Chief’s Rounds with

Dr Henry Fraimow, MDProfessor of Medicine, Division of Infectious Diseases

Nimit Shah

10/12/2009

The Comeback Of TB

Reported TB Cases* United States, 1982–2008

10,000

12,000

14,000

16,000

18,000

20,000

22,000

24,000

26,000

28,000

1984 1987 1990 1993 1996 1999 2002 2005 2008

Year

No

. of

Ca

ses

*Updated as of May 20, 2009. (CDC)

HIV pandemic

TB MorbidityUnited States, 2003–2008

Year No. Rate*2003 14,836 5.12004 14,500 4.92005 14,067 4.72006 13,727 4.62007 13,288 4.42008 12,904 4.2

*Cases per 100,000, updated as of May 20, 2009. (CDC)

NJ stats

Reported TB Cases by Age Group, United States, 2008

25–44 yrs (33%)

<15 yrs

(6%)15–24 yrs

(11%)

45–64 yrs (30%)

>65 yrs (19%)

CDC

Reported TB Cases by Race/Ethnicity* United States, 2008

Hispanic or Latino(29%) Black or

African-American(25%)

Asian(26%)

White(17%)

American Indian or Alaska Native (1%)

Native Hawaiian orOther Pacific Islander

(<1%)

*All races are non-Hispanic. Persons reporting two or more races accounted for less than 1% of all cases.

Number of TB Cases inU.S.-born vs. Foreign-born Persons United States, 1993–2008*

0

5000

10000

15000

20000

1993 1996 1999 2002 2005 2008

U.S.-born Foreign-born

No

. o

f C

ases

*Updated as of May 20, 2009.

Epidemiology

Proportion of TB among US-natives vs foreign born

41%

59%

29%

26%

25%

20%

Hispanics

Asians

AA

Others

US Natives

42%

17%

AA

Hispanic

White

Others

53417563US nativesForeign born

33%

17%

Foreign Born

Quick facts In 2008, TB case rate declined from 4.4 4.2 per

100,000 persons. Of these, 2.0 per 100,000 US born 20.3 per 100,000 Foreign born

Top 5 countries

Mexico

China

Vietnam

Philippines

India

Estimated HIV Coinfection in Persons Reported with TB, US1993–2008*

0

10

20

30

1993 1996 1999 2002 2005 2008

All Ages Aged 25–44

% C

oin

fect

ion

*Updated as of May 20, 2009.

Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group.

Quick facts MDR TB: Rate 2.5% 1%

No previous history of TB and resistance to at least Isoniazid and Rifampin

Extensively Drug Resistant TB: 2 4 cases Resistance to Isoniazid and Rifamprin + at least 1/3

injectable 2nd line anti TB drugs.

HIV testing offered to suspected/confirmed TB.

Organs affected by TB

Case 1 (DoA: 12/19/2007) 55 yo male with wt loss >20 lbs in 3 m, cough,

yellow sputum for few months. Saw PCP 2 ½ weeks ago, treated outpt with po

Bactrim for pneumonia without improvement. PMH: Hep C, TB 7 yrs ago-treated, daily ETOH,

HIV-ve FH: Mother dies of TB, >30yrs ago Meds: Diazepam, folate, naprosyn, Bactrim, Vit B RoS: Fatigue, gen weakness, DoE, N/V, headache.

Decreased PO intake, No F/C/nightsweats

Case 1 (DoA: 12/19/2007) VS: 95.2, 101, 83/60, 16, 95% on RA PE: cachectic, no LAN, Rt sided end exp fine

crackles, dullness on percussion on rt side, Abd soft benign.

132

4.3

95

22

42

4.4113

10.211.9

34.2241

•ESR: >100

•TSH: 2.04

•AST: 89

•ALT: 76

•Alb: 2.6

CXR: B/l Patchy infiltrate, multiple focal cavities

CT chest showing cavitary lesion in RML

Questions What does this pt have? When to isolate? When to stop isolation? Role of PPD? What labs are helpful for rapid detection? What is the treatment? For how long? What are the complications? Does this pt need to stay in hospital?

Course ID consult (12/22/09): Recurrent TB. Pt was put in isolation on presumption of

MTB on 12/22/09, after sputum smear, cultures, LFTs.

4-drug regimen started on 12/25/09, later on Levofloxacin was added.

AFB smears +ve: 12/25 1/8. Turned –ve.

MTB Complex (M Tuberculosis, M Bovis, M Africanum, M Microti and M Canetti)

MTB: Robert Koch, 1882 Human: only natural reservoir Cell envelop: mycolic acid Delayed cell-mediated immunity Gm +ve, AFB (ZN stain), auramine-O, serology Slow growers on cultures, Newer NAA tachniques help with faster diagnosis

Natural historyInitial inhalation of droplets alveoli:

Immediate clearance

Latent infection

Rapidly Progressive

Reactivation

Immune-compromised

HIV, Lypmohoma, DM, ESRD, steroids

Miliary TB: All forms of progressive widely disseminated hematogenous TB.

Pulmonary TB Most common: upto 75% of all TB S/s: wide range: low grade fever, pleuritic CP, productive

cough, wt loss, night sweats CXR: varied: infiltrates, cavity, effusion, LAN (65%),

collapse, PTX, fibrosis, granulomas Primary: usually upper zone of lower, lower zones of upper Secondary: usually upper zones of upper lobes Ghon’s focus, Simon’s focus Labs: May be normal, normocytic anemia/ACD,

monocytosis, SIADH, low alb

Isolation Transmission: Inhalation: droplet: 1-5 micron Isolation for: Persons with active untreated respiratory tract

disease are considered contagious: cavitary, AFB +ve Procedures: intubation, bronchoscopy, aerosol Rx AII room with HEPA filters/UV irradiated Surgical mask to pt, and/or N95 to others/visitors (95%

efficiency to 1 micron particle) Instruction to cover mouth/nose when sneeze/cough Promptly report: local PH dept Infectivity starts

AFB +ve: 3 months before smear +ve AFB –ve: 1 month before onset of s/s

Discontinuing isolation If MTB ruled out Pt with active MTB + all of below:

On effective therapy Clinically improving 3 consecutive sputum samples on diff days come –ve

Initial +ve AFB: at least 2 weeks MDR-TB/XDR-TB: All throughout hospitalization Anti TB is highly bactericidal, and kills MTB burden rapidly

in initial days, so pt can be discharged home provided… Pt will be compliant No at risk contacts at home Pt wont leave home without mask Confirmed outpt appt Sufficient anti TB meds until appt Local PH department notified has done an assessment and agrees with discharge

and is ready to assume administration of therapy

Diagnosis of latent TBPPD: Delayed hypersensitivity response. 5 TU (0.1 mL) intradermal

3-7 weeks after primary infection required for seroconversion

Once positive, never repeated. +ve: induration ≥ 10 mm False –ve: immunesuppression,

error-method, material, measurement

False +ve: NTM, BCG IGRA to distinguish b/w infection

and BCG

PPD +ve: CXRSensitivity Specificity When to consider positive

5 mm 98% <-> HIV, Close contact to active diseaseOld TB (fibrotic CXR)Immunosuppressed, on TNF – α, steroids, transplant recipient

10 mm 90% ↑↑ Reactivation riskESRD on HDDMMalignancyUnderweightIVDA children < 4 yrsHealthcare workers, jail, shelters

15 mm 50-60% ↑↑↑ Healthy persons with low risk

Lab Diagnosis Microbiology Specimens

Mycobacterial stains Mycobacterial cultures

Pathologic specimens Direct evidence: Mycobacterial stains “Circumstantial” evidence: granulomatous

inflammation Nucleic Acid Amplification Techniques

Mycobacterial stains Traditional Acid-Fast stain: Carbol-fuschin stains

Ziehl-Neelson > Kinyoun stain Sensitivity: 1 x 105 Organisms/ml (300 fields) Not completely specific for mycobacteria

Fluorochrome (auramine, rhodamine-auramine) stain Based on binding of mycolic acids to phenol-

auramine Yellow or Green on a dark background Sensitivity: ? One log more sensitive than ZN Some atypicals (esp. rapid growers) may be

negative Appearance of Mycobacteria on stain

Small, beaded rods (MTB, but also other species) Cording suggests MTB (or chelonae) Other morphologies (longer, fatter, filaments, etc)

suggestive of an Atypical organism (esp. a rapid grower)

Microbiology Media

Solid Media: Lowenstein-Jensen Glycerol and egg based media (fatty acids and

protein) and antimicrobial inhibitors Liquid Media: Can decrease growth time by as

much as 50% MGIT Other Automated Liquid media systems

Sensitivity of Culture: 100 organisms/ ml Growth suppression: BACTEC CO2 production: Septi chek, MB/BacT O2 utilization: Mycobacterial growth

indicator tubes, Versa TREK

Diagnosis of active TBNucleic Acid Amplification tests (RNA or DNA based PCR)

Positive Negative (NTM)

Anti TB treatment

4 drugs for 2 months

2 drugs for 4 months

NTM Common: Await culture confirmation

NTM rare: Start anti TB Rx

Low clinical suspicion:

Why NAA?

High clinical suspicion: Start anti TB treatment

AF

B s

mea

r

Pos

itiv

eN

egat

ive Φ

Additional testing if high suspicion:

bronchoscopy/biopsy

Treatment (DOT: Directly Observed Treatment)

Primary drugs

Isoniazid (INH)

Rifampin (R)

Pyrazinamide (P)

Ethambutol (E)

Streptomycin (S)2nd line agents FQ, amikacin, kanamycin,Ethionamide,Cycloserine3rd LineLinezolidAugmentinClarithromycin

Adult Prevention and Treatment of Opportunistic Infections Guidelines Working Group. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents [DRAFT]. June 18, 2008; pp 1-289. Available at: http://aidsinfo.nih.gov/contentfiles/Adult_OI.pdf. Accessed (10/7/08).

LTBI treatment INH: daily for 9 months plus pyridoxine (300 mg)

No major interactions with HAART though toxicities may overlap (INH is a CYP 3A inhibitor)

Rifampin: daily for 4 months (600 mg) Used when INH resistance suspected or toxicity

concerns (Hepatitis/ chronic liver disease common in HIV)

Effectiveness: Risk of developing TB disease decreased by at least 60%. Efficacy increases to 80-90% if adherence is high

Failure of LTBI Rx Already have active TB disease (not LTBI) Adherence to regimen Absorption and tolerability issues Drug Resistance Re-infection (lower CD4 counts)

*Successful completion of treatment is responsibility of medical providers and HCW, NOT of patient

Standard MTB treatment

*Successful completion of treatment is responsibility of medical providers and HCW, NOT of patient

Initial Phase

Continuation Phase

2 months - INH, RIF, PZA, EMB daily (56 doses, within 8 weeks)

Options:

1) 4 months - INH, RIF daily (126 doses, within 18 weeks)

2) 4 months - INH, RIF twice / week (36 doses, within 18 weeks)

3) 7 months - INH, RIF daily (217 doses, within 31 weeks)*

4) 7 months - INH, RIF twice / week (62 doses, within 31 weeks)*

DOTS (Directly Observed Therapy, Short course)

Outcomes: ↓ incidence of Pulm TB (4219/100000) ↓ Rate of drug resistance (9.4 1.5/100000) ↓ treatment failure (112%) ↓ MDR-TB (10 4.3/100000)

DR-TB INH mono resistance:

R + P + E for 6-9 mths or 4 mths after culture conversion May add FQ

Rifampin mono resistance: commonly in HIV (CD4+ < 400) INH + P + Strepto for 9 mths INH + P + E for 12 – 18 mths after culture conversion

PZA mono resistance: INH + R for 9 mths

Other (E, S mono resistance) INH + R + P for 2 mths INH + R for 4 mths

MDR-TB (At least INH and Rifampin resistance)

Drug susceptibility testing (DST) DOTS mandatory Children = adults Surgery (localised , culture +ve > 3mths) No randomised trials: treat depending upon

DST Median duration 12-18 months

Rx

XDR-TB 4 cases in 2008 in US. DST vital role Risk: prior treatment, contact with a drug resistant TB, homeless,

HIV, alcohol HIV+: high rates of extra pulm, smear-ve, 98% mortality Many pts die before lab diagnosis is confirmed Clinically indistinguishable Median # of drugs:6. (include 1 injectable, 1 first line) Duration:

HIV-ve: 18 mths after sputum conversion HIV+ve: 18 mths after adequate CD4+ (>100) + HAART

(At least INH and Rifampin resistance + FQ + injectable aminoglycoside /capreomycin or both)

Treatment failure Culture become positive after stayed –ve while on Anti TB Rx Culture never turn –ve while on AKT Continous symptoms or reappearance after –ve for sometime

while on Rx

BCG vaccination 70-80% protective in children against meningitis and disseminated disease

Complications of Pulm TB Hemoptysis: 5-15%,

Usually cavitary ds usually small amounts. Massive bleeding: Rasmussen’s aneurysm Occasionally represents as reactivation Other reasons: bronchiectasis, aspergilloma, ruptured broncholith,

Ca. Pneumothorax: <1% hospitalised pts

Rupture of a peripheral cavity/ subpleural caseous focus Bronchiectasis: Secondary > primary

Primary: Extrinsic compression by LAN Secondary: destruction, fibrosis of lung parenchyma

Extensive pulm destruction: Rarely, Chr reactivation Pulm gangrene: due to extensive necrosis after dense

consolidation

Miliary TB 1-3 % of all TB cases Hematogenous spread after erosion of the

infection into a pulmonary vein Lung: hypoxia, ARDS GI: Hepatomegaly, cholestasis,

peritonitis, pancreatitis, cholecystitis CNS: meningitis Skin: lichenoid CVS: pericarditis, myocarditis,

endocatditis Adrenal: insufficiency Choroid tubercles in eye: most specific Aortic vasa vasorum, aneurysm

Case 2 (Presented outpt on 10/8/2008) 62 yo Nigerian lady, visiting US to celebrate her grandchild’s

birth. Was braught by family to outpt clinic for chronic low back pain for 4 years. Worse past 1 year, radiating to rt leg, asso with mild RLE weakness. No sensory loss/incontinence.

PMH: HTN, nonsmmoker, nonalcoholic, no h/o HIV or PPD or TB exposure.

RoS: no F/C/N/V/Wt loss/LAN/sputum/cough VS stable PE: lower back tenderness, rt paraspinal area, and rt

sacroiliac tenderness. Rt hip flexors 4+/5 o/w 5/5 *4, Sensation, reflexes, rectal tone grossly normal

Got PPD, came back positive on 10/18/08, also got MRI LS spine...

CT LS showing vertebral degeneration

Questions What is this disease called? What parts of spine are more common than

other? When would you need urgent surgical

management? How would you treat it?

Course Got IR biopsy on 10/29/08, awaiting results of

Culture sensitivity: pan sensitive, Path: Granuloma Pt was started on 4 drug regimen for at least 6

months INH 300 mg PO daily Rifampin 600 PO daily PZA 1500 mg PO daily Ethambutol 1200 mg PO daily Pyridoxin 50 mg PO daily

Pt went back to Nigeria in 3 weeks.

Pott’s disease 2% of all TB; 25% of extrapulm; 50% of all

musculoskeletal Mostly affects lumbar and lower thoracic; Cervical,

upper thoracic more disabling Due to hematogenous spread but can present many

years later Mainly anteroinferior aspects of vertebral body,

tracks down anterior vertebral ligament Vertebral body destruction, collapse, Gibbous

disc herniation Delayed diagnosis, sometimes devastating

Tuberculous abscess Epidural: Cord compression urgent

decompression Extra spinal Soft tissue mass: Rib erosion Psoas abscess: track down into groin

Clinically, Pain, muscle spasm, rigidity, Pott’s paraplegia

Diagnosis PPD +ve in >90% HIV-ve Plain x-ray

Early: soft tissue swelling, osteopenia Later: collapse, sclerotic, wedging, angulation

CT guided biopsy: Stain, path, culture, PCR Sensory/motor evoked potentials (prognostic

value)

Treatment Medical: same as Pulm TB (usually 9 mths) –

must include Rifampin Surgery indiactions:

Worsening or advanced neurological deficits Kyphosis >40 Chest wall cold abscess

Normal SEP,MEP more likely to recover at 6 mths

Case 3 (Presented to outpt on 5/31/06) 33 yo male was referred to TB clinic for rt neck

swelling/nodule. PPD positive >20 mm, LN FNA showed smear +ve AFB. Cultures pending.

Pt was started on meds: INH 300 mg po daily Rifampin 600 mg po Daily PZA 2 gm po daily Ethambutol 1600 mg po daily Pyridoxin 50 mg po daily

Pt was continued on INH and Rifampin to complete 6 months LAN gradually improved, and at 6 months completely gone.

Later on stopped because Pan sensitive cultures.

CT neck with iv contrast

18 mm SubmanibuarLAN

Questions How would you approach a pt with TB LAN? What are the primary sites to look for? FNAC vs excisional biopsy? What is the treatment?

TB LAN Median age:

Developing: children (4.4 /1000 in <14yrs) Developed 20-40 yrs

Asian pacific islanders, females 60-70% cervical, firm, discrete, unilateral, matted/indurated Other sites: axillary, inguinal, inframammary, mesentric,

mediastinal, paraaortic HIV-ve:

Cervical:usually reactivation/tonsils/adenoids or Waldeyer’s ring Mesentric: infected milk/sputum

HIV+ve: gen infection/miliary

TB-LAN D/D H&N Malignancy HL , NHL NTB Cat scratch Fungal Sarcoidosis Bacterial LAN Kikuchi’s disease

Diagnosis PPD+ve in majority of HIV-ve CXR: unremarkable in HIV-ve: apical fibrosis FNAC: Standard of care for all HIV +ve NAA tests increases sensitivity If results are –ve excisional biopsy Sputum AFB +ve <10% , mostly if miliary

TB CT, MRI in case of intarabdominal/thoracic

Treatment Similar as Pulm TB 4 drugs, 6 mths (daily vs twice weekly) Longer if immunocompromised, resistance Paradoxical increase in LN size/ appearance

in 30% due to immune response Relapse rates: <3.5%

A few key points on HIV-MTB TB accelerates HIV infection in both lymphocytes

and macrophages. HIV progressively diminishes the host ability to

control TB by lowering CD4+ counts, Histopathology of TB in advanced HIV: lots of

organisms, poorly formed (or no) granulomas Risk for progression from LTBI to TB disease in

HIV infected (7-10% annual risk) is much greater than for HIV-negative patients (lifetime risk 5-10%)

1/3 primary vs. 2/3 reactivation of TB

HIV-MTB CD4+ >350 ~ manifests same as non HIV Lower CD4+: ↑ rates of extra pulm TB CD4+ < 50: diffuse LAN, pleuritis, meningitis,

pericarditis, dissemnation, bacteremia Sputum smear negative with +ve cultures Delayed diagnosis Increased mortality

CXR Clear in 20-30% (Cultures +ve) Diffuse interstitial infiltrates Absence of upper lobe cavitation/fibrosis Lymphadenopathy Effusion Miliary pattern

Lab testing for MTB in HIV PPD

Considered +ve at 5mm CD4+ <200 only upto 20% PPD +ve

Ig G Release Assays (IGRA) Sensitivity falls with CD4+ (same as PPD)

MTB related IRIS in HIV Can be severe and prolonged (months) and even fatal

Incidence: 8-43%, mostly in advanced HIV (CD4+ <35, VL >500k)

15-30 days after starting HAART

Treatment: NSAIDs, ?steroids

Manifests as New or worsening lymphadenopathy, including spontaneously draining

lesions

High fevers

New or worsening pulmonary infiltrates

Serositis – pleural effusion, peritonitis

Cutaneous lesions

Central nervous system lesions (tuberculomas)

MTB and HIV: Timing of RxPatients already on HAART when TB is

diagnosed should continue on HAARTFor those not on HAART when TB is

diagnosed, TB therapy should always be started as quickly as

possible In most instances HAART also should be started,

but when?

Reasons to Delay HAART when Treating Active MTB

Multiple drugs, multiple toxicities and interactions Decreased adherence with multiple medications TB is the priority, HIV is a chronic disease and can wait Initiation of HAART can lead to IRIS and confound the clinical picture

Reasons not to delay HAART Early initiation of HAART improves the prognosis of patients Early initiation of HAART may improve outcome of TB and/or improve overall mortality (regardless of CD4 counts)

Current Recommendations

CD4 > 350 Delay HAART at least 8-24 weeks or to end of Rx

CD4 100-350 Delay HAART at least 8 weeksCD4 < 100 Delay HAART 2 weeks

XDR-MTB and HIV

1st Major outbreak of XDR-TB reported from South Africa. 52 of 1st 53 cases died of their disease, mean 25 days from

diagnosis; all HIV + XDR-TB subsequently found much more wide spread than

suspected, and not confined to HIV + Mortality still remains high even in HIV negative High risk for transmission and rapid mortality in HIV co-infected

65

HIV and MTB Co-Infection: Key Points

TB is the most common manifestation of HIV infection in highly TB endemic areas

HIV and TB each enhance the pathogenicity of the other, HIV is the strongest known risk factor for progression from LTBI to TB disease

Presentation of TB is atypical and disease is more difficult to diagnose and more lethal in advanced HIV infection

Medical management of TB and HIV is complicated by drug interactions,

HIV + should be screened for LTBI but testing is imperfect, LTBI should always be treated if diagnosed in HIV+

66

Thank you.