Extrapulmonary Tuberculosis
Timothy H. Dellit, MD Associate Medical Director Harborview Medical Center
No financial conflicts
Tuberculosis in King County 1984-2013
2013: 114 cases, 5.8 per 100,000
2013: 84% Foreign Born
PHSKC Seattle & King County Annual Tuberculosis Report 2013
Incidence of Pulmonary vs. Extrapulmonary TB
Nationally: Pulmonary (and EXPTB) 79%, EXPTB only 21%
King County 2011: Pulmonary 40%, EXPTB 49%, Both 11%
Harborview 2014: Pulmonary 62%, EXPTB, 29%, Both 10%
Clin Infect Dis 2009;49:1350-7
CDC Reported tuberculosis in the United States 2013
1 Risk Factors for Extrapulmonary TB TB reference center in Portugal 1/2008 - 1/2012 260 (67.4%) pulmonary 126 (32.6%) extrapulmonary
Rev Port Pneumol 2015;21:90-93
Sites of Extrapulmonary TB United States 2013 Other 20% Necrotizing granulomas Lymphatic 36% Laryngeal 0%
MiMeningea l 5%
Peritoneal 6%
Genitourinary 5% Pleural Bone and Joint 17% 11% CDC Reported tuberculosis in the United States 2013
Masquerading Extrapulmonary TB
No initial airborne precautions in 10/14 (71%)
Shizuoka Cancer Center Hospital 2008-2012
Am J Infect Control 2014;42:1133-1135
2 35 year old Vietnamese man presents to emergency department with three week history of worsening non- productive cough, fever, night sweats, and right-sided chest pain.
Thoracentesis is performed • 1200 WBC 88% lymphocytes • Total protein 5.4 • LDH 358
Diagnosis of Pleural TB Diagnostic Approach Sensitivity Pleural fluid culture 10-40% Pleural biopsy culture 55-85% Pleural biopsy histology 50-80% Combined pleural biopsy 80-95% culture and histology
Other tests: •PCR • Pleural fluid -Sensitivity 62%, specificity 98% -More sensitive in cases of culture-positive pleural fluid • Pleural biopsy sensitivity 90%, specificity 100% • Adenosine deaminase (ADA) • Sensitivity 92%, specificity 90% Respir Med 2008;102:744-54 BMC Infect Dis 2004;4:6 Chest 2003;124:2105-11
Sputum and Pleural TB y Sputum culture positive 10-30% ◦ Thought to be dependent on presence of infiltrate ◦ Are patients without concomitant pulmonary infiltrates non-infectious?
84 P ati ent s with Pleura l TB Pleural biopsy histology 66 (78%) Pleural biopsy culture 52 (62%) Pleural fluid culture 10 (12%) Induced sputum culture 44 (52%)
No infiltrate on CXR: AFB smear (7/64) 11%, culture 35/64 (54%)
Am J Resir Crit Care Med 2003;167:723-5
3 43 y o woman from Eritrea with 3 week h/o non-productive cough, fever, and night sweats
Now What?
AFB smear neg x 5 (3 sputum, 2 BAL) Sputum PCR neg
Miliary Tuberculosis y Lymphohematogenous dissemination y Millet seeds in lungs ◦ Impaired diffusion ◦ Sputum smear positive in only 1/3 y High blood flow organs ◦ Spleen, liver, bone marrow, kidneys, adrenals y Meningitis in 10-30% y Increased TST anergy
Lancet Infect dis 2005;5:415-30
4 26 y o woman from Ethiopia with left neck swelling
Cervical Tuberculous Lymphadenopathy
100 80 60 40 20 Symptoms % Symptoms 0
y Importance of epidemiology y Often multiple-matted lymphnodes Postgrad Med J 2001;77:185-7 y FNA sensitivity > 90% y Medical therapy for 6 months Clin Infect Dis 2011;555-562 y Paradoxical reaction in 20%
19 y o man from Guatamala with “fainting spell” 2 weeks PTA, then progressive frontal headaches with nausea and emesis.
PE: T 39.6, left VI nerve palsy MRI with leptomeningeal enhancement in left temporal lobe
CSF WBC 338 L60, protein 136, glucose 32
CSF HSV negative
CSF TB PCR negative
5 CSF Characteristics California Encephalitis Project
Characteristic CNS TB HSV-1 Enterovirus No. Cases 20 39 44
CSF leukocytes per ml, median 201 47 85
CSF protein, mg/dl, median 174 71 60
CSF glucose, mg/dl, median 35 69 67
• 20 CNS TB cases all culture positive • 4/17 (24%) CSF TB PCR positive
Emerg Infect Dis 2008;14:1473-5
In this patient…
Sppputum AFB smear 1/3 positive Sputum AFB culture 3/3 positive
CSF AFB culture positive
20 y o woman from Peru with 3 week history of fever, headache, nausea, and altered mental status. No respiratory symptoms.
CSF: WBC 195 N70 prot 144, gluc 39
MRI: leptomeningeal enhancement along skull base involving cerebellar sulci and cranial nerves
“r/o TB – check quantiFERON”
6 IGRAs and Extrapulmonary TB
Sensitivity Specificity
QFT-Ga 69% 82%
QFT-2Gb 86% 84%
TSTb 57% 49%
aDiagn Microbiol Infect Dis. 2009;63:182-7 bRespirology 2009;14:276-81
Pulmonary Involvement in Extrapulmonary TB
• 72 patients with XPTB 25% 36 lymph nodes 20% 12 pleura 6 CNS 15% 6 GI 10%
5% • 57 had sputum collection 0% • Weight loss associated with positive sputum cx OR 4.3 (1.01-18.72)
49% had abnormal CXR Chest 2008;134:589-94
Sputum AFB Smear
Smear+ Culture + Smear - Culture + Smear - Culture - y Smear positive 70 ◦ 5,000-10,000 organisms per 60 ml of sputum must be 50 40 present 30 ent of Cases
c 20 y Smear negative, culture- 10 positive TB Per 0 2007 2008 2009 2010 2011 ◦ Responsible for roughly 17% of TB transmission in San 40-50% of pulmonary TB Francisco and Vancouver cases in King County are smear negative
Am Rev Respir Dis 1966;95:998 Lancet 1999;353;444, Thorax 2004;59:286
7 Rapid Molecular Detection of Pulmonary TB and Rifampin Resistance
Multi-center study of 1462 patients with suspected pulmonary TB - 567 (38.8%) smear and culture positive - 174 (11.9%) smear-negative, culture positive
Sensitivity Smear positive, culture positive 98.2% Smear negative, culture positive (first sample) 72.5% Second sample 85.1% Third sample 90.2% Rifampin-resistance c/w phenotypic testing 97.6%
N Engl J Med 2010;363:1005-15
Xpert MTB/RIF for Extrapulmonary TB
• Johannesburg, South Africa • Tb incidence 993 per 100,000
J Clin Microbiol 2014;52:1818-1823
19 y o man from Philipines presented with 8 weeks of HA and progressive LE weakness
CSF WBC 120, 90L Protein 1500 Glucose 40
MRI with extensive basal leptomeningeal enhancement
8 What about Tuberculomas?
43 y o woman from Egypt with 2 day h/o right leg weakness and heaviness along with one episode of nausea and emesis.
CSF: WBC 2 L85, prot 29, gluc 123
CSF AFB culture negative
TB PCR of CSF positive
TB Drugs and CNS
y Isoniazid and pyrazinamide bactericidal and penetrate inflamed and uninflamed meninges
y Rifampin, streptomycin, and ethambutol levels roughly around MIC and do not penetrate uninflamed meninges as well
y After induction phase with 4 drugs, some may consider continuing INH, Rifampin, and Pyrazinamide
y Fluoroquinolones?
CNS TB and Paradoxical Response
y Balance between host immunologic response and direct effects of mycobacterial products ◦ Neurological decline ◦ Increase in size, number, or appearance of tuberculomas ◦ Typically occur within 3 months of therapy ◦ In setting of tapering or discontinuing steroids y Does not represent failure of therapy ◦ Do not need to change regimen y TB meningitis ◦ May be associated with neutrophilic predominance ◦ More frequent development of tuberculomas
Clin Infect Dis 1994;19:1092-9 Infection 2003;31:387-91
9 29 y o man from Somali presents with seizures, chronic back pain, and difficulty urinating
Pott’s Disease with Paravertebral Abscess
• Classically begins with anterior vertebral body and disk • Progressive collapse, anterior wedging, and gibbus formation • Posterior involvement of vertebral arch and spinous process
N Am J Med Sci 2013; 5: 404–411
Spinal Tuberculosis y Accounts for 50% of skeletal tuberculosis ◦ Hip 15%, knee 10% y Hematogenously spread ◦ Batson’s plexus y Paucibacillary disease, slow growing ◦ 12-18 months of therapy y Medical therapy alone curative > 90% ◦ Surgery limited to neurologic compromise, spinal stability, tissue diagnosis ◦ MRI may initially demonstrate increase in bony destruction and size of abscess despite clinical improvement
Clinical Orthopaedics and Related Research 2007;460:29-38 Clinical Orthopaedics and Related Research 2002;398:11-19
10 44 y o Vietnamese man with 6 month h/o pain and swelling of left medial thigh associated with fevers and night sweats
27 y o man from Ethiopia with 2 day h/o severe abdominal pain, nausea and emesis
Also 2 month h/o fever, night sweats, 15 lb wt loss, and dry cough
Could he have pulmonary involvement?
11 Tuberculosis of Small Bowel
y Pathogenesis ◦ Swallowing infected sputum ◦ Ingestion of contaminated milk ◦ Hematogenous spread ◦ Direct extension y Ileocecal and jejuno-ileum most common sites y Patterns ◦ Ulceroconstrictive lesions, with perforation and fistulae in 5% ◦ Obstruction in 20% ◦ Right lower quadrant abdominal mass 25% ◦ “Doughy abdomen” classic, but less common y Mimics ◦ Periappendiceal abscess, Crohn’s disease, Yersinia, Amebiasis
Peritoneal Tuberculosis
Ascitic Fluid 100 80 Exudative 60 • Lymphocytic pleocytosis 40 • Protein > 2.5 – 3 g/dl
ymptom % 20 • SAG < 1 .1 g/dl S 0
Diagnositics • AFB smear < 3% • AFB culture 20-83% • ADA 93-100% • Laparoscopy with biopsy 85-95%
Am J Gastroenterol 1993;88:989-99 Colorectal Dis 2007;9:773-83
25 y o man from Mexico with 2 month history of fever, chills, night sweats, cough, and 30 lb wt loss Also dysuria with 3+ WBC and RBC
Sputum 4+ AFB
12 Urogenital Tuberculosis y May present with dysuria, hematuria, or flank pain y Asymptomatic patients with classic sterile pyuria y Men ◦ Kidney, prostate, seminal vesicles, epididymis, testes ◦ OOligospermialigospermia y Women ◦ Endosalpinx with spread to peritoneum, endometrium, ovaries, cervix, vagina ◦ Pelvic pain, infertility, vaginal bleeding y Mycobacterial culture of early morning urine specimens
Am Fam Physician 2005;72:1761-8
Tuberculous Meningitis and Steroids
Seven Randomized Studies
RR CI
Death 0.78 0.67-0.91
Stage 1 (mild) 0.52 0.30-0.89
Stage 2 (moderate) 0.73 0.56-0.97
Stage 3 (severe) 0.70 0.54-0.90
Death or disabling neurologic deficit 0.82 0.70-.0.97
Death stratified by HIV status 0.82 0.66-1.02
Cochrane Database Syst Rev. 2008 Jan 23;(1):CD002244
Tuberculous Meningitis and Steroids
• 545 patients randomized to double-blind placebo controlled study of adjunctive dexamethasone with 5 year follow up (9.2% lost) • Two-year survival: 0.63 vs. 0.55 (p=0.07) • Five-year survival: 0.54 vs. 0.51 (p=0.51)
PLoS One 2011;6:e27821
13 TB Pericarditis and Steroids: Changing recommendations
Multicenter randomized study comparing prednisolone vs. placebo in 1400 adults with TB pericarditis
NEJM 2014;371:1121-30
Summary
y Tuberculosis can occur anywhere within the body y Diagnosis can be extremely challenging ◦ Microbiology ◦ Pathology ◦ Nucleic amplification ◦ TST vs. interferon-gamma release assays? y Evaluate for pulmonary disease y Coordinated management with public health
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