arun and Vijay Ivaturi from the University of Maryland, Kishor Mane and Joel Freundlich from Rutgers University, and Charles Peloquin from University of Florida.

The study was funded by the U.S. National Institutes of Health R01-AI145435-A1, R01-AI153349, R01-HL131829, R21-AI149760, and K08-AI139371.

No Johns Hopkins University authors declared conflicts of interest under Johns Hopkins University School of Medicine policies.

Source:

Journal reference:

Chen, X., et al. (2024). Dynamic PET reveals compartmentalized brain and lung tissue antibiotic exposures of tuberculosis drugs. Nature Communications. Doi.Org/10.1038/s41467-024-50989-4.

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