George Alangaden MDProfessor of Medicine

Division of Infectious DiseasesWayne State University

Detroit MI

galangaden@med.wayne.edu

Review factors that can delay diagnosis of TBDiscuss features that suggest “Think TB”Clinical presentationsEpidemiological Correlates

Utility of newer diagnostic tests for effective triage of patients with suspected TB in HCF 

57 yr‐old Malaysian male, resident in USA for 15 yrsAutologous hematopoeitic stem cell transplant for non‐Hodgkin’s lymphomaRelapsed NHL left chest wall, treated with radiationUndergoes allogeneic HSCT for progressive NHLD+17 after HSCT develops fever, no other complaints.Fever responds to empiric cefepimeRe‐admitted after 1 week with fever

Fever resolves with antibiotic therapyRe‐admitted after a month with high fevers and mildSOB 

Lung biopsy fibrosis, reactive changes, possible nuclear inclusions, no lymphoma.

Culture of lung tissue at 4 weeks grows M. tuberculosis.

Total time from onset of symptom to diagnosis of TB = 44 days

Absence of coughOther explanations for feverResponse to empiric antibioticsAFB smear negativeNo granulomas on histopathologyUnderlying conditions that could have caused infiltrates in an immunocompromisedpatient e.g. fibrosis, lymphoma, fungal infection, etc

184 culture+ TB patients, NYC, 1994Type of delay No. days

AFB smear+ AFB smear ‐ P value

Total delay 57 35 79 <0.001

HC P delay* 15 6 31 <0.001

Patient delay 25 NA NA NA

Factors associated with HCP delay Adjusted Odds Ratio

Homelessness 7.1

No CXR at first visit 2.4

Negative AFB smear 10.2

Absence of cough 2.9

Sherman LF Int J Tuberc Lung Dis 1999;3:1088-1095 *HCP = healthcare provider

158 patients TB culture positive, Maryland, 2000‐01Covariate associated with HCP delay Days of delay

Private physician visit /  ED visit / Public Health clinic visit 51 / 18 / 10

CXR done / not done 15 /  69

CXR cavitation / no cavitation 6 / 17

AFB smear + / AFB smear ‐ 18 / 37

AFB culture done / not done 6 / 56

Antibiotics prescribed / not prescribed  39 / 15

Golub JE. Int J Tuberc Lung Dis 2005;9:992-98

183 patients, culture positive TB, London UK20/42 (48%) who got antibiotics had symptom improvement unrelated to drug classMedian time to TB diagnosis >8 weeks in 50% of those who got antibiotics vs zero if no antibiotics

233 patients culture positive for TB, Baltimore, US16/33 treated with fluoroquinolone for suspected CAPMedian time to TB diagnosis 21 days in FQ treated patients vs 5 days in non‐ FQ treated patientsEmergence of resistance to FQ in 11%3

1Craig SE. Int J Tuberc Lung Dis, 2009;13:208-13. 2Dooley KE. Clin Infect Dis 2002;34:1607-12.3Ginsburg AS. Clin Infect Dis 2003;37:1448-52.

Clinical features %

Cough 78

Weight loss 74

Fatigue 68

Fever 60

Night sweats 55

Chills 51

Anorexia 46

Chest pain 40

SOB 37

Hemoptysis 28

Barnes PF, et al. Chest 1988:94:316-320

•188 adults with pulmonary TB, Los Angeles, prospective evaluation

Yr 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Rate 3.6 2.9 3.3 3.2 2.4 2.7 2.5 2.2 2.3 1.9

No. 351 287 330 315 243 272 246 221 226 185

*Rate/100,000 population

http://www.michigan.gov/mdch (accessed June 7, 2010)

National rate 2008 was 4.4 = (12,904 cases)

185 new cases of TB

http://www.michigan.gov/mdch (accessed June 7, 2010)

Recent close or prolonged contact with TB patientPrior inadequately treated TBChest radiographs with features of prior TBImmunosuppression (prednisone>15mg/d/30d) Conditions associated with risk of reactivation 

Diabetes mellitus, silicosisHead and neck cancer, lymphomas, leukemias, ESRD Intestinal bypass, gastrectomyMalabsorption, Low body‐weight

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Adapted from CDC Surveillance Datahttp://www.cdc.gov/tb/statistics/surv/surv2008 accessed 9-10-10

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1993 1996 1999 2002 2005 2008

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WhiteBlack or African-AmericanHispanic

American Indian/Alaska NativeAsian/Pacific Islander

Adapted from CDC Surveillance Datahttp://www.cdc.gov/tb/statistics/surv/surv2008 accessed 9-10-10

No.

of C

ases

Adapted from CDC Surveillance Datahttp://www.cdc.gov/tb/statistics/surv/surv2008 accessed 9-10-10

Mexico(23%)

Philippines(11%)

India(8%)

Vietnam(8%)

China(5%)

Guatemala(3%)

Haiti(3%)

OtherCountries(38%)

Adapted from CDC Surveillance Datahttp://www.cdc.gov/tb/statistics/surv/surv2008 accessed 9-10-10

% C

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n

Adapted from CDC Surveillance Datahttp://www.cdc.gov/tb/statistics/surv/surv2008 accessed 9-10-10

Characteristic National No. cases (%)

Michigan No. cases (%)

Correctional facility 498 (4.1) 5 (2.8)

Homeless 680 (5.7) 12 (6.9)

LTCF 257 (2.1) 11 (6.4)

IDU 212 (1.8) 8 (4.6)

Non‐IDU 858 (7.3) 14 (8.3)

Excess alcohol use 1,577 (13.1) 32 (19)

HIV positive (age 25‐44 yrs) NA (0‐27) 5 (10.6)

Unemployed NA (52.5) NA

HCW NA (3.4) NA

http://www.cdc.gov/tb/statistics/reports/2008 accessed 9-10-10

French registry – 3 year review69 cases of TB in patients receiving inflixamab, adalimumab or etanerceptNone received treatment for LTBI

Agent Incidence ratios for TBInfliximab 18.6Adalimumab 29.3Etanercept 1.8

Tubarch F. Arthritis Rheum 2009;60:1884-94

Wallis RS. Clin Infect Dis 2005;41:S194-8

1NYC (Single Center 1988‐2007)4925 SOTs* – 13 TB cases ‐ Incidence 264/100,000 OR for kidney transplant 4.59Median time to onset of TB after SOT – 11 mo

2Spain (Multicenter 2003‐06)4388 SOTs – 21 TB cases ‐ Incidence 512/100,000RR lung transplant 73.395% occurred <1 yr of SOTMost pulmonary TB

* Solid organ transplants1 Lopez de Castillo. Transplant Infect Dis 2010;12:106-1122 Torres-Cisneros Clin Infect Dis 2009;48:1657-65

Test Time to result

Sputum specimens x 3, 8‐24 hrs apart for AFB microscopy

1‐3 days

Mycobacterial cultures 2‐4 weeks

Drug‐susceptibility testing for INH, RIF, and EMB

4‐8 weeks

Sputum specimens x 3, 8 hrs apart, one specimen early‐morning sample  plusIn house TB lab 24/7

1. Reduction in time to AFB smear status2. Earlier removal of patient from AFB 

isolation

AFB smear microscopy of respiratory specimens:Sensitivity of 45%‐80% in culture positive TBPPV 50%‐80% for TB where NTM is common

NAAT in AFB smear positive cases:PPV of >95% in settings where NTM is common

NAAT In AFB smear negative casesSensitivity is 74% and specificity 94%

Can rapidly confirm MTB in 50%‐80% of AFB smear negative and culture positive respiratory specimens

MMWR. 2009;58:7-10. Dinnes j. Health Technology Assessment 2007:11;1-196.Moore DF. Diagn Microbiol Infect Dis 2005;52:247-54

Varghese G.M. et al. Value of differential identification of MTB and NTM using enhanced amplified mycobacterium tuberculosis direct test (EMTD). ICAAC, 2007, Abstract# D-1573

Test Mean turn around time  P‐value

E‐MTD 1.5   days <0.001

Culture identification 19.9 days

Result Culture Identification – No. specimens

MTB NTM*

E‐MTD positive 42 0

E‐MTD negative 0 20

* M. avium complex=17, M. chelonae=1, M. xenopi=1, M.kansasii=1

Send first AFB smear positive sputum sample to MDCH TB lab for MTB PCR MDCH report of MTB ± status within 24 hr

1. Significant reduction in time to confirmation of TB 

2. Early removal of patient from AFB isolation3. Avoidance of unnecessary empiric TB therapy4. Avoidance of unnecessary contact investigation

Hospital No. AFB Smear  positive

MTB NTM 

A 2 1 1   [MAC]

B 13 2 11 [MAC‐5, MG‐3, MF‐1, MK‐1, MS‐1]

C 12 3 9   [MAC‐3, MG‐3, MF‐1, NA‐2]

Total 27 6 (22%) 21 (78%)

MTB=M. tuberculosis, NTM=non-tuberculous mycobacteria, MAC=M.avium complex, MG=M. gordonae, MF=M. fortuitum, MK=M. kansasii, MS=M. szulgai, NA=Not available

Detroit Medical Center October 2009-August 2010

Liverpool UK, NAAT test also detected rifampinresistance

MTB confirmed or ruled out in <2 weeks in 86% of NAAT tested suspected pulmonary TB cases vs 7% using cultureClinical impact in 39% of 51 patients tested using NAAT▪ 3 patients unnecessary TB treatment stopped▪ 7 patients treatment continued▪ 4 situations contact investigation averted▪ 2 patients  MDR‐TB detected▪ 31 patients at risk for resistance MDR‐TB ruled out 

Taegtmeyer M. Thorax 2008;63:317-321

1151 respiratory specimens/638 pulmonary TB suspected patients, MarylandNAAT – amplified MTB Direct test (MDT) of respiratory specimens compared to non‐MTD use period

Test used

Duration of non‐indicated TB treatment 

NAAT 6 daysCulture 31 days

Guerra RL. Chest 2007;132:946-51

58 patients with AFB smear‐positive on respiratory sample admitted to AFB isolation

Mean isolation time for 5.4 days since use of E‐MTD vs 19 days using culture identification

Estimated cost savings per patient ‐ $6800  

Diagnosis of TB or “Think TB” is a cumulative pathway that includes:Clinical picture Epidemiological factorsRadiographySmear microscopy + NAATCulture

Newer NAATs results in rapid and more effective management of pulmonary TB in healthcare settings