Far-advanced pulmonary tuberculosisp y

P bli h lth li i l d b i di iPublic health, clinical and basic medicine

胸腔病院 趙文震醫師胸腔病院 趙文震醫師

2010/09/252010/09/25

.

50 y/o male; worker Cough 11 months

30 y/o male; Trunk driver Cough 6 months

43 y/o male; sales in the marketCough 8 months

1.Public health : Delay diagnosis condition and why ?

BWL 10 kgs, DM(+) BWL 11kgs BWL 9 kgs

2.Clinical medicine: Expected Tx response? Tx: guideline only ?

3.Basic medicine: Biomarker for severity and cavitation ? Is DM important?

3

Public health :Public health : Delay diagnosis condition and why ?

Clinical medicine:Expected Tx response? Tx: guideline only ?Expected Tx response? Tx: guideline only ?

Basic medicine: Biomarker? Why BWL? DM and TB?

A systematic review of delay in the diagnosis and treatment of tuberculosis

BMC Public Health. 2008 Jan 14;8:15

Patient and health system delays in the diagnosisPatient and health system delays in the diagnosis and treatment of tuberculosis in Southern Taiwan.

Chiang, C-Y.1; Chang, C-T.2; Chang, R-E.3; Li, C-T.2; Huang, R-M.2

Int J Tuberc Lung Dis. 2005 Sep;9(9):1006-12.Int J Tuberc Lung Dis. 2005 Sep;9(9):1006 12.

CONCLUSION: Patient delay was substantially shorter thanPatient delay was substantially shorter than

health system delay.

To reduce health system delay clinics needTo reduce health system delay, clinics need to be involved and the referral mechanism must be strengthened.

Physicians should maintain high alert for TB and perform prompt sputum smear examinations

Should “clinics” be blamed?Should clinics be blamed?

Economy : 66 NT/3daysEconomy : 66 NT/3days

CXR : E i ?CXR : Equipment ?

Sputum exams : Stigmata of TB ?

Patient factors ?H l h ki b h iHealth care seeking behaviors

In far-advanced TB patients, delay diagnosis is a serious problem, p , y g p ,and health care seeking behaviors education should be intensified.

Public health : Delay diagnosis condition and why ?Delay diagnosis condition and why ?

Clinical medicine:Clinical medicine:Expected Tx response? Tx: guideline only ?Tx: guideline only ?

Basic medicine:Basic medicine: Biomarker? Why BWL? DM and TB?

Expected Tx response 65 y/o female CC :Cough and body weight loss for 1 year

p p

CC :Cough and body weight loss for 1 year(15kgs within one year) ( Housewife)

Past historyPast history 1.DM 2009/04 HbAlC 5.6 2.HBV carrier 3.HTN 4.Osteoporosis

** 2009/01 :AFS 4+,TB-PCR = positive** HERZ from 2009/01

2009/05 = AFS 3+ 1.Treatment failure ? 2.Add 2nd line medication ?

Sputum smear and culture conversion proportion over time

2009/01 2009/05 2009/092009/01 2009/05 2009/09 AFS 4+ AFS 3+ AFS (-)

Culture : MTB ,all S Culture (-) Culture (-)

In far-advanced PTB, slow treatment response is expected and S(+)C(-) is common between 2nd to 5th months after treatment.

Treatment : HERZ*2M + HER *7Treatment : HERZ 2M + HER 7

Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-times weekly regimens for smear-positive pulmonary tuberculosis including an assessment of aregimens for smear positive pulmonary tuberculosis, including an assessment of a

combined preparation of isoniazid, rifampin, and pyrazinamide.

Am Rev Respir Dis 1991;143:700 706Am Rev Respir Dis 1991;143:700–706

(Randomized trial performed in Hong Kong)(1 386 Chinese patients with AFS (+))

Tx failure Relapse (30M) Relapse (30M)

(1,386 Chinese patients with AFS (+))

Combination Separate

H6,R6,Sm4,Z2 0% 3% (2/71) 3% (4/149), , , ( ) ( )

H6,R6,Sm4,Z4 0% 3% (2/72) 6% (8/133)

H6 R6 S 4 Z6 0% 6% (4/66) 1% (2/142)H6,R6,Sm4,Z6 0% 6% (4/66) 1% (2/142)

H6,R6,Z6 2%(4/224) 9% (6/64) 4% (6/135)

Reasonable duration of PZA RIFINHINHSm

PZA

PZA for 6 months may be reasonable in far-advancedPZA for 6 months may be reasonable in far advanced pulmonary TB, but needs evidence to prove it.

Public health : Delay diagnosis condition and why ?Delay diagnosis condition and why ?

Clinical medicine:Clinical medicine:Expected Tx response? Tx: guideline only ?Tx: guideline only ?

Basic medicine:Basic medicine: Biomarker? DM and TB?

Public health : Delay diagnosis condition and why ?

Clinical medicine:Expected Tx response? Tx: guideline only ?

Basic medicine: Bi k f TBBiomarker for TB : Macrophage/CavitationDM and TB.

Neopterin : Marcrophage marker

Immune response associated production of neopterin. Release from macrophage primarily under control of interferon-gammafrom macrophage primarily under control of interferon-gamma.

J Exp Med 1984; 160: 310–316

P l it i d t i l ti ith ti l dProcalcitonin and neopterin correlation with aetiology and severity of pneumonia.

J Infect. 2006 Mar;52(3):169-77.

The diagnostic values of serum pleural fluid and urineThe diagnostic values of serum, pleural fluid and urine neopterin measurements in tuberculous pleurisy.

Int J Tuberc Lung Dis. 2005 Sep;9(9):1040-5.

Serial evaluation of serum neopterin in HIV pseronegative patients treated for tuberculosis

Int J Tuberc Lung Dis. 2001 Feb;5(2):185-90.

Serum neopterin level in PTB patients

(Raw data at Chest hospital)

Biomarkers for cavitationBiomarkers for cavitation

PAI-1 = Plasminogen activator inhibitor-1 g

Inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA)Physiological role hypercoagulationPhysiological role = hypercoagulation

PAI-1 is associated with increased occurrence of thrombosis (DVT/Stroke/AMI) i b i d h b li din DM, obesity, and the metabolic syndrome.

In inflammatory conditions in which fibrin is deposited in tissues, PAI-1 appears to play a significant role in the progression to fibrosis (pathological formation of connective tissue : tissue remodeling

Serum PAI-1 as a biomarker for cavitation in TB

(Raw data at Chest hospital) ( p )

Protease : more than marker for cavitation

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung gran lomas in micegranulomas in mice

J. Clin. Invest. 2010. 119:33–46

MTB >> Granuloma >> Central necrosis >> Liquefy >> Cavity >> Transmissionq y y

MTB growth controlled

Granuloma pathology is arrested

Caseum mineralization /granuloma calcification

Elevated of PAI-1 in DM angiopathyElevated of PAI 1 in DM angiopathy

DM and TB : Resistin

Resistin was originally described as an adipocyte-derived polypeptide that provided the link between obesity and insulin resistance.

Nature. 2001 Jan 18;409(6818):307-12

R i i i i fl k f th l i i hResistin is an inflammatory marker of atherosclerosis in humans.Circulation. 2005 Feb 22;111(7):932-9

Serum resistin levels in critically ill patients are associated withSerum resistin levels in critically ill patients are associated with inflammation, organ dysfunction and metabolism and may predict survival of non-septic patients.

Crit Care. 2009;13(3)Crit Care. 2009;13(3)

Resistin Inhibits Essential Functions of Polymorphonuclear LeukocytesThe Journal of Immunology, 2008, 181, 3761 -3768 f gy

Serum resistin level in PTB

(Raw data at Chest hospital)

DM and TB

DM

DM and TB

DM

ResistinPAI-1

Insulin resistance Angiopathyg p y

.

Public health : Delay diagnosis condition and why ?

Clinical medicine: Expected Tx response? Tx: guideline only ?

Basic medicine:Basic medicine: Biomarker: Macrophage/Cavitation.DM and TB. d .

Thank you for your attention.

Nutrient markers in chronic inflammatory diseases

Ghrelin (胖素) VS Leptin (瘦體素)

Relation of ghrelin, leptin and inflammatory markers to nutritional status in active pulmonary tuberculosisnutritional status in active pulmonary tuberculosis

Clin Nutr 2010 Aug;29(4)Clin Nutr. 2010 Aug;29(4)

Post-treatment changes of appetite-related “hormones” and “inflammatory biomarkers”“hormones” and “inflammatory biomarkers”

Serum ghrelin in PTB g

(Raw data in Chest hospital)

Tuberculosis and the risk of ischemic stroke: 3 fa 3-year follow-up study.

Sheu JJ, Chiou HY, Kang JH, Chen YH, Lin HC.Department of Neurology, Taipei Medical

Stroke. 2010 Feb;41(2):244-9.