Managing Lymph Node Tuberculosis

Ankur gupta

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.

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.

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 20th 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).

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.

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

• 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.

Global Epidemiology of Tuberculous Lymphadenitis

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

• 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.

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

Microbiology

• M. tuberculosis is the usual cause of tuberculouslymphadenitis.

• Other infectious causes of chronic lymphadenitis include :

– Nontuberculous mycobacteria (including M. scrofulaceum, M. avium, and M. haemophilum)

– Pseudomonas pseudomallei

– Toxoplasma species

– Bartonella species

– Fungi.

Tuberculous granuloma

•

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.

LNTB PROGRESSION

GRANULOMA

SOLID CASEOUS TISSUE (CMI – CytotoxicT 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, 5th Edition, 2007; 18-51.

Stage I Enlarged firm mobile discrete nodes(Lymphoid hyperplasia with formation of tubercles & granuloma)

Stage IILarge rubbery nodes fixed to surrounding tissue due to periadenitis(Caseationstarts)

Stage IIICentral softening due to abscess formation(progressive Caseationnecrosis)

Stage IVCollar stud abscess formation. skin over is inflamed(Rupture of caseousmaterial)

Stage VSinus tract formation

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 supraclavicularregion; 20% of cases are bilateral.

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.

• 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.

• 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

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

• 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

STERNAL COLD ABSCESS

STERNAL ABSCESS

STERNAL ABSCESS

SUPRASTERNAL NOTCH ABSCESS

SUPRASTERNAL NOTCH ABSCESS

SUPRACLAVICULAR ABSCESS

SUPRASTERNAL NOTCH & SUPRACLAVICULAR

(Abscess and post operative scar)

MULTINODAL INVOLVEMENT WITH SINUSES AND SCARS

MULTIPLE ABSCESS (with communicating tract)

Signs and symptoms

Jose-Mario Fontanilla et al, 2011

1990

Dandapat

et al

n=80

1991

V.K.

Arora

n=1530

1993

Subramany

am

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

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.

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.

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.

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.

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.

MRI

• MRI appearances are similar to those of CT,

ranging form homogeneously enlarged nodes,

to cystic transformation with peripheral

enhancement.

PET CT

• Is an important noninvasive diagnostic tool.

• Enlarged FDG 18 avid LN having standardized uptakevalue (SUV) of <5 are diagnostic of tuberculosis.

• More useful in detecting reactivation of LNTB duringimmunosuppressive diseases like HIV, cancer etc.(Anergy may limit usefulness of MT test, IFN Y assaymay end up with intermediate results).

• Serial decline in SUV is useful in monitoring drugresponse (Cut of value 1.8).

• Metabolic response may indicate clinical response andguide duration of ATT.

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%).

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 equivocalDiagn Mol Pathol. 2008, Sept. 17(3); 174-8

• 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.

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%

FNAC techniq FNAC techniqueues-

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.

• 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.

Ancillary Diagnostic Tests

• Sensitivity and Specificity of Tuberculin test

were 86% and 67%, respectively, and of

IGRAs, 86% and 87%, respectively.

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

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.

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.

• 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

• 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

• 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%)

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.

• 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

Increase in size of LN, appearance of new LNCold abscess/ collarstud abscess formation

Necrotising/ Caseous reaction

Local inflammation

Production of TNF-Alpha, IL-2, IL-6, IL-8, IFN Y & other cytokines

Release of mycobacterial products

Rapid mycobacterial killing

Successful chemotherapy ( ATT)

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 2nd : 6th

edn 2013 PP 247-248.

• 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.

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.

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 2S2H2R2Z2/ 4H2R2 ,No atypical mycobacteria ,all sensitive

Tuberculous cervical abscess: comparing the results oftotal 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

2218

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%

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.

Diagnosis

1. Simple diagnostic biopsy / incision and

drainage - may lead to fistula formation.

2. FNAC is controversial.

3. Skin tests with NTM antigens.

4. NTM antigen specific Gamma interferon.

Treatment

Treatment of NTM adenitis is surgical and

achieves cure rate > 70%.

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

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.

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.

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.

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.

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