Post on 16-Mar-2018
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Extrapulmonary Tuberculosis
Randall Reves, MD, Colorado University Denver, volunteer TB Clinician Denver Metro TB Control Program
Slides adapted from originals by Timothy H. Dellit, MD, Harborview Medical Center
No financial conflicts
US Reported TB Cases by Site1993-2006 (14 yrs)
Total US reported cases – 253,299 EPTB only – 47,293 (19%) Both EPTB & PTB – 14,910 (6%) Disseminated TB – 4,478 (2%)
PTB only – 186,540 (74%) Unknown - < 1%
Peto, et. al CID 2009;49:1350-7
Peto. CLIN INFECT DIS 49(9):1350-1357. 2009
Extrapulmonary TB, U.S. 1993-2006 (n=47,293, 19% of cases))
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Incidence of Pulmonary vs. Extrapulmonary TB
Clin Infect Dis 2009;49:1350-7
CDC Reported Tuberculosis in the United States 2014
Nationally: Pulmonary 69%, EXPTB 21%, Both 10%
Extrapulmonary TB and Vitamin D Deficiency?
Birmingham UK 1980-2009US CDC 1993-2008
Extrapulmonary disease associated with: Female gender Non-white ethnicity Foreign-born Vitamin D deficiency
Doubling serum 25(OH)D reduced risk (OR 0.55 CI 0.41 to 0.73)
Thorax 2015;70:1171-1180
Mycobacterium bovis: more likely extrapulm. but most still pulmonary
Clin Infect Dis 2008;47:168-175
• Part of MTB complex• 1-2% of human
tuberculosis in US due to M. bovis
• Unpasteurized dairy• Mono-resistance to PZA
Emerg Infect Dis 2015;21:435-443
62.5% pulm.
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Thoracentesis:• 1200 WBC 88% lymphs • Total protein 5.4• LDH 358
35 year old Vietnamese man in ED: 3 weeks of worsening non-productive cough, fever, night sweats, and right-sided chest pain.
40 y.o. homeless woman with TST conversion but no symptoms
April ‘09 April ‘09
40 y.o. homeless woman: pleural bx non-diagnostic, sputum sm (-)/cult +
April ‘09 July ‘09
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Diagnosis of Pleural TBDiagnostic Approach SensitivityPleural fluid culture 10-40%
Pleural biopsy culture 55-85%
Pleural biopsy histology 50-80%
Combined pleural biopsyculture and histology
80-95%
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;102:744-54BMC Infect Dis 2004;4:6Chest 2003;124:2105-11
43 y o woman from Eritrea with 3 week h/onon-productive cough, fever, and night sweats
Now What?
AFB smear neg x 5 (3 sputum, 2 BAL)
Sputum PCR neg
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Miliary Tuberculosis Lymphohematogenous
dissemination Millet seeds in lungs*◦ Impaired diffusion
◦ Sputum smear positive in 1/3
High blood flow organs◦ Spleen, liver*, bone marrow*,
kidneys*, adrenals
Meningitis* in 10-30%
Increased TST anergy
*Potential positive specimens: sputum, BAL, urine, stool, CSF, tissue biopsies, rarely blood
Lancet Infect dis 2005;5:415-30
42 y.o. man with chronic renal failure
Chronic hemodialysis for polycystic disease
Hepatitis C due to IDU Hospitalized from prison for fever and
hemoptysis Left pleural effusion developed Fever persistent despite ceftriaxone &
azithro Worsening anemia, mild pancytopenia,
rising alkaline phosphatase
42 y.o. man with chronic renal failure
Sputum AFB smear & culture negative
PPD 8 mm Transudative pleural
fluid – not cultured for TB
Bone marrow biopsy neg for granuloma –no AFB culture done!
Discharged after response to levofloxacin
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42 y.o. man with CRF: clues for TB
Right apical scar Rising alk phos –?
granulomatous hepatitis
Liver biopsy recommended
43 y.o. with CRF: readmitted 2 wks later liver biopsy done transjugular: granulomas, AFB stain & culture-negative
43 y.o. man with CRF treated empirically for TB
Symptoms resolved Anemia improved Alkaline phos returned to normal All cultures remained negative Reported as a clinical case of TB
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47 yr old woman
Swollen cervical lymph node x 1 month
Denies other symptoms
Born in Vietnam and previously treated for TB 20 years ago
47 yr old female: sputum negative
Node biopsy is smear (+) and confirms INH resistant TB
HIV (-)
6 weeks into therapy, the inflammation is worse
47 yr old female: needle drainage
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Cervical Tuberculous Lymphadenopathy
Importance of epidemiology Often multiple-matted lymphnodes FNA sensitivity > 90% Medical therapy for 6 months Paradoxical reaction in 20%
Postgrad Med J 2001;77:185-7
Clin Infect Dis 2011;555-562
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20
40
60
80
100
Sym
ptom
s %
CSF WBC 338 L60, protein 136, glucose 32
CSF HSV negative
CSF TB PCR negative
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 palsyMRI with leptomeningeal enhancement in left temporal lobe
CSF Characteristics
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
Emerg Infect Dis 2008;14:1473-5
California Encephalitis Project
• 20 CNS TB cases all culture positive• 4/17 (24%) CSF TB PCR positive
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75 y.o. Peruvian-born woman with erythema induratum for 6 years
May ‘09 Nov ‘09
75 y.o. woman: cultures negative, response to IRE for 2 mo., IR for 4
Nov ‘09
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
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Pulmonary Involvement in Extrapulmonary TB
• 72 patients with XPTB36 lymph nodes12 pleura6 CNS6 GI
• 57 had sputum collection
• Weight loss associated with positive sputum cxOR 4.3 (1.01-18.72)
Chest 2008;134:589-9449% had abnormal CXR
0%
5%
10%
15%
20%
25%
Xpert MTB/RIF for Extrapulmonary TB
Eur Respir J 2014;44:435-446Ann Intern Med 2015;162:JC11
Meta-analysis of 18 studies and 4461 samples
WHO 2013Xpert MTB/RIF should be used in preference to conventional microscopy and culture as the initial diagnostic test for CSF specimens from patients suspected of having TB meningitis (alternative for lymph nodes and other tissues)
19 y o man from Philipines presented with 8 weeks of HA and progressive LE weakness
CSFWBC 120, 90LProtein 1500Glucose 40
MRI with extensive basal leptomeningeal enhancement
Role of intrathecal therapy?Role of CSF drug levels?
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TB Drugs and CNS
INH & PZA - bactericidal and penetrate inflamed and uninflamed meninges
RIF, streptomycin & EMB - do not penetrate uninflamed meninges as well
Fluoroquinolones penetrate CSF
Is there a role for treatment intensification” Higher dose RIF, adding FLQ?
Continuing PZA and/or adding cycloserine or ethionamide throughout 9 months of therapy?
Intensified Initial Therapy in TB Meningitis: No Benefit
N Engl J Med 2016;374:124-134
Randomized, double-blind, placebo controlled study in Vietnam, n=817, 43% HIV+
Standard Therapy 3 monthsINHRifampin (10 mg /kg)PZAEthambutol
Followed by 7 months INH and rifampinAll received dexamethasone for 6-8 weeks
Mortality 28% in STD and IntensiveNote: INH-res.: 39% (16/41) vs 24% (11/45),
p=0.06
Intensified8 weeksRifampin 15 mg/kgLevo 20 mg/kg
CNS TB and Paradoxical Response 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
Does not represent failure of therapy◦ Do not need to change regimen
TB meningitis◦ May be associated with neutrophilic predominance
◦ More frequent development of tuberculomas
Clin Infect Dis 1994;19:1092-9Infection 2003;31:387-91
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33 y.o. man with LTBI & DM
TST 16 mm 7 yrs ago Developed diabetes mellitus Started on INH with 25 mg pyridoxine Had a seizure at home after 2 weeks PCP thought cause was hypoglycemia Repeat seizure 3 weeks later
33 y.o. with 2nd seizure
33 y.o. on INH with brain mass
Seizures controlled with phenytoin Tuberculoma removed at craniotomy AFB stains negative IRZE started post-op Are there drug interactions to consider?
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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 Accounts for 50% of skeletal tuberculosis◦ Hip 15%, knee 10%
Hematogenously spread◦ Batson’s plexus
Paucibacillary disease, slow growing◦ 12-18 months of therapy
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;460:29-38Clinical Orthopaedics and Related Research 2002;398:11-19
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44 y o Vietnamese man with 6 month h/o pain and swelling of left medial thigh associated with fevers and night sweats
Also 2 month h/o fever, night sweats, 15 lb wt loss, and dry cough
27 y o man from Ethiopia with 2 day h/o severe abdominal pain, nausea and emesis
Could he have pulmonary involvement?
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Tuberculosis of Small Bowel Pathogenesis◦ Swallowing infected sputum◦ Ingestion of contaminated milk◦ Hematogenous spread◦ Direct extension
Ileocecal and jejuno-ileum most common sites Patterns◦ Ulceroconstrictive lesions, with perforation and fistulae in 5%◦ Obstruction in 20%◦ Right lower quadrant abdominal mass 25%◦ “Doughy abdomen” classic, but less common
Mimics◦ Periappendiceal abscess, Crohn’s disease, Yersinia, Amebiasis
Peritoneal Tuberculosis
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20
40
60
80
100Ascitic Fluid
Exudative • Lymphocytic pleocytosis• Protein > 2.5 – 3 g/dl• SAG < 1.1 g/dl
Diagnositics• AFB smear < 3%• AFB culture 20-83%• ADA 93-100%• Laparoscopy with biopsy 85-95%
Am J Gastroenterol 1993;88:989-99Colorectal Dis 2007;9:773-83
Sym
ptom
%
96 y.o. woman: nursing home pneumonia BAL culture: K.
pneumonia Living independently till
admission 3 mo. earlier for “failure to thrive” –pancreatic mass, no biopsy
Imipenem/cilastin + gentamicin
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96 y.o. woman: nursing home pneumonia
Improved over 1 wk Expired on 9th day BAL culture grew M.
tuberculosis, drug-susceptible
No known TB exposure
Visited twin sister in IL one month prior to health deterioration
96 y.o. woman: presumptive pancreatic TB
Complex mass/fluid extending into LUQ, ? infection
Mass contained calcifications, consistent with pancreatic TB
Assessment: death due to pancreatic TB with dissemination; probably infected in childhood
25 y o man from Mexico with 2 month history of fever, chills, night sweats, cough, and 30 lb wt lossAlso dysuria with 3+ WBC and RBC
Sputum 4+ AFB
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Urogenital Tuberculosis
May present with dysuria, hematuria, or flank pain Asymptomatic patients with classic sterile pyuria Men◦ Kidney, prostate, seminal vesicles, epididymis, testes◦ Oligospermia
Women◦ Endosalpinx with spread to peritoneum, endometrium, ovaries,
cervix, vagina◦ Pelvic pain, infertility, vaginal bleeding
Mycobacterial culture of early morning urine specimens
Am Fam Physician 2005;72:1761-8
Tuberculous Meningitis and Steroids
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
Seven Randomized Studies
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
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TB Pericarditis and Steroids:Changing recommendationsMulticenter randomized study comparing prednisolone vs. placebo in 1400 adults with TB pericarditis
NEJM 2014;371:1121-30
80 y.o. Cambodian-born woman in US 30 yrs4 months s/p 2nd CABG & Mitral Valve Repl.
High-pressure fluid collection in pacemaker pouch• Epicardial wires
removed• M.tb on culture
Presumed origin: pericardial TB
Kestler, Int J TubercLung Dis. 2009
Summary
Tuberculosis can occur anywhere within the body Diagnosis can be extremely challenging◦ Microbiology◦ Pathology
◦ Nucleic amplification
◦ TST vs. interferon-gamma release assays?
Evaluate for pulmonary disease Coordinated management with public health