extrapulmonary tb curry 9 6 19 newnid...9/6/2019 9 pleural tb who: young, primary tb s/s:...
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Extrapulmonary Tuberculosis
Charles L. Daley, M.D.
National Jewish Health
University of Colorado, Denver
Icahn School of Medicine, Mt, Sinai
Conflict of Interest Disclosures
⢠Research Grant
â Insmed
â Spero
⢠Advisory Board:
â Insmed
â Johnson and Johnson
â Spero Pharmaceuticals
â Horizon Pharmaceuticals
â Paratek
â Meiji
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Extrapulmonary TuberculosisOutline
⢠Brief Epidemiology
⢠Extrapulmonary Disease
â Lymph Node
â Pleural
â Bone and Joint
â Gastrointestinal
â Genitoâurinary
â Pericardial
â CNS
â Disseminated
Extrapulmonary TB
Extrapulmonary TB â disease involving structures other than lung parenchyma and occurs because of the spread of tubercle bacilli throughout the body during the initial tuberculous infection
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Percentage of Extrapulmonary TB Among New and Relapse TB Case, 2017
WHO Global TB Report, 2018
Pulmonary and Extrapulmonary TB in the United States, 1993â2017
0
5000
10000
15000
20000
25000
30000
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
Total TB Pulmonary Extrapulmonary
CDC
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Frequency of Extrapulmonary Disease in US and EU
Site of Disease United States, 2017 European Union, European Economic Area (2003â14)*
Total 20.8% 16.8%
Lymph node/Lymphatic 37.8% 29.5%
Pleural 15.6% 40.0%
Bone and Joint/Osteoâarticular
9.2% 8.7%
Genitourinary 4.1% 6.3%
Peritoneal/Digestive 5.9% 2.9%
Meningeal/Central Nervous System
4.3% 3.3%
Disseminated â** 1.3%
Other 23.0% 8.0%*Includes 27 countries** Included in âotherâ
⢠Autopsy on adult inpatients: 4/12â5/13
⢠N: 125
⢠64% male, 81% HIV +78 (62%) had TB
20/78 (26%) undiagnosed TB
13/78 (13%) undiagnosed MDR TB
35/78 (45%) XPTB
XPTB higher in HIV patients (OR 5.14)
Lancet Infect Dis 2015; 15: 544â51.
Tuberculosis at Post Mortem in Inpatients in Zambia: A prospective descriptive study
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Risk factors for Extrapulmonary TB
⢠Untreated Human immunodeficiency virus (HIV) infection*⢠Corticosteroids or other iatrogenic immunosuppression
â (i.e, TNFâÎą blocking agents)*
⢠Infancy*⢠Female sex⢠Alcohol abuse⢠Malignancy⢠Connective tissue disease
â (with or without iatrogenic immunosuppression)
⢠Renal failure⢠Diabetes⢠Pregnancy⢠Vitamin D deficiency*
*Pareek M, et al. Thorax 2015;70:1171â1180
Diagnosis of Extrapulmonary TBChallenges
⢠Signs and symptoms are nonspecific
⢠Appropriate specimens must be obtained for microscopy/culture and histology
⢠Variable sensitivities and specificities of diagnostic test
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Diagnostic Evaluation of Suspected Extrapulmonary TB
Test CSF Pleural Pericardial Peritoneal Joint fluid
Lymph Node
Cell count â â â â â â
Chemistries â â â â â â
ADA â â â â â â
Interferon â đž â â â â â â
AFB smear â â â â â âAFB culture â â â â â âGene Xpert â â â â â â
Lewinsohn D, et al CID 2017
Extrapulmonary TB in New DelhiSix years experience in a reference lab
Indian J Med Res. 2015 Nov;142(5):568-74.
0
50
100
150
200
Total INHâR MDR XDR
Total cases
30%
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XPERT MTB RIF in XPTB diagnosisMetaâanalysis
XPERT MTB/RIFSensitivity
XPERT MTB/RIFSpecificity
Pleural fluid 0.34 (95% CI, 0.24â0.44) 0.98 (0.96 â 0.99)
Non pleural serous fluid 0.67 (IQR, 0.00â1.00) 1.00 ( 1.00 â 1.00)
Gastric aspirate 0.78 (IQR, 0.68 â 0.85) 1.00 (0.99 â 1.00)
CNS fluid 0.85 (IQR, 0.75â1.00 1.00 (0.98 â 1.00)
Lymphatic TB 0.96 (95% CI, 0.72â0.99) 1.00 (0.94 â 1.00)
Smear + specimen 0.95
Smear â specimen 0.69
BMC Infect Dis. 2014;14:709
Treatment of Extrapulmonary TBGeneral Approach
⢠6 Months of standard TB chemotherapy
â Bone/Joint: consider extending treatment to 9 months
â CNS disease 9â12 months
⢠The preferred frequency of dosing for extrapulmonary tuberculosis is once daily for both the intensive and continuation phases
Nahid CID 2016;63(7):e147â95
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âThe Kings Evilâ
ââŚstrangely visited people all swolân and ulcerous, pitiful to the eye,
the mere despair of surgery, he cures,
hanging a golden stamp about their necks,
put on with holy prayers; and âtis spoken,
to the succeeding royalty he leaves
the healing benedictionâŚâ
Shakespeare, Macbeth
Lymphatic TB
Who: Young, females, HIV +
S/S: Painless adenopathy, cervical (uni>bilateral)
Lab: PPD often + (75-100%)
Dx: Aspirate or biopsy, smear and culture of LN (42%-83%)
Rx: Chemotherapy (6 m), rarely steroids, rarest â surgery
Paradoxical reactions: Up to 23%
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Pleural TB
Who: Young, primary TB
S/S: Non-productive cough, fever, and pleuritic chest pain
Lab: Fluid with high protein, LDH, interferon-đž, ADA, low glucose, lymphocytic pleocytosis
Dx: Pleural liquid/tissue histopathology and culture, Parenchymal disease in 20 to 50%
Rx: Chemotherapy (6 m), rarely steroids
Diagnosis of Pleural TB
Metaâanalysis in pleural TB (n= 1626)
Sensitivity Specificity
ADA 92 90
INFâđ˛ 89 97
Zhou Scientific reports 2015
AFB smear (%) AFB culture (%) Histology (%)
Pleural fluid 0â10 23â58
Pleural tissue 14â39 40â85 69â97
Lewinsohn CID 2017
Sensitivity Gene Xpert Culture
Pleural TB 46 21
Denkinger Eur Resp J 2014
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Bone and Joint TuberculosisSpinal TB (Pottâs Disease)
Who: Increases with ageS/S: Back or joint pain, cold abscess, nerve root compression constitutional symptoms if advanced, GibbusImaging: Childhood to adolescence -thoracic vertebra, Adults â lumbar. May be associated with paraspinousand/or psoas abscessesDx: Needle biopsy and aspiration, exploration, other TB sites
AFB smear â 20-25%AFB culture â 60-80%
Rx: Chemotherapy (8-9 m), surgery to drain abscess and stabilize spine
Gibbus Deformity
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Bone and Joint TuberculosisNon-spinal TB
Who: Young and old
S/S: Pain and swelling of joint, soft tissue abscess near joint, usually hip/knee
X-ray: widening of joint space, destruction and erosion, cysts of subchondral cortex or metaphysis
Dx: synovial biopsy and culture (60-80%)
Rx: Chemotherapy (6-9 m) and immobilization. Rare excision or fusion
Gastrointestinal Tuberculosis
Who: Middle aged, elderly
S/S: Fever, abdominal pain, swelling, mass, wt loss
Lab: Lymphocytic exudate (beware of dilution in cirrhotics). ADA 100% sensitive, interferon 93%
Dx: Smear and culture of fluid; peritoneal biopsy
â Smear usually negative.
â Culture + 45-69%
â Peritonea biopsy > 90%
Rx: Chemotherapy (6 m)
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Genito-Urinary Tuberculosis
Who: men - renal, epididymal, prostate TB, women - renal, cervical, endometrial, fallopian TB
S/S: Pain, altered urination, constitutional symptoms
Lab: Sterile pyuria, hematuria, renal calcification, abnormal IVP or cystogram
Dx: Urine culture usually positive (80-90%), biopsy
Rx: Chemotherapy (6 m), steroids, endoscopy for strictures
Pericardial Tuberculosis
S/S: Cough, wt loss, dyspnea, orthopnea, chest pain, edema, fever
Tachycardia, cardiomegaly, JVD, muffled sounds, 1/2 with friction rub
Lab: ECG: ST/TW depression, CXR enlarged heart, echo: effusion, constrictive pericarditis
Dx: Pericardial fluid culture positive in 50â65%
Rx: Chemotherapy (6 mo) Âą steroids
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Diagnosis of Pericardial TB
Sensitivity AFB smear (%) AFB culture (%) Histology (%)
Pericardial Fluid 0â42 50â65 73â100
Lewinsohn CID 2017
Suspected Pericardial TB(151 suspect/74 definite/50 probable)
Sensitivity Specificity
ADA (>35 IU/L) 95.7 84
IFNâđ¸ (>44 Âľg/ml) 95.7 96.3
Gene Xpert 63.8 100
Pandie BMC Med 2014
Adjunctive Steroids in Pericarditis?
⢠Small studies had shown a mortality benefit in patients who received corticosteroids.
⢠Recent RCT (n=1400) did not find a difference in the combined primary endpoint of mortality, cardiac tamponade, or constrictive pericarditis
Mayosi N Engl J Med 2014; 371:2534Nahid CID 2016;63(7):e147â95
2016 Guidelines:⢠Adjunctive corticosteroids should not be used routinely in the treatment of
patients with pericardial tuberculosis ⢠However, selective use of corticosteroids in patients who are at the highest
risk for inflammatory complications might be appropriate
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CNS Tuberculosis
Who: Young children more likely to present with meningitis
S/S: Meningitis is the most common manifestation of CNS TB â Most common symptoms are fever, headache, and altered mental status
Lab: CSF â lymphocytic, high protein, low glucose
Dx: AFB smear 10â30%, Culture positive in 45â70%, Xpert 80â85%
Rx: chemotherapy (9â12 m), steroids
CNS TuberculosisThree Phases of Disease
Phase I
Phase II
Phase III
FeverMalaiseAnorexiaIrritabilityHeadacheBackacheNauseaVomiting
HeadacheLethargyBehavior changesImpaired memoryConfusion
StuporComa
Weeks to months
Mortality
HIGH
LOW
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Diagnosis of TB in the CSF
Suspected TB Meningitis (1490 suspect/92 diagnosed)
Sensitivity (%) Specificity (%)
ADA (>2U/L) 85.9 77
Ekermans BMC 2017
AFB smear (%) AFB culture (%) Histology (%)
CSF 10â30 45â70 â
Lewinsohn CID 2017
Sensitivity Gene Xpert (%) Culture (%)
CSF 81 63
Denkinger Eur Resp J 2014
Intensified AntiâTB Therapy in Adults with TB Meningitis
⢠Randomized, controlled trial of a 9 month regimen for adults with TB meningitis in Vietnam
â INH, RIF (10 mg/kg), EMB, PZA Âą SM for 3 months followed by INH, RIF for 6
â INH, RIF (15 mg/kg), EMB, PZA Âą SM + Levo (20 mg/kg) for 3 months followed by INH, RIF for 6
Standard Intensified Hazard Ratio P value
Primary OutcomeNo. of death/N
114/409 113/408 0.94 (0.73â1.22) 0.66
HIV infected 68/174 68/175 0.91 (0.65â1.27) 0.57
Isoniazid resistance 16/41 11/45 0.45 (0.20â1.02) 0.06
N Engl J Med 2016;374:124-34.
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Intensified AntiâTB Regimen in Persons with TB Meningitis
⢠Randomized, controlled, open label trial of 9 months of therapy in persons > 14 y/o in Indonesia
⢠Regimen: INH 300 mg, PZA 1500 mg and one of the following
â Oral rifampin 450 mg plus either no moxi, moxi 400 mg, or moxi 800 mg or
â IV rifampin 600 mg plus either no moxi, moxi 400 mg, or moxi 800 mg
Lancet Infect Dis 2013;13: 27â35
Deaths Multivariate P value
Oral rifampin 20 (65%) 1.00 0.03
IV rifampin 10 (34%) 0.42
No moxi 10 (45%) 1.00 0.55
Moxi 400 mg 9 (42%) 0.76
Moxi 800 mg 12 (63%) 1.27
âHigherâ dose of rifampin lowered mortalityNo difference in mortality by moxi dose
2016 ATS/IDSA/CDC GuidelinesTreatment of TB Meningitis
⢠INH, RIF, PZA, and EMB in an initial 2âmonth phase
⢠INH and RIF continued for an additional 7â10 months
⢠Adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6â8 weeks
⢠Repeated lumbar punctures early in the disease should be considered to document response to therapy.
Nahid CID 2016;63(7):e147â95
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Treatment Outcomes in Childhood TB Meningitis â Metaâanalysis
⢠19 studies (1636 children)
⢠Risk of death: 19.3%
â Advanced stage associated with mortality
⢠Probability of survival/no neuro sequelae: 36.7%
⢠Among survivors, risk of neuro sequelae: 53.9%
⢠CSF AFB smear positive 8.9%
⢠CSF culture positive 35.1%
Chiang SS, Lancet Infect Dis 2014;14:947-57
Pediatr Infect Dis J 2014;33:248â252
⢠184 Children
⢠80% having stage 2â3 (BRMC classification)
⢠6 months /4 drug treatment â isoniazid (15 to 20 mg/kg)
â rifampin (20 mg/kg)
â pyrazinamide (40 mg/kg)
â ethionamide (20 mg/kg)
⢠Overall mortality 3.8%
Short Intensified Treatment in Children with Drug-Susceptible TB Meningitis
American Academy of Pediatrics recommends an
initial 4âdrug regimen of INH, RIF, PZA, and an
aminoglycoside or ethionamide for 2 months, followed by 7â10
months of INH and RIF
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Disseminated Tuberculosis
⢠Primary or secondary hematogenous infection
⢠Insidious, cryptic fever, weight loss
⢠Rare: ARDS, DIC, pancytopenia
⢠CXR often atypical or normal
⢠AFB smear + 20â25%, sputum culture positive 60%, urine culture positive 25%
⢠Investigate involved organs
⢠Chemotherapy (6 m)http://www.mevis-research.de
Early Clues in Disseminated TBChoroidal Tubercules
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Treatment Duration and Adjunctive Steroids by Site of Disease
Site of Disease Treatment Duration, months
Adjunctive Corticosteroids
CDC WHO CDC WHO
Lymph Nodes 6 6 No No
Pleural 6 6 No No
Pericardial 6 6 Maybe Maybe
Meningeal 9â12 12 Yes Yes
GU 6 6 No No
GI 6 6 No No
Bone/joint/spine 6â9 6 No No
Disseminated 6 6 No No
Adjunctive corticosteroids
⢠Steroids recommended with CNS disease (+/âpericardial disease)â Dexamethasone for CNS: 0.3 to 0.4 mg/kg/day for two weeks, then 0.2 mg/kg/day week three, then 0.1 mg/kg/day week four, then 4 mg per day and taper 1 mg off the daily dose each week; total duration approximately eight weeks.
â Prednisone or prednisolone for pericardial disease (60 g/day and taper 10 mg per week; total duration of 6 weeks)
http://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/325/tb
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Outbreak of XPTB associated with acupuncture, China
⢠33 XPTB cases
â all confirmed MTB, Beijing strain
Clin Microbiol Infect. 2014 Nov 14
Extrapulmonary TBSummary
⢠TB can involve any site but lymphatic and pleural TB are the most common sites
⢠Diagnosis requires culture of involved liquid or tissue
⢠Rapid diagnostics (Xpert MTB) are recommended in meningeal and lymph node disease
⢠Treatment is the same as for pulmonary disease except the duration is extended in bone/joint and CNS disease
⢠Adjunctive steroids are recommended in CNS disease and considered in pericardial disease