Tuberculosis Chris Spitters, MD/MPH PHSKC TB Clinic

Tuberculosis

Chris Spitters, MD/MPH

PHSKC TB Clinic

Objectives

• Review basics of evaluation and initial management of TB suspects

• Describe relevant lab services for TB• Describe local epidemiology and

structure for working with PHSKC TB Control on TB cases

• Case studies touching on common problems in TB management

Case 1

• 24 y/o Tibetan arrived 12 months ago

• Cough, sputum, fever, night sweats, weight loss

• No prior TB treatment history

Criteria for Isolating Hospitalized TB Suspects and Cases

• Pulmonary TB suspected and AFB smears (x 3)* pending or positive

• Smears* negative but intend to treat for pulmonary TB and patient has received <2 weeks of therapy

• Includes pleural TB suspects with negative smears and <2 weeks treatment

• Following significant interruptions in treatment until smears negative and back on therapy x2 weeks

*ideally qAMx3, but at least 8 hours apart

Case 1--Laboratory Results

• Sputum smear 4+

• Normocytic anemia (Hgb 9, MCV 81)

• Albumin 2.8

• HIV negative

• CBC/CMP otherwise negative

• HBsAg neg, HCV neg

Questions

• Any further testing needed?

• Should he be hospitalized?

• Should treatment be started?

• With what?

• What else do you need to do?

Baseline Diagnostic Examinations for TB

• Chest x-ray• Sputum specimens

– AFB smear, culture, and susceptibilities– nucleic acid amplification (MTD)

• Extrapulmonary specimens– chemistry and cell count and cytology on fluids– Routine pathology – AFB stain/smear and culture – PCR– Special studies: ADA, molecular beacon

• PPD,CBC with differential, CMP, HIV, HBsAg, anti-HCV, visual acuity/color vision

Douglas Moore, unpublished

NAA

AFB

Liquid media

Solid media

Mycobacteriology FlowSpecimen

AFB smear/stain PCR/MTD

Broth and plate cultivation

rRNA hybridization

M. tuberculosis complex M. avium complexM. gordonae

Other MOTT

Broth sensitivitiesfor SIRE & Z Plate confirmation/proportional method

SIREZ and key second line drugs

Questions

• Any further testing needed?

• Should she be hospitalized?

• Should treatment be started?

• With what?

• What else do you need to do?

Criteria for Hospitalizing TB Patients

• Severe illness (e.g., resp distress, altered mental status, unstable vital signs, inanition, etc.)

• Nowhere to go– Homeless/quasi homeless– Vulnerable population at home– Congregate setting (e.g., LTCF, jail)

Questions

• Any further testing needed?

• Should he be hospitalized?

• Should treatment be started?

• With what?

• What else do you need to do?

Spontaneous mutations develop as bacilli proliferate to >108

Drug Mutation Rate

Rifampin 10-8

Isoniazid 10-6

Pyrazinamide 10-6

INHRIFPZA

INH

Drug-resistant mutants in large bacterial population

Multidrug therapy: No bacteria resistant to all 3 drugs

Monotherapy: INH-resistant bacteria proliferate

INHRIF

INH

Spontaneous mutations develop as bacilli proliferate to >108

INH mono-resist. mutants killed, RIF-resist. mutants proliferate MDR TB

INH resistant bacteria multiply to large numbers

Drug Resistance:Contributing Factors

• Monotherapy• Inadequate dosing• Malabsorption • Heavy bacillary load• Frequent treatment interruptions

– Non-adherence– Intolerance-based interruptions

HR

ZE

S

MOST COMMON REGIMENS• Standard

– 2 HRZ(E)5-7 + 4-7 HR2

– 0.5 HRZ(E)5-7 + 1.5 HRZ(E)2 + 4-7 HR2

• Alternative regimens– 6RZE– 9HR– 12RE(+/-MOXI)– 18HE– 2HZSE + 7HZS

Questions

• Any further testing needed?

• Should he be hospitalized?

• Should treatment be started?

• With what?

• What else do you need to do?

Public Health Responsibilities

• Notify the local TB control program by telephone within 24 hours of suspicion of TB.

• PHSKC TB Control: (206) 744-4579

• Treatment and discharge plans must be approved by the TB Control Officer

• TB Control usually needs 48 hours

General Criteria for Hospital Discharge

• Medically stable (and tolerating anti-TB therapy if started)

• Other acute medical problems addressed• DOT, case management, and clinical follow-

up arranged• Adequate housing and, if necessary, home

care• Household contacts <5y/o or

immunosupressed have been addressed

Directly Observed Therapy

Chaulk CP, et al. JAMA 1998;279:943

•Preferred for all cases when resources permit•King County DOT prioritization:

•Pulmonary involvement•HIV+•Homeless•EPTB with adherence problems

Case 1--Follow-up

• She was placed on 4 TB drugs (INH, RIF, EMB, PZA).

• Discharged back to place of residence• No high risk contacts• 4 wks into therapy, symptoms

unchanged• Still 4+ AFB in sputum

ONE MONTH INTO THERAPY

Case 1--Sensitivity Results

• Broth sensitivities return: IRES resistant; PZA and plates with first and second-line drugs pending

• What now?

Keys to MDR Management• Use any first line drugs available• Injectable• Fluoroquinolone• If not on ≥4-5 effective drugs, add one or more of the

following:– Ethionamide– Cycloserine– Para-aminosalicylate

• Repeat sensitivities• Continue injectable for 6 months and oral drugs for

18-24 months post-sputum culture conversion.• Consider referral for surgical excision

Case 1--Expanded Regimen

• Started capreomycin, moxifloxacin, cycloserine and PAS

• Severe nausea and anorexia with normal LFTs--switched PAS to ethionamide

• Depression/anxiety--SSRI started• Hypothyroid--T4 started• Final susceptibilities

– 100% res: INH, RIF, PZA, Strep, amikacin– Partial resistance: EMB, PAS, capreomycin– 0% res: ofloxacin, ethionamide, cycloserine

1 MONTH AFTER REGIMEN CHANGE

2 MONTHS AFTER REGIMEN CHANGE

Case 1

• Cultures converted 2 months after expanded regimen started

• Capreomycin discontinued 6 months later

• MOXI, CS, ETA, EMB discontinued p 24mos

• Residual RUL fibrosis• Now under surveillance x24 months

6 MONTHS AFTER CULTURE CONVERSION

15 MONTHS AFTER CULTURE CONVERSION

END OF THERAPY

Local Epidemiology of TB

Tuberculosis Epidemiologic Profile, 2006; WA DOH

Tuberculosis Epidemiologic Profile, 2006; WA DOH

Tuberculosis Cases Washington State 2006

Tuberculosis Epidemiologic Profile, 2006; WA DOH

Tuberculosis Case RatesKing County 2001-07

0

20

40

60

80

100

120

140

160

180

2001 2002 2003 2004 2005 2006 2007012345678910

CASESKC RATE

PHSKC TB Control Program

*

*King County

King County

0

1

2

3

4

5

6

7

8

MarMayJulSepNovJanMarMayJulSeptNovJanMarMayJulSeptNovJanMarMayJulSeptNovJanMarMayJulSeptNovJanMarMayJulSeptNov

Non-outbreak strain Outbreak strain Clinical case Genotype pending

No

. C

ases

Homeless TB in King County by Treatment Start Date

2002

Treatment Start Date

2003 2004 2005 2006 2007

Horsburgh, NEJM 2004

Case 2

• 43 y/o US born, homeless male

• Fever, chest pain, neck swelling, nausea, and anorexia for about 3 weeks

• HIV positive since 1998

• Not on ARV therapy

Laboratory Findings

• Sputum AFB smears negative• Pleural and peritoneal fluid: lymphocytic

exudate, AFB smear negative• Cervical LN: necrotizing granulomata/AFB-• Mild normocytic anemia (HCT 36)• Mildly elevated transaminases (ALT 72, AST

62); T. bili 1.7, AP 344; • HCV neg; HBsAg/HBcIgM neg• CD4 73; VL 68K

Case 2: Questions

• TB treatment?

• HIV issues– What should you start right now?– When would you consider starting ARVs?– Assuming ARV naïve, what ARV

regimen(s) would you consider?

WHO GUIDELINES ON ART DURING TB THERAPY

CD 4 COUNT ART TIMING

<200 YES 2-8 WEEKS

200-350 YES ≥8 WEEKS

>350 DEFER POST RX

UNKNOWN ART 2-8 WEEKS

WHO 2007. Tuberculosis Care with TB-HIV Co-management.

Keys to TB-HIV Co-management from the TB Control Perspective

• Communication between TB Clinic and Madison Clinic

• EFV + 2NRTI preferred when feasible and clinically appropriate

• Avoid other NNRTI- and PI-based regimens• Reinforce INH/RFB 150 TIW regimens with

EMB when there is any question about adherence to PI-based regimens

• Rifamycin-free regimens a last resort

Case 3

• 54 y/o Vietnamese male moved to US 2003

• Right neck swelling x 4 weeks

• Denies other symptoms

• Failed to respond to 7d course of amoxicillin

Case 3

• Right neck FNA shows necrotic debris, AFB smear negative

• PPD 22 mm

• What do you do?

• What is still missing in the work-up?

PHSKC TB Control Program, 2006

Case 5

• 44 y/o Chinese male presents to local ER with several week history of back pain and fever

• Also reports headache

MRI Brain

Spine

Chest

Case 5 (cont’d-2)

• CSF: RBC 1, WBC 93 (76%L), protein 115, glucose 38

• Vertebral aspirate: necrotic debris, AFB smear negative

• LFTs, BUN/Cr normal• CBC: WBC 5.4; Hgb 11.9, plts 192K• HIV EIA & PCR negative

Case 5 (cont’d-3)

• Hospital day 2, patient becomes obtunded with decreased level of consciousness

• Dexamethasone 4mg q6h iv

• IRZE via nasogastric tube

• Phenytoin initiated

• Improves within 48 hours

ATS 2003

Case 4 (cont’d-4)

• Hospital day 6

• ALT 487, AST 236, T. bilirubin 2.3, AP 288

• What do you do now?

Case 4 (cont’d-4)

• IRZE held• Started on cycloserine, moxifloxacin,

amikacin (and ethambutol continued)• Discharged home 3 days later with

normal level of consciousness, ALT 190

Case 4 (cont’d-5)• One week post-discharge follow-up• RX = DOT M-F; packets on wknds• ALT 233• Oral thrush• Palatal lesion (HSV I positive)• Afebrile• HIV RNA negative• Started on nystatin and valacyclovir• Other medications continued (AMK switched

to capreo)

Case 4 (cont’d-6)

• Two week post-discharge follow-up• CC: not too happy with progress • ALT 267• ANC 230 with bands and metamyelocytes• Lymphs 500; platelets and Hgb/HCT ok• Oral thrush persists--can’t eat or drink• Palatal lesion healing slowly

Case 4 (cont’d-7)

• Dilantin discontinued• Three weeks follow-up• ALT 75, ANC 1300• Thrush resolved, oral intake improved• HSV lesion healed• Tinnitus, fails Romberg, drifts with marching

in place, can’t balance on one foot, and 20db increase in hearing thresholds

• Capreo held; cycloserine/moxi/EMB continued

Case 4 (cont’d-7)

• Now 4 weeks into therapy• Tolerates INH restart (INH,CS,MOXI, EMB)• LFT/CBC normal • Brain MRI; decreased edema• Fully sensitive organism recovered from

lumbar vertebral aspirate• Dexamethasone tapered over ensuing 3

weeks

Case 4 (cont’d-8)

• Now 8 weeks into therapy• Rifampin re-introduction tolerated• EMB dc’d• Regimen: INH, RIF, Cs, MOXI• Dexamethasone taper ended 10 days ago• Nausea, vomiting, headache, T 103, wide

based slow gait, frightened

F/U MRI #1 @ 2MONTHS

F/U MRI #1 @ 2MONTHS

F/U MRI #1 @ 2MONTHS

Case 4 (cont’d-9)

• Differential diagnosis?– Treatment failure– Non-TB intracranial process– Paradoxical worsening in wake of steroid

withdrawal

• Management– Dexamethasone resumed– Clinically 90% improved within one week

F/U MRI#2 @ 5 MONTHS

F/U MRI#2 @ 5 MONTHS

F/U MRI#2 @ 5 MONTHS

Case 4 (cont’d-10)• Remains on INH, RIF, CS• F/U brain imaging improved• Dexamethasone tapered over 12 wks• At 9 months into therapy, still has some

fatigue and facial paraesthesiae• Summary

– CNS and spinal TB– Paradoxical reaction--improving– ?PZA induced liver injury--resolved– AMK intolerance--audiovestibular– Phenytoin intolerance-liver injury(?) and

leukopenia

• 12 month course of INH, RIF, CS, MOXI

F/U MRI#2 @ 7 MONTHS

F/U MRI#2 @ 7 MONTHS

F/U MRI#2 @ 7 MONTHS