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Adrenal Tuberculosis Diagnostic Tools and Treatment Modalities

Adrenal Tuberculosis Diagnostic Tools and Treatment Modalities

Posted By Rupa Jaiswal Posted on Aug 23, 2021

According to the 2019 Global tuberculosis report of World Health Organization (WHO), Tuberculosis (TB) still remains a major public health problem, especially in developing and underdeveloped countries. TB is one of the leading causes of death (alongside HIV) among any other causes by any single pathogen. Although globally the TB epidemic may be on decline, India still harbors the highest TB burden (27%) worldwide. TB is an infectious airborne disease caused by the organism Mycobacterium tuberculosis that generally affects the lungs (pulmonary). Extrapulmonary (any other site excluding lungs) occurrence of TB in the past decade has been on rise accounting for every one in five of the newly diagnosed TB patients and commonly affect sites such as lymph nodes, bone and joints, urogenital tract, and meninges, etc. TB infection of endocrine glands including the hypothalamus, pituitary, thyroid and adrenals have also been reported. TB bacteria once acquired by an individual may remain latent in their body or manifest in active TB disease which can have fatal consequences.

Adrenal Tuberculosis Diagnostic Tools and Treatment Modalities

What is adrenal tuberculosis?
Located on top of each kidney, adrenal glands produce steroid hormones Cortisol, aldosterone, sex hormones and catecholamines. These hormones help in regulation of metabolism, blood pressure, respond to stress and immune system suppression. Among all other endocrine glands, adrenal glands are the most commonly involved. Adrenal glands may be directly or indirectly affected by TB infection causing tissue damage and alteration in endocrine function. Such a condition is also known as Tuberculous adrenalitis. Diagnosis of adrenal TB is often overlooked or delayed. Immunocompromised individuals happen to be at greater risk for developing adrenal TB, however, lately individuals with normal immune function are also found to manifest such infection. Early diagnosis of adrenal TB is difficult due to no prominent clinical symptoms at early stages of the disease and clinical manifestations due to infection may take some years to become apparent. Study by Lam et al. reported 6% of overall patients with active TB to have adrenal involvement. Similarly, adrenal involvement have been noted in both acute and chronic TB infections. Immunocompromised patients (AIDS) are more prone to these infections. An increased risk of adrenal TB persists in patients with previous history of TB infection of lungs (pulmonary) or pleural effusion (extrapulmonary).

Alternatively adrenal TB may occur together with the presence of other extra-adrenal TB .
Pathology and Clinical Presentations Mycobacterium disseminates to the adrenal gland hematogenously or lymphogenously where it can reside without noticeable clinical symptoms for many years. Adrenal TB is a major cause of adrenal insufficiency (Addison's disease). Adrenal insufficiency was first described by Thomas Addison in the year 1855 in patients with M. tuberculosis infection in the adrenal glands. Adrenal insufficiency is a condition wherein adrenal glands do not produce sufficient amount of steroid hormones. Adrenal insufficiency thus may result in unspecific clinical features like weakness, fatigue, anorexia, weight loss, nausea, vomiting, abdominal pain, hypotension, and skin hyperpigmentation. Symptoms of adrenal insufficiency occur only when almost 90% of adrenal gland is destroyed. Hence most of the reported cases have been found to present adrenal TB only after 10-15 years after initial infection. If left untreated, adrenal insufficiency due to TB may result in increased risk of mortality. Hence,adrenal TB needs to be identified early to facilitate a prompt and aggressive treatment for complete recovery of adrenal function.

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Bilateral involvement of adrenal glands is commonly seen in patients with adrenal TB. Histological examination of adrenal glands with TB show a peculiar pattern. These include presence of granulomas (caseating or non-caseating), enlarged adrenal glands with peripheral marginal enhancement, granulomatous inflammation with Langhans-type giant cells, mass lesions secondary to the development of cold abscesses and atrophy of adrenal gland.

Diagnostic Procedures and Findings for Adrenal Tuberculosis
Radiographic imaging serves as a useful non-invasive solution to facilitate diagnosis of adrenal TB. These include
A) Computed Tomography (CT): It is the go to modality of choice for identification and characterizing the patterns of TB involvement in the adrenal gland. Two types i.e. non- contrast and contrast-enhanced CT are available. Typical radiologic features include bilateral enlargement of the adrenal glands (generally asymmetrical) that show peripheral enhancement and central necrotic areas in acute or sub-acute phases of the TB disease. In the later stages, the size of the gland diminishes and is replaced by gross calcifications.
B) Magnetic Resonance Imaging (MRI): It has superior contrast resolution and tissue characterization potential can reveal bilateral involvement of adrenal masses with prolonged enhancement.
C) Positron Emission Tomography (PET): Use of "F fluorodeoxyglucose guided PET scan (FDG-PET) can reveal presence of active TB infection based on the uptake of FDG in adrenal glands.

What are Adrenal Tuberculosis Diagnostic Tools?
Adrenal Biopsy: Adrenal biopsy is usually the last resort in patients to prove adrenal involvement by TB when CT and MRI is not conclusive. Subsequent adrenal biopsy specimens may reveal necrosis, infiltration of histiocytes and presence of granulomas. Biopsy will result in a definitive diagnosis.

Lab tests: Measurement of basal serum cortisol levels or an Adrenocorticotropic Hormone (ACTH) stimulation test will aid in prompt evaulation of adrenal function to rule out adrenal insufficiency. Recently, focus has shifted more on the use of Interferon Gamma Release Assay (GRA) which detects both latent and active TB infection. Tuberculin skin test (Mantoux) is a conventional screening test majorly used for detecting TB worldwide. Other phenotypic tests such as Acid Fast Bacilli (AFB) smear (microscopy) and AFB culture and genotypic test such as TB PCR, GeneXpert or Line Probe Assay may also be used for diagnosis.

Endocrinology and Associated Immunological Changes M. tuberculosis is an acid-fast bacterium with highly impermeable cell membrane. Exposure to Lipoarabinomannan (LAM), component of the cell wall of M. tuberculosis, stimulates the human T lymphocytes to secrete a wide range of cytokines. Thi cells confer cell-mediated immune responses with the help of excessive release of cytokines like interferon (IFN-Y, IL-2 and tumor necrosis factor (TNF-a) that facilitate macrophage aggregation and granuloma formation to contain the TB infection. On the other hand, Th2 cells are required for immunity against TB (humoral immunity) and confer more of anti-inflammatory response. In addition, released cytokines IL-1, IL-2, IL-6 and TNF-a further activate the Hypothalamic-pituitary-Adrenal axis (HPA axis). The HPA axis is composed of the hypothalamus, the pituitary gland and the adrenal glands and is a major regulator of endocrine stress response. Stress induced by TB infection will manifest an increase in the functioning of the HPA-axis leading to an overall release of Corticotropin Releasing Factor (CRF) from the hypothalamus. CRF in turn activates ACTH secretion from the anterior pituitary gland. ACTH mediates synthesis and release of cortisol (glucocorticoids) from adrenal cortex. Thus, adrenal glands are maximally stimulated by endogenous ACTH in response to TB infection leading to high plasma cortisol levels. Exogenous ACTH may therefore fail to further stimulate the adrenal glands to secrete Cortisol. Adrenal glands get enlarged not only due to TB infection but also due to accumulation of ACTH and cortisol in response to stress. Both Th1 and Th2 cell types regulate each other which is important in the final balance of host resistance against pathogens. Hormone dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS), released from the anterior pituitary gland, have an antiglucocorticoid effect. Increased cortisol levels and stress shifts the balance towards a Th2 response. This shift, along with age-related changes in DHEAS, enhances the infectivity of M. tuberculosis. Thus, T cell dysfunction due to high cortisol and low DHEAS levels may be responsible for immunologically-mediated tissue damage in TB. Low levels of DHEAS often occur in patients with TB, suggesting a role for both increased cortisol and decreased androgens in the pathogenesis of the disease.

Available Treatment Modalities Hormone replacement therapy: A long-term low dose oral glucocorticoid (hydrocortisone) and mineral corticoid (fludrocortisone) replacement therapy for management of adrenal insufficiency.

Anti-tuberculous therapy: First line of standard therapy include use of a 4-drug regimen of isoniazid, rifampicin, Pyrazinamide and ethambutol for a fixed duration of months. This may accompany periodic radiological examination to evaluate the prognosis.

Adrenalectomy: Sometimes adrenal insufficiency due to TB infection may result in irreversible damage and loss of adrenal function. In such cases, removal of one (unilateral) or both (bilateral) adrenal glands is opted with lifelong supplementation of adrenal hormones.

Tuberculosis (TB) remains to be a substantial global health challenge. India is the country with the highest burden of both, TB and Multidrug-resistant TB (MDR-TB) worldwide and accounts for about a quarter of the global TB burden. Among the notified cases of pulmonary TB each year, there are an estimated 79,000 MDR-TB patients. Therefore, along with addressing the disease burden caused by drug-sensitive TB, it is crucial to tackle the increasing threat of MDR-TB and latent TB infection (LTBI) as well.

The most important strategy to control TB is early detection and the appropriate treatment of infectious cases. India is constantly trying to control the two primary routes required to reduce TB incidence and death, that are diagnosis and treatment. This has brought about several promising advances in diagnostic centre recently, which has led to a significant improvement in the overall scenario. This article provides an overview on the paradigm shift of TB diagnosis from conventional microscopy to next generation sequencing techniques.

TB Diagnosis - The Journey On 24" March 1882, marked as World Tuberculosis Day, Robert Koch declared the discovery of Tubercle bacillus. He used the tissues infected with TB to investigate the bacteria. After several trial and error in the different staining techniques and the stains used, he found the appropriate technique which made it possible to observe the rod shaped TB bacilli. This led to the genesis of TB diagnosis and served as the basis for the conventional phenotypic procedures.

Laboratory Techniques Phenotypic Testing Laboratory plays a decisive role in TB diagnosis and identification, and Drug Sensitivity Testing (DST) of Mycobacterium tuberculosis (MTB). Laboratories used only microscopy and culture- based diagnosis for a long time.

Novel Microscopy and Imaging Tools Sputum Smear Microscopy (SSM) is the primary diagnostic method for identifying pulmonary TB and is based on direct visualization of acid-fast bacilli. Conventional SSM has low cost, limited infrastructural needs, and 20-30 slides can be read per day by trained microscopists. However, it has highly variable sensitivity (20-80%) and poor accuracy among individuals with HIV infection. This led to the use of fluorescent dyes over conventional staining, thus enabling easier reading at lower magnification. Also, fluorescent microscopy (FM) has about 10% more sensitivity than light microscopy. But traditional FM microscopes faced challenges like high cost and dark room requirement which were overcome by Light Emitting Diode (LED) microscopes like the Primo Star iLED and CyScope TB Fluorescence Microscope.

Culture-Based Technologies Cultures are sensitive and can detect even low levels of MTB. Hence, they are considered the gold standard for TB diagnosis and DST. However, they have some important limitations including slow turnaround time, requirement of bio-safety level 3 environment and trained personnel for the processing and monitoring of culture specimens.

Solid cultures provide limited clinical value and are time-consuming whereas the use of liquid culture media allows for more rapid results along with upto 10% more sensitivity than solid cultures. Liquid cultures therefore play an important role in identifying microbial resistance. Automated liquid culture platforms, specifically the mycobacterial growth indicator tube Bactec MGIT, scans processed MGIT sputum bottles and determines MTB growth by measuring 0, depletion. Another system, BacT/Alert 3D measures MTB levels based on CO, accumulation. However, liquid culture systems are more complex and expensive as compared to solid culture and can have high contamination rates.

Due to the slow growth of mycobacteria, laboratory procedures may require 3-4 weeks or longer to yield results. This made it necessary to search for new and rapid diagnostic methods.

Molecular Techniques - Genotypic Testing In the beginning of the 90s, molecular-based diagnosis became available, providing rapid detection, identification and DST of MTB. Nucleic Acid Amplification Tests (NAATS) amplify genome-specific targets through different methods which include Polymerase Chain Reaction (PCR), Transcription- mediated Amplification (TMA), Loop-mediated Amplification (LAMP), Nucleic Acid Sequence-based Amplification (NASBA), and Strand Displacement Amplification (SDA).

Line Probe Assays (LPAs) LPAs extract the genomic DNA, select DNA targets, and label them with biotin to create amplicons. These amplicons are then applied to strips with specific oligonucleotide probes. Subsequently, bound amplicons are detected through attachment of a label and visualization of a dark band against a scoring chart. These assays allow for identification of mutations, thereby aiding in DST. However, due to the high sensitivity of the test, any contamination may alter test results, and highly trained personnel are required to run the assay, thus limiting the use of LPAs in reference or intermediate laboratories.

The Genotype MTBDRplus assay was endorsed by the WHO for rapid detection of MDR-TB in smear-positive Samples and culture isolates. Another test, the Genotype MTB-DRsi, allows for the detection of resistance of second-line drugs to increase the diagnosis of Extensively Drug Resistant TB (XDR-TB) and MDR-TB.

Nucleic Acid Amplification Tests (NAATS) Commercial NAATs for Reference and Intermediate-tier Laboratories. The first NAATS designed for reference and intermediate-tier laboratories included Hologic Gen-Probe and COBAS TaqMan MTB test, which targeted highincome countries and their markets.

Microarray Platforms- TruArray is a microarray platform used for MDR-TB diagnosis, which is able to distinguish between MTB and Mycobacterium avium through the use of a single tube PCR reaction, which incorporates a fluorescent label to facilitate visualization. However, none of the microarray products are adequately validated.

Automated NAATS. Modular, cartridge-based NAATs simplify and automate all the steps involved in NAATs, and increase bio-safety and ease of use. Xpert MTB/RIF, the first such TB NAAT utilizes Real Time Polymerase Chain Reaction and is a combined TB and rifampicin (RIF) resistance assay. All parts of the test are performed on a single cartridge, which is able to produce results in approximately two hours. In 2013, Xpert was endorsed by WHO, indicating that it should be used instead of conventional microscopy and culture for initial diagnosis in adults and children suspected with TB. It was also endorsed for specific types of extrapulmonary samples i.e., CSF, lymph nodes, and tissues) based on good accuracy data. Based on a meta-analysis, Xpert has a sensitivity of 89% and a specificity of 99% for detecting pulmonary TB, and a sensitivity of 95% and specificity of 98% for RIF resistance. Recently, Xpert MTB/RIF Ultra was launched, a next-generation test with increased sensitivity to aid TB detection in smear-negative patients.

NAATs for lower-tier Laboratories and Microscopy Centers- Most high-TB burden countries primarily use Xpert as a rapid DST tool, mainly due to its high cost. As the technology is challenging to deploy at the microscopy center level, several tools are being developed that can be used in lower-tier laboratories, specifically in high-TB burden countries like India. Such tools include the TrueNAT assay, Genedrive platform, and Easy NAT and are already on the market but the evidence base is weak, and further evaluations are necessary for policy development.

Sequencing Methods Next Generation Sequencing (NGS) methods led to large amounts of DNA data being processed, profiled, characterized, and evaluated for protein interactions. They enable both high-throughput and low-cost DNA sequencing, and will be particularly useful for assessing resistance to newer TB drugs. Shotgun sequencing is being used along with next-generation methods. NGS also holds a lot of potential for diagnostic and broader surveillance. It was found by a molecular epidemiologic study that using sequencing information gave better contact tracing information regarding TB infection compared to classic genotyping

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Whole genome sequencing allows for the identification of de novo mutations associated with phenotypic drug resistance. For example, a study showed that second-line drugs were exerting selection effects for mutations which induce drug resistance. Characterization of these new resistant strains will allow for the design of diagnostics that can screen for specific mutations. Novel sequencing techniques also allow for heteroresistance detection, which may be misclassified using non-molecular methods. Along with these tools, computational algorithms are utilized to analyze data, and cloudbased systems to share data with larger data repositories.

TB Diagnosis in India - Recent Advances In 2018, Universal Drug Susceptibility Testing was implemented whereby Drug Resistance and Drug Susceptibility tests were made available to patients throughout the country, free of cost. Around 24 lakh CBNAAT tests were performed and approximately 66,000 RIF Resistant cases were detected early.

TrueNat MTB/Rif test is an indigenously developed technology in 2018, by the Indian firm MolBio Diagnostic Pvt. Ltd. under the "Make in India" initiative. It is a new molecular test that can diagnose TB in an hour and test for RIF resistance as well. It can be used as an initial test for TB, at the same health system level as Xpert MTB/RIF. This led to further decentralisation and increased access to highly sensitive molecular tests with augmented capacity for resistance testing at the peripheral level.

Gaps in TB case finding and the emergence of drug-resistant TB have created an urgent need for robust and accurate diagnostics. This led to a paradigm shift to newer tests such as Xpert MTB/RIF that has proved to be useful in increasing case detection and reducing the time to treatment. Their use should increase countries to reach the goal of universal DST. Although these new molecular techniques are useful for a rapid result, providing preliminary information and improving patient management, they cannot replace the conventional methods. Hence, culture-based diagnosis still remains the gold standard for the diagnosis and follow up on TB.

Focus TB powered by Thyrocare offers MTB detection testing using both Phenotypic Testing including Microscopy, MGIT culture with DST and Genotypic Testing including LPA, GeneXpert, TB-PCR at affordable rates.

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