Tuberculosis continues to be one of the most challenging health problems more prevalent in developing countries. Pakistan ranks 5th in tuberculosis prevalence among the high-burden countries. Prosthetic joint infection of the knee by acid fast bacilli is a rare and distressing complication, occurring in nearly 1% of primary joint
arthroplasties requiring prolonged medical treatment and multiple surgeries. A recent publication extensively reviewed English literature from 1952 to 2016, and
repor ted only 64 prosthetic joint infec tion with tuberculosis, of which 27 cases involved the knee. Tuberculosis is a global health problem adding to the
challenges that arthroplasty surgeons face in our resource-constrained setting. Furthermore, it presents as other inflammatory arthritis with almost same laboratory and radiological findings. The current paper was planned to highlight the preoperative and postoperative challenges that the arthroplasty surgeon may have in diagnosis and management of this rare infection. We included studies from 1996 to date which reported knee tuberculosis prosthetic joint infection that were managed by medication alone or with surgical intervention in patients who had undergone arthroplasty.
Keywords: Knee arthroplasty, TB prosthetic joint infection, Endemic, Inflammatory arthritis.
Tuberculosis ( TB) continues to be one of the most challenging health problems and is more prevalent in developing countries. Pakistan ranks fifth in TB prevalence amongst the high-burden countries.1 In this day and age joint replacement surgeries have become popular in developing countries where TB also has high prevalence. Prosthetic joint infection (PJI) of the knee by acid fast bacilli (AFB) is a rare and distressing complication occurring in nearly 1% of primary joint arthroplasties2,3 requiring prolonged medical treatment and multiplesurgeries. Patients can present with a palpable mass (cold abscess), draining sinus/fistula, and painful erythema. Therefore high clinical suspicion is mandatory for diagnosis of PJI by mycobacterium. Adding to this challenge is inflammatory arthritis affecting the knee joint present with almost identical features on clinical
examination, laboratory tests and radiographic findings. Laboratory tests include tuberculin skin test (TST ), erythrocytes sedimentation rate (ESR) and cultures of synovial fluid, cytology and histology with different rates of accuracy. In endemic areas with mycobacterium TB (MTB), the low threshold of suspicious is indeed helpful for early diagnosis and management of this catastrophic infection. Factors contributing to delayed diagnosis include its low incidence, varied clinical manifestations, co-infection with pyogenic bacteria accounting for 37% cases, and
low index of suspicion.4 First case of peri-PJI with MTB was reported in 1977(5). A recently 2018 publication extensively reviewed Englishlanguage literature from 1952 to 2016, and reported only 64 PJI with TB, of which 27 cases involved the knee.6
Pathology: Three pathogenic mechanisms have been reported: active TB arthritis present at the time of surgery but not known to clinician; TB spread by haematogenous route from foci elsewhere; and surgical trauma to old granulomas resulting in recurrence of TB arthritis.5-8 Recent studie shave highligh ted human immunodeficiency virus (HIV) as an important risk factor for re-activation of TB in previously infected joints.9,10 Estimated risk of re-activation has been reported between 0% and 31%, with total knee arthroplasty (TKA)
more at risk than total hip arthroplasty (THA) (27% and 6%).11 Staphylococcus is the most common organism for prosthetic infections followed by gram-negative and streptococcus species, while atypical infections are rare.18,12MTB has limited biofilm-formation capacity which, if formed, is very thin and has a lesser tendency to adhere to implants compared to the biofilmforming staphylococci which have ample biofilm-forming capacity and stronger ability to multiply and adhere on surface of all types of implants.13-15Because of these factors, MTB is more susceptible to anti-TB agents and, if implant is stable, removal of hardware is not needed.13 , 16 Nevertheless, emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has complicated its management.16
Clinical presentation: PJI of knee with MTB has a varied clinical presentation. Constitutional symptoms, including fever, weight loss and night sweats, are not seen in all cases and a previous history of pulmonary Koch\'s is often absent.17,18 Patients can present with a palpable mass (cold abscess), draining sinus/fistula, and painful erythema. Therefore high clinical suspicion is mandatory for diagnosis of PJI by mycobacterium. Onset of symptoms within 2 month after ar throplasty is considered "early presentation" whereas onset of
symptoms after 2 months is labelled as "delayed presentation".7,19
Role of lab investigation: The ESR level may be elevated, but has a low specificity. ESR levels remain elevated for about 90 days or more than a year after arthroplasty,
making it a less valuable test at least during this timeframe.14,20 TST is sensitive, but has a reduced positive predictive value (PPV) in populations with a low infection rate. It may report false negative results in patients who are immune-compromised, malnourished or HIVpositive. 3 It is also not able to differentiate between active and latent TB. Clinical utility of different tests in diagnosing extra-pulmonar y TB also need to be considered (Table 1).
Role of radiological investigation: Plain radiographs either of knee or chest are not specific. Radiological findings may show subchondral cysts, subchondral erosions or implant loosening, but these findings may also be present with pyogenic infection, aseptic loosening and will be absent in early presentation where the implant is stable.21,22 Magnetic resonance imaging (MRI) has low sensitivity due to artefacts caused by the implant. MRI findings reveal large intra-articular effusions, peri-articular osteo porosis, and gross thickening of the remainingsynovial membrane which are not clinically relevant in isolation after arthroplasty.8 Nuclear medicine is the most valuable diagnostic procedure to detect the prosthesis involvement and loosening,23 but literature review has reported their use to be limited. Bone scans findings with technecium-99m or indium-111 are non-specific because findings mimic pyogenic infection, metastatic disease and non-specific inflammation.5
Grams staining / histological diagnosis:
Aspiration of synovial fluid is another modality, but yield is low, with reported sensitivity of 80%. Literature reports synovial biopsy as gold standard in diagnosing PJI of knees.24-26 It has sensitivity of about 90%, but should always be added with cultures to get information about antibiotic resistance.27,28 Culture specimens taken from draining sinuses are usually contaminated.3,6 Staining and visualisation of mycobacterium with Ziehl-nelson is time-saving and cost-effective, but yield of positive test is less than culture 17Polymerase chain reaction (PCR), though one of the recent diagnostic modalities, has significant specificity, but is less sensitive at 60%. There are limited studies mentioning its use in the diagnosis of PJI.29-32 Treatment: Since PJI of knee with mycobacterium is rare, ith varied presentation and delayed diagnoses; therere no specific guidelines for its management. Several different treatment plans have been advised for PJI of knee by AFB. Management varies from case to case. Literature reports treatment options that range from chemotherapy alone to arthrodesis or revision in addition to chemotherapy.
Conservative management: Early onset PJI of knee has been managed by retention of the implant with prolonged chemotherapy. There is great controversy regarding treatment duration of chemotherapy and combination of drugs in the literature. Cases of PJI with MTB managed with medications alone are worth taking
a look at (Table 2).
Surgical management: Surgical treatment options include debridement alone, single-stage or two-stage implant exchange or removal of prosthesis and arthrodesis. Chemotherapy alone or with surgical debridement has been used in early onset PJI. In late onset PJI, implant usually gets loose, and removal of implant is often required.33 Wolfgang shared his
experience of late onset PJI in knee, managed with removal of implant, extensive debridement and twostage revisions with adjuvant chemotherapy and good
results at 1-year follow-up.32 A successful case of staged procedure in TB arthritis is also known.
Figure 1 and 2 summarize a case of 55 years old lady presented with
right knee pain, stiffness and difficulty walking not responding to conservative measures. Right knee was swollen, warm and tender with moderate effusion. Active
range of motion 0-110 degrees. No varus/valgus or AP instability was seen on clinical examination. Blood tests were normal except for ESR and CRP, 75mm/hr and
2.14mg/dL, respectively. These features suggested erosive arthritis, which could be inflammatory. However TB should be considered high up in the differentials par ticularly in endemic areas with MTB. Patient underwent debridement and open biopsy at first stage, which confirmed the diagnosis of TB. Multidisciplinary approach including the surgeon, infectious disease team and microbiologist was followed. Following ATT for 10 months, patient had a successful TKA with an excellent outcome. This strengthens the concept that not every erosive arthritis is a systemic inflammatory rheumatoid type, particularly so in our endemic areas of TB. Patient had no varus/valgus or AnteroPosterior (AP) instability on clinical examination. Blood tests were normal except for raised ESR and CRP. Pre-operative knee X-ray showed juxta-articular osteopenia, peripheral osseous erosions and narrowing of joint space. These features suggested erosive arthritis, which could be inflammatory. However, TB should be considered high up in the differentials, par ticularly in endemic areas with MTB. Patient underwent debridement and open biopsy at first stage, which confirmed the diagnosis of TB. In endemic areas, one, therefore, has to make sure that TB is considered in the differential diagnosis of inflammatory arthritis as the radiological features alone are not enough to differentiate between these conditions. Indeed, these two different pathologies of arthritis present with same laboratory and radiological findings include elevated ESR and CRP, as well as erosive arthritis without formation of osteophytes and with mono-articular involvement.Cases of TB-PJI managed surgically by debridement and retention of implant, debridement and explant, staged procedure (debridement followed by TKA) or arthrodesis have been known (Table 3).
Surgical treatment depends on the status of implant fixation. Implant may be retained if it is stable and only debridement followed by chemotherapy may be required. This strategy has been reported successfully in multiple cases and studies.19,29,35,36 In case of implant loosening or co-infection with pyogenic organism, removal of loose implant and staged revision have been reported.37,38 In recurrent infection cases in severely sick patients, arthrodesis, if bone stock is available, or above-knee amputation, in cases with significant bone loss and destruction, can be potential options to improve patients\' quality of life.
Figure 3 and 4 showing a 68 year old lady with multiple comorbids. Right TKA done for reported advanced OA outside our institution. Presented with pain and swelling of right knee within 11 months postoperatively. Patient u nder went d ebridement and implant removal. Peroperative cultures grew MTB. Planned for revision TKA once free from disease or arthrodesis. Patient was kept on ATT but was not compliant and had multiple hospital admissions due to heart failure, asthma, electrolyte imbalance and drowsiness. This unfortunate sick lady had recurrent TB infection with significant bone loss and ultimately underwent above knee amputation.
Obtaining synovial specimens and specifically requesting TB culture and histology are the most pertinent investigations. Early diagnosis and treatment may prevent prosthetic loosening and avoid revision surgery with significant benefit to the patient and optimising outcomes and resources. Adding to this challenge is inflammatory arthritis affecting the knee joint present with almost identical features on clinical examination, laboratory tests and radiographical findings. TB should always be amongst differential diagnosis in cases of erosive inflammatory arthritis in endemic areas. Needless to say that this issue should be dealt with in multi-disciplinary setting including experienced surgeon, infection disease control consultant, histopathologist and public health workers to improve the outcome of these patients in a developing country.
Disclaimer: We declare that this paper was not previously
presented or published anywhere. This was not part of any other projects.
Conflict of Interest: No conflicts of interest to disclose.
Sources of Funding: No funding from any source for this
1. World Health Organization. Global tuberculosis control: epidemiology, planning, financing: WHO report 2009. [Internet] Geneva: World Health Organization; 2009 [cited 2018 December 30] Available from: http://www.who.int/iris/handle/10665/44035
2. Barnes S, Salemi C, Fithian D, Akiyama L, Barron D, Eck E, et al. An enhanced benchmark for prosthetic joint replacement infection rates. Am J Infect Control 2006;34:669-72.
3. Miandad M, Burke F, Nawaz-ul-Huda S, Azam M. Tuberculosis incidence in Karachi: a spatio-temporal analysis. Geografia Malays J Soc Space 2017;10:1-8.
4. Salemi C, Anderson D, Flores D. American Society of Anesthesiology scoring discrepancies affecting the National Nosocomial Infection Surveillance System: surgical-site-infection risk index rates. Infect Control Hosp Epidemiol 1997;18:246-7.
5. McCullough C. Tuberculosis as a late complication of total hip r e p l a c e m e n t . A c t a O r t h o p S c a n d 1 9 7 7 ; 4 8 : 5 0 8 - 1 0 .
6. Veloci S, Mencarini J, Lagi F, Beltrami G, Campanacci DA, Bartoloni A, et al. Tubercular prosthetic joint infection: two case reports and literature review. Infection 2018;46:55-68.
7. Horsburgh Jr CR, Rubin EJ. Latent tuberculosis infection in the United States. N Engl J Med 2011;364:1441-8 .
8. Khater FJ, Samnani IQ, Mehta JB, Moorman JP, Myers JW. Prosthetic joint infection by Mycobacterium tuberculosis: an unusual case report with literature review. South Med J 2007;100:66-9.
9. Berbari EF, Hanssen AD, Duffy MC, Steckelberg JM, Osmon DR. Prosthetic joint infection due to Mycobacterium tuberculosis: a case series and review of the literature. Am J Orthop (Belle Mead
10. Johnson R, Barnes K, Owen R. Reactivation of tuberculosis after total hip replacement. J Bone Joint Surg Br 1979;61-B:148-50.
11. Burger JD, de Jongh H. Total knee replacement infected with Mycobacterium tuberculosis: a case study and review of the literature. SA Orthop J 2013;12:64-8.
12. Poultsides LA, Kar ydakis G, Karachalios T, Kaitelidou D, Papakonstantinou V, Liaropoulosb L, et al. The impact of infection after total knee arthroplasty on hospital and surgeon resource utilization. A micro costing analysis. Orthop Proc 2009;91-B(Suppl II):314.
13. Ha KY, Chung YG, Ryoo SJ. Adherence and biofilm formation of Staphylococcus epidermidis and Mycobacterium tuberculosis on various spinal implants. Spine (Phila Pa 1976) 2005;30:38-43.
14. Marmor M, Parnes N, Dekel S. Tuberculosis infection complicating total knee arthroplasty: report of 3 cases and review of the literature. J Arthroplasty 2004;19:397-400.
15. Koruk ST, Sipahio?lu S, Cali?ir C. Periprosthetic tuberculosis of the knee joint treated with antituberculosis drugs: a case report. Acta Orthop Traumatol Turc 2013;47:440-3.
16. Kadakia AP, Williams R, Langkamer VG. Tuberculous infection in a total knee replacement performed for medial tibial plateau fracture: a case report. Acta Orthop Belg 2007;73:661-4.
17. Barr DA, Whittington AM, White B, Patterson B, Davidson RN. Extrapulmonary tuberculosis developing at sites of previous trauma. J Infect 2013;66:313-9.
18. Neogi DS, Kumar A, Yadav CS, Singh S. Delayed periprosthetic tuberculosis after total knee replacement: is conservative treatment possible? Acta Orthop Belg 2009;75:136-40.
19. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416.
20. de Haan J, Vreeling A, van Hellemondt GG. Reactivation of ancient joint tuberculosis of the knee following total knee arthroplasty after 61 years: a case report. Knee 2008;15:336-8.
21. Sundfeldt M, Carlsson LV, Johansson CB, Thomsen P, Gretzer C.
Aseptic loosening, not only a question of wear: a review of different theories. Acta Orthop 2006;77:177-97.
22. Trampuz A, Zimmerli W. Prosthetic joint infections: update in diagnosis and treatment. Swiss Med Wkly 2005;135:243-51.
23. Krappel FA, Harland U. Failure of osteosynthesis and prosthetic joint infection due to Mycobacterium tuberculosis following a subtrochanteric fracture: a case report and review of the literature. Arch Orthop Trauma Surg 2000;120:470-2.
24. Ahmad SS, Shaker A, Saffarini M, Chen AF, Hirschmann MT, Kohl S. Accuracy of diagnostic tests for prosthetic joint infection: a systematic review. Knee Surg Sports Traumatol Arthrosc 2016;24:3064-74.
25. Della Valle C, Parvizi J, Bauer TW, Dicesare PE, Evans RP, Segreti J, et al. Diagnosis of periprosthetic joint infections of the hip and knee. J Am Acad Orthop Surg 2010;18:760-70.
26. Suren C, Harrasser N, Pohlig F, Banke IJ, Lenze U, Lenze F, et al. Prospective analysis of a sterile, semi-automated tissue biopsy homogenization method in the diagnosis of prosthetic joint infections. In Vivo 2017;31:937-42.
27. Lee JE, Kim HJ, Lee SW. The clinical utility of tuberculin skin test and interferon-? release assay in the diagnosis of active tuberculosis among young adults: a prospective observational study. BMC Infect Dis 2011;11:96. doi: 10.1186/1471-2334-11-96.
28. Li Y, Jia W, Lei G, Zhao D, Wang G, Qin S. Diagnostic efficiency of Xpert MTB/RIF assay for osteoarticular tuberculosis in patients with inflammatory arthritis in China. PLoS One 2018;13:e0198600. doi 10.1371/journal.pone.0198600.
29. Nocera RM, Sayle B, Rogers C, Wilkey D. Tc-99m MDP and indium-
111 chloride scintigraphy in skeletal tuberculosis. Clin Nucl Med 1983;8:418-20.
30. Palestro CJ. Nuclear medicine and the failed joint replacement: past, present, and future. World J Radiol 2014;6:446-58.
31. Tokumoto JI, Follansbee SE, Jacobs RA. Prosthetic joint infection due to Mycobacterium tuberculosis: report of three cases. Clin Infect Dis 1995;21:134-6.
32. Wolfgang GL. Tuberculosis joint infection following total knee a r t hrop l a s t y. Cl i n O r t ho p R el at Re s 1 9 8 5 ;20 1 : 1 6 2 - 6.
33. Chen WH, Jiang LS, Dai LY. Influence of bacteria on spinal implantcentered
infection: an in vitro and in vivo experimental comparison between Staphylococcus aureus and Mycobacterium tuberculosis. Spine (Phila Pa 1976) 2011;36:103-8.
34. Kim SJ, Kim JH. Late onset Mycobacterium tuberculosis infection after total knee arthroplasty: a systematic review and pooled analysis. Scand J Infect Dis 2013;45:907-14.
35. Titov AG, Vyshnevskaya EB, Mazurenko SI, Santavirta S, Konttinen Y. Use of polymerase chain reaction to diagnose tuberculous arthritis from joint tissues and synovial fluid. Arch Pathol Lab Med 2004;128:205-9.
36. Uppal S, Garg R. Tubercular infection presenting as sinus over ankle joint after knee replacement surgery. J Glob Infect Dis 2010;2:71- 2.
37. Carrega G, Bartolacci V, Burastero G, Finocchio GC, Ronca A, Riccio G. Prosthetic joint infections due to Mycobacterium tuberculosis: a report of 5 cases. Int J Surg Case Rep 2013;4:178-81.
38. Klein GR, Jacquette GM. Prosthetic knee infection in the young immigrant patient - do not forget tuberculosis! J Arthroplasty
201 2 ; 2 7 : 1 4 1 4 . e 1 - 4 . d o i : 1 0 . 1 0 1 6 / j . a r t h . 2 0 1 1 . 0 9 . 0 2 0 .
39. Held M, Laubscher M, Mears S, Dix-Peek S, Workman L, Zar H, et al. Diagnostic accuracy of the Xpert MTB/RIF assay for extrapulmonary tuberculosis in children with musculoskeletal infections. Pediatr Infect Dis J 2016;35:1165-8.
40. Marschall J, Evison JM, Droz S, Studer U, Zimmerli S. Disseminated tuberculosis following total knee arthroplasty in an HIV patient. Infection 2008;36:274-8.
41. Egües Dubuc C, Uriarte Ecenarro M, Errazquin Aguirre N, Belzunegui Otano J. Prosthesis infection by Mycobacterium tuberculosis in a patient with rheumatoid arthritis: a case report and literature review. Reumatol Clin 2014;10:347-9.
42. Su JY, Huang TL, Lin SY. Total knee arthroplasty in tuberculous arthritis. Clin Orthop Relat Res 1996;323:181-7.
43. Lusk RH, Wienke EC, Milligan TW, Albus TE. Tuberculous and foreign?body granulomatous reactions involving a total knee prosthesis. Arthritis Rheum 1995;38:1325-7.
44. Spinner RJ, Sexton DJ, Goldner RD, Levin LS. Periprosthetic infections due to Mycobacterium tuberculosis in patients with no prior history of tuberculosis. J Arthroplasty 1996;11:217-22.
45. Al-Shaikh R, Goodman SB. Delayed-onset Mycobacterium tuberculosis infection with staphylococcal superinfection after total knee replacement. Am J Orthop (Belle Mead NJ) 2003;32:302-5.
46. Wang PH, Shih KS, Tsai CC, Wang HC. Pulmonary tuberculosis with delayed tuberculosis infection of total knee arthroplasty. J Formos Med Assoc 2007;106:82-5.
47. Lee CL, Wei YS, Ho YJ, Lee CH. Postoperative Mycobacterium tuberculosis infection after total knee arthroplasty. Knee 2009;16:87-9.
48. Harwin SF, Banerjee S, Issa K, Kapadia BH, Pivec R, Khanuja HS, et al. Tubercular prosthetic knee joint infection. Orthopedics 201 3;36:e14 64-9. doi: 10.39 28/0 1477447 -201310 21-35.