Tubercular lymphadenitis management

tuberculas lymphadenitis, differenciating features from NTM lymphadenitis and BCG lymphadenitis

1. Managing Lymph Node Tuberculosis Ankur gupta

2. An Overview Commonest form of Extrapulmonary TB with vivid clinical manifestations, resulting from multiple, complex & variable pathogenetic – immunologic pathways. Epidemiological characteristics differ from PTB. Diagnosis may be challenging & management may be far from satisfactory. Multimodality treatment options frequently required.

3. Historical Perspective 2700 BC – Mentioned in Chinese literature 1500 BC – Ebes papyrus 484- 425 BC – Herodotus (Exclusion of those affected with leprous or scrofulous lesion from general population). 460-377 BC – Hippocrates 300BC to 620AD – Indian Literature “ Kanth Mala” 466-511 SD – Clovis I (France) Scrofulous tumours , started royal touch. “Kings evil” or “royal disease”. 936-1018 AD –Abdul Quasin AI Zahrani discussed surgical excision. In medieval Europe practice of royal touch continued.

4. Historical Perspective 1757 - 1836 – In France Louis XVI and his successors continued to touch the persons with scrofula. 1786 -1851 – Jean Lugol - Iodine solution treatment Early in 20 th century – surgical excision. 1937 – Griffith 50% of cervical adenitis was due to M- bovis 1950-70 – ATT + various surgical procedures 1975 – 75% isolates for adult LNTB – Mycobacterium tuberculosis (public health lab service, UK & Republic of Ireland).

5. Tubercular Lymphadenitis Peripheral tuberculous lymphadenitis—previously termed ‘‘ scrofula ’’—is a unique manifestation of disease due to organisms of the Mycobacterium tuberculosis complex. Current Imaging modalities have dramatically altered management of deep TBLN. Epidemiologic characteristics differ from those of pulmonary tuberculosis. Clinical manifestations are variable. Diagnosis may be challenging. Treatment may be frustrating.

6. Epidemiology Worldwide, including western countries, the proportion of extrapulmonary cases, with their principal subset, lymphadenitis, has increased. In low TB burden countries, the majority of patients are foreign-born, with a pattern consistent with reactivation disease . U.S.A – Adults 95% MTB ; Children 92% NTM

7. Immigrants from SouthEast Asia and India appear to have a special predilection for tuberculous lymphadenitis ( U.S., Canada & Britain). Africans may also have an increased risk of lymph node tuberculosis. The basis for enhanced risk among women, Asians and Africans is not known.

8. Global Epidemiology of Tuberculous Lymphadenitis Ref :Current diagnosis & management of peripheral tuberculous lymphadenitis CID 2011: 53 (15 september ). 555-562 Fontanilla et al

9. Possible host factors include : Occupations or cultural practices favoring oropharyngeal exposures to M. tuberculosis complex ( eg . exposure to Mycobacterium bovis or M. tuberculosis from milking cows). Genetically determined organ tropism. Hormonal influences Effects related to bacillus Calmette-Gue´rin (BCG) immunization. Differences in health-seeking behavior.

10. LNTB, HIV & Diabetes mellitus Extrapulmonary tuberculosis, including lymphatic tuberculosis, is more common among immunocompromised patients, including those with HIV infection. Although diabetes mellitus is a risk factor for pulmonary tuberculosis, studies suggest that it may reduce the relative risk of tuberculous lymphadenitis.* Anti – TNF α antagonist therapy may lead to TBLN.** * Int J Tuberc Lung Dis 2003; 7:987–93. Medicine (Baltimore) 2005; 84:350–62 ** Lancet, infect Dis 2003, 3,148-155

11. Microbiology M. tuberculosis is the usual cause of tuberculous lymphadenitis. Other infectious causes of chronic lymphadenitis include : Nontuberculous mycobacteria (including M. scrofulaceum , M. avium , and M. haemophilum ) Pseudomonas pseudomallei Toxoplasma species Bartonella species Fungi.

12.   Tuberculous granuloma

13. Clinical features Usually presents as a slowly progressive, painless swelling of a single group of lymph nodes. The duration of symptoms at the time of presentation is typically 1–2 months, varying from 3 weeks to 8 months. The mean duration of symptoms is usually longer in men than in women.

14. LNTB PROGRESSION GRANULOMA SOLID CASEOUS TISSUE (CMI – Cytotoxic T Cells) LIQUIFIED CASEOUS MATERIAL (DTH) COLD ABSCESS X X Therapeutic agent that reduce amount of liquifaction would be of considerable help. Tubercle bacilli are dormant Persistent LNTB Tubercle bacilli multiply logarithmically & in extra-cellular environment reaching in tremendous numbers Yukari C. Manabe & Arthur M. Dannenberg Jr. Pathophysiology : Basic Aspects in David Schlossberg – Tuberculosis & NTM Infections, Tata McGraw Hill, 5 th Edition, 2007; 18-51.

15. Stage I Enlarged firm mobile discrete nodes (Lymphoid hyperplasia with formation of tubercles & granuloma ) Stage II Large rubbery nodes fixed to surrounding tissue due to periadenitis ( Caseation starts) Stage III Central softening due to abscess formation (progressive Caseation necrosis) Stage IV Collar stud abscess formation. skin over is inflamed (Rupture of caseous material) Stage V Sinus tract formation

16. Symptomatology Patients do not generally report significant pain at presentation. Node tenderness during examination is noted in only 10%–35% of cases. A draining sinus may be present in 4%–11% of cases. Unilateral involvement of 1–3 nodes has been noted in 85% of cases. Cervical chain involvement is most common (45%–70%) with 12%–26% in the supraclavicular region; 20% of cases are bilateral.

17. Progressive Generalized Lymphadenopathy Symmetrical adenopathy with nodes typically < 3 cm. Reported in 94% of patients with HIV-induced lymphadenopathy , compared with 29% of patients with HIV-associated tuberculous lymphadenitis. Regresses with progression of HIV disease.

18. Fever & weight loss were reported in 40%-60% of HIV-positive patients in series from India. HIV-positive patients with tuberculous lymphadenitis typically have a higher rate of disseminated disease than do HIV-negative patients.

19. HIV infection has been presumed to be responsible for the rise in number of tuberculous lymphadenitis cases. Clinical manifestations depends on CD 4+ count. >250 – granuloma &/or caseation necrosis-AFB ± < 200–poor granuloma formation – AFB + <100 –acute pyogenic abscess – AFB +++ Trends of EPTB under RNTCP: A study from south Delhi, V.K. Arora & Rajnish Gupta. Ind J Tube vol 53 No. 2 April 2006: 76-83

20. Deep TBLN – Clinical Manifestations Mediastinal LN : - Cough, dyspnoea & Occasional dysphagia - Endobronchial TB, RML Syndrome - Caseous pneumonia & Obstructive Lobar emphysema Intercostal LN : - Chronic chest pain - Parasternal & mammary cold abscess. Paratracheal LN communicate with deep cervical & abdominal LN

21. Abdominal LN : Porta hepatis : Progressive obstructive jaundice ( Pathognomonic of HIV ) Mesentric : Subacute intestinal obstruction Para aortic : Chylothorax , Chylous ascitis & chyluria . Retroperitoneal : Chronic abdominal pain, Psoas abscess. Femoral triangle : LN of Poplat – UL lower limb swelling

22. STERNAL COLD ABSCESS

23. STERNAL ABSCESS

24. STERNAL ABSCESS

25. SUPRASTERNAL NOTCH ABSCESS

26. SUPRASTERNAL NOTCH ABSCESS

27. SUPRACLAVICULAR ABSCESS

28. SUPRASTERNAL NOTCH & SUPRACLAVICULAR ( Abscess and post operative scar )

29. MULTINODAL INVOLVEMENT WITH SINUSES AND SCARS

30. MULTIPLE ABSCESS (with communicating tract)

31. Signs and symptoms Jose-Mario Fontanilla et al, 2011

32. 1990 Dandapat et al n=80 1991 V.K. Arora n=1530 1993 Subramanyam n=105 2008 Ajmer n=1482 2014 Ajmer n=3204 Site of involvement (%) Cervical 70 94.4 93.3 83.8 86 Axillary 06 4.3 3.8 6.6 4.0 Inguinal 09 ND 2.9 5.2 3.8 Multiple sites 15 ND ND 4.1 6.2 Physical findings (%) Matting & fixity 55 ND 68 43.6 51.6 Discrete nodes 22.5 ND 32 32.2 32.4 Abscess formation 15 ND 15.2 7.1 7.2 Sinuses 13 ND 10.5 6.6 2.2 Ulcers ND ND 7.6 4.3 1.8 Lymph node TB in HIV seronegative

33. Diagnostic Studies A definitive diagnosis of tuberculous lymphadenitis can be made by culture or polymerase chain reaction demonstration of M. tuberculosis in an affected lymph node, thereby permitting distinction from other mycobacteria that may cause lymphadenitis.

34. Ultrasound Ultrasound is an excellent first-line investigation as it assess cervical lymphadenopathy and also enables guided fine needle aspiration cytology. The combination of grey-scale imaging and FNAC as a sensitivity of 92% and specificity 97% in distinguishing benign from malignant nodal disease. Differentiating features from neck metastasis include: Nodal matting Surrounding soft tissue oedema (less marked than one would expect given the size of the collections) Homogeneity Intranodal cystic necrosis and Posterior enhancement.

35. Ultrasound Doppler examination is particularly useful in helping distinguish tuberculous infection from necrotic metastatic disease. Reactive nodes (including those in tuberculous lymphadenitis) demonstrate prominent vascularity , but mostly confined to the hilum , whereas malignant nodes demonstrate more peripheral/capsular vascularity .

36. CT SCAN CT appearances of tuberculous lymphadenitis is variable depending on the degree of caseation . Nodes may initially appear merely enlarged, often with attenuation similar to muscle. Eventually, central caseation develops and the nodes become centrally low density and eventually frankly cystic. They are , usually, matted together with only minor surrounding inflammatory changes.

37. CT Features of Abdominal lymphadenitis WithContrast -enhanced CT, tuberculous lymphadenitis is associated with higher incidence of peripheral enhancement with multilocular appearance and heterogeneous attenuation, compared with lymphoma .

38. MRI MRI appearances are similar to those of CT, ranging form homogeneously enlarged nodes, to cystic transformation with peripheral enhancement.

39. PET CT Is an important noninvasive diagnostic tool. Enlarged FDG 18 avid LN having standardized uptake value (SUV) of <5 are diagnostic of tuberculosis. More useful in detecting reactivation of LNTB during immunosuppressive diseases like HIV, cancer etc. ( Anergy may limit usefulness of MT test, IFN Y assay may end up with intermediate results). Serial decline in SUV is useful in monitoring drug response (Cut of value 1.8). Metabolic response may indicate clinical response and guide duration of ATT.

40. Nucleic acid amplification Nucleic acid amplification tests (NAATs) may provide a rapid, specific, and sensitive means of diagnosis. A systematic review of NAAT in tuberculous lymphadenitis revealed highly variable and inconsistent results (sensitivity, 2%–100%; specificity, 28%–100%).

41. LNTB newer diagnostic techniques Nested PCR (Mexico) Smear PCR* (Norway) Sensitivity 96% 85% Specificity 93% 95% Positive predictive value 96% 96% Negative predictive value 93% 59% Conventional Methods Z-N smear 15% 15.3% MTB Culture 26% 24.4% Cytology / Histopathology 62% *PCR using DNA eluted from dried FNAC smears of patients with LNTB Results were compared with Nested PCR on DNA from Biopsies from the case as a gold standard Useful when cytology is equivocal Diagn Mol Pathol. 2008, Sept. 17(3); 174-8

42. Excisional biopsy is the most invasive approach to diagnosis; however, it has the highest sensitivity and may produce a more rapid and favorable symptomatic response and has been recommended in cases involving multiple nodes. Complications of biopsy include postsurgical pain, wound infection, sinus formation and scar.

43. FNAC FNA is first-line diagnostic technique, especially in tuberculosis-endemic countries, where the test is both sensitive and specific. FNA is safer, less invasive, and more practical than biopsy, especially in resource-limited settings. Yield : 48 - 83%

44. FNAC techniq FNAC technique ues - Guidelines 5 ml syringe- 18 to 21 g needle- 3 microscopy glass slides ( AFB, gram’s, cytology) Hold the gland between thumb & index finger Site – centre of node – point of maximum fluctuation (through healthy skin) Pull back on the syringe piston – if no aspirate obtained – move the needle in both direction while gently compressing the LN 5 ml syringe- 18 to 21 g needle- 3 microscopy glass slides ( AFB, gram’s, cytology). Hold the gland between thumb & index finger. Site – centre of node – point of maximum fluctuation (through healthy skin). Pull back on the syringe piston – if no aspirate obtained – move the needle in both direction while gently compressing the LN.

45. Culture remains the gold standard for diagnosis, but may take 2–4 weeks to yield results. A positive acid-fast bacilli (AFB) stain result indicates a mycobacterial etiology and has excellent specificity for M. tuberculosis in adults. Following Histologic features support a diagnosis of probable tuberculosis in AFB-negative, culture-negative cases, nonspecific lymphoid infiltrates, noncaseating granulomas , Langerhan giant cells in areas of extensive caseous necrosis.

46. Ancillary Diagnostic Tests Sensitivity and Specificity of Tuberculin test were 86% and 67%, respectively, and of IGRAs, 86% and 87%, respectively.

47. Drug Treatment Isoniazid , Rifampin , Pyrazinamide and Ethambutol for 2 months, followed by Isoniazid and Rifampin for another 4 months. The 6-month recommendation is supported by studies that showed no difference between 6 and 9 months of treatment in cure rates (89%–94%) or relapse rates (3%). Practical Endpoints

48. Steroid Therapy The benefit of routine corticosteroid therapy for peripheral tuberculous lymphadenitis is unknown. A double blind, placebo controlled trial involving 117 children with endobronchial tuberculosis revealed a significantly greater improvement in those who received a 37-day tapering course of steroids.

49. Possible Mechanism for the Beneficial Effect of Corticosteroids Adjunctive use of corticosteroids in TB may have anti inflammatory effect Inhibitory actions on the release and activity of lymphokines and cytokines leading to rapid regression of LN size & obviate potential complications. Directly suppress the pathologic effects of cytokine TNF & from activated CD4+ Even in Rifampicin containing regimen significant clinical advantage is observed. Prevent Paradoxical reactions.

50. Ethical committee approval obtained No. of patients included: 334 INCLUSION CRITERIA : Proven tissue diagnosis of tubercular lymphadenitis Started on att EXCLUSION CRITERIA: Cold abscess HIV,DM &other immunosuppressive illness, malignancy Intra LN injection of Methylprednisolone MATERIALS AND METHODS

51. Inj METHYLPREDNISOLONE ACETATE 0.5 – 4 ml injected into lymph nodes according to the size (measured using divider & scale) Size of LN(cm) Amount injected(ml) 1-2 1 2-3 2 3-4 3 4-5 4

52. At interval of 2 weeks. Maximum 3 doses. Followed up fortnightly. Successful outcome : Reduction in size of 50% or more. 50% size reduction in – 2 weeks – 151 patients (45%) 4 weeks – 116 patients (35%) 6 weeks – 34 patients (10%) 301 patients (90%) has got >50% node size reduction in 6 weeks time Complete regression in 83 patients (24.85%)

53. Paradoxical Upgrading Reactions Worsening of symptoms during treatment ( ie , paradoxical upgrading reaction [PUR]). One definition is the development of enlarging nodes, new nodes, or a new draining sinus in patients who have received at least 10 days of treatment.

54. PUR has been reported in 20%–23% of HIV-negative patients. It occurred at a median of 1.5 months Manifestations of PUR have included enlarging lymph nodes in 32%–68% of cases New nodes in 27%–36% pain in 60% draining sinuses in 12%–60% In addition, increased adenopathy has also been reported in 9%–11% of patients a mean of 27 months after successful treatment

55. Flow diagram showing possible mechanism of adverse events during effective ATT Ref : Dr. Rakesh Gupta, N Gupta R dixit et al in Richard W. Light’s Pleural Diseases, Vol 2 nd : 6 th edn 2013 PP 247-248. . )

56. Biopsy or culture of nodes involved in PUR typically shows granuloma formation and negative culture results with or without positive AFB stains. Steroids have been considered as a means to reduce the robust immune response in PUR, but their use is controversial. Intra LN injection of depot Methylprednisolone averts most of these, if given at earliest warning signal.

57. Surgical Therapy Guidelines recommend surgical excision only in unusual circumstances : For patients who have discomfort from tense, fluctuant lymph nodes. For paradoxical upgrade reactions. As an adjunct to antibiotic therapy for disease cause by drug resistant Organisms. Cervical lymphadenitis due to nontuberculous mycobacteria .

58. DEPTT. OF SURGERY, QUEEN MARY HOSPITAL, UNIVERSITY OF HONGKONG (1978-1984) 199 LNTB CASES  181 CERVICAL LNTB 40 (22.1%) had abscess or discharging sinus Put on 2S 2 H 2 R 2 Z 2 / 4H 2 R 2 ,No atypical mycobacteria ,all sensitive Tuberculous cervical abscess: comparing the results of total excision against simple incision and drainage. Br. J. Surg. 1988, Vol. 75, Jun, 554. Alternating patients Total Excision  GA abscess wall + adjacent deep seated LNs were excised  Primary wound closure 22 18 Incision & drainage  LA & wounds were kept open for drainage Persistent sinus with track connecting to deeper tissue Developed new abscess Re-excision (mean time of 3.2 weeks) Follow-up Results Excision Group (n=18) Incision Group (n=22) Persistent wound problem after 3 weeks 6.0% 73% Asymptomatic at 2 years 78% 77% Residual LN at 2 years 17% 18%

59. NTM Lymphadenitis M. avium complex. – commonest M. scrofulaceum (predominant before 1970), M. malmonse & M. kansasii Unilateral & nontender Submandibular , submaxillary Cervical or preauricular LN in young children of 1-5 years of age Truly localized disease 92% U.S. children (1-5yrs age) have NTM disease. In Australia & Canada NTM LN are 10 times more common. Mycobacterial adenitis, caused by nontuberculous mycobacteria , such as M. avium complex, is typically seen in non-BCG immunized children in developed countries.

60. Diagnosis Simple diagnostic biopsy / incision and drainage - may lead to fistula formation. FNAC is controversial. Skin tests with NTM antigens. NTM antigen specific Gamma interferon. Treatment Treatment of NTM adenitis is surgical and achieves cure rate > 70%.

61. LN TB in Children Lung route / Tonsillar route In recent & acute infection – Greater degree of periadenitis . Later or sooner LN softens and forms abscess. Anti- gravity aspiration just delay the process and may lead to sinus formation. Majority of LN TB is regional component of primary complex rather than result of hematogenous dissemination. Ref :Miller 1983 ; TB in Children

62. Bacille Calmette-Guérin lymphadenitis Most common complication of BCG vaccination. Two forms of BCG lymphadenitis can be recognised in its natural course : 1. Simple or non- suppurative lymphadenitis, usually regresses spontaneously. 2. Suppurative BCG lymphadenitis distinguished by the development of fluctuations in the swelling, with erythema and oedema of overlying skin.

63. Diagnosis of BCG lymphadenitis Isolated axillary (or supraclavicular /cervical) lymph node enlargement. History of BCG vaccination on the same side. Absence of tenderness and raised temperature over the swelling. Absence of fever and other constitutional symptoms. Chest radiography, Mantoux reaction, and haematological analysis are not helpful. Fine needle aspiration cytology corroborates the clinical diagnosis in doubtful cases.

64. Management of BCG lymphadenitis No role for antibiotics or Antituberculous drugs. Needle aspiration – Recommended for suppurative BCG lymphadenitis. Prevents discharge and associated complications. Shortens the duration of healing. Safe. Surgical excision Useful in cases with failed needle aspiration, multiloculated or matted lymph nodes, and draining sinuses. Non- suppurative BCG lymphadenitis is a benign condition and regresses spontaneously without any treatment.

65. Conclusion Good FNAC / needle biopsy / ZN staining / MT test & ESR make diagnosis in almost all cases. Optimal management of comorbid conditions. LNTB enlarge during ATT or appear afresh will eventually respond to treatment. Development of fluctuation requires immediate attention - Early surgical intervention. Residual LN at end of ATT should be closely monitored.

66. Thank You IT IS A GOOD IDEA TO MAKE THE MOST OF WHAT WE HAVE…..