Tuberculous Lymphadenitis - PBworks - New England TB...
Transcript of Tuberculous Lymphadenitis - PBworks - New England TB...
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
References
1. Kazwala RR, Daborn CJ, Sharp JM, Kambarage DM, Jiwa SF, Mbembati NA. Isolation of Mycobacterium bovis from human cases of cervical adenitis in Tanzania: a cause for concern?
Int J Tuberc Lung Dis. 2001 Jan;5(1):87-91.
2. Antas PR, Castello-Branco LR. New vaccines against tuberculosis: lessons learned from BCG immunisation in Brazil. Trans R Soc Trop Med Hyg. 2008 Jul;102(7):628-30. Epub 2008 Apr 28. Review.
3. Schaaf HS et al A decade of experience with Mycobacterium tuberculosis culture from children: A seasonal influence on incidence of childhood tuberculosis Tubercle and Lung DiseaseVolume 77, Issue 1, February 1996, Pages 43-46
4. Nagayama N, Ohmori M: Seasonality in various forms of tuberculosis.
Int J Tuberc Lung Dis 2006, 10:1117-1122
5. Gonzalez OY, Adams G, Teeter LD, Bui TT, Musser JM, Graviss EA. Extra-pulmonary manifestations in a large metropolitan area with a low incidence of tuberculosis. Int J Tuberc Lung Dis 2003;7:1178-85.
6. Cook VJ, Manfreda J, Hershfield ES. Tuberculous lymphadenitis in Manitoba: Incidence, clinical characteristics and treatment. Can Respir J 2004;11:279-86.
7: Mukherjee S, Sarkar S. Treating tuberculous lymphadenitis--ifs and buts. J Indian Med Assoc
2003;101:16-7
Menon K, Bem C, Gouldesbrough D, Strachan DR (2007) A clinical review of 128 cases of head and neck tuberculosis presenting over a 10-year period in Bradford, UK. J Laryngol Otol 121(4):362–368
Lazarus AA, Thilagar B. Tuberculous lymphadenitis. Dis Mon 2007;/53:/105
Polesky A, Grove W, Bhatia G. Peripheral tuberculous lymphadenitis:epidemiology, diagnosis, treatment, and outcome. Medicine [Baltimore] 2005; 84: 350–362.
Golden M P, Vikram H R. Extrapulmonary tuberculosis: an overview. Am Fam Physician 2005;72:1761–8
Sridhar CB, Kini U, Subhash K. Comparative cytological study of lymph node tuberculosis in
HIV-infected individuals and in patients with diabetes in a developing country. Diagn Cytopathol
2002;26:75-80
Habte A, Geletu M, Olobo JO, Kidane D, Negesse Y, Yassin MA, Kifle B, Abate G, Harboe M, Aseff A T cell mediated immune responses in patients with tuberculous lymphadenitis from Butajira, southern Ethiopia Ethiop Med J. 2004 Apr;42 Suppl 1:29-35.
Lee PP, Chan KW, Jiang L, Chen T, Li C, Lee TL, Mak PH, Fok SF, Yang X, Lau YL.Susceptibility to mycobacterial infections in children with X-linked chronic granulomatous disease: a review of 17 patients living in a region endemic for tuberculosis Pediatr Infect Dis J. 2008 Mar;27(3):224-30.
Hofmeyr A, Eddie Lau WF, Slavin MA. Mycobacterium tuberculosis infection in patients with cancer, the role of 18-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring treatment response. Tuberculosis (Edinb). 2007 Jul 11
A.F. Nicol, G.J. Nuovob, J.M.C. Coelhoc, V.C. Rollad and C. Ho .SOCS in situ expression in tuberculous lymphadenitis in an endemic area Experimental and Molecular PathologyVolume 84, Issue 3, June 2008, Pages 240-244
Mustafa T, Mogga SJ, Mfinanga SG, Morkve O, Sviland L. Immunohistochemical analysis of cytokines and apoptosis in tuberculous lymphadenitis. Immunology. 2006;117:454–62
Shende N, Upadhye V, Kumar S, Harinath BC. A low molecular weight ES-20 protein released in vivo and in vitro with diagnostic potential in lymph node tuberculosis Indian Journal of Medical Microbiology, Vol. 26, No. 1, January-March, 2008, pp. 29-33
Daley PTS, Pai M. Nucleic acid amplification tests for the diagnosis of tuberculous lymphadenitis: a systematic review. Int J Tuberc Lung Dis. 2007;11:1–11.
Barbara Maria Bergamini et al .Performance of Commercial Blood Tests for the Diagnosis of Latent Tuberculosis Infection in Children and Adolescents. PEDIATRICS Vol. 123 No. 3 March 2009, pp. e419-e424
Cicero R, et al A Frequency of Mycobacterium bovis as an etiologic agent in extrapulmonary tuberculosis in HIV-positive and -negative Mexican patients.. Eur J Clin Microbiol Infect Dis. 2009 May;28(5):455-60.
Rodwell TC; Moore M; Moser KS; Brodine SK; Strathdee SA Tuberculosis from Mycobacterium bovis in binational communities, United States. Emerg Infect Dis. 2008 Jun;14(6):909-16.
Guerrero A; Cobo J; Fortun J; Navas E; Quereda C; Asensio A; Canon J; Blazquez J; Gomez-Mampaso E Nosocomial transmission of Mycobacterium bovis resistant to 11 drugs in people with advanced HIV-1 infection. SOLancet. 1997 Dec 13;350(9093):1738-42