TB CPG 3rd Edition March 24th 2013
Dr Ong Choo KhoonChest Physician
Hospital Pulau Pinang
Launched 24th March 2013
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World TB Day 2015
“ FIND TB. TREAT TB. WORKING TOGETHER TO ELIMINATE TB”
TB: EPIDEMIOLOGY & INVESTIGATIONS
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OBJECTIVES
• Epidemiology of TB
• Investigations of TB
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TB AS A GLOBAL HEALTH ISSUE
Fig 1: Ten leading causes of death
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World Deaths in millions % of deathsIschaemic heart disease 7.25 12.8%Stroke & other cerebrovascular disease 6.15 10.8%
Lower respiratory infections 3.46 6.1%Chronic obstructive pulmonary disease 3.28 5.8%
Diarrhoeal diseases 2.46 4.3%HIV/AIDS 1.78 3.1%lung cancers 1.39 2.4%Tuberculosis 1.34 2.4%Diabetes mellitus 1.26 2.2%Road traffic accidents 1.21 2.1%
WHO Factsheet 2008
• Among top three causes of death for women aged 15 to 44
• One quarter of all deaths in people living with HIV
• Multi-drug resistant TB (MDR-TB)
• TB death rate dropped 41% between 1990 & 2011
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INTRODUCTION: TB AS A GLOBAL HEALTH ISSUE
Fig 2: Estimated TB Incidence Rate, 2011
Fig 3: Number & Notification Rateof TB Cases, Malaysia 1960 - 2010
Fig 4: Number of TB Cases (2011)
Fig 5: Notification of New TB Cases in Malaysia, 2005 - 2011
Fig 6: Percentage of TB Cases among Children , 0 - 4 yrs & 5 - 14 yrs, 2000 - 2010
TB AMONG NON-MALAYSIANFig 8: Number & Proportion of TB Cases
Among Non-Citizen, 1993 - 2010Fig 9: Foreign Worker Screening & Proportion Unfit due “TB”, 2001 - 2010
MDR TB Year Notified TB Cases
(All Forms)Isolates tested for
DST MDRCases
% MDR (By number of culture positive tested for DST)
2004 15429 5083 13 0.32005 15875 6309 17 0.32006 16665 6386 42 0.72007 16918 6687 41 0.62008 17506 6264 56 0.92009 18102 7137 55 0.82010 19337 6963 51 0.72011 20666 10477 141 1.32012 22710 9722 74 0.8
MDR threat – requires second line drugs which include injection route, longer treatment duration, more drug side effects, hospitalization, increase cost, unfavorable treatment outcome.
Only 1/3 of TB cases tested for DST.
Top 10 Infectious Disease in Malaysia
*Health Fact Sheet, MOH Malaysia 2011** Incidence of Dengue 2012 – 75.8 per 100,000
1. Not achieving WHO estimated incidence case
2. WHO Estimation Notification Rate (NR)– downwards trend
3. Actual NR increasing (CDR 2011: 85%, 2012 :95%)
1. WHO estimated mortality rate (MR) is excluding TBHIV mortality
2. Actual MR : 1990-2011 including TBHIV mortality; 2012 excluding TBHIV mortality.
3. WHO estimated MR – downward trend
4. Actual MR : plateau since 1990
KPI YBMK 2013
• 1) CURE RATE - 85%• 2) CDR (ALL FORMS) – 95%
CDR has improved over the years, contributed by increasing number of diagnosing & treatment centres , other resources including skills and knowledge of health personnel and expansion of services into public health.
TB Burden
inGeneral
Population :77 per 100,000
*HCW- Health Care Worker*DM-Diabetes Mellitus
High Risk Groups
HIGH RISK GROUPS
• Close TB contacts • Immunocompromised patients
• Diabetes mellitus• HIV• Chronic obstructive pulmonary disease• End-stage renal disease• Malignancy• Malnutrition
• Substance abusers & cigarette smokers• Poor people living in overcrowded conditions
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INVESTIGATIONS FOR TB
• Sputum collection
• Lab investigations
• Imaging modalities
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SPUTUM COLLECTION
• Sputum:• At least 2 specimens• At least one early morning specimen
• For patients who are unable to spontaneously expectorate adequate sputum specimens• Sputum induction with nebulised hypertonic
saline• Fiberoptic bronchoscopy with bronchoalveolar
lavage • Gastric lavage
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LAB INVESTIGATIONS FOR TB
• Sputum • Ziehl-Neelsen staining for AFB• Microscopy
• Light emitting diode-based fluorescencemicroscopy (LED FM)
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LAB INVESTIGATIONS FOR TB
• Culture• Drug-susceptibility testing
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LAB INVESTIGATIONS FOR TB
• Molecular Nucleic Acid Amplification Test (NAAT)
• Line Probe Assay (LPA)
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LAB INVESTIGATIONS FOR TB
• WHO policy statement (2011)“commercial serological tests for TB providesinconsistent & imprecise estimates of sensitivity &specificity which can adversely impact patientsafety”
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IMAGING IN TB - CXR
• Chest radiography– primary imaging modality for PTB– can suggest the possibility of the disease (not confirmatory)– hallmark - consolidation with cavitation– can be normal (up to 15%)
• Severity grading– Minimal– Moderate– Advanced
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IMAGING IN TB - CT SCAN
• Computerised tomography (CT) • endobronchial spread, lymphadenopathy, pleural
complication• high clinical suspicion of TB with normal CXR
• HRCT
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IMAGING IN TB - MRI
• In special circumstances (children & pregnant women)
• Better soft tissue characterisation
• Pleural & lymph node complications
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TAKE HOME MESSAGE
• TB is prevalent in Malaysia
• High risk groups* should be considered to be screened for active tuberculosis
• Sputum culture is diagnostic for TB
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TREATMENT OF TBIN ADULTS
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TB IS AN ANCIENT DISEASE
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INTRODUCTION
• Important to provide a standardised TB regimen for all TB cases
• This section will cover all aspects of treatment:– New cases– Previously treated cases– Standard regimens & duration– Extrapulmonary TB (EPTB)– Adverse drug reactions (ADRs) & Multidrug-
resistant (MDR-TB)39
NEW CASES
• 6-month regimen consisting of 2 months of EHRZ (2EHRZ) followed by 4 months of HR (4HR) is recommended for newly-diagnosed PTB.
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MAINTENANCE PHASE
• In new patients with PTB, WHO recommends daily dosing throughout the course of antiTB treatment.
• However, a daily intensive phase followed by thrice weekly maintenance phase is an option provided that each dose is directly observed & patient has improved clinically.
• A maintenance phase with twice weekly dosing is not recommended.
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RECOMMENDED ANTITB DRUGS
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DRUG
RECOMMENDED DOSES
Daily 3X a week
Dose (range) in mg/kg body weight
Maximum in mg
Dose (range) in mg/kg body weight
Maximum in mg
Isoniazid (H) 5 (4 - 6) 300 10 (8 - 12) 900Rifampicin (R) 10 (8 - 12) 600 10 (8 - 12) 600Pyrazinamide (Z)
25 (20 - 30) 2000 35 (30 – 40) 3000
Ethambutol (E)
15 (15 - 20) 1600 30 (25 – 35) 2400
Streptomycin (S)
15 (12 - 18) 1000 15 (12 – 18) 1500
IMPORTANT POINTS
• Rifampicin should be used for whole duration of treatment.
• No significant difference in effectiveness & safety between rifampicin & other antibiotics in rifamycin group.
• Whenever possible, rifampicin dosage should not be lower than recommended dosage (8 - 12 mg/kg).
• Pyrazinamide beyond 2 months during intensive phase did not confer further advantage if organism is fully susceptible.
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PREVIOUSLY TREATED CASES
• New cases who have taken treatment for more than 1 month & are currently smear or culture positive again (i.e. failure, relapse or return after default)
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TREATMENT
• Recommend: retreatment regimen containing first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR-TB in these patients or if such data is not available.
• Drug sensitivity test (DST) must be done for patients. When results become available, drug regimen should be adjusted appropriately.
*This is WHO statement, no retrievable evidence available.
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TO START OR NOT?
• Interruption in intensive phase:– If ≥14 days, to restart from beginning i.e. Day 1– If <14 days, to continue form last dose
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TO START OR NOT?
• Interruption in maintenance phase:– If interruption occurs after patient receives 80% of total
planned doses, treatment may be stopped if sputum AFB smear was negative at initial presentation. If sputum AFB smear was positive, treatment should be continued to achieve total number of doses.
– If total doses <80% & interruption lapse is ≥2 months, restart treatment from beginning.
– If total doses is <80% & interruption lapse is <2 months, continue treatment from date it stops to complete full course.
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OPTIMAL DURATION
• Patients with sputum positive PTB should receive antiTB drugs for a minimum duration of 6 months.
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FIXED-DOSE COMBINATIONS (FDC)
• FDCs are preferred to separate-drugs combination for treatment of TB.
• In patients who develop toxicity, intolerance
or contraindication to specific component drugs, FDCs can be substituted with separate-drug regimens.
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DIRECTLY OBSERVED THERAPY (DOT)
• When possible, DOT, either by healthcare worker or family member, should be adopted to improve compliance in TB management.– patient-centred, incorporating negotiations, &
patient’s characteristics & preferences
• Reminder system for clinic appointments should be encouraged.
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DOT
• Prompt reminders should be sent to TB patients who default treatment. Failing that, home visit by healthcare workers should be carried out.
• Contact tracing should be done intensively, including home visits to retrieve contacts who do not come for screening.
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EPTB
• All EPTB should be treated with antiTB treatment for a minimum of 6 months except for bone (including spine) & joint TBs for 6 - 9 months & TB meningitis for 9 - 12 months.
• Streptomycin should be used instead of ethambutol in adult TB meningitis.
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STEROIDS IN EPTB
• Corticosteroids should be used in TB meningitis or pericarditis.
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TB TREATMENT IN LIVER & KIDNEY IMPAIRMENT
• The more unstable or severe the liver disease is, the fewer hepatotoxic drugs should be used.
• Various alternative regimes are described in detail.
• Recommendations for renal impairment & failure are also mentioned.
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Regimes for Liver Failure• 2 hepatotoxic drugs :
– 9 months INH & Rif + ethambutol until INH Resistance ruled out.
– 2 months SHER then 6 HR– 6-9 months ERZ
• One hepatotoxic drug– 2 SHE then 10 EH
• No hepatotoxic drug– 18-24 SE + flluoroquinolones.
Regimes for Kidney failure
• Significant renal excretion of Ethambutol & PZA metabolites.
• Thus for renal failure same dosage per weight but at 3 X a week.
• All 4 anti-Tb drugs to be given after haemodialysis.
• Avoid SM.
ADVERSE EVENTS
• Anti-TB drugs are notorious for adverse events.
• Main side effects are drug induced rashes & drug induced hepatitis. Detection & management of these ADRs including algorithms are explained in detail.
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Skin reaction
• Discontinue if severe• Reintroduce sequentially to identify culprit
drug.• Must include both INH and RIF.• If reaction due to RIF and INH, then only
consider desensitisation.
Drug induced hepatitis
• Discontinue– ALT > 3 X with symptoms– ALT > 5X without symptoms.
• Restart when ALT recovers and symptoms resolve.
• Timing of restarting depends on many factors.
Regimen for DIH• SHE / SRE• SHER• SEF• SEFH / SEFR• SEFHR
• Basically remove PZA and hope for the best• If PZA is removed, KIV increase total duration to 9
months.• Liver transplant may be required if severe DIH.
LATENT TB INFECTION (LTBI)
• LTBI should be diagnosed based on absence of symptoms, normal/static CXR findings & positive tuberculin skin test (TST)/interferon-gamma release assays (IGRA) .
• LTBI screening should only be performed on high risk individuals.
• TST should be used as the preferred test in diagnosing LTBI.
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LATENT TB INFECTION (LTBI)
• IGRA could be used as an alternative test for LTBI especially in certain situations.
• If LTBI testing is inconclusive, patient should be referred to a specialist with experience with TB management.
• Patients with LTBI may be offered treatment.
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TST POSITIVE READINGS
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MDR-TB
• In Malaysia, 1.3% of all cultures performed was confirmed to be MDR-TB in 2011.
• Incidence is increasing worldwide, in some parts at alarming rates.
• Detection & principles of management of MDR is included. However, MDR must be referred to a respiratory physician with experience in such cases.
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General Principles In MDR Rx
• Fluoroquinolone (levo or moxi)• Ethaniomide• Injectable (kanamycin or amikacin)• PZA• Either cycloserine or PAS• May be used : Ethambutol, linezolid,
clarithromycin, imipenam, amoxycillin/clavulanate.
Monitoring and duration
• Injectable is for 8 months• Total duration is 20 months• Monthly sputum d/s and cultures until
conversion.• Then 3 monthly smears and cultures.
SURGERY IN TB
• Diagnosis & obtaining tissue for culture & drug sensitivity
• Management of TB complications
• Treatment of the disease itself where drug therapy alone may be deemed insufficient to achieve cure
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MAIN CHANGES IN CPG 2012
• Evidence-based
• Treatment regimes (maintenance) has been changed to daily or 3X a week
• Treatment after interruption is explained in more detail
• Duration of treatment for EPTB more concise– Use of steroids recommended for TB meningitis &
pericarditis
• DOT is covered in more detail & done to suit Malaysian context
• FDCs is mentioned 68
TAKE HOME MESSAGE
• Stick to standard regimen, following proper doses & duration, ensure adherence
• However often treatment needs to be individualised, please consult a physician with experience in treatment
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TB-H V Co-infection
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TB & HIV: A DEADLY HUMAN SYNDEMIC
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TB is one of the leading TB is one of the leading causes of death among HIV causes of death among HIV patientspatients
TB- H V INTERACTION
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HIV infection accelerates the development of TB from
infection to advanced disease
TB depletes the CD4 count & intensifying the
immunodepressant effect of HIV
TB- H V INTERACTION
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• HIV-positive patients have more than 2X risk of primary MDR-TB.1,2
• Risk of mortality is 2.6X higher in HIV-positive patients who develop TB compared to those who do not.3
1Conaty SJ et al., Epidemiol Infect, 2004 2Suchindran S et al., PLoS ONE, 20093Straetemans et al., PLoS ONE, 2010
TB- H V INTERACTION
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Both PTB & EPTB (2.7 - 3.0%)
PTB (44.0 - 79.5%) EPTB (14.0 - 18.8%)
Zhou J et al., BMC Infect Dis, 2009
DIAGNOSTIC CHALLENGES
Many HIV-TB co-infected patients:• Have no cough & negative sputum
AFB smears• Have lower AFB { } in sputum
– AFB density in sputum decreases with decreasing CD4
• Have normal CXR even in culture-confirmed PTB
• Have less cavitary disease on initial CXR
TB CULTURES
• Sputum/BAL TB cultures should be obtained in all TB suspects with a normal CXR, particularly HIV-positive persons.1
• Any biopsy specimen from extrapulmonary sites should be sent for TB culture.
761Pepper T et al., Int J Tuberc Lung Dis, 2008
ANTITB FOR TB-H V CO-INFECTION
• Require prompt initiation of TB treatment1
• Treatment complicated by higher rate of TB relapse & increased mortality rate during treatment
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1 Panel on Antiretroviral Guidelines for Adults and Adolescents
ANTITB FOR TB-H V CO-INFECTION
• 6 month regimen consisting of1,2 – 2EHRZ / 4 HR when the disease is caused by organisms that are
known or presumed to be susceptible to the first-line drugs
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1Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, CDC2Blumberg HM et al, ,Am J Respir Crit Care Med, 2003
ANTITB FOR TB-H V CO-INFECTION
• Prolong the continuation phase if:-– there is a slow or suboptimal response (e.g. cultures are still positive after 2 months of therapy) – patients with EPTB
• All HIV patients should receive DAILY TB treatment in maintenance phase.
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DAILY TX
RIFAMYCIN & ANTIRETROVIRAL (ARV) DRUGS
• Regimens in which rifampin is only used for the first 2 months higher rates of Rx failure & relapse1
• Rifamycin = Rifampin (rifampicin) + rifabutin*
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o Potent inducer of CYP450o Significant interactions with PIs
o A weaker enzyme inducer o Much less drug interaction with ARVso As effective as rifampicin1Jindani A et al., Lancet, 2004
*Not registered in Malaysia
RIFAMYCIN & ANTIRETROVIRAL (ARV) DRUGS
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*Not registered in Malaysia
Latent TB
Active TB
Risk of TB reactivation
Lifetime risk 5 - 10%
Annual risk of TB reactivation
5 - 10%1
1Narain JP et al., Tuber Lung Dis, 1992
CONCERN OF TB REACTIVATION
ISONIAZID PROPHYLAXIS THERAPY (IPT) FOR H V INFECTED PATIENTS
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ANTITB + HAART = SURVIVAL
• Highly Active Antiretroviral Therapy (HAART) during TB treatment1
o protective against mortality o result in earlier conversion of sputum & cultures
to negative
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1Nahid P et al., Am J Respir Crit Care Med, 2007
TIMING OF HAART
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CD4 count (cells/µl)
Timing of HAART initiation
<50 2 weeks after starting intensive phase of antiTB treatment
>50 but <350
After completion of intensive phase of antiTB treatment
>350 Continue antiTB treatment & monitor CD4. Commence HAART if CD4 drops <350 cells/µl.
ANTIRETROVIRAL REGIME
• Nucleoside Reverse Transcriptase Inhibitors (NRTIs): No clinically significant interactions with rifampicin
• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Efavirenz is preferred
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IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)
• An augmented inflammatory response occurs in patients started on HAART & antiTB
• Occurs within 3 months of TB Rx after starting HAART
• Major manifestations of IRIS are fever & lymphadenitis1
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1Dibyendu D et al., Braz J Infect Dis 2011
CO-TRIMOXAZOLE (CTX) PROPHYLAXIS IN TB-H V CO-INFECTION
• Associated with a 21% reduction in all cause mortality1
• Generally safe & well-tolerated1,2
• Should be initiated as soon as possible & given throughout TB treatment3
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1Nunn AJ et al., BMJ, 20082Boeree MJ et al., Trop Med Int Health 20053 WHO, 2010
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Follow up, Referrals
and Prevention
CONTENTS
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• How to follow up newly diagnosed PTB patients
• When to refer to specialists• Prevention of TB
FOLLOW UP
• All patients on anti-TB treatment should be monitored to assess their response to treatment and to identify problems associated with it.
• All patients should be aware of symptoms indicative of PTB and adverse drug reactions
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NEW PATIENTS WITH PTB
• WHO recommends daily dosing throughout the course of anti-TB treatment.
• A daily intensive phase followed by thrice weekly maintenance phase is an option.
• A maintenance phase with twice weekly dosing is not recommended since missing one dose means the patient receives only half the total dose for that week.
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MALAYSIAN CPG TB 2002
• Follow-up was recommended at two, four and six months during treatment. Sputum smear and chest radiograph were recommended to be done during each follow-up clinic visit.
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MALAYSIAN CPG TB 2012
• Follow-up was recommended at two, four and six months during treatment
• In order to detect early adverse drug reactions and to enhance compliance, follow-up within one month of starting treatment is advisable.
• Sputum smear and chest radiograph should be done at two and six months if patient is clinically improving.
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FLOW CHART
FOLLOW UP
• Patients with initial sputum smear negative should have repeat sputum smear at two months of anti-TB treatment. If still negative, no further sputum sample is required.
• If sputum smear remains positive at 2 months, refer to specialists with experience in TB management and repeat sputum AFB and sputum MTB C&S at three months.
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FOLLOW UP
• Patients with initial sputum positive should have repeat sputum smear at two and six months of anti-TB treatment
• Patients who remain sputum smear positive should be referred to specialists with interest in TB management
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COMPLETION OF ANTI-TB TREATMENT
• Follow up clinic visits should not be conducted routinely after treatment completion.
• Patients should be told to watch for symptoms of relapse and how to contact the TB service rapidly through primary care or a TB clinic.
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WHEN TO REFER
• Unsure of TB diagnosis• Retreatment of TB• Adverse events following anti-TB drugs• MDR and EDR TB• Extra-pulmonary TB except TB
lymphadenitis• Renal and/or liver impairment with TB
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WHEN TO REFER
• HIV-TB co-infection• Smear negative TB• Smear positive TB after 2 months of anti-
TB treatment• All children diagnosed as TB• Maternal TB• Complex TB cases requiring surgical
intervention100
PREVENTION
The primary emphasis of TB infection control plan should include:•Prompt detection of infectious patients including screening•Airborne precautions•Treatment of people who have suspected or confirmed disease
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SCREENING OF TB CONTACTS
• Screening of TB contacts is important among those exposed to patients with PTB for early detection of TB and to reduce transmission.
• Index TB patients include both smear positive and negative cases
• Contacts with diabetes are at higher risk of getting TB especially in the first 3 months compared to those without diabetes
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RECOMMENDATION
Screening for TB should be done among all close contacts (especially household contacts) and high risk groups
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CONTACT TRACING
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INVESTIGATIONS FOR CONTACT TRACING
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SCREENING TESTS FOR CONTACTS AND HIGH RISK GROUPS
TB screening tests are used to identify those most likely to have either an active disease or LTBI. TB screening should be targeted at high risk population.•CXR•TST•IGRA
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TB PREVENTION STRATEGIES FOR HCW
• Healthcare workers (HCWs) are exposed to patients with TB and are at risk of nosocomial infection.
• A TB program should not only emphasize on detection and treatment but also on preventive measures of TB at the workplace.
• In a meta-analysis of 14 studies in low-and middle-income countries, the pooled prevalence of LTBI among all HCWs was 54%
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RECOMMENDATION
•All health care facilities should have administrative, engineering and personal protective measures in place to reduce tuberculosis occupational risk of health care workers.
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TAKE HOME MESSAGE
• All patients on anti-TB treatment should be monitored to assess their response to treatment and to identify problems associated with it.
• WHO recommends daily dosing throughout the course of anti-TB treatment.
• Screening of TB contacts is important among those exposed to patients with PTB for early detection of TB and to reduce transmission.
• Healthcare workers (HCWs) are exposed to patients with TB and are at risk of nosocomial infection.
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THANK YOU
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