Bone and joint tuberculosis

INTRODUCTION — Skeletal tuberculosis (TB) refers to TB involvement of the bones and/or joints. It is an ancient disease; features of spinal TB have been identified in Egyptian mummies dating back 9000 years [1,2], and analysis of 483 pre-Columbian skeletons in Chile showed lesions consistent with bony TB in 2 percent of cases [3]. Subsequently, molecular studies have established the presence of Mycobacterium tuberculosis complex deoxyribonucleic acid (DNA) in ancient bony specimens [2,4].

Clinical issues related to skeletal TB will be reviewed here. Other aspects of TB are discussed separately. (See related topics.)

EPIDEMIOLOGY — Worldwide, skeletal TB accounts for 10 to 35 percent of cases of extrapulmonary TB (9.6 percent of United States extrapulmonary cases [n=185] and 2.0 percent of all United States TB cases reported in 2017) [5-10]. Reported rates of extrapulmonary TB are higher among immigrants from highly endemic areas to developed countries; this may be due in part to immigration screening procedures for pulmonary TB [11]. One retrospective review of skeletal TB between 1980 and 1994 in France noted 103 cases of spinal TB; 68 percent of patients were foreign born, the majority from Africa [12]. The proportion of skeletal TB among individuals with human immunodeficiency virus (HIV) infection is comparable with the proportion of skeletal TB among individuals without HIV infection [13,14].

The most common form of skeletal TB is Pott disease, a disease of the spine; this entity comprises approximately half of musculoskeletal TB cases. The next most common form of musculoskeletal TB is tuberculous arthritis, followed by extraspinal tuberculous osteomyelitis [15].

PATHOGENESIS — During primary M. tuberculosis infection, bacillemia may lead to seeding of organisms in bone and/or synovial tissue. In most cases, small foci of infection are confined by local adaptive immune processes, and infection is subclinical. Following primary infection, reactivating foci are usually contained by the cellular immune response. CD4 and CD8 lymphocytes play important roles, as does interferon-gamma [16]. The likelihood of reactivation of infection with progression to clinically apparent disease increases when local immune defenses fail, as in the setting of malnutrition, advancing age, HIV infection, or advanced kidney disease [17].

Active TB disease can develop immediately or after decades of latent infection. In highly endemic regions, musculoskeletal TB usually manifests clinically in the year following primary lung infection and therefore occurs more frequently in relatively young patients [18]. Outside highly endemic areas, musculoskeletal TB is more commonly associated with late reactivation of infection and occurs mainly in adults.

Two types of bone and joint involvement associated with TB infection have been described: the caseous exudative type and the granular type [19]. The caseous exudative type is characterized by bone destruction, local swelling, abscess formation, sinus formation, and constitutional symptoms; it occurs most often in children. The granular type is more insidious and less destructive than the caseous exudative type, and abscess formation is less common; it occurs most often in adults. However, host-parasite interactions in TB are dynamic, often with mixed patterns and transitions along a continuum [20].

Rarely, bones and joints are involved in contiguous spread of TB from another site. Contiguous spread from an apical pulmonary focus of active TB, for example, can lead to atlantoaxial TB, involving the joint between the first and second cervical vertebrae [21].

CLINICAL MANIFESTATIONS — Forms of skeletal TB include spondylitis (Pott disease), arthritis, and osteomyelitis. From published series of spinal TB, there is wide variation in reported rates of active concomitant pulmonary TB at the time of diagnosis of the spinal TB [12,22,23]. The largest report series including nearly 700 cases had the lowest reported rate (2.7 percent) [23]. The proportion is likely to be similarly variable for other TB bone and joint infections, but series are too small to provide reliable data. Virtually any bone can be infected with M. tuberculosis. The diagnosis may be delayed when unusual bones such as the hyoid or digits are infected or when multifocal bony involvement is present.

Spondylitis (Pott disease) — Tuberculous spondylitis (Pott disease) most commonly affects the lower thoracic and upper lumbar region; involvement of cervical and upper thoracic region is less common [24,25]. Progression of infection generally begins with inflammation of the anterior aspect of intervertebral joints; typically, it spreads behind the anterior ligament to involve the adjacent vertebral body. Once two adjacent vertebrae are involved, infection enters the adjoining intervertebral disc space. This tends to occur later in Pott disease than in bacterial vertebral osteomyelitis and may have the radiographic appearance of relative disc sparing. Eventually, the avascular disc tissue dies; there is vertebral narrowing and subsequent vertebral collapse. Gibbus deformity, a form of structural kyphosis, distorts spinal canal anatomy (image 1). The spinal cord is then at risk of compression resulting in paraplegia, especially with involvement of the mid-thoracic region where the spinal canal is relatively "tight" around the cord [26]. Occasionally, late-onset paraplegia occurs due to osteophytes and other chronic degenerative changes at a site of prior infection. Formation of a "cold abscess" (soft tissue mass) at the site is common. Noncontiguous spinal disease (eg, disease at more than one level) is uncommon, although in one South African series it was described in 16 of 98 cases [27].

The most common symptom is local pain, which increases in severity over weeks to months, sometimes in association with muscle spasm and rigidity. The muscle spasm can extend beyond the diseased area. In some cases, a characteristic erect posture and "alderman's" gait may be observed in which the patient walks with short, deliberate steps to avoid jarring of the spine [28]. Constitutional symptoms such as fever and weight loss are present in less than 40 percent of cases [13,22,29-31].

The diagnosis of Pott disease is frequently delayed as a result of its subacute course, especially in regions where the incidence of TB is relatively low [13,22]. In endemic areas, the clinical presentation also tends to be relatively late due to limited access to medical care; in these settings, patients have symptoms and signs of cord compression at the time of diagnosis in 40 to 70 percent of cases [22,32]. Thus, late diagnosis is a major factor in determining the outcome of the disease [33].

Arthritis

Infectious — Tuberculous arthritis can occur in virtually any joint, but it tends to occur in the hip or the knee; usually, it is monoarticular. However, multifocal lesions are reported in 10 to 15 percent of cases in resource-limited countries [34]. Hip involvement is the most common presentation, the most difficult to diagnose, and the most debilitating [6]. Clinical manifestations include swelling, pain, and/or loss of joint function that progresses over weeks to months. The joint is generally "cold" (eg, erythema, warmth, and other signs of acute infection are usually absent). Constitutional symptoms, fever, and weight loss occur in only about 30 percent of cases [29].

Patients who present late in the course of disease often have evidence of joint destruction including local deformity and restricted range of motion. Some patients with advanced disease have draining sinuses. Granulomatous changes typically accompany synovial proliferation in tuberculous arthritis, with joint effusion and erosion of cartilage. The consequences are slowly progressive destruction, disorganization of joint architecture, and potential deformity.

Some data suggest that total hip replacement in the setting of active TB is acceptable if undertaken in association with appropriate debridement and antituberculous therapy [35].

Inflammatory (Poncet disease) — Poncet disease is an acute symmetric polyarthritis involving large and small joints associated with active extrapulmonary, pulmonary, or miliary TB. In general, there is inflammation of the involved joints but no objective evidence of active TB [36-39]. Poncet disease is relatively rare, and the pathogenesis is unclear; it is probably immune mediated [38]. HIV coinfection is also a risk factor [40,41]. The arthritis generally resolves within a few weeks of initiation of anti-TB therapy, with no residual joint destruction [37,42].

Prosthetic joint infection — Rarely, M. tuberculosis can cause infection at the site of a prosthetic joint [43]. Diagnosis has been described at the time of initial arthroplasty as well as subsequent to hardware placement [44].

For cases in which TB is identified at the time of initial arthroplasty, the diagnosis is typically a surprise to the surgeon who sends abnormal-appearing bone for histopathologic examination or culture at the time of joint replacement. These patients generally have a favorable outcome after standard antituberculous chemotherapy, even if the joint prosthesis is not removed [44].

For cases in which infection is identified following hardware placement, a dormant nidus of infection reactivates, and patients subsequently present with clinical findings of an infected prosthesis. These patients often have painful, malfunctioning prostheses, and hardware removal is required for cure. Some patients with late-onset tuberculous prosthetic joint infections have coexisting bacterial infection that may mask or obscure the underlying coinfection with M. tuberculosis.

Osteomyelitis — In addition to tuberculous vertebral osteomyelitis (Pott disease), tuberculous osteomyelitis can occur in virtually any bone, including the ribs, skull, tubular bones of the hands and feet (dactylitis), wrist, phalanx, pelvis, and long bones. The onset is often insidious but, in rare cases, the onset may be acute or subacute [45]. Typically, osteomyelitis occurs at a single site. However, rarely bony involvement can be multifocal. The location and presentation can be variable as illustrated by the following case reports:

●Sternal osteomyelitis due to M. tuberculosis may follow coronary artery bypass surgery [46] as a presentation of underlying mediastinal TB [47] or as primary sternal osteomyelitis [48].

●Bony TB of the rib may present as a breast mass or chest wall mass [49,50].

●TB of the small bones of the hand can occur spontaneously in patients with no clinical signs of pulmonary TB [51].

●Tuberculous mastoiditis can extend into the skull and produce facial nerve palsy [52].

●Lytic bony tubercular lesions in areas as unusual as the symphysis pubis, sacroiliac joint, and elbow can be misdiagnosed as metastatic malignancy [53].

In some cases, bony infection may spread to contiguous soft tissues or even adjacent joints. Rarely, involvement of multiple bones may be associated with erroneous diagnosis of metastatic malignancy [54-56].

An antecedent history of trauma may lead to diagnostic confusion; TB can develop in a bone or joint injured by previous trauma or surgery. Tuberculous osteomyelitis frequently presents as a "cold abscess" with swelling, modest erythema or pain, and little or no local warmth [15]. Spontaneous drainage may occur.

Other clinical manifestations — Musculoskeletal TB can occur as an abscess in the epidural space (creating pressure on the spinal cord), as an extraspinal soft tissue mass (eroding ribs and adjacent structures), or as a psoas abscess (which can track down to the groin). (See "Psoas abscess".)

Radiography — Radiographic imaging can be useful to identify and establish the anatomy of musculoskeletal TB, although there are no pathognomonic radiographic findings [57].

In the setting of tuberculous spondylitis (Pott disease), radiographic abnormalities are usually first observed in the anterior aspect of a vertebral body, with demineralization of the end plate and loss of definition of the bony margin [58]. Subsequently, the opposing vertebra becomes involved and, in some cases, a paravertebral abscess may be seen. Involvement of contiguous vertebrae is common, although it is not uncommon to see noncontiguous spinal TB at multiple levels. As infection progresses, the disc space becomes obliterated with anterior wedging and angulation. Reactive sclerotic changes remain localized and the remainder of the vertebral structures is often spared (image 2).

In some patients, spinal TB presents with osteolytic lesions in the absence of disc space involvement; these lesions may occur at multiple sites. In one study of 103 French patients with spinal TB, no disc involvement was observed in about half of cases; plain radiographs demonstrated osteolytic lesions and multiple involved sites [12].

In the setting of tuberculous arthritis, local soft tissue swelling, osteopenia, and bone destruction (with relative preservation of cartilage space) are observed. Subsequent findings include structural collapse, sclerotic changes, and soft tissue calcification (image 3). In some cases, Phemister triad may be observed: juxta-articular osteopenia, peripherally located osseous erosions, and gradual narrowing of the joint space (image 4) [59,60].

In the setting of tuberculous osteomyelitis in children, cystic changes may be seen in the metaphyses of long bones and in flat bones, such as the skull. In tuberculous osteomyelitis involving a hand or foot, phalangeal bone(s) may have a ballooned appearance.

Computerized tomography, myelography, and magnetic resonance imaging (MRI) are all useful tools in the diagnosis of musculoskeletal TB [24,61-65]. MRI is particularly valuable in demonstrating soft tissue extension and encroachment on nearby vital structures, such as the spinal cord (image 5 and image 6 and image 7 and image 8) [66,67].

Chest radiography is not a sensitive test for the diagnosis of skeletal TB since there is no evidence of active chest disease in the majority of cases [5,15,22,68]. However, chest radiography should be obtained since it may inform decisions regarding isolation, and collection of sputum specimens for mycobacterial culture should be attempted as the organism can sometimes be isolated from sputum despite a normal chest radiograph. The diagnosis of skeletal TB should be considered in patients with focal bony or joint abnormalities and a chest radiograph compatible with old or active TB. (See "Diagnosis of pulmonary tuberculosis in adults".)

DIAGNOSIS

General principles — The greatest challenge in diagnosis of skeletal TB is to consider the diagnosis, especially since there is no evidence of active chest disease in the majority cases. In addition, delays in diagnosis are common given the indolent nature of tuberculous bone and joint disease [69]. Clinical clues usually come from the history, which should include questions about the country of origin and history of prior known or possible TB infection or contact. In addition, the diagnosis of skeletal TB may be overlooked in patients with HIV infection and relatively high CD4 counts and no other signs or symptoms of TB.

The diagnosis of musculoskeletal TB is established by microscopy and culture of infected material. Tissue may be obtained by needle aspiration and/or biopsy; computed tomography (CT) guidance is useful in regions where available.

Biopsy and culture — The diagnosis of musculoskeletal TB is established by microscopy and culture of infected material [70-72]. Drug susceptibility testing of isolates is essential. Tissue may be obtained by needle aspiration and/or biopsy. CT guidance is useful in regions where available [73,74].

The diagnosis of tuberculous arthritis can be established by synovial biopsy. Synovial fluid may be examined [75], but findings are usually nonspecific; the white cell count can be high or low, with preponderance of either neutrophils or lymphocytes [76].

In the setting of one or more draining sinuses, culture of this material may be useful, although, in some cases, cultures may demonstrate colonizing bacteria or fungi that are erroneously assumed to be the causative pathogen.

The high cost and technical demands of rapid automated growth systems and nucleic acid detection methods often limits their use in the poorest countries with the highest incidence of TB [77]. The Xpert MTB/RIF assay is an automated nucleic acid amplification test that can simultaneously identify M. tuberculosis and rifampin resistance; data on use of this assay in skeletal TB are limited and the test platform is not approved by the Food and Drug Administration in the United States for use with specimens other than sputum. However, the available data suggest that Xpert and the more sensitive Xpert Ultra may be useful adjuncts to diagnosis of skeletal TB, with sensitivity of 79 and 91 percent, respectively [78]. The Xpert MTB/RIF assay is discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults".)

Additional issues related to diagnostic microbiology are discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults".)

Differential diagnosis — The differential diagnosis of skeletal TB includes subacute or chronic infections due to pathogens or diseases such as Staphylococcus aureus osteomyelitis, brucellosis, melioidosis, actinomycosis, candidiasis, and histoplasmosis, depending upon epidemiologic factors. Multifocal bone involvement may be confused for metastatic malignancy.

The differential diagnosis of Pott disease includes degenerative disc and facet joint disease, spondyloarthropathy, vertebral body collapse due to osteopenia (with a variety of causes such as osteoporosis and chronic corticosteroid therapy), pyogenic spinal infection, and malignancy. Each of these can present with similar clinical features; the main challenge for diagnosis of TB is consideration of the diagnosis. Most of these conditions can be distinguished with imaging studies where available.

TREATMENT

General approach — Treatment of musculoskeletal TB consists of antimicrobial therapy. In some cases, surgical intervention is also warranted.

Antimicrobial therapy — The approach to selection of antituberculous therapy for treatment of musculoskeletal TB is generally the same as that for pulmonary TB. The drug regimen may require modification based on concurrent medications (eg, HIV coinfection) or drug resistance. These issues are discussed in detail separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Treatment of drug-resistant pulmonary tuberculosis in adults".)

The optimal duration of therapy for treatment of musculoskeletal TB is uncertain. For most patients receiving first-line agents, six to nine months of therapy is sufficient [79]. A longer duration of therapy (9 to 12 months) is warranted for patients on regimens that do not include rifampin and/or for patients with extensive or advanced disease, particularly if it is difficult to assess the response to therapy [79,80].

Data are limited on the optimal drug regimen and duration for treatment of musculoskeletal infections due to drug-resistant M. tuberculosis. In one small series, 14 of 15 patients were cured with combined medical/surgical therapy (eight patients) or medical therapy alone (seven patients). Treatment was continued for 18 to 24 months; follow-up ranged from 5 months to 4.5 years [81].

Previously, longer therapeutic courses (12 to 18 months) have been favored for musculoskeletal TB because of concerns about poor drug penetration into osseous and fibrous tissues. However, several studies have shown that six- to nine-month regimens containing rifampin are at least as effective as longer courses without rifampin [82-87]. The efficacy of shorter-course therapy is illustrated by the following:

●A large prospective cohort study in Hong Kong demonstrated that 6 months of antituberculous therapy combined with surgery (radical resection of the lesion and insertion of autologous bone grafts) was comparable in efficacy with 9 to 18 months of antituberculous therapy alone [82].

●In three randomized trials of short-course chemotherapy for spinal TB in Hong Kong, India, and Korea reported after five years of follow-up, six- and nine-month regimens with isoniazid and rifampin produced comparable results with 18 months of isoniazid with either ethambutol or para-aminosalicylic acid [85].

●In a randomized trial of 203 Korean patients comparing four different treatment regimens [(1) isoniazid plus rifampin for six months, (2) isoniazid plus rifampin for nine months, (3) isoniazid plus ethambutol or para-aminosalicylic acid for nine months, or (4) isoniazid plus ethambutol or para-aminosalicylic acid for 18 months], a favorable outcome was achieved in 77 percent of cases after three years from the start of therapy; those who received the nine-month regimen with isoniazid plus ethambutol or para-aminosalicylic acid required additional treatment [86].

One small retrospective study from the United Kingdom did report a high rate of relapse with a six-month course of therapy (62 percent); no relapse was observed among patients who received nine months of treatment [87]. In contrast, a Chinese study reported that, in selected patients and combined with appropriate surgical intervention, ultra-short-course therapy of 4.5 months was as successful as a 9-month course and associated with fewer side effects [88].

Surgery — Surgical intervention is warranted for patients in the following circumstances [26,50,89,90]:

●Patients with spinal disease and advanced neurological deficits

●Patients with spinal disease and worsening neurological deficits progressing while on appropriate therapy

●Patients with spinal disease and kyphosis >40 degrees at the time of presentation

●Patients with chest wall cold abscess

Forms of surgical intervention may include decompression, use of hardware for stabilization of spine, abscess drainage, and/or debridement of infected material [25,90]. For the most part, surgical intervention is safe and sometimes effective in improving neurological deficits; various approaches have been described, depending on site of infection and related abscess formation [91-93]. In some circumstances, reconstructive surgery may be important once antimicrobial therapy has been completed [5]. Hardware is rarely needed for stabilization of debrided bony lesions [94]. Minimally invasive surgical approaches such as video-assisted thoracoscopic anterior surgery have been used successfully to manage patients with neurological symptoms and/or extensive bony destruction involving the thoracic or lumbar spine [95].

The role of surgery in treatment of other presentations of musculoskeletal TB is not always clear [96]. In one retrospective review of 70 adults with thoracic spinal TB in India, medical therapy alone was successful in 69 of 70 patients (mean follow-up of 40 months) [89]. Criteria for exclusion included advanced neurologic deficits, worsening neurologic deficits while on antituberculous therapy, and kyphosis greater than 40 degrees on presentation. Abscess was observed on presentation in 44 patients (21 of which were epidural), and 7 patients had signs of cord compression at the time of presentation. Routine surgical intervention is not warranted [94,97].

Similar results were noted in a retrospective analysis of 52 children with TB of the knee [98]. The outcome of medical therapy without synovectomy was excellent in children who presented with signs and symptoms of synovitis as long as the joint space was normal.

Monitoring clinical response — The response to therapy may be monitored by clinical indicators such as pain, constitutional symptoms, mobility, and neurologic findings. Typically, responses to therapy are relatively slow (several months). The role of inflammatory markers in monitoring the response to TB therapy is limited. It is not useful to perform serial radiographs since radiographic findings may appear to progress during appropriate treatment [99].

In one study of 43 patients with Pott paraplegia, the most important prognostic factor that predicted six-month outcome included muscle power, paraplegia score, sensory-evoked potentials, and motor-evoked potentials [100]. Patients with mild weakness and lower paraplegia scores were more likely to recover completely by six months than patients with more severe prognostic indicators.

For patients on antituberculous therapy for skeletal TB in the setting of antiretroviral treatment (ART) for HIV infection, it is important to monitor for immune reconstruction inflammatory syndrome (IRIS). IRIS typically presents with paradoxical progression of TB clinical manifestations and constitutional symptoms in the first few weeks following initiation of ART. In the setting of skeletal TB, new clinical manifestations may appear and/or resolved manifestations may reappear. IRIS is discussed further separately. (See "Immune reconstitution inflammatory syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)

SUMMARY AND RECOMMENDATIONS

●Skeletal tuberculosis (TB) refers to TB involvement of the bones and/or joints. Musculoskeletal TB accounts for 10 to 35 percent of cases of extrapulmonary TB and for almost 2 percent of TB cases overall. The proportion of skeletal TB among individuals with HIV infection is comparable with the proportion of skeletal TB among individuals without HIV infection. (See 'Epidemiology' above.)

●Tuberculous spondylitis (Pott disease) is the most common form of skeletal TB; it usually affects the lower thoracic and upper lumbar region. Infection begins with inflammation of the intervertebral joints and can spread to involve the adjacent vertebral body. Once two adjacent vertebrae are involved, infection can involve the adjoining intervertebral disc space, leading to vertebral collapse. Subsequent kyphosis can lead to cord compression and paraplegia. (See 'Spondylitis (Pott disease)' above.)

●The most common symptom of tuberculous spondylitis (Pott disease) is local pain, which increases in severity over weeks to months, sometimes in association with muscle spasm and rigidity. A characteristic erect posture and "alderman's" gait may be observed in which the patient walks with short, deliberate steps to avoid jarring of the spine. Constitutional symptoms such as fever and weight loss are relatively uncommon. (See 'Spondylitis (Pott disease)' above.)

●Tuberculous arthritis tends to occur in the hip or the knee and is usually monoarticular. Clinical manifestations include swelling, pain, and/or loss of joint function that progresses over weeks to months. The joint is generally "cold" (eg, erythema, warmth, and other signs of acute infection are usually absent). (See 'Arthritis' above.)

●Tuberculous osteomyelitis can occur in virtually any bone, including the ribs, skull, phalanx, pelvis, and long bones. Typically, osteomyelitis occurs at a single site. The onset is often insidious but, in rare cases, the onset may be acute or subacute. Tuberculous osteomyelitis frequently presents as a "cold abscess" with swelling, modest erythema or pain, and little or no local warmth. (See 'Osteomyelitis' above.)

●The diagnosis of musculoskeletal TB is established by microscopy and culture of infected material. Tissue may be obtained by needle aspiration and/or biopsy; guidance with computed tomography or ultrasound to obtain tissue is useful in regions where available. Radiographic imaging can be useful to identify and establish the anatomy of musculoskeletal TB, although there are no pathognomonic radiographic findings. (See 'Diagnosis' above.)

●Treatment of musculoskeletal TB consists of antituberculous therapy. The approach to selection of therapy for treatment of musculoskeletal TB is generally the same as that for pulmonary TB and is discussed in detail separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Treatment of drug-resistant pulmonary tuberculosis in adults".)

●The optimal duration of therapy for treatment of musculoskeletal TB is uncertain. For patients receiving treatment with first-line agents in the absence of extensive or advanced disease, we suggest six months of therapy (rather than 9 or 12 months) (Grade 2B). A longer duration of therapy (9 to 12 months) is warranted for patients on regimens that do not include rifampin and/or for patients with extensive or advanced disease. (See 'Antimicrobial therapy' above.)

●Surgical intervention is warranted for patients with spinal disease and advanced neurological deficits or worsening neurological deficits progressing while on appropriate therapy, as well as for patients with spinal disease and kyphosis >40 degrees at the time of presentation. (See 'Surgery' above.)