Tuberculosis has many forms of extrapulmonary manifestations, affecting almost every organ of the body. It has been reported that there are significant differences in the susceptibility to EPTB in different parts of the body by age, race/ethnicity, sex, and country of origin [2, 10, 18].According to the patient cohort of this study, the number of male EPTB patients were more than female with a male to female sex ratio of 1.32,which is consistent with the World Health Organization's report that there are more cases of TB in males than females [1]. Tuberculous pleurisy is a common manifestation of extrapulmonary tuberculosis and is the most common cause of pleural effusion [19]. Our data showed that tuberculous pleurisy is the predominant form of extrapulmonary TB. Tuberculous pleurisy is thought to be caused by a delayed type (type IV) of hypersensitivity reaction following the release of mycobacterial antigens into the pleural space as a result of the rupture of a TB-infected subpleural focus in the lung [20].
It was found that females have a higher risk of developing EPTB through epidemiological studies conducted in industrialized countries and resource-limited countries with high burdens of TB [10, 21]. According to the data of this study, females with EPTB (aOR = 1.129, 95%CI: 1.081–1.178) were also more likely to have concurrent EPTB. Consistent with studies in the United States [10], Germany [18], Denmark [22], the European Union [2], and India [23], an association between female gender and EPTB is observed. Although the reason for this has not been clearly determined, it is believed that genetic and endocrine factors may contribute to this [18,24−25].
The proportions of concurrent EPTB in different EPTB diseases were different. Some EPTB diseases existed mainly in concurrence with other types of EPTB. Urogenital tuberculosis is a type of common extrapulmonary presentation of tuberculosis [26]. Ureteral tuberculosis generally does not occur alone and is normally concurrent with renal TB. It was reported that about 50% patients with renal TB have ureteric involvement [27, 28]. Our results showed that ureteral tuberculosis concurrent with other types of EPTB accounted for 78.87% of ureteral tuberculosis disease. The reason for this may be that Mtb from renal medullary lesions spread downstream with the urine to the ureters, the ureterovesical junction, and into the bladder [29–32]. Starting from primary pulmonary tuberculosis, bacillemia is responsible for bacillus distribution in parenchymatous organs, with possible colonization of the kidneys and prostate. Renal lesions are then initially bilateral, cortical, glomerular, and pericapillary, initiating hematogenous dissemination and are concomitant with other hematogenic foci in the prostate and other organs outside the urogenital system [33].Furthermore, involvement of the contralateral ureter occurs through retrograde ascending dissemination secondary to contracted bladder and vesicoureteral reflux [34]. Moreover, Mtb is introduced to the ureter via the bloodstream and lymphatic system, leading to ureteric tuberculosis [35–37].Finally, the bacilli enter the periglomerular capillaries of the kidney, causing abscess formation and gradually involve the ureter, bladder, prostate, seminal vesicle, epididymis, testes, or extra urinary organs, such as the lymph nodes, spleen, liver, and vertebrae [38–39]. Therefore, ureteral tuberculosis often occurs simultaneously with renal tuberculosis.
Additionally, tuberculosis in the sacroiliac joint is not a rare finding [40]. It is reported that sacroiliac involvement is associated with 8%-10% of the cases of spinal tuberculosis [41]. Spinal tuberculosis usually follows hematogenous spread from the lung or genitourinary tract [42]. It is also possible that lymphatic drainage of the pleura or kidney may involve the para-aortic lymph nodes which may secondarily involve the vertebrae [43]. Usually, two or more contiguous vertebrae are involved in spinal tuberculosis, owing to hematogenous spread through one intervertebral artery feeding two adjacent vertebrae [44]. Once a vertebra has been sufficiently eroded by the process, the infection spreads gradually into the adjacent vertebrae via vascular and subligamentous routes [45].Involvement of the sacrum is usually secondary tothelumbar spine and mainly caused by direct spread of infection [46]. Therefore, sacral tuberculosis is often accompanied by lumbar tuberculosis. The proportion of sacral tuberculosis concurrent with other tuberculosis is as high as 78.60% in this study.The psoas muscle lies in close proximity to a number of structures, including the diaphragm, pancreas, large and small intestines, kidney, ureter, spinal column, hip, and neighboring muscles (quadrates lumborum, erector spinae, and iliacus) [47–49]. Tuberculous abscess of the psoas major is more common in clinic settings [50–51]. The psoas major abscess is not the primary lesion, but often is caused by pus from the intervertebral space of lumbar or thoracic tuberculosis [50–51]. The psoas major abscess is generally distributed from top to bottom. However, it is important to note that some psoas major abscessesmay spread both upward and downward [51]. The abscessmay rupture into the peritoneal cavity [52]. Therefore, tuberculous abscess of the psoas major concurrent with other tuberculosis accounts for a high proportion of EPTB cases; in this study, the proportion of tuberculous abscess of the psoas major concurrent with other types of extrapulmonary tuberculosis was 70.77%.
The association network diagram of EPTB diseases concurrent with other types of EPTB shows that almost all the EPTB diseases may be concurrent with other types of EPTB. Tuberculous pleurisy, tuberculous lymphadenitis of the neck and lumbar vertebra tuberculosis ranked among the top three EPTBs concurrent with a number of other types of EPTB disease. Tuberculous pleurisy is the most common extrapulmonary tuberculosis [53]. It is believed that delayed hypersensitivity plays a large role in the pathogenesis of tuberculous pleural effusion [54]. Fluid that enters the pleural space can originate in the pleural capillaries, the interstitial spaces of the lung, the intrathoracic lymphatics, the intrathoracic blood vessels, the peritoneal cavity [55], or the pericardial cavity [56]. The TB bacillus invades the pleuralspace after the rupture of a pulmonary caseous focus (Ghon focus) in the subpleural region, by contiguity of the pulmonary lesion, by rupture of a mediastinal lymph node, or via hematogenous dissemination [57–59]. Tuberculous pleurisy may cause other types of extrapulmonary tuberculosis via lymphaticor hematogenous dissemination. Pleural lesions can affect not only the abdominal cavity and the subdiaphragmatic organs such as the liver [60], but also the chest wall and even ribs or sternum. Therefore, tuberculous pleurisy is prone to concurrence with other types of extrapulmonary tuberculosis.
Peripheral lymph node tuberculosis is one of the most common manifestations of extrapulmonary tuberculosis and one of the most common diseases affecting peripheral lymph nodes [61–63].The pathogenesis of peripheral mycobacterial lymphadenitis is incompletely understood. Most cases in adults may be the result of the reactivation of lymph node disease sown during lymphatic transmission from a primary respiratory infection [63–64].Tuberculous lymphadenitis of the neck may be spread not only by the lymphatic route but also by the hematogenous route from a focus in the lung, genitourinary tract, the skeletal system, or elsewhere [64]. Tuberculous lymphadenitis of the neck may also affect the surrounding skin and soft tissue and can also affect most organs in the head and neck region, such as the lymph nodes, larynx, middle ear, oral cavity, and pharynx [65]. Tuberculous lymphadenitis of the neck may invade the lymphatic system (known as lymphatic metastasis), causing lymph node tuberculosis in other parts and distant extrapulmonary tuberculosis through hematogenous metastasis [64]. For the above reasons, tuberculous lymphadenitis of the neck is also more likely to be concurrent with other extrapulmonary tuberculoses.
The proportion of lumbar tuberculosis reported in the literature ranges from 22.8–45% among all the patients with spinal tuberculosis [66–67]. Lumbar tuberculosis concurrent with other types of extrapulmonary tuberculosis is related to the following factors. Firstly, Mtb spreads to the lumbar spine through the blood system, causing lumbar vertebra tuberculosis. This disease is not only transmitted through arteries [68], but some investigators favor the possibility that spread of lumbar vertebra tuberculosis occurs via Batson’s valveless venous vertebral plexus [69–70]. Secondly, lumbar vertebra tuberculosis may originate from adjacent vertebrae bodies and directly invade the lower thoracic vertebrae. Lumbar vertebra tuberculosis can cause paraspinal abscess, sacral vertebra tuberculosis [71], abdominal cavity viscera tuberculosis, and surrounding soft tissue tuberculosis. Finally, lumbar vertebra tuberculosis may result in the formation of cold abscesses, which release bacteria into the blood that spread via the hematogenous route to remote organs or tissues, leading to distant extrapulmonary tuberculosis [72–73].
Our study found that about 13% EPTB patients had at least two EPTB lesions. The most common types of EPTB concurrent with other types of EPTB was tuberculous peritonitis concurrent with tuberculous pleurisy (1.64%), tuberculous pericarditis concurrent with tuberculous pleurisy (1.48%), and thoracic vertebra tuberculosis concurrent with lumbar tuberculosis (0.70%). Abdominal tuberculosis may occur directly or indirectly via spread from the primary lesion which generally affects the following organs: lymphnodes, peritoneum, ileocecal junction, colon, liver, spleen, and adrenalglands; solid viscera are affected to a greater extent than the gastrointestinal tract [74]. Tuberculous peritonitis concurrent with tuberculous pleurisy may be caused by lymphatic spread or hematogenous dissemination due to low immunity. Pericardial involvement is caused by the retrograde lymphatic spread of Mycobacterium tuberculosis from peritracheal, peribronchial, or mediastinal lymph nodes or from the hematogenous spread of primary tuberculosis infection[75].The diffusion of Mtb to the pericardium occursmainly through the rupture of adjacent mediastinal lymph nodes[76].Tuberculous pericarditis develops secondary to contiguous spread from the mediastinal nodes, lungs, spine, or sternum or during miliary dissemination [77]. The mediastinal pleura and pericardium are adjacent to one another. Tuberculous pericarditis can directly invade the mediastinal pleura, resulting in tuberculous pleurisy. Moreover, it may spread through the blood when the patient's immunity is low, resulting in their concurrence. Approximately 1–3% of the patients with TB involve infection of the skeletal system, and the spine is the most common target of osteoarticular tuberculosis, especially the thoracolumbar spine [78]. There are two possible reasons for thoracic tuberculosis concurrence with lumbar tuberculosis: firstly, spinal tuberculosis occurs through hematogenous dissemination, which can be transmitted from the lungs or via activation of a dormant infection in the bone or joint post trauma [79]. Secondly, the thoracic vertebrae and lumbar vertebrae are adjacentto one anotherand can be directly invaded [80].
The association rules (confidence and lift) were different between concurrent EPTBs. Our study found that sacral tuberculosis with concurrent lumbar vertebra tuberculosis accounted for 68.56% of sacral tuberculosis cases. The confidence value for ureteric tuberculosis concurrent with renal tuberculosis cases was the second highest (50.52%). Sacral involvement is usually secondary to the lumbar spine and is mainly caused by the direct spread of infection [81]. Urogenital tuberculosis accounts for 30–40% of all extrapulmonary cases [82].Renal lesions, initially bilateral, cortical, glomerular and pericapillary, are typically hematogenously spread, accompanied by other hematogenous lesions from other organs aside from the prostate and urogenital system [83]. Starting with a pulmonary focus, 2%-20% of patients developed urogenital tuberculosis through hematogenous spread to the kidney, prostate, and epididymis. The spread continued through the descending collection system to the ureter, bladder, and urethra and finally through the ejaculatory duct to the genital organs [84]. Ureteral and vesical tuberculosis are secondary to downward infection through the collection system. In ureteral tuberculosis, multiple strictures develop throughout the ureter; these are mainly anatomical strictures such as vesicoureteral junctions, followed by uretero-renal junctions and strictures at the midureter[85–86].
Strengths And Limitations
This study had several strengths, including its large-scale multi-center representative sample, its detailed analysis of diagnostic types of concurrent EPTB, and its novel determinations of confidence/lift values of concurrent EPTB. However, the study also had several limitations. First, it may have been subject to Berkson’s bias since the study population was all hospitalized TB patients of which concurrent EPTB cases had a high likelihood of being hospitalized, causing the subsequent overestimation of their proportions within the general population. Secondly, most hospitals in our study were TB-specialized hospitals; thus, our findings may not represent the general TB patient population or apply to settings elsewhere in the country. Thirdly, the analysis did not consider low-frequency disease complications and comorbidities in China (e.g.,HIV) and other factors such as initial treatment or retreatment, income, smoking, etc. Fourthly, we could not determine the order of concurrent EPTB for the observational study.