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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

– Insmed

– Spero

• Advisory Board:

– Insmed

– Johnson and Johnson

– Spero Pharmaceuticals

– Horizon Pharmaceuticals

– Paratek

– Meiji

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Extrapulmonary TuberculosisOutline

• Brief Epidemiology

• Extrapulmonary Disease

– Lymph Node

– Pleural

– Bone and Joint

– Gastrointestinal

– Genito‐urinary

– Pericardial

– CNS

– Disseminated

Extrapulmonary TB

Extrapulmonary TB ‐ 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, 1993‐2017

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 (2003‐14)*

Total 20.8% 16.8%

Lymph node/Lymphatic 37.8% 29.5%

Pleural 15.6% 40.0%

Bone and Joint/Osteo‐articular

9.2% 8.7%

Genitourinary 4.1% 6.3%

Peritoneal/Digestive 5.9% 2.9%

Meningeal/Central Nervous System

4.3% 3.3%

Disseminated ‐** 1.3%

Other 23.0% 8.0%*Includes 27 countries** Included in “other”

• Autopsy on adult inpatients:  4/12‐5/13

• 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: 544–51.

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 

– (i.e, TNF‐α blocking agents)*

• Infancy*• Female sex• Alcohol abuse• Malignancy• Connective tissue disease 

– (with or without iatrogenic immunosuppression)

• Renal failure• Diabetes• Pregnancy• Vitamin D deficiency*

*Pareek M, et al. Thorax 2015;70:1171–1180

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 ✓ ✓ – ✓ ✓ –

Chemistries ✓ ✓ – ✓ ✓ –

ADA ✓ ✓ ✓ ✓ – –

Interferon ‐ 𝛾 – ✓ – ✓ – –

AFB smear ✓ ✓ ✓ ✓ ✓ ✓AFB culture ✓ ✓ ✓ ✓ ✓ ✓Gene Xpert ✓ – – – – ✓

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 INH‐R MDR XDR

Total cases

30%

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XPERT MTB RIF in XPTB diagnosisMeta‐analysis 

XPERT MTB/RIFSensitivity

XPERT MTB/RIFSpecificity

Pleural fluid 0.34 (95% CI, 0.24–0.44) 0.98 (0.96 – 0.99)

Non pleural serous fluid 0.67 (IQR, 0.00‐1.00) 1.00 ( 1.00 – 1.00)

Gastric aspirate 0.78 (IQR, 0.68 – 0.85) 1.00 (0.99 – 1.00)

CNS fluid 0.85 (IQR, 0.75‐1.00 1.00 (0.98 – 1.00)

Lymphatic TB 0.96 (95% CI, 0.72‐0.99) 1.00 (0.94 – 1.00)

Smear + specimen 0.95

Smear – specimen 0.69

BMC Infect Dis. 2014;14:709

Treatment of Extrapulmonary TBGeneral Approach 

• 6 Months of standard TB chemotherapy

– Bone/Joint: consider extending treatment to 9 months

– CNS disease 9‐12 months

• The preferred frequency of dosing for extrapulmonary tuberculosis is once daily for both the intensive and continuation phases 

Nahid CID 2016;63(7):e147–95

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“The Kings Evil”

“…strangely visited people all swol’n 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 ‘tis spoken,

to the succeeding royalty he leaves

the healing benediction…”

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 – 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-𝛾, 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

Meta‐analysis in pleural TB (n= 1626)

Sensitivity Specificity

ADA 92 90

INF‐𝝲 89 97

Zhou Scientific reports 2015

AFB smear (%) AFB culture  (%) Histology (%)

Pleural fluid 0‐10 23‐58

Pleural tissue 14‐39 40‐85 69‐97

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 (Pott’s 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 – lumbar. May be associated with paraspinousand/or psoas abscessesDx: Needle biopsy and aspiration, exploration, other TB sites

AFB smear – 20-25%AFB culture – 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

– Smear usually negative.

– Culture + 45-69%

– 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 50‐65%

Rx: Chemotherapy (6 mo) ± steroids

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Diagnosis of Pericardial TB

Sensitivity AFB smear (%) AFB culture (%) Histology (%)

Pericardial Fluid 0‐42 50‐65 73‐100

Lewinsohn CID 2017

Suspected Pericardial TB(151 suspect/74 definite/50 probable)

Sensitivity Specificity

ADA (>35 IU/L) 95.7 84

IFN‐𝜸 (>44 µg/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):e147–95

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 ‐ Most common symptoms are fever, headache, and altered mental status

Lab: CSF ‐ lymphocytic, high protein, low glucose

Dx: AFB smear 10‐30%, Culture positive in 45‐70%, Xpert 80‐85%

Rx: chemotherapy (9‐12 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 10‐30 45‐70 –

Lewinsohn CID 2017

Sensitivity Gene Xpert (%) Culture (%)

CSF 81 63

Denkinger Eur Resp J 2014

Intensified Anti‐TB Therapy in Adults with TB Meningitis 

• Randomized, controlled trial of a 9 month regimen for adults with TB meningitis in Vietnam

– INH, RIF (10 mg/kg), EMB, PZA ± SM for 3 months followed by INH, RIF for 6

– INH, RIF (15 mg/kg), EMB, PZA ± 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 (0.73–1.22) 0.66

HIV infected 68/174 68/175 0.91 (0.65–1.27)  0.57

Isoniazid resistance 16/41  11/45 0.45 (0.20–1.02) 0.06

N Engl J Med 2016;374:124-34.

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Intensified Anti‐TB 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

– Oral rifampin 450 mg plus either no moxi, moxi 400 mg, or moxi 800 mg or

– IV rifampin 600 mg plus either no moxi, moxi 400 mg, or moxi 800 mg

Lancet Infect Dis 2013;13: 27–35

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

”Higher” 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 2‐month phase 

• INH and RIF continued for an additional 7–10 months

• Adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6–8 weeks 

• Repeated lumbar punctures early in the disease should be considered to document response to therapy.

Nahid CID 2016;63(7):e147–95

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Treatment Outcomes in Childhood TB Meningitis ‐ Meta‐analysis

• 19 studies (1636 children)

• Risk of death: 19.3%

– 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;33:248–252

• 184 Children

• 80% having stage 2‐3  (BRMC classification)

• 6 months /4 drug treatment – isoniazid (15 to 20 mg/kg)

– rifampin (20 mg/kg) 

– pyrazinamide (40 mg/kg)

– 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 4‐drug regimen of INH, RIF, PZA, and an 

aminoglycoside or ethionamide for 2 months, followed by 7–10 

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 + 20‐25%, 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 9‐12 12 Yes Yes

GU 6 6 No No

GI 6 6 No No

Bone/joint/spine 6‐9 6 No No

Disseminated 6 6 No No

Adjunctive corticosteroids

• Steroids recommended with CNS disease (+/‐pericardial disease)– 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.

– 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

– 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