Tuberculous Lymphadenitis

and the role of M.bovis

The King’s Evil

Introduction

TB lymphadenitis refers to involvement of lymph nodes by members of the M.tuberculosiscomplex which include M.tuberculosis, M.bovis, M.africanum, M.canetti and M.caprae.

It may be associated with pulmonary TB or other organ involvement but is usually an isolated finding-20% of all TB cases are extrapulmonary TB

Case 1

32 year old female who emigrated from Vietnam in 1994 was being treated for Hepatitis B with Lamivudine when she developed painful swelling in her right supra-clavicular region in January 09

She underwent a lymph node biopsy in February 09 which revealed caseating necrosis and cultures were positive for M. tuberculosis

Case 1 -3/11/09

Epidemiology

In the US, non-tuberculous mycobacteria are the most common cause of mycobacterial lymphadenitis in children

Per the CDC 2000 surveillance, extrapulmonary TB ( EPTB) rates have not declined in the US like Pulmonary TB(PTB) -0.9% Vs 4%

HIV positive patients with MTB are more likely to have EPTB than HIV negative patients – 45-70% Vs 15%

Epidemiology

In HIV positive patients TBLN is associated with CD4 < 300 ( usually <100)

A US based study in Houston revealed the following characteristics in HIV negative patients-

Predictive factors: Female ( OR 2.6),birth in Africa/SE Asia ( OR 4.6/33.7)

Protective factors: White Race ( OR 0.1) and Diabetes Mellitus ( OR 0.3)

Extrathoracic

TBLN

PTB

Race Asian> African Africa>Asia

Gender Men: Women = 31:68 Men :Women= 65:35

Drug Resistance

INH

MDR

XDR

10%

1.4%

rare

10-11% Non US born

1-2%

Rare

BCG vaccinated 37% 21%

HIV positive <1%-5% 12% positive

Epidemiology

Pathogenesis

3 suspected routes:

1) Reactivation of PTB or hilar extension is most common

2)Deep cervical involvement from laryngeal infection

3) hematogenous

Histo-pathology

4 distinct cytological patterns noted on aspirate, ranging from

- Pattern 1: occasional granulomas with early epitheloid cells, extensive necrosis and foam cells, numerous AFB- seen in HIV positive patients with TBLN

-Pattern 4: Numerous granulomata with most epitheloid cells and minimal necrosis + absence of AFB mostly- seen in HIV negative patients with TBLN

Clinical features

Pediatric TBLN is mostly an isolated infection in the anterior cervical chain

Adult infection is similar with 70% anterior cervical chain- 58% of which is in the jugulodigastric region

HIV co-infection is associated with a more severe/disseminated disease

[i]

Clinical Differences between TBLN and Pulmonary TB

TBLN PTB

Sputum culture

Positive

12% 64%

Cough > 2 weeks 26% 50-66% in reactivation

Systemic symptoms

Fever >2 weeks

Wt loss

Night sweats >

2weeks

19%

17%

8%-19%

70% in Primary, 50% in

Reactivation TB

43%

72%

Abnormal CXR 49% 65% in primary TB and

80-90% in secondary

TB

Clinical Features

Abnormal CXR did not correlate with sputum positivity but wt loss did ( OR 4.3)

Disease associations: Chronic granulomatous disease, lymphoma, HIV

Diabetes, Renal Insufficiency and Alcoholism and low iron and Vitamin D levels are also associated with MTB

Diagnosis

About 20% have positive sputum cultures but only 9-15% had positive AFB sputum smears.

Biopsy is the gold standard for diagnosis

FNA biopsy lead to TB diagnosis in 79% of cases compared to surgical biopsy in 83%

Histology more sensitive than culture (OR 11.9)

Diagnosis

Nucleic acid amplification tests for TB lymphadenitis are rapid but yield variable and inconsistent results

Immune based blood tests include T cell based cellular response ( IGRA- Interferon Gamma Release Assay) and humoral antibody response

Treatment

Drug resistance in 13% of 147 cases of TBLN in Manitoba – only in foreign born

Standard per British Thoracic Society for uncomplicated TBLN – Rifampin+ Isoniazid+ Ethambutol for 2 months followed by Isonizid and Ethambutol for 6 months

Standard abbreviations include: S = streptomycin, H or INH= isoniazid, R or RFM= Rifampin, Z or PZA= Pyrazinamide, E= Ethambutol

Treatment

Extend to 6-12 months if LN persists, rebiopsy and place on a CAT II regimen: 2 months of SHRZE then 1 month of RHZE followed by 5 months of RHE

Alternate regimen is 4RHZE +2 RH: 5 year remission rate was 89%

Steroids not recommended by IDSA currently ( Evidence DIII) however has had anecdotal benefit

Treatment

Steroids decrease pain and discomfort anecdotally though these outcomes have not been studied in larger trials.

Surgery has no role for MTB unlike non TB mycobacteria ( Evidence BIII per IDSA)

Interferon gamma and GCSF are under investigation

Paradoxical Response (PR)

Defined as development of enlarging nodes or new nodes during treatment; seen in 23-30%

Among HIV negative patients: Baseline peripheral monocytosis is a significant predictor for PR but NOT age, sex, node size, low Vitamin D, AFB smear/culture positive, ANC or ALC.

Case 1 0 4/2/09

Paradoxical Response

Among HIV positive patients: PRs noted in 7% not on HAART Vs 36% on HAART.

Steroid use did not change duration of PRs

Aspiration, I&D and excision were associated with a shorter duration of PR but not significantly so ( p=0.1)

Outcomes

Cure rates vary from 81% -95% with surgery + Anti TB regimen for 12-18 months

Relapse rates noted to be 8.1 per 1000 person yrs of follow up

Residual palpable adenopathy in 5-30% of cases

Spontaneous drainage in 17%

Implications

TBLN even in the absence of pulmonary symptoms carries an infection risk as they may have Pulmonary TB and should be placed under respiratory precautions till pulmonary TB is ruled out.

Caution: Risk of transmission is 13% in smear negative but sputum culture positive patients

An alternate pathogen

The BCG vaccine, which has been derived from M. bovis has also been associated with infection in immunocompromised patients- especially children with Chronic Granulomatous Disease

M.bovis

M. bovis is associated with bovine TB and spreads to humans via infected dairy products and direct droplet spread

A study in San Diego revealed a rise in incidence of M. bovis from 5 to 11% from 1994-2005

M. bovis is more commonly associated with TBLN than with pulmonary TB ( 16% of all TBLN cases Vs 4% of all pulmonary TB cases)

M.bovis

Clinically: it is indistinguishable from M.tuberculosishowever is more frequently associated with TBLN and with treatment failures.

Diagnosis: The commonly used MTB probe cannot distinguish between different variants of MTB and it is often underdiagnosed. It has an intrinsic resistance to Pyrazinamide ( PZA) and should be suspected whenever sensitivity results reveal a mono-resistance to PZA.

M.bovis and HIV

HIV positive patients with M.bovis were more likely to have lymphadenitis (63%) compared to their HIV negative cohort ( 50%)

HIV positive patients had a PPD reaction that was 1/10 that of the cut off for MTB ( >5 mm)

Treatment for M. bovis

Due to its intrinsic resistance to PZA, the standard 6 month regimen for MTB is not feasible

Standard treatment includes Isoniazid ( INH) ,Rifampin (RFM) and Ethambutol for 2 months followed by INH + RFM for seven months.

Streptomycin can been added instead of PZA

Prognosis and Implications

Persons with M. bovis are 2.55 times as likely to die during treatment than those with M. tuberculosis

An outbreak of M. bovis in patients with advanced HIV in 1994 had a 100% case fatality

Summary and Recommendations

Test all patients with peripheral lymphadenopathy and TB risk factors for MTB : PPD, FNA, CXR and HIV test if positive for MTB

If histology consistent with TB then start treatment pending cultures

If cultures negative then perform excisional biopsy

If persistent paradoxical response, repeat FNA and extend treatment

Consider steroids for symptomatic relief

Standard treatment regimens are of 6 months but often extended to 18 months based on clinical response.

Special Thanks to

Dr. Ford Von Reyn

Dr. Elizabeth Talbot

Dr. J F Fontanilla

Dr. J Parsonnet

for both past and ongoing input

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