Chief

1
Chiefs Rounds with Dr Henry Fraimow,
MDProfessor of Medicine, Division of Infectious
Diseases
The Comeback Of TB

• Nimit Shah
• 10/12/2009

2
Reported TB Cases United States, 19822008
No. of Cases
HIV pandemic
Year
Updated as of May 20, 2009. (CDC)
3
TB MorbidityUnited States, 20032008
Year No. Rate

• 2003 14,836 5.1
• 2004 14,500 4.9
• 2005 14,067 4.7
• 13,727 4.6
• 13,288 4.4
• 12,904 4.2

Cases per 100,000, updated as of May 20, 2009.
(CDC)
4
NJ stats
5
Reported TB Cases by Age Group, United States,
2008
lt15 yrs (6)
gt65 yrs (19)
1524 yrs (11)
2544 yrs (33)
4564 yrs (30)
CDC
6
Reported TB Cases by Race/Ethnicity United
States, 2008
American Indian or Alaska Native (1)
White (17)
Asian (26)
Native Hawaiian or Other Pacific Islander (lt1)
Hispanic or Latino (29)
Black or African-American (25)
All races are non-Hispanic. Persons reporting
two or more races accounted for less than 1 of
all cases.
7
Number of TB Cases inU.S.-born vs. Foreign-born
Persons United States, 19932008
No. of Cases
Updated as of May 20, 2009.
8
Epidemiology
5341
7563
US natives
Foreign born
Foreign Born
17
33
9
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

China
Vietnam
Mexico
Philippines
India
10
Estimated HIV Coinfection in Persons Reported
with TB, US19932008
Coinfection
Updated as of May 20, 2009. Note Minimum
estimates based on reported HIV-positive status
among all TB cases in the age group.
11
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.

12
Organs affected by TB
13
Case 1 (DoA 12/19/2007)

• 55 yo male with wt loss gt20 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, gt30yrs ago
• Meds Diazepam, folate, naprosyn, Bactrim, Vit B
• RoS Fatigue, gen weakness, DoE, N/V, headache.
  Decreased PO intake, No F/C/nightsweats

14
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.

• ESR gt100
• TSH 2.04
• AST 89
• ALT 76
• Alb 2.6

11.9
42
132
95
10.2
241
113
34.2
4.3
22
4.4
15
CXR B/l Patchy infiltrate, multiple focal
cavities
16
CT chest showing cavitary lesion in RML
17
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?

18
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.

19
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

20
Natural history

• Initial inhalation of droplets ? alveoli

Immediate clearance
Latent infection
Rapidly Progressive
Immune-compromised HIV, Lypmohoma, DM, ESRD,
steroids
Reactivation
Miliary TB All forms of progressive widely
disseminated hematogenous TB.
21
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
• Ghons focus, Simons focus
• Labs May be normal, normocytic anemia/ACD,
  monocytosis, SIADH, low alb

22
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

23
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

24
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

25
PPD ve ? CXR
Sensitivity Specificity When to consider positive
5 mm 98 lt-gt HIV, Close contact to active disease Old TB (fibrotic CXR) Immunosuppressed, on TNF a, steroids, transplant recipient
10 mm 90 ?? Reactivation risk ESRD on HD DM Malignancy Underweight IVDA children lt 4 yrs Healthcare workers, jail, shelters
15 mm 50-60 ??? Healthy persons with low risk
26
Lab Diagnosis

• Microbiology Specimens
• Mycobacterial stains
• Mycobacterial cultures
• Pathologic specimens
• Direct evidence Mycobacterial stains
• Circumstantial evidence granulomatous
  inflammation
• Nucleic Acid Amplification Techniques

27
Mycobacterial stains

• Traditional Acid-Fast stain Carbol-fuschin
  stains
• Ziehl-Neelson gt 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)

28
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

29
Diagnosis of active TB
Nucleic Acid Amplification tests (RNA or DNA based PCR) Nucleic Acid Amplification tests (RNA or DNA based PCR) Nucleic 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
Anti TB treatment 4 drugs for 2 months 2 drugs for 4 months NTM rare Start anti TB Rx
Low clinical suspicion Why NAA?
High clinical suspicion Start anti TB treatment
Positive
AFB smear
F
Negative
Additional testing if high suspicion
bronchoscopy/biopsy
30
Treatment (DOT Directly Observed Treatment)
Primary drugs Isoniazid (INH) Rifampin
(R) Pyrazinamide (P) Ethambutol (E) Streptomycin
(S) 2nd line agents FQ, amikacin,
kanamycin, Ethionamide, Cycloserine 3rd
Line Linezolid Augmentin Clarithromycin
31
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).
32
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

33
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
34
Standard MTB treatment
Initial Phase
2 months - INH, RIF, PZA, EMB daily (56 doses,
within 8 weeks)
Continuation Phase

• Options
• 4 months - INH, RIF daily (126 doses, within 18
  weeks)
• 4 months - INH, RIF twice / week (36 doses,
  within 18 weeks)
• 7 months - INH, RIF daily (217 doses, within 31
  weeks)
• 7 months - INH, RIF twice / week (62 doses,
  within 31 weeks)

Successful completion of treatment is
responsibility of medical providers and HCW, NOT
of patient
35
DOTS (Directly Observed Therapy, Short course)

• Outcomes
• ? incidence of Pulm TB (42?19/100000)
• ? Rate of drug resistance (9.4? 1.5/100000)
• ? treatment failure (11?2)
• ? MDR-TB (10 ? 4.3/100000)

36
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 lt
  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

37
MDR-TB (At least INH and Rifampin resistance)

• Drug susceptibility testing (DST)
• DOTS mandatory
• Children adults
• Surgery (localised , culture ve gt 3mths)
• No randomised trials treat depending upon DST
• Median duration 12-18 months

Rx
38
XDR-TB
(At least INH and Rifampin resistance FQ
injectable aminoglycoside /capreomycin or both)

• 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 drugs6. (include 1 injectable, 1
  first line)
• Duration
• HIV-ve 18 mths after sputum conversion
• HIVve 18 mths after adequate CD4 (gt100)
  HAART

39
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

40
Complications of Pulm TB

• Hemoptysis 5-15,
• Usually cavitary ds
• usually small amounts.
• Massive bleeding Rasmussens aneurysm
• Occasionally represents as reactivation
• Other reasons bronchiectasis, aspergilloma,
  ruptured broncholith, Ca.
• Pneumothorax lt1 hospitalised pts
• Rupture of a peripheral cavity/ subpleural
  caseous focus
• Bronchiectasis Secondary gt 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

41
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

42
Case 2 (Presented outpt on 10/8/2008)

• 62 yo Nigerian lady, visiting US to celebrate her
  grandchilds 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...

43
CT LS showing vertebral degeneration
44
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?

45
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.

46
Potts 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

47
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, Potts paraplegia

48
Diagnosis

• PPD ve in gt90 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)

49
Treatment

• Medical same as Pulm TB (usually 9 mths) must
  include Rifampin
• Surgery indiactions
• Worsening or advanced neurological deficits
• Kyphosis gt40
• Chest wall cold abscess
• Normal SEP,MEP more likely to recover at 6 mths

50
Case 3 (Presented to outpt on 5/31/06)

• 33 yo male was referred to TB clinic for rt neck
  swelling/nodule. PPD positive gt20 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.
51
CT neck with iv contrast
18 mm SubmanibuarLAN
52
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?

53
TB LAN

• Median age
• Developing children (4.4 /1000 in lt14yrs)
• 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
• Cervicalusually reactivation/tonsils/adenoids or
  Waldeyers ring
• Mesentric infected milk/sputum
• HIVve gen infection/miliary

54
TB-LAN D/D

• HN Malignancy
• HL , NHL
• NTB
• Cat scratch
• Fungal
• Sarcoidosis
• Bacterial LAN
• Kikuchis disease

55
Diagnosis

• PPDve 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 lt10 , mostly if miliary TB
• CT, MRI in case of intarabdominal/thoracic

56
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 lt3.5

57
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

58
HIV-MTB

• CD4 gt350 manifests same as non HIV
• Lower CD4 ? rates of extra pulm TB
• CD4 lt 50 diffuse LAN, pleuritis, meningitis,
  pericarditis, dissemnation, bacteremia
• Sputum smear negative with ve cultures
• Delayed diagnosis
• Increased mortality

59
CXR

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

60
Lab testing for MTB in HIV

• PPD
• Considered ve at 5mm
• CD4 lt200 ? only upto 20 PPD ve
• Ig G Release Assays (IGRA)
• Sensitivity falls with CD4 (same as PPD)

61
MTB related IRIS in HIV

• Can be severe and prolonged (months) and even
  fatal
• Incidence 8-43, mostly in advanced HIV (CD4
  lt35, VL gt500k)
• 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)

62
MTB and HIV Timing of Rx

• Patients already on HAART when TB is diagnosed
  should continue on HAART
• For 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?

63
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)

64
Current Recommendations

• CD4 gt 350? Delay HAART at least 8-24 weeks or to
  end of Rx
• CD4 100-350? Delay HAART at least 8 weeks
• CD4 lt 100? Delay HAART 2 weeks

65
XDR-MTB and HIV
65

• 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

66
HIV and MTB Co-Infection Key Points
66

• 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

67
Thank you.