Hubbry Logo
Extrapulmonary tuberculosisExtrapulmonary tuberculosisMain
Open search
Extrapulmonary tuberculosis
Community hub
Extrapulmonary tuberculosis
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Extrapulmonary tuberculosis
Extrapulmonary tuberculosis
Extrapulmonary tuberculosis
View on Wikipedia
from Wikipedia
CT scan of peritoneal tuberculosis, with thickened omentum and peritoneal surfaces[1]

Extrapulmonary tuberculosis is tuberculosis (TB) within a location in the body other than the lungs. It accounts for an increasing fraction of active cases, from 20 to 40% according to published reports,[2] and causes other kinds of TB.[3][4] These are collectively denoted as "extrapulmonary tuberculosis".[4] Extrapulmonary TB occurs more commonly in immunosuppressed persons and young children. In those with HIV, this occurs in more than 50% of cases.[4] Notable extrapulmonary infection sites include the pleura (in tuberculous pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system (in scrofula of the neck), the genitourinary system (in urogenital tuberculosis), and the bones and joints (in Pott disease of the spine), among others.

Infection of the lymph nodes, known as tubercular lymphadenitis, is the most common extrapulmonary form of tuberculosis.[4][5] An ulcer originating from nearby infected lymph nodes may occur and is painless. It typically enlarges slowly and has an appearance of "wash leather".[6]

Histopathological specimen showing tuberculosis of the duodenum. Lamina propria is stuffed with wall-to-wall histiocytes. This Kinyoun carbolfuchsin stain shows innumerable acid-fast bacilli.

When it spreads to the bones, it is known as skeletal tuberculosis,[4] a form of osteomyelitis.[7] Tuberculosis has been present in humans since ancient times.[8]

Central nervous system infections include tuberculous meningitis, intracranial tuberculomas, and spinal tuberculous arachnoiditis.[4]

Gastrointestinal

[edit]
See also: Paratuberculosis

Abdominal infections include gastrointestinal tuberculosis (which is important to distinguish from Crohn's disease, since immunosuppressive therapy used for the latter can lead to dissemination), tuberculous peritonitis, and genitourinary tuberculosis.[4]

A potentially more serious, widespread form of TB is called "disseminated tuberculosis", also known as miliary tuberculosis.[9] Miliary TB currently makes up about 10% of extrapulmonary cases.[10]

Urogenital

[edit]
Main article: Urogenital tuberculosis

Urogenital tuberculosis represents the second most frequent form of extrapulmonary tuberculosis, accounting for 30-40% of cases. Primarily affecting males in their fourth and fifth decades, decades after initial infection and pulmonary manifestations, the disease reactivates from bacteria colonizing the kidneys, prostate, and/or epididymis, with subsequent descending infection through the renal collecting system. The insidious progression typically produces symptoms only at advanced stages, and is frequently misdiagnosed as a common UTI, leading to diagnostic delay and organ destruction. Key clinical presentations include storage symptoms (frequency, nocturia, urgency) in 50.5% of cases, hematuria (35.6%), lumbar or flank pain (34.4%), and scrotal abnormalities (48.9% of males). Diagnosis requires culture or PCR detection of Mycobacterium tuberculosis in urine, supplemented by imaging studies showing characteristic findings such as calyceal irregularities, renal infundibular stenosis, and multiple ureteral strictures. If untreated, the condition can progress from unilateral renal involvement to fibrotic bladder damage with contraction, and potentially bilateral kidney involvement through vesicoureteral reflux, culminating in end-stage renal failure.[11]

Pleural effusion

[edit]

This condition is one of the common forms of extrapulmonary tuberculosis. It occurs during acute phases of the disease, with fever, cough, and pain while breathing (pleurisy). Pleural fluid usually contains mainly lymphocytes and the Mycobacterium bacteria. Gold standard of diagnosis is the detection of Mycobacterium in pleural fluid. Other diagnostic tests include the detection of adenosine deaminase (above 40 U/L) and interferon gamma in pleural fluid.[12]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Extrapulmonary tuberculosis

View on Grokipedia
from Grokipedia
Extrapulmonary tuberculosis (EPTB) is a form of disease caused by the bacterium that involves and in organs, tissues, or structures other than the lungs, such as the lymph nodes, pleura, , genitourinary tract, bones and joints, , or . Unlike pulmonary tuberculosis, which primarily affects the and is the most common manifestation, EPTB often presents with nonspecific symptoms depending on the site of involvement and can be more challenging to diagnose due to its extrathoracic location. Globally, EPTB accounts for approximately 16% of all notified tuberculosis cases, with an estimated 1.33 million new EPTB episodes in 2024 based on the 8.3 million total new and relapse TB notifications reported to the (WHO) as of the 2025 Global Tuberculosis Report. The proportion of EPTB varies by region and population, ranging from 8% in the Western Pacific to 25% in the South-East Asia Region, and it is more prevalent among people living with (up to 50% of TB cases in high-HIV-burden settings), children, and females. Incidence rates are higher in low- and middle-income countries, where limited access to diagnostics contributes to underreporting, and EPTB often disseminates from a primary pulmonary focus via hematogenous or lymphatic spread. The most common sites of EPTB are the (particularly cervical and intrathoracic lymph nodes, accounting for 20-40% of cases) and pleura (15-20%), followed by abdominal organs (e.g., , intestines), genitourinary tract, musculoskeletal system (e.g., spine, known as ), and (e.g., ). Diagnosis typically requires a combination of clinical evaluation, imaging, microbiological confirmation (e.g., via acid-fast smear, , or nucleic acid amplification tests on tissue/fluid samples), and showing caseating granulomas, though yields are lower than in pulmonary TB due to paucibacillary nature. Treatment follows standard anti-TB regimens (e.g., isoniazid, rifampin, pyrazinamide, ethambutol for 6-9 months), but duration may extend for certain sites like bone or meningeal involvement, with adjunctive therapies such as corticosteroids for severe cases. EPTB carries significant morbidity, including chronic disability and higher mortality in disseminated forms, underscoring the need for early detection and integrated management in high-burden settings.

Introduction

Definition and Classification

Extrapulmonary tuberculosis (EPTB) is defined as an infectious disease caused by that involves organs other than the lungs, encompassing any bacteriologically confirmed or clinically diagnosed case of (TB) affecting extrapulmonary sites, either in isolation or without concurrent active pulmonary involvement. According to (WHO) guidelines, cases with both pulmonary and extrapulmonary manifestations are classified primarily as pulmonary TB for reporting purposes, thereby distinguishing EPTB as TB with primary involvement of non-pulmonary sites. Globally, EPTB accounts for approximately 16% of all notified TB cases, representing a significant proportion of the disease burden. EPTB is classified primarily based on anatomical sites of involvement, with common forms including lymphatic (e.g., cervical lymphadenitis), pleural, skeletal (e.g., spinal or osteoarticular), genitourinary, abdominal (e.g., peritoneal or intestinal), and tuberculosis. Additional classification considers disseminated or miliary TB, a severe hematogenous form of EPTB characterized by widespread micronodular lesions across multiple organs, often resulting from uncontrolled bacillary dissemination. These site-based and dissemination-based systems facilitate clinical management and epidemiological tracking, aligning with WHO frameworks that emphasize organ-specific diagnostics and treatment considerations. Historically, extrapulmonary manifestations of TB were first systematically described in the , building on earlier observations of conditions like scrofula (cervical lymph node TB), with René Laennec's 1819 treatise on providing detailed accounts of various extrapulmonary sites. Modern WHO classification, established in the late , further refines this by separating EPTB from pulmonary TB in to improve case detection and reporting accuracy. EPTB is notably more prevalent among immunocompromised individuals. HIV co-infection increases the risk of developing active TB by up to 20-fold compared to those without , and EPTB comprises a higher proportion of TB cases in people living with due to impaired cellular immunity facilitating bacillary spread beyond the lungs. This heightened susceptibility underscores the interplay between EPTB and underlying host factors in disease presentation.

Epidemiology and Risk Factors

Extrapulmonary tuberculosis (EPTB) accounts for approximately 16% of notified cases globally, with about 1.3 million EPTB notifications out of 8.2 million total new and relapse TB notifications in 2023. This proportion is higher in high-income countries, where improved control of pulmonary TB leads to a relatively greater share of EPTB diagnoses, often exceeding 20-25% of cases. Regionally, the proportion of EPTB among notified cases varies, ranging from 7% in the Western Pacific Region to 23% in the Region, with 20% in South-East Asia and 12% in the African Region (2023 data). , bearing about 26% of the global TB burden in 2023, contributes a substantial share of worldwide EPTB cases, driven by high and limited healthcare access in some areas. EPTB notifications are also rising among migrants and refugees, particularly in and , due to delayed screenings and socioeconomic vulnerabilities in these groups. Demographically, EPTB is more prevalent in females, with a 2:1 female-to-male ratio specifically for lymphatic forms, attributed to differences in immune responses and healthcare-seeking behaviors. It disproportionately affects children under 5 years and the elderly, who face higher dissemination risks from primary infection. In HIV-TB co-infected patients, EPTB comprises 20-30% of cases, compared to 15-16% overall, due to impaired cellular immunity facilitating hematogenous spread. Beyond , key non-HIV risk factors include , which weakens host defenses and promotes extrapulmonary dissemination; diabetes mellitus, increasing EPTB risk threefold through hyperglycemia-induced immune dysregulation; and iatrogenic from corticosteroids or inhibitors. exacerbates transmission and progression to EPTB in vulnerable populations. Post-2020, disruptions from the have contributed to increases in EPTB notifications in some settings due to delayed diagnoses and more advanced disease presentations.

Pathogenesis

Transmission Pathways

Extrapulmonary tuberculosis (EPTB) primarily originates from the inhalation of aerosolized bacilli, transmitted as droplet nuclei (1-5 microns in size) generated by individuals with active pulmonary tuberculosis through coughing, sneezing, or speaking. These droplets, containing as few as 10 viable bacilli, are inhaled and deposit in the alveoli, establishing a primary pulmonary focus of . In most cases (approximately 90%), the immune response contains the infection as (LTBI), but 5-10% of infections progress to active disease, with dissemination to extrapulmonary sites occurring via hematogenous or lymphatic routes. The routes of spread from the initial pulmonary site to extrapulmonary locations include direct extension from the lungs, such as to the pleura in cases of pleural tuberculosis, and more commonly, lymphohematogenous during the primary phase, which is particularly prevalent in young children due to immature immune responses. In adults, EPTB often results from reactivation of dormant in latent foci seeded during earlier hematogenous spread, leading to localized disease in organs like the lymph nodes, bones, or genitourinary tract. represents an extreme form of widespread hematogenous , where shower through the bloodstream, affecting multiple organs simultaneously and often arising from a high-bacillary-load primary . A high bacillary load during primary significantly elevates the likelihood of EPTB by overwhelming initial immune containment, facilitating broader dissemination; for instance, strains with enhanced or cavitary pulmonary lesions harboring thousands of per milliliter increase this risk. Environmental factors, such as prolonged close contact in crowded, poorly ventilated settings in TB-endemic regions, promote the initial leading to pulmonary and subsequent extrapulmonary spread, though most EPTB forms are not directly contagious person-to-person, with the notable exception of laryngeal tuberculosis. Immunocompromising conditions like further heighten dissemination risk, with up to 40% of TB cases in HIV-positive individuals involving extrapulmonary sites.

Mechanisms of Extrapulmonary Dissemination

Extrapulmonary tuberculosis arises primarily from the dissemination of beyond the lungs, a process facilitated by the bacterium's ability to survive intracellularly within host macrophages. Upon inhalation and phagocytosis by alveolar macrophages, M. tuberculosis evades destruction by inhibiting phagosome-lysosome fusion, a critical step in phagosomal maturation. This inhibition is mediated by lipoarabinomannan (LAM), a that suppresses and prevents the recruitment of class III phosphatidylinositol 3-kinase (hVPS34), thereby blocking the production of phosphatidylinositol 3-phosphate (PI3P) essential for lysosomal fusion. Additionally, the secreted SapM dephosphorylates PI3P, further arresting phagosome maturation and allowing bacterial replication within the modified . This intracellular persistence enables M. tuberculosis to form granulomas, where it replicates protected from host defenses. Hematogenous spread occurs during primary bacteremia, shortly after initial lung infection, when viable enter the bloodstream and seed distant organs. Infected macrophages and monocytes act as "Trojan horses," transporting M. tuberculosis across the alveolar barrier via diapedesis and into the circulation, often without eliciting strong immediate immune responses. The ESAT-6 secretion system (ESX-1) and culture filtrate protein 10 (CFP10), encoded by RD1 genes, promote escape from phagosomes and facilitate dissemination from granulomas into the bloodstream. This early systemic dissemination precedes adaptive immunity and can establish foci in sites such as lymph nodes, pleura, and , even in immunocompetent hosts. Immune modulation plays a pivotal role in enabling dissemination, as M. tuberculosis exploits host responses to promote bacterial spread. Delayed-type (DTH), driven by T-cell mediated , leads to caseation within , liquefying necrotic tissue and releasing into surrounding tissues or vasculature. In immunocompromised states, such as infection, elevated tumor necrosis factor-alpha (TNF-α) levels—paradoxically, a key in maintenance—can exacerbate dissemination when dysregulated; neutralization of TNF-α in animal models increases extrapulmonary bacterial loads by impairing integrity. Furthermore, M. tuberculosis inhibits interferon-gamma (IFN-γ) signaling through mannose-capped LAM and myeloid differentiation factor 88, dampening activation and facilitating unchecked spread. Site-specific tropism determines the predilection of M. tuberculosis for certain extrapulmonary locations, mediated by bacterial adherence proteins that interact with host components. Fibronectin-binding proteins, such as those in the antigen 85 complex (Ag85), enable adhesion to in tissues like lymph nodes and , promoting invasion and colonization. The heparin-binding (HBHA) adhesin further targets non-phagocytic cells in the and other sites, enhancing epithelial and tissue-specific during hematogenous transit. Phenolic glycolipids (PGLs) also contribute to , with strains producing PGL showing increased affinity for brain tissue, leading to higher burdens. Following dissemination, M. tuberculosis can enter a latent state in extrapulmonary sites, persisting dormantly within granulomas for years or decades. Latency involves metabolic and immune by host CD4+ and CD8+ T cells, but reactivation occurs under conditions of immune stress, such as aging, HIV-induced , or TNF-α blockade, allowing dormant to resume replication and cause active disease. Approximately 15% of reactivations manifest as extrapulmonary tuberculosis without concurrent pulmonary involvement, highlighting the bacterium's ability to independently reactivate in seeded sites.

Clinical Manifestations

Lymphatic Tuberculosis

Lymphatic tuberculosis, also known as , is the most common form of extrapulmonary tuberculosis (EPTB), accounting for approximately 25-40% of all EPTB cases worldwide. It predominantly affects the , often referred to as scrofula, which represent up to 80% of cases, while axillary and inguinal nodes are less frequently involved. This condition is more prevalent in children and immunocompromised individuals, particularly those living with , where EPTB accounts for up to 50% of tuberculosis cases due to impaired cellular immunity. In high-burden regions, it constitutes a significant proportion of peripheral etiologies, often mimicking other infectious or neoplastic processes. Pathologically, lymphatic tuberculosis is characterized by granulomatous in the affected lymph nodes, featuring epithelioid cells, multinucleated giant cells, and central . The infection typically arises from hematogenous or lymphatic spread from a primary pulmonary focus, leading to progressive nodal enlargement. In early stages, a hallmark is the formation of a "cold abscess"—a fluctuant collection of caseous without significant overlying , warmth, or acute systemic fever, distinguishing it from pyogenic abscesses. As the disease advances, nodes may become matted together due to surrounding , and suppuration can occur without prominent constitutional symptoms initially. Clinically, patients often present with painless, slowly enlarging swelling of the lymph nodes, most commonly in the cervical chain, leading to a firm, rubbery mass that may adhere to overlying skin. In chronic cases, particularly if untreated, nodes can soften, rupture, and form fistulas or sinus tracts draining caseous material, resulting in characteristic scarring and cosmetic . Systemic symptoms such as low-grade fever, , or are present in about 30-40% of cases, more frequently in disseminated disease or HIV-co-infected patients. Children may exhibit more indolent progression, while adults in HIV-endemic areas often show multifocal involvement. Unique complications include chronic sinus tract formation, which can lead to secondary bacterial or permanent lymphatic obstruction and scarring. Historically, scrofula was managed surgically in the pre-antibiotic era through or excision of affected nodes, as medical options were limited to supportive care.

Pleural Tuberculosis

Pleural tuberculosis accounts for approximately 20-25% of all cases of extrapulmonary (EPTB), representing one of the most common manifestations outside the lungs. It typically presents as a unilateral , particularly in young adults, and is often the initial sign of infection in endemic regions. This form arises primarily through hematogenous dissemination of from a primary pulmonary focus, leading to involvement of the pleural space. The of pleural tuberculosis involves a delayed-type reaction to mycobacterial antigens that seed the pleural space, resulting in an inflammatory characterized by lymphocytic predominance. This reaction increases and recruits immune cells, producing a protein-rich fluid with elevated (ADA) levels, where values greater than 40 U/L are highly suggestive of tuberculous etiology. The is typically an meeting Light's criteria, with pleural fluid protein exceeding 3 g/dL and lymphocytes comprising more than 50% of the cellular content, aiding in differentiation from other causes. Patients with pleural tuberculosis commonly experience acute pleuritic , dyspnea, and a non-productive , often accompanied by systemic symptoms such as fever and . is rare, as the process is confined to the pleura without significant parenchymal involvement. The condition manifests in various forms, with tuberculous pleural effusion being the most prevalent, presenting as an acute, lymphocyte-predominant accumulation of fluid. In chronic or untreated cases, organization of the can lead to , causing pleural thickening and restricted lung expansion. Less commonly, progression to tuberculous occurs, characterized by frank pus in the pleural space due to direct bacterial proliferation. Diagnosis relies heavily on pleural fluid analysis, which demonstrates the characteristic high protein and lymphocytic profile, with ADA testing offering high sensitivity in resource-limited settings. Microbiological confirmation through acid-fast smear, culture, or amplification tests from the fluid provides definitive evidence, though yields vary. Imaging, such as chest radiography or computed tomography, reveals the unilateral effusion, supporting clinical suspicion in at-risk populations.

Genitourinary Tuberculosis

Genitourinary tuberculosis (GUTB), also known as urogenital tuberculosis, represents a form of extrapulmonary (EPTB) that primarily involves the urinary tract, including the kidneys, ureters, and , as well as the genital organs in both sexes. It arises from hematogenous dissemination of from a primary pulmonary focus, often remaining latent for years before manifesting. In endemic areas, GUTB accounts for 20-40% of all EPTB cases, making it the second most common site after lymphatic involvement, with over 90% of global cases occurring in developing countries. The infection typically originates in the kidneys and spreads contiguously to the lower urinary tract and genitalia via the , affecting males twice as frequently as females and peaking in incidence around age 40. Pathologically, GUTB begins with granulomatous inflammation in the or papillae, forming caseating granulomas that erode into the collecting system and lead to calyceal distortion, papillary necrosis, and . This renal involvement is often bilateral (in up to 73% of cases at autopsy) and progresses to chronic tubulointerstitial , scarring, and , sometimes resulting in a non-functioning "autonephrectomy" or "putty ." In the , the infection causes ulcerative lesions that heal with , leading to and reduced capacity; ureteral strictures may also develop, causing . Genital tract involvement includes endometrial and granulomas in females (affecting over 90% of genital cases), while in males, it manifests as , , or seminal vesiculitis. Clinically, GUTB is frequently asymptomatic in its early stages, delaying diagnosis and allowing silent progression. When symptomatic, patients commonly present with urinary tract irritation, including dysuria, urinary frequency, and sterile pyuria—a hallmark finding characterized by white blood cells in the urine without bacterial growth on standard cultures, occurring in up to 90% of cases. Hematuria is reported in 50-70% (microscopic in most, gross in about 10%), often accompanied by flank or suprapubic pain. In females, endometrial tuberculosis can cause infertility, menstrual irregularities, and pelvic pain; in males, epididymitis presents as scrotal swelling or pain, contributing to infertility in up to 10% of cases. Without treatment, the disease advances to obstructive uropathy, chronic kidney disease, and end-stage renal disease (ESRD) in 5-7% of renal tuberculosis cases overall, though rates may reach higher in bilateral untreated involvement. Diagnosis of GUTB is challenging due to its insidious onset and non-specific symptoms, often mimicking urinary tract infections, malignancies, or . A key diagnostic clue is sterile on , prompting further investigation with acid-fast (AFB) smear of , which shows positivity in only 20-50% of cases, necessitating multiple (3-5) early-morning samples for improved yield. remains the gold standard, with sensitivity of 80-90% and specificity of 100%, though results may take 6 weeks; molecular tests like Xpert MTB/RIF offer faster detection with 70-90% sensitivity in . Imaging, such as intravenous pyelography or CT urography, reveals characteristic calyceal irregularities or ureteral strictures, while confirms granulomatous changes. Early recognition is critical to prevent irreversible renal damage.

Abdominal Tuberculosis

Abdominal tuberculosis (TB) encompasses involvement of the , intestines, and solid abdominal organs, accounting for approximately 5-10% of extrapulmonary TB cases. It primarily affects the , with the ileocecal region being the most common site, involved in about 60-64% of intestinal cases due to the abundance of lymphoid tissue and slower transit time in this area. Subtypes include intestinal TB, which manifests as ulcerative, hypertrophic, ulcero-hypertrophic, or stricturing forms; peritoneal TB, classified as wet (ascitic) with free or loculated fluid or dry (adhesive) with fibrous bands; and visceral involvement of hepatic or splenic organs, often presenting as miliary nodules or abscesses via hematogenous spread. Pathologically, intestinal TB features ulcerohypertrophic lesions that combine mucosal ulcers with hyperplastic masses, particularly in the , leading to and circumferential strictures that cause partial or complete . Peritoneal TB in its wet form involves exudative with high-protein , while the dry form results in omental and peritoneal adhesions, forming a "" or fibroadhesive . Hepatic and splenic TB typically shows granulomatous with caseation, mimicking malignancies or other infections. These changes arise from ingestion of mycobacteria from pulmonary secretions or hematogenous dissemination, with the ileocecal area's lymphoid aggregates facilitating bacterial persistence. Clinically, patients present with nonspecific symptoms such as chronic , distension, significant , fever, , and anorexia, often delaying diagnosis for months. Intestinal involvement may mimic , featuring , , or subacute obstruction, while peritoneal disease causes or a palpable doughy on due to adhesions. in suspected cases reveals characteristic findings like peritoneal thickening, omental caking, and yellow-white tubercles, aiding in differentiation from other abdominal pathologies. Hepatic or splenic TB can lead to , , or localized pain. Risk factors include immigration from high-endemic regions such as , where incidence rates exceed 100 per 100,000 in countries like , alongside infection, immunosuppression, and malnutrition, which impair immune containment of . The disease is more prevalent in young adults and shows female predominance in peritoneal forms. Complications, though uncommon, are severe; bowel perforation occurs in 4-7.6% of intestinal cases and carries a mortality rate of up to 30%, often presenting as acute requiring emergent . Other issues include fistulae, massive hemorrhage, and chronic malabsorption leading to failure to thrive.

Musculoskeletal Tuberculosis

Musculoskeletal tuberculosis, also known as skeletal tuberculosis, refers to the infection of bones, joints, and soft tissues by Mycobacterium tuberculosis, typically resulting from hematogenous dissemination from a primary pulmonary focus. It accounts for approximately 10% of all extrapulmonary cases and 1-3% of total infections globally. This form is more prevalent in adults than in children and is often associated with risk factors such as (e.g., infection), , and residence in endemic areas. Delayed is common due to its insidious onset, leading to significant morbidity, including up to 50% of cases resulting in permanent disability from deformities or neurological complications. The most frequently affected site is the spine, involved in about 50% of musculoskeletal tuberculosis cases, where it manifests as or spinal tuberculosis, predominantly in the thoracic and lumbar regions. Other common sites include the (15% of cases) and (10-15%), with psoas abscesses occurring as a complication in up to 25% of spinal cases due to spread along the psoas muscle sheath. Less commonly, it affects the shoulders, elbows, or soft tissues like the tenosynovium. In extraspinal involvement, such as the or , the infection targets the synovial lining, leading to and destruction. Pathologically, musculoskeletal tuberculosis begins with granulomatous inflammation in the cancellous bone or synovium, progressing to and formation. In spinal cases, paradiscal vertebral involvement leads to destruction of the and adjacent vertebrae, often resulting in vertebral collapse and the characteristic gibbus deformity—a sharp angular —when two or more vertebrae are affected. Joint involvement causes synovial inflammation, formation, and erosion of articular , mimicking chronic . Cold abscesses, lacking the inflammatory signs of pyogenic infections, form from liquefied caseous material and may track along fascial planes without causing acute pain. Neurological deficits arise in 10-30% of spinal cases due to compression from abscesses, bone fragments, or instability. Clinically, patients present with chronic, progressive symptoms, including localized pain (e.g., in 80-100% of spinal cases) that worsens at night or with movement, often accompanied by a limp in lower limb involvement. Systemic features such as low-grade fever, , and occur in about 20-50% of advanced cases, though they may be absent in localized disease. Cold abscesses present as painless swellings, while neurological deficits like paraparesis or affect 10-20% of spinal patients, sometimes progressing to . A unique feature is paradoxical worsening during or after antitubercular therapy, occurring in up to 20% of cases due to , manifesting as new abscesses or worsening pain despite microbiological improvement.

Central Nervous System Tuberculosis

Central nervous system (CNS) tuberculosis encompasses several distinct forms, with (TBM) accounting for approximately 70-80% of cases, followed by intracranial tuberculomas (20-30%) and spinal . TBM arises from the hematogenous dissemination of , leading to inflammation of the , while tuberculomas represent focal granulomatous lesions that mimic brain tumors, and spinal arachnoiditis involves chronic inflammation of the spinal and nerve roots. These manifestations are more prevalent in children and immunocompromised individuals, often resulting from primary pulmonary infection or reactivation of latent foci. Pathologically, TBM is characterized by thick basal exudates that encase the and , obstructing (CSF) pathways and causing in 60-75% of cases. These exudates, composed of inflammatory cells, , and , also induce in the basal arteries, leading to ischemic infarcts in 15-28% of patients, particularly in the and . In tuberculomas, caseating forms space-occupying masses, potentially causing or seizures, whereas spinal results in adhesions and loculations that compress the . Clinical symptoms typically begin insidiously with fever, , and , progressing to altered consciousness, , and focal neurological deficits. Cranial nerve palsies occur in 20-30% of TBM cases, with the sixth nerve (abducens) most commonly affected due to its basal location, leading to . Meningeal signs such as (pain on knee extension with hip flexed) are present in advanced stages, alongside , , and . Severity is assessed using the Medical Research Council () grading system: grade I (alert, no focal deficits), grade II (drowsy, mild deficits), and grade III ( or , severe deficits). Even with antitubercular therapy, mortality from CNS remains high at 20-50%, with rates approaching 40% in children due to rapid progression and diagnostic delays. Survivors often face neurological sequelae, including and motor deficits, emphasizing the need for early intervention. worsens in grade III disease and with complications like or infarcts.

Cutaneous and Other Rare Forms

Cutaneous tuberculosis is a rare form of extrapulmonary , comprising approximately 1-1.5% of all cases and often occurring secondary to primary pulmonary or lymphatic foci. It typically results from hematogenous or lymphatic dissemination of , leading to various clinical presentations depending on the host's immune status and the route of . Among the cutaneous forms, presents as chronic, reddish-brown plaques, most commonly on the face, and develops in individuals with prior sensitization to , exhibiting a high degree of sensitivity. Scrofuloderma arises from direct extension of from underlying subcutaneous tissues or lymph nodes, manifesting as painless, firm nodules that soften and form fistulas with ulceration, particularly in children. Miliary cutaneous , a disseminated variant, features widespread millet-seed-like papules and vesicles, often in immunocompromised patients, reflecting acute hematogenous spread. Ocular tuberculosis, accounting for 1-2% of extrapulmonary cases, primarily involves the and presents as granulomatous , potentially leading to vision-threatening complications if untreated. Laryngeal tuberculosis, another uncommon site, typically causes hoarseness due to granulomatous inflammation of the and surrounding structures, often mimicking in smokers. Cardiac involvement, mainly as tuberculous , occurs in 1-2% of extrapulmonary and may result in or , with symptoms including and dyspnea. Miliary tuberculosis represents a severe disseminated form of extrapulmonary , characterized by widespread millet-seed-sized granulomas in multiple organs via hematogenous spread, with clinical features such as high fever, , and respiratory distress; untreated mortality approaches 100%, while treated rates remain around 20%. These rare forms collectively account for less than 5% of extrapulmonary and pose diagnostic challenges due to low bacillary loads in affected tissues, necessitating or tissue biopsy for histopathological examination showing caseating granulomas, alongside microbiological confirmation via or PCR.

Diagnosis

Clinical Presentation and History

Extrapulmonary tuberculosis (EPTB) often presents with nonspecific constitutional symptoms, including fever, , , , and anorexia. These symptoms can persist for more than one month and mimic other chronic conditions, contributing to diagnostic challenges. Site-specific manifestations vary widely depending on the affected organ; for instance, lymphadenitis may cause painless cervical swelling, while abdominal involvement can lead to pain, , or . A thorough history is essential for suspecting EPTB, focusing on risk factors such as recent travel to or origin from TB-endemic regions like , , or ; close contact with known TB cases; and underlying immunosuppression from conditions like infection, , , or immunosuppressive medications. Patients may report a subacute onset with gradual progression, often without prominent respiratory symptoms, unlike pulmonary TB. Differential diagnoses for EPTB include malignancies such as , other infections like or fungal diseases, and autoimmune disorders like , particularly when symptoms are chronic or involve . Red flags in the history, such as unexplained exceeding 10% of body weight, persistent fever, or localized lasting over several weeks, should prompt consideration of EPTB in at-risk individuals. In children, EPTB is more likely to present as disseminated , with common sites including lymph nodes (up to 72% of pediatric cases) and the , alongside higher risks of involvement and associated mortality in those under 5 years. Adults, in contrast, typically exhibit more localized involvement, such as pleural or skeletal sites, with constitutional symptoms predominating in immunosuppressed patients. Delayed diagnosis is common in EPTB due to its nonspecific and variable presentation, with median total delays ranging from 39 to 62 days from symptom onset to treatment initiation, often exacerbated by low clinical suspicion and initial misattribution to other conditions. This delay can worsen outcomes, particularly in vulnerable populations like children and those with .

Imaging and Laboratory Tests

Imaging plays a crucial role in localizing extrapulmonary (EPTB) and guiding further investigations, though findings are often nonspecific and require correlation with clinical features. Chest is typically the initial imaging modality but is often normal in EPTB without pulmonary involvement, with approximately 50-90% of cases showing no parenchymal abnormalities. (USG) is particularly useful for detecting peripheral , , and pleural effusions in lymphatic and abdominal EPTB, revealing features such as hypoechoic nodes or anechoic fluid collections that aid in site-specific evaluation. Computed tomography (CT) enhances detection of subtle abnormalities, such as nodal or loculated effusions in pleural and abdominal forms, while () is preferred for musculoskeletal and () EPTB, demonstrating vertebral erosions, , or meningeal enhancement in spinal and cases. For genitourinary EPTB, intravenous pyelography (IVP) classically shows moth-eaten calyces due to papillary and infundibular strictures, though CT urography has largely supplanted it for better visualization of renal parenchymal involvement. However, imaging sensitivities are limited; for instance, chest misses approximately 80% of lymphatic EPTB cases, particularly in cervical or peripheral nodes, necessitating advanced modalities for occult disease. Laboratory tests provide supportive evidence for EPTB suspicion through nonspecific inflammatory markers. Elevated (ESR) and (CRP) are common, observed in 79% and 63% of EPTB patients respectively, reflecting chronic inflammation. affects about 50% of cases, often normocytic and associated with elevated CRP levels, contributing to and diagnostic clues in systemic EPTB. In CNS EPTB, occurs in 39-73% of tuberculous meningitis patients, primarily due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting, and serves as an early indicator requiring electrolyte monitoring. Site-specific laboratory analyses further localize EPTB. In with , analysis of ascitic fluid typically reveals a low (SAAG <1.1 g/dL), distinguishing it from portal hypertension-related causes and suggesting peritoneal involvement, often with lymphocytic predominance. Recent advances, including positron emission tomography-computed tomography (PET-CT), improve detection of multifocal or EPTB sites with sensitivities of 60-90%, as highlighted in 2024 guidelines for assessing treatment response and disease extent in complex cases.

Microbiological and Histopathological Confirmation

Microbiological and histopathological confirmation provides definitive evidence of infection in extrapulmonary tuberculosis (EPTB), distinguishing it from other granulomatous diseases through direct detection or characteristic tissue changes. These methods are crucial in paucibacillary forms of EPTB, where bacterial loads are low, but they often require invasive sampling from sites like lymph nodes, pleura, or . Gold-standard approaches include , , molecular assays, and examination, though yields vary by specimen type and site. Smear microscopy for acid-fast (AFB) remains a rapid initial test but has limited sensitivity in EPTB due to the low bacillary burden, typically detecting only 10-40% of cases compared to . In extrapulmonary specimens such as pleural fluid or tissue biopsies, the yield is further reduced to around 10-30%, making it insufficient for definitive in most instances. This low performance underscores the need for complementary methods, as false negatives are common in non-respiratory samples. Mycobacterial culture serves as the reference standard for confirming M. tuberculosis and assessing drug susceptibility, with liquid systems like the BACTEC MGIT providing higher yields and faster results than solid media. In EPTB, culture positivity rates range from 30-80% depending on the site, achieving 50-70% from fluids or , though it requires 2-6 weeks for growth. Contamination by non-tuberculous mycobacteria or other flora poses a significant challenge, necessitating rigorous , while biosafety level 3 facilities are essential to mitigate during processing. Molecular diagnostics, particularly the GeneXpert MTB/RIF assay, offer rapid detection of M. tuberculosis DNA and rifampin resistance directly from clinical samples, with sensitivities of 80-90% in EPTB fluids like cerebrospinal or pleural effusions. This cartridge-based system provides results in under 2 hours, outperforming smear microscopy and enabling same-day initiation of targeted therapy in high-burden settings. For tissue samples, sensitivities may drop to 60-80%, but integration with PCR enhances specificity above 95%. Histopathological examination of biopsies reveals caseating granulomas—aggregates of epithelioid histiocytes with central —as a hallmark of EPTB, offering diagnostic value in 60-80% of confirmed cases when combined with AFB staining or PCR. Caseous exhibits high specificity (up to 94%) for over other granulomatous conditions like , though non-caseating forms reduce certainty and require microbiological correlation. PCR on formalin-fixed tissues further boosts confirmation rates to 70-90% by amplifying M. tuberculosis-specific genes. Diagnostic challenges in EPTB microbiological confirmation include sample contamination, which can invalidate up to 10-20% of cultures, and stringent requirements that limit accessibility in resource-poor areas. Incomplete penetration of antitubercular drugs in sequestered sites may also yield false negatives. As of 2025, emerging CRISPR-based assays, such as ActCRISPR-TB, address these gaps by enabling ultra-sensitive, point-of-care detection from non-invasive samples like or in under an hour, with sensitivities exceeding 95% for M. tuberculosis DNA, showing promise for EPTB rapid diagnostics.

Treatment

Standard Antitubercular Therapy

The standard antitubercular therapy for drug-susceptible (EPTB) follows the same core regimen as for pulmonary tuberculosis, consisting of an intensive phase followed by a continuation phase. The intensive phase lasts 2 months and includes daily administration of four first-line drugs: isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E), collectively known as HRZE. This is followed by a 4-month continuation phase of isoniazid and rifampin (HR). As of 2025, shorter 4-month regimens are recommended by CDC and IDSA for drug-susceptible pulmonary TB in adults and non-severe TB in children, but the standard 6-month regimen remains for most EPTB sites due to differences in disease dynamics. The total duration of is typically 6 months for most forms of EPTB, such as lymphatic, pleural, or genitourinary involvement, assuming susceptibility and adequate response. However, for (CNS) tuberculosis, including , treatment is extended to 9-12 months to ensure complete resolution and reduce relapse risk. For musculoskeletal tuberculosis, such as or involvement, treatment is extended to 6-9 months. These extensions account for slower penetration and higher bacterial burden in these sites. Dosing is weight-based to optimize while minimizing , with adjustments for renal or hepatic impairment. For adults, isoniazid is dosed at 5 mg/kg (maximum 300 mg daily), rifampin at 10 mg/kg (maximum 600 mg daily), pyrazinamide at 25 mg/kg (maximum 2,000 mg daily), and ethambutol at 15-20 mg/kg (maximum 1,600 mg daily).
DrugDaily Dose (Adults ≥30 kg)Maximum Daily Dose
Isoniazid4-6 mg/kg300 mg
Rifampin8-12 mg/kg600 mg
Pyrazinamide20-30 mg/kg2,000 mg
Ethambutol15-20 mg/kg1,600 mg
In patients with renal impairment (creatinine clearance <30 mL/min), pyrazinamide and ethambutol doses are reduced or given thrice weekly to avoid accumulation, while isoniazid and rifampin require no adjustment. For hepatic impairment, pyrazinamide is often omitted or the regimen modified based on severity (Child-Pugh class), with close monitoring to prevent further . Monitoring during is essential to detect adverse effects and ensure adherence. (LFTs), including and aspartate aminotransferase, should be checked monthly due to the hepatotoxic potential of isoniazid, rifampin, and pyrazinamide. For ethambutol, baseline and periodic assessments of and are required to screen for , particularly in patients on prolonged . Adherence is promoted through directly observed (DOT), where healthcare providers witness medication ingestion, reducing the risk of treatment failure. With standard therapy, treatment success rates for drug-susceptible EPTB are generally high (85-95%), comparable to pulmonary TB when diagnosed early and susceptibility is confirmed. Multidrug-resistant EPTB (MDR-EPTB), defined as resistance to at least isoniazid and rifampin, affects a proportion similar to pulmonary TB, estimated at 3-4% among new global cases, though higher (up to 15-20%) in previously treated or high-burden settings, with rising incidence necessitating susceptibility testing before or early in treatment. While the regimen remains the medical backbone across EPTB sites, variations in penetration may influence adjunctive approaches for specific complications.

Surgical and Adjunctive Interventions

Surgical interventions in extrapulmonary tuberculosis (EPTB) are typically reserved for cases where standard antitubercular therapy () alone is insufficient, such as when complications like abscesses, obstructions, or neurological threats arise, or for diagnostic purposes when microbiological confirmation is challenging. These procedures aim to alleviate symptoms, prevent further damage, and facilitate drug penetration, often performed after initiating for 2-4 weeks to reduce bacterial load and operative risks. Indications for surgery include abscess drainage, particularly for psoas abscesses associated with spinal or abdominal TB, where percutaneous or open drainage relieves pain and prevents sepsis. In musculoskeletal TB, such as (spinal TB), is indicated for instability, severe , or neurological deficits to remove necrotic tissue and stabilize the spine via instrumentation. For (CNS) TB, shunting is essential in cases of caused by , while excision or stereotactic aspiration may be needed for large tuberculomas causing mass effect. Other procedures encompass for symptomatic pleural effusions in pleural TB to relieve respiratory distress and aid through fluid analysis, and rarely, for genitourinary TB involving a completely destroyed , occurring in less than 5% of cases due to effective medical management. Adjunctive therapies complement and by addressing inflammation and supportive needs. Corticosteroids, such as dexamethasone for CNS TB (administered at 12 mg/day, tapered over 6-8 weeks) or for pericardial TB (1 mg/kg/day, tapered over 10 weeks), reduce mortality by approximately 25% in by mitigating and inflammation. Nutritional support, including high-calorie supplements, enhances recovery by improving , immune function, and treatment adherence, particularly in malnourished patients with abdominal or disseminated EPTB. Outcomes of surgical interventions are generally favorable when combined with ATT, with resolution rates exceeding 80% in complicated or drug-resistant cases, though success depends on timely intervention and patient factors like comorbidities. For instance, in spinal TB yields neurological improvement in most patients, while shunting for can prevent irreversible brain damage. Postoperative ATT continuation for 6-12 months is standard to prevent relapse. Emerging approaches include minimally invasive techniques like endoscopic balloon dilatation for abdominal TB strictures, which recent trials show to be safe and effective for short-segment (<3 cm) lesions, avoiding open and reducing recovery time.

Prognosis and Prevention

Prognostic Factors and Outcomes

The of extrapulmonary tuberculosis (EPTB) varies by site and patient factors, with overall mortality rates ranging from 5% to 15% in treated cases, though higher in disseminated forms. (CNS) involvement carries a mortality of approximately 30%, primarily due to , while has a mortality around 20% even with antitubercular therapy (ATT). Cure rates exceed 90% when treatment is initiated early and adhered to, reflecting the of standard regimens in non-resistant cases. Several predictors are associated with poor outcomes in EPTB. HIV co-infection elevates the odds of death, with adjusted hazard ratios around 3.7 to 4.5 compared to HIV-uninfected individuals, due to impaired immune responses. Multidrug-resistant TB (MDR-TB) worsens through prolonged treatment and higher failure rates, while extremes of age—particularly in children under 5 years and adults over 65—correlate with increased fatality from reduced resilience or delayed recognition. Morbidity remains a substantial burden among EPTB survivors, often leading to chronic sequelae. Female genital tuberculosis, a subset of genitourinary TB, contributes to 13-20% of cases among women in high-burden settings and results in in approximately 88% of affected cases due to tubal scarring and endometrial damage. CNS TB survivors experience neurological deficits in about 40%, including , cranial nerve palsies, and cognitive impairments, which persist despite treatment completion. Long-term outcomes in EPTB include subtle but significant health impacts beyond acute resolution. Recent analyses indicate relapse rates of approximately 2-5% within five years post-treatment for treated TB cases, often linked to reinfection in high-burden settings or incomplete adherence. Advancements in have markedly improved EPTB prognosis; prior to the introduction of effective drugs like in the 1940s, mortality for severe forms like CNS TB approached 100%, reducing to 20-50% with early regimens by the 1950s-1970s, and current regimens have reduced overall fatality to under 15% through early detection and standardized multidrug therapy.

Preventive Strategies

The Bacillus Calmette-Guérin ( remains the cornerstone of tuberculosis prevention, particularly for extrapulmonary forms in children. Administered at birth in high-burden countries, BCG provides substantial protection against severe disseminated disease, such as and involvement, with efficacy estimates ranging from 70% to 86% in infants and young children. However, its effectiveness wanes in adolescents and adults, offering limited prevention against extrapulmonary tuberculosis (EPTB) in these groups, and it does not reliably halt transmission. Ongoing research into next-generation vaccines addresses these gaps; for instance, the M72/AS01E candidate demonstrated 50% efficacy against active pulmonary tuberculosis in a phase IIb trial among latently infected adults and is advancing in phase III trials, with potential implications for EPTB prevention across age groups. Screening for infection (LTBI) is essential for high-risk populations to prevent progression to EPTB. Interferon-gamma release assays (IGRA) or tests (TST) are recommended for individuals with , recent migrants from endemic areas, and close contacts of active cases, enabling early identification and intervention. Isoniazid preventive (IPT), typically 6-9 months of daily isoniazid, reduces the risk of developing EPTB by approximately 60% in LTBI-positive individuals, including those with , by targeting dormant bacilli before dissemination. In immunocompromised patients, such as those on immunosuppressive or with organ transplants, LTBI screening followed by prophylaxis is prioritized to mitigate EPTB risk, with rifamycin-based regimens preferred for shorter duration and better adherence. Public health measures form a multifaceted approach to curbing EPTB incidence. identifies exposed individuals for prompt screening and prophylaxis, while environmental controls like improved ventilation in high-density settings such as prisons reduce . Post-2020, digital tools inspired by responses—such as mobile apps for geolocation-based tracing—have enhanced TB contact investigations in hotspots, enabling faster identification of EPTB risks in urban and migrant communities. The World Health Organization's End TB Strategy aims for a 90% reduction in global TB incidence and 95% decrease in TB deaths by 2035, emphasizing integrated prevention through , screening, and socioeconomic interventions. In endemic areas, nutritional programs target undernutrition as a modifiable ; as of October 2025, WHO guidelines recommend assessment and supplementation for TB household contacts in food-insecure households, as evidence from trials shows reduced EPTB incidence with energy-dense nutritional support. The WHO Global Tuberculosis Report 2025 highlights ongoing challenges in EPTB detection and prevention, with 1.4 million estimated new EPTB episodes in 2024, underscoring the need for enhanced strategies in high-burden regions.

References

  1. https://www.cdc.gov/tb/hcp/clinical-overview/tuberculosis-disease.html
  2. https://www.ncbi.nlm.nih.gov/books/NBK556055/
  3. https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global-tuberculosis-report-2025/tb-diagnosis-and-treatment/2-1-case-notifications
  4. https://www.who.int/news-room/fact-sheets/detail/tuberculosis
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC9472030/
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889451/
  7. https://www.ncbi.nlm.nih.gov/books/NBK579383/
  8. https://bestpractice.bmj.com/topics/en-us/166
  9. https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global-tuberculosis-report-2024/tb-diagnosis-and-treatment/2-1-case-notifications
  10. https://www.aafp.org/pubs/afp/issues/2005/1101/p1761.html
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC5432783/
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC3493181/
  13. https://wwwnc.cdc.gov/eid/article/25/3/18-0572_article
  14. https://tbcindia.mohfw.gov.in/wp-content/uploads/2023/05/5646719104TB_AR_2023_04-04-2023_LRP_final.pdf
  15. https://www.sciencedirect.com/science/article/pii/S1201971208016846
  16. https://www.elsevier.es/en-revista-enfermedades-infecciosas-microbiologia-clinica-28-articulo-extrapulmonary-tuberculosis-epidemiology-risk-factors-S0213005X1100125X
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC6225852/
  18. https://www.tandfonline.com/doi/full/10.1080/14787210.2018.1476737
  19. https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2024
  20. https://www.cdc.gov/tb/media/pdfs/Self_Study_Module_1_Transmission_and_Pathogenesis_of_Tuberculosis.pdf
  21. https://emedicine.medscape.com/article/230802-overview
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC4636013/
  23. https://medicalguidelines.msf.org/en/viewport/TUB/english/2-2-extrapulmonary-tuberculosis-20320217.html
  24. https://www.tandfonline.com/doi/full/10.1080/24745332.2022.2035540
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC3225291/
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC6712944/
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC7053427/
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC12298959/
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC3604417/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC4450036/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC6390737/
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC10281827/
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC3108380/
  34. https://emedicine.medscape.com/article/858234-overview
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC4766275/
  36. https://pubmed.ncbi.nlm.nih.gov/36167273/
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC10727992/
  38. https://www.pepysdiary.com/encyclopedia/14136/
  39. https://pubmed.ncbi.nlm.nih.gov/19793000/
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC10729824/
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC4958858/
  42. https://pmc.ncbi.nlm.nih.gov/articles/PMC4466424/
  43. https://pmc.ncbi.nlm.nih.gov/articles/PMC5783039/
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC4021261/
  45. https://pubmed.ncbi.nlm.nih.gov/38125799/
  46. https://www.ncbi.nlm.nih.gov/books/NBK557558/
  47. https://pmc.ncbi.nlm.nih.gov/articles/PMC8614939/
  48. https://pmc.ncbi.nlm.nih.gov/articles/PMC3921817/
  49. https://www.ncbi.nlm.nih.gov/books/NBK556115/
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC5423344/
  51. https://pmc.ncbi.nlm.nih.gov/articles/PMC6830173/
  52. https://pmc.ncbi.nlm.nih.gov/articles/PMC5578524/
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC6609850/
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC8700228/
  55. https://pmc.ncbi.nlm.nih.gov/articles/PMC9098107/
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC11687488/
  57. https://www.ncbi.nlm.nih.gov/books/NBK538331/
  58. https://pmc.ncbi.nlm.nih.gov/articles/PMC9955044/
  59. https://pmc.ncbi.nlm.nih.gov/articles/PMC9510170/
  60. https://www.ncbi.nlm.nih.gov/books/NBK585138/
  61. https://www.ncbi.nlm.nih.gov/books/NBK541015/
  62. https://journals.asm.org/doi/10.1128/jcm.01771-20
  63. https://pmc.ncbi.nlm.nih.gov/articles/PMC8611515/
  64. https://www.ncbi.nlm.nih.gov/books/NBK482220/
  65. https://pmc.ncbi.nlm.nih.gov/articles/PMC11687432/
  66. https://pmc.ncbi.nlm.nih.gov/articles/PMC2923933/
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC4008050/
  68. https://www.ncbi.nlm.nih.gov/books/NBK559303/
  69. https://pmc.ncbi.nlm.nih.gov/articles/PMC10624933/
  70. https://pmc.ncbi.nlm.nih.gov/articles/PMC8947333/
  71. https://www.ncbi.nlm.nih.gov/books/NBK562300/
  72. https://pmc.ncbi.nlm.nih.gov/articles/PMC4148266/
  73. https://insightsimaging.springeropen.com/articles/10.1186/s13244-022-01172-0
  74. https://pmc.ncbi.nlm.nih.gov/articles/PMC10287908/
  75. https://journals.lww.com/pidj/fulltext/2022/08000/age_specific_clinical_presentation_and_risk.4.aspx
  76. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203593
  77. https://pmc.ncbi.nlm.nih.gov/articles/PMC9346302/
  78. https://pmc.ncbi.nlm.nih.gov/articles/PMC4388900/
  79. https://pmc.ncbi.nlm.nih.gov/articles/PMC11449295/
  80. https://pmc.ncbi.nlm.nih.gov/articles/PMC3737618/
  81. https://www.ijorl.com/index.php/ijorl/article/download/2893/1685/12669
  82. https://pubmed.ncbi.nlm.nih.gov/15227732/
  83. https://academic.oup.com/ofid/article/11/12/ofae673/7901191
  84. https://pmc.ncbi.nlm.nih.gov/articles/PMC8077663/
  85. https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-024-19495-6
  86. https://www.nptccd.health.gov.lk/wp-content/uploads/2025/05/National-Guideline-on-Management-of-Extra-Pulmonary-Tuberculosis-2024_compressed.pdf
  87. https://www.who.int/publications/i/item/9789240048126
  88. https://www.ncbi.nlm.nih.gov/books/NBK138753/
  89. https://www.cdc.gov/tb/hcp/treatment/tuberculosis-disease.html
  90. https://www.cdc.gov/tb/php/dear-colleague-letters/2025-treatment-guidelines.html
  91. https://www.idsociety.org/practice-guideline/treatment-of-drug-susceptible-tb/treatment-of-drug-resistant-and-drug-susceptible-tb-2025-update/
  92. https://www.tandfonline.com/doi/full/10.1080/24745332.2022.2036073
  93. https://www.ncbi.nlm.nih.gov/books/NBK247416/
  94. https://www.merckmanuals.com/professional/multimedia/table/dosing-of-oral-first-line-anti-tb-drugs
  95. https://www.ncbi.nlm.nih.gov/books/NBK138749/
  96. https://www.atsjournals.org/doi/10.1164/rccm.200510-1666ST
  97. https://emedicine.medscape.com/article/230802-treatment
  98. https://www.idsociety.org/practice-guideline/treatment-of-drug-susceptible-tb/
  99. https://www.who.int/publications/i/item/9789240107243
  100. https://pmc.ncbi.nlm.nih.gov/articles/PMC8322202/
  101. https://pmc.ncbi.nlm.nih.gov/articles/PMC3670072/
  102. https://eurjmedres.biomedcentral.com/articles/10.1186/s40001-024-02198-4
  103. https://pmc.ncbi.nlm.nih.gov/articles/PMC2684360/
  104. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD002244.pub4/full
  105. https://pmc.ncbi.nlm.nih.gov/articles/PMC4794866/
  106. https://academic.oup.com/cid/article/62/7/887/2462976
  107. https://pmc.ncbi.nlm.nih.gov/articles/PMC9066257/
  108. https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-022-02140-0
  109. https://pubmed.ncbi.nlm.nih.gov/17072539/
  110. https://pmc.ncbi.nlm.nih.gov/articles/PMC8920747/
  111. https://pmc.ncbi.nlm.nih.gov/articles/PMC6830168/
  112. https://pmc.ncbi.nlm.nih.gov/articles/PMC10246159/
  113. https://pmc.ncbi.nlm.nih.gov/articles/PMC5526484/
  114. https://pmc.ncbi.nlm.nih.gov/articles/PMC9423760/
  115. https://pmc.ncbi.nlm.nih.gov/articles/PMC7423296/
  116. https://pmc.ncbi.nlm.nih.gov/articles/PMC10901333/
  117. https://www.cdc.gov/mmwr/preview/mmwrhtml/00041047.htm
  118. https://pmc.ncbi.nlm.nih.gov/articles/PMC11967564/
  119. https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/research-innovation/vaccines
  120. https://www.nejm.org/doi/full/10.1056/NEJMoa1909953
  121. https://www.aafp.org/pubs/afp/issues/2009/0515/p879.html
  122. https://www.cdc.gov/immigrant-refugee-health/hcp/domestic-guidance/tuberculosis.html
  123. https://tbksp.who.int/en/node/1271
  124. https://academic.oup.com/cid/article/71/8/e351/5695919
  125. https://jamanetwork.com/journals/jama/fullarticle/2800774
  126. https://wwwnc.cdc.gov/eid/article/27/3/20-3456_article
  127. http://www.stoptb.org/ending-tb
  128. https://www.who.int/news/item/08-10-2025-who-releases-new-guidelines-on-tuberculosis-and-undernutrition
  129. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01276-9/fulltext
  130. https://www.who.int/publications/i/item/9789240116924
Add your contribution
Related Hubs
User Avatar
No comments yet.