SABAH’S HANDBOOK ON MANAGEMENT OF TUBERCULOSIS IN ADULTS (1st Edition, 2022) By Respiratory Department, QEH & TB and Leprosy Sector, JKN Sabah
Sabah’s Handbook on Management of Tuberculosis in Adults (1st Edition, 2022) By Respiratory Department, QEH & TB and Leprosy Sector, JKN Sabah
Sabah’s handbook on Management of Tuberculosis in Adults was created through a collaboration between Respiratory Department, QEH and TB/Leprosy Sector, JKN Sabah. The views expressed in written materials or publications do not necessarily always reflect the official policies of the World Health Organisation (WHO) and Ministry of Health Malaysia (MOH) Red, Dark blue, light blue and white are used in this handbook to represent all the colours on State of Sabah flag. Permission is granted for nonprofit educational use and library duplication and distribution. Respiratory Department Queen Elizabeth Hospital Kota Kinabalu, Sabah [email protected] TB and Leprosy Sector Sabah State Heath Department Kota Kinabalu, Sabah
Table of Contents Handbook Development Team.......................................................5 Foreword........................................................................................9 Abbreviations................................................................................11 Chapter 1 : Introduction................................................................12 Chapter 2 : Epidemiology & High Risk Groups ............................14 Chapter 3 : Investigations ............................................................17 Chapter 4 : Treatment of TB in Adults ..........................................30 Chapter 5 : Latent TB Infection in Adults......................................40 Chapter 6 : TB in Pregnancy, Lactation & Use of Oral Contraceptive Pills .......................................................................52 Chapter 7 : Pre-existing Liver and Renal Impairment ..................61 Chapter 8 : TB and HIV infection .................................................67 Chapter 9 : Follow Up & Adverse Drug Events ............................76 Chapter 10 : Drug Resistant TB...................................................99 Chapter 11 : Long Term Complications of PTB..........................129 Chapter 12 : Preventions ...........................................................142 Chapter 13 : Referral Criteria.....................................................155 Referrence .................................................................................169
Handbook Development Team Chairperson Dr Muhammad Khairul Taufiq Rosli Physician in Respiratory Department, HQE Advisor Dr Kunji Kannan Sivaraman Kannan Consultant Pulmonologist, HQE Dr Hema Yamini Ramarmuty Consultant Pulmonologist, HQE Dr Huan Nai Chien Consultant Pulmonologist, HQE Members (in alphabetical order) Dr Amabel Seow Min Hui Assistant Director, TB and Leprosy Sector, JKNS Dr Ho Rong Lih Physician in Respiratory Department, HQE Dr Lo Shan Min Physician in Respiratory Department, HQE Dr Roddy Teo Principal Assistant Director, TB and Leprosy Sector, JKNS Dr Shivaanand Letcheminan Physician in Respiratory Department, HQE Dr Subramaniam Ponnuvelu Physician in Respiratory Department, HQE Dr Suzalinna Sulaiman Ex-Principal Assistant Director, TB and Leprosy Sector, JKNS Dr Tang Jeat Thong Physician in Respiratory Department, HQE 5
Co- Contributor (in alphabetical order) Dawn Carmel Paul Science Microbiology Officer, MKAK KK Dr Aini Simon Sumeh FMS, KK Penampang Dr. Chia Shin Tong FMS, KK Luyang Dr Emilina Tan Pei Tzu FMS, KK Menggatal Dr Eric Henry FMS, KK Sook Dr Farah Waheeda binti Ghulam Khan FMS, KK Kinarut Dr Fatin Imthital Adnan FMS, KK Lahad Datu Dr Fazilawati@ Amira Ab.Latiff FMS, KK Telupid Dr George George Mathew FMS, KK Tamparuli Dr Grace Jikinong FMS, KK Tandek Dr Haryati Hamzah FMS, KK Tawau Dr. Jonathan Tan Yuet Han FMS, KK Sungai Manilla Dr. Khor Linghui Amanda FMS, KK Luyang Dr Larry Ellee Ak Nyanti Senior Lecturer & Physician, Universiti Malaysia Sabah Dr Lee Wai Khew Consultant FMS, KK Luyang Dr Leon Min Chiee FMS, KK Telipok Dr Meryl Grace Lansing Senior Lecturer & Physician, Universiti Malaysia Sabah Dr Mirah Papo FMS, KK Tawau Dr Mohamad Zikri Mohamad Isa FMS, KK Tamparuli 6
Dr Mohd Safiee Daud FMS, KK Tawau Dr. Muhamad Faiz Mahayidin FMS, KK Semporna Dr Nadia Hamimah Kamaludin FMS, KK Putatan Dr Ng Yoke Lan FMS, KK Inanam Dr Nicholas M. Jagang FMS, KK Membakut Dr Nik Farah Nik Yusof Fuad FMS, KK Putatan Dr Noreen Ooi Zhi Min FMS, KK Sandakan Dr Norlaily Hassan FMS, KK Lahad Datu Dr Nur Harnani Abdullah FMS, KK Luyang Dr Nurul Akmanidar Zainuddin FMS, KK Penampang Dr Radhiyah Hussin FMS, KK Apas Balung Dr Sarah Jane Chan Jia Chyi FMS, KK Menggatal Dr Sheikh Shariman Sheikh Aminuddin FMS, KK Nabawan Dr Sii Hie Ping FMS, KK Inanam Dr Suhashini Sivasegaran FMS, KK Sandakan Dr Tan Huey Yee FMS, KK Tamparuli Dr Vanessa Rohini Kamalan FMS, KK Tamparuli Ling Corrine Pharmacist, HQE 7
Peer Reviewer Prof Dato' Dr Haji Abdul Razak Abdul Muttalif Senior Consultant Pulmonologist MAHSA University, Kuala Lumpur Dr. Irfhan Ali Hyder Consultant Pulmonologist & Head of Respiratory Service Hospital Pulau Pinang, Pulau Pinang Dr. Mat Zuki Mat Jaeb Consultant Pulmonologist Hospital Raja Perempuan Zainab II, Kelantan Dr. Razul Md Nazri Md Kassim Consultant Pulmonologist Kedah Medical Centre, Kedah Dr. Zamzurina Abu Bakar Consultant Pulmonologist Institut Perubatan Respiratori, Kuala Lumpur Dr Arvindran Alaga Consultant Pulmonologist Hospital Sultanah Bahiyah, Kedah Dr Lee Heng Gee Consultant Infectious Disease Physician Hospital Queen Elizabeth, Sabah Dr Zaiton Yahaya Consultant Family Medicine Specialist Klinik Kesihatan Sandakan, Sabah 8
Foreword The Sabah Tuberculosis (TB) Control Program was started in the year 1961, with the aim of reducing the TB burden of disease and deaths caused by Mycobacterium tuberculosis infection in the community. In 2021, a total of 4,547 cases of tuberculosis were reported compared to 4,469 cases in 2020. Out of this, 3,186 cases (70.1%) were of the contagious form (smear positive pulmonary TB) and 205 (4.5%) of them were among children under 15 years old. About a third of the cases (1,535, 33.8%) were detected among non-citizens who were mostly Filipinos, Indonesians, Pakistanis, Nepalese and Bruneians. The treatment interruption rate was reported at 2.97% and mostly observed from districts with high population density such as Kota Kinabalu, Sandakan and Tawau. 53% of these treatment interrupted cases were among local citizens. We are aware of the challenges faced by the State of Sabah in controlling and treating this disease due to the unique population composition consisting of citizens and stateless population, high socio-economic gradients and geographical structure of the state. These challenges are different from those faced by other states in Peninsular Malaysia, even by our neighbouring state, Sarawak. In that light, a special guideline for the state of Sabah is necessary, and should be used concurrently with the existing guidelines published by the Ministry of Health, Malaysia. The use of these guidelines is expected to strengthen the delivery of health services and TB treatment, based on the resources available in the state, with the hope to achieve the goal of the National TB Control Program to make Malaysia Tuberculosis free by the year 2035. Ybhg. Datuk Dr. Rose Nani Binti Mudin Director Sabah Department of Health 9
Foreword Assalamualaikum and Salam Sejahtera, As a Physician working in Sabah for nearly 5 years, I have visited many district hospitals in Sabah and have realised the uniqeness of each district in Sabah. Having the highest number of tuberculosis cases in Malaysia with issues of limited facilities, human resources and access to direct information, comes the idea of producing a guidebook to help all the doctors and paramedics who are working in the district healthcare centre. Special thanks to all the handbook development team, cocontributor & peer reviewer for making this book a reality. Only God Almighty can repay your kindness. I personally hope that this book will provide you the knowledge and guidance from basics to the common issues and questions that may arise during the management of TB patients. With this book, I believe that it will ease and equip the healthcare workers anywhere in Sabah in treating patients with TB. Together, we can make Malaysia, a Tuberculosis free country by 2035. Dr Muhammad Khairul Taufiq Bin Rosli Chairperson Sabah’s Handbook on Management of Tuberculosis in Adults 10
Abbreviations TB Tuberculosis TPT TB Preventive Therapy PTB Pulmonary Tuberculosis ICF Intensified Case Finding EPTB Extrapulmonary Tuberculosis DRTB Drug Resistant Tuberculosis MTB Mycobacteium Tuberculosis PCR Polymerase Chain Reaction NTM Non-Tuberculous Mycobacterium KPAS Occupational Health Unit C&S Culture and Sensitivity LTBI Latent TB Infection SCR Sputum Conversion Rate PLHI V People Living With HIV ATT Anti-Tuberculosis Therapy HQE Hospital Queen Elizabeth ± With or Without NTP National TB program CXR Chest X-ray PR1 Pusat Rawatan 1 CT Computed Tomography PR2 Pusat Rawatan 2 FBC Full Blood Count JKNS Sabah State Department of Health RP Renal Profile KKM/ MOH Ministry of Health, Malaysia LFT Liver Function Test ART Anti-Retroviral Therapy HIV Human Immunodeficiency Virus WHO World Health Organization FBS Fasting Blood Sugar PPC Pre-Pregnancy Clinic RBS Random Blood Sugar XDR Extensive Drug Resistant HepB Hepatitis B CNS Central Nervous System HepC Hepatitis C MDR Multidrug Resistant LTAT Lab Turn Around Time ESRF End Stage Renal Failure PCR Polymerase Chain Reaction VTE Venous Thromboembolism AFB Acid Fast Bacilli BSA Body Surface Area H Isoniazid P Rifapentine R Rifampicin L Levofloxacin E Ethambutol S Streptomycin Z Pyrazinamide SLD Second Line drug 11
Chapter 1 : Introduction Dr Taufiq Rosli The landscape of TB diagnostics continues to evolve, with new technologies at various stages in the products development pipeline. A high-quality laboratory system that uses modern diagnostics is a prerequisite for the early, rapid and accurate detection of TB and drug resistance. Uptake of TB diagnostic technologies requires appropriate laboratory infrastructure, sufficient human resources and adequate policy reforms at the national as well as state level to enable their effective use in TB screening and diagnostic algorithms. This handbook is tailored to the local setting in Sabah with the available facilities and resources. 12
Globally in 2020, 5.8 million people with a new episode of TB (i.e. new and relapse cases) were notified to national TB programmes (NTPs) and reported to the World Health Organization (WHO), an 18% decline from 7.1 million in 2019. Best estimates for 2020 are 1.3 million TB deaths among HIVnegative people (up from 1.2 million in 2019) and an additional 214 000 among HIV-positive people (up from 209 000 in 2019). WHO’s End TB Strategy calls for early diagnosis of TB and universal drug-susceptibility testing (DST), highlighting the critical role of laboratories in the rapidly and accurately detecting TB and drug resistance. A range of new diagnostic technologies have been endorsed by the WHO during the past 10 years. Both LPAs and Xpert MTBRIF Ultra are available in Sabah. TB and Leprosy Sector, JKNS and Respiratory Department, QEH will continue to provide the necessary diagnostic tools and updated management of TB in Sabah. 13
Chapter 2 : Epidemiology & High Risk Groups Dr Roddy Teo & Dr Shivaanand Letcheminan Tuberculosis remains one of the top ten causes of mortality worldwide. Even though Malaysia is not of the Top 30 high TB burden countries in the WHO list, death rate due to TB is the highest in Malaysia as compared to the other infectious diseases. In Malaysia, Sabah has recorded the highest number of TB cases followed by Selangor in the year of 2021. 14
High risk groups to be infected with TB are close contacts to TB patients, the immunocompromised such as HIV and diabetes, malnourished, substance abusers, cigarette smokers, people living in overcrowded conditions such as prisons, shelters, homelessness and immigrants. TB Case Notification In the year 2021, a total 4,547 cases of tuberculosis were reported in Sabah, compared to 4,469 cases the previous year 2020. This is an increase of 78 cases (1.7%) from previous year. Of this 3,186 cases (70.1%) were smear positive cases. 205 cases (4.5%) were detected among children below the age of 15 years. Among the total cases, 1,535 cases (33.8%) were cases among foreigners. Most of them 1,177 cases (76.7%) were Philippine nationals. This is followed by Indonesians 342 cases (22.3%) and 16 other cases comprising Pakistan, Nepal, Brunei and other nationalities. Among Malaysians, majority of cases were detected among the ethnic Kadazan/ Dusun population 786 cases (26.1%) followed by Bajau 685 cases (22.7%), Chinese 192 cases (6.4%), Murut 145 cases (4.8%), Bugis 138 cases (4.6%), Sungai 92 cases (3.1%), Brunei/ Kedayan 61 cases (2.0%), Malay 38 cases (1.3%) and Indians 5 cases (0.2%). There were 16 cases (0.5%) detected among Sarawak ethnic groups. Remaining 232 cases were from other ethnicities in Sabah. The district with the highest TB cases was Kota Kinabalu with 793 cases followed by Sandakan 485 cases, Tawau 445 cases, Lahad Datu 353 cases, Semporna 334 cases and Keningau 277 cases. The other district only reported less than 200 cases per year. There were 437 mortalities reported in 2021 compared to 321 cases in 2020. 101 cases of TB with HIV and 16 MDR TB cases were reported as well. Among healthcare workers, 34 cases of TB were reported in 2021. Of this 17 were Trained Nurses, 5 Medical Officers, 2 Assistant Enviromental Health Officer, 2 Community Nurses, 2 Health Nurse Assistant and 1 case each from Lab Technician, Medical Assistant, Administrative Officer, Driver, Assistant Accountant and Public Health Assistant. 15
2020 SCR and DOT Achievement For the year 2021, Sputum Conversion Rate (SCR) for cases that qualify for analysis was 89.3% compared to 92.5% for the year 2020. While the percentage of DOT (Directly Observed Treatment) was 91.6% compared to 92.3% in 2020. Successful Treatment Achievement Treatment success rate for registered TB cases from January till December 2020 in Sabah was 90.1% for Malaysian citizens achieved the target of 90% and among non citizens it was 87.6% which is beyond the National TB target of 75%. The treatment success rate among Malaysians according to districs are Keningau (89.7%), Kunak (88.9%), Penampang (88.7%), Beluran (88.7%), Kota Kinabalu (87.5%), Putatan (86.1%), Sipitang (86.1%), Tambunan (85.4%), Pitas (84.8%), Kudat (84.0%), Kuala Penyu (81.3%) and Tenom ( 79.4% ). 16
Chapter 3 : Investigations Dr Taufiq Rosli Diagnosis of tuberculosis involves clinical, radiological and bacteriological evidence. Investigation of TB depends on type of TB and other organ involved. 17
Table 3.1: Clinical manifestations of active tuberculosis 18 Pulmonary Extrapulmonary Lung symptoms: • Prolonged cough • Chest pain • Haemoptysis (advanced) Systemic symptoms: • Fever • Night sweats • Anorexia • Weight loss Lymph nodes: smooth palpable nodes GI: pain, bloating, diarrhoea, ascites Pericardial: Chest pain, cardiac failure CNS: headache, focal neurology, coma Miliary: weight loss, fever Bone/ joint: painful mass, swelling, discharging sinus, fracture Pleura: Chest pain, shortness of breath Larynx: hoarseness of voice, odynophagia, dysphagia ± systemic symptoms
Hemoptysis Hemoptysis is commonly associated with late presentation of PTB. Urgent attention needed when patient presented with hemoptysis. Careful assessment needed to clearly differentiate it from hematemesis or epistaxis. Picture 3.1: Approach to hemoptysis for healthcare centre in Sabah 19
Table 3.2: A guide to severity of hemoptysis Investigations Table 3.3: Summary investigations for newly diagnosed PTB 20 No. Investigations Details 1. Sputum Direct Smears for Acid Fast Bacilli (AFB) At least 2 samples: 1 Spot during visit 1 Early morning sample at home or clinic *in the setting that centre unable to process SAFB on the same day, person incharge should put specimen container filled with sputum in refrigerator and send to lab within 48 hours • LTAT 1 day once sample reached lab 2. Mycobacterial culture and sensitivity (phenotyphic) • Taken at initiation of TB treatment • To confirm presence of Mycobacterium Tuberculosis • To test for drug sensitivity • LTAT for culture is 14 days while LTAT sensitivity is 42 days to 68 days Grade Amount (total for 24H) Remark Mild <50ml Moderate 50-200ml Severe **/ Major*** >200ml*** 150ml per 12H or **>400ml per 24H Massive >600ml Life threatening 200ml/H or 50ml/H with respiratory failure
Table 3.4: Summary investigations for newly diagnosed PTB (cont.) * For Xpert MTBRIF Ultra & LPA testing, please discuss with specialist for indications 21 No. Investigations Details 3 Mycobacterial culture and sensitivity (genotypic) *not all cases, please see indications 1) Xpert MTBRIF Ultra*: • Single automated PCR test • Detect rifampicin resistance from unprocessed samples < 2 hours. • Highly sensitive and specific. • LTAT 1-2 days once sample reach lab 2) Line probe assay (LPA)*: • Rapidly detect RIF as well as isoniazid resistance. • LTAT 14 days once sample reach lab 5 Blood • FBS/ RBS • FBC, RP, LFT • HIV • Hep B/ Hep C *if patient having risk factor 6 Urine pregnancy test All female childbearing age
Table 3.5: Summary investigations for newly diagnosed PTB (cont.) *for better view, please refer e-version Investigations Details 7 Minimal • Minimal lesions without demonstrable cavitations and confined to a small part of one or both lungs. The total extent of the lesions should not exceed the volume of the lung on one side which lies above the second chondrosternal junction and the spine of the fourth or the body of the fifth thoracic vertebrae. Moderately Advanced • One or both lungs may be involved but the total extent of the lesions should not exceed the following limits: • disseminated lesions of minimal to moderate density not exceeding the total volume of one lung or the equivalent in both lungs • dense and confluence lesions not exceeding one third of the volume of one lung • total diameter of cavitations, if present, must be <4 cm Far Advanced • Lesions are more extensive than moderately advanced. Plain Chest Radiography* 22
Sputum Microscopy (AFB) Interpretation All smear done in goverment facility in Sabah will have second reader regardless grading. Interpretation of sputum AFB is usually quite simple but on few occasion, interpretation can be challenging when the result is scanty. Table 3.6: Sputum AFB quatification scale Table 3.7: Scanty AFB interpretation 23 Microscope Magnifying Glass Grading 20X 40X No AFB/ 1 line No AFB/ 1 line No AFB (negative) 1-4 AFB / 1 line 1-2 AFB/ 1 line Scanty 5-9 AFB / 1 line 3-24 AFB/ 1 line Scanty 3-24 AFB/ 1 field 1-6 AFB/ 1 field 1+ 25-250 AFB/ 1 field 7-60 AFB/ 1 field 2+ >250 field/ 1 field >60 AFB/ 1 field 3+ Sputum AFB Clinical CXR Interpretation Scanty Suggestive Suggestive Likely PTB diagnosis Scanty Suggestive Not suggestive Likely PTB diagnosis *Except when other diagnosis is considered Scanty Not suggestive Suggestive Likely PTB diagnosis *Except when other diagnosis is considered Scanty Not suggestive Not suggestive Unlikely PTB. Work up for alternative diagnosis. * consider PTB diagnosis in immunosuppressed eg PLHIV.
Xpert MTBRIF Ultra Xpert MTBRIF Ultra is available in Sabah. The four districts that offer this service are Kota Kinabalu, Tawau, Keningau & Sandakan. The respective district will also cover their neighbouring district. However due to limited availability, for time being Xpert will be prioritised in detecting Rifampicin resistance TB. The indication for Xpert/RIF are shown in Picture 3.2 & 3.3 . Table 3.8: Interpretation of Xpert MTBRIF Ultra MTB Detected Rifampicin resistance Remark High/Medium Not detected No Rifampicin resistance detected in this sample. High/Medium Detected Rifampicin resistance detected. High/Medium Indeterminate Possibly Rifampicin resistance detected. Consider repeat sample or send for other molecular/phenotypic method. Low/Very Low/Trace Not detected No Rifampicin resistance detected in this sample. Low/Very Low/Trace Detected Rifampicin resistance detected. Low/Very Low/Trace Indeterminate Possibly No Rifampicin resistance detected in this sample. Correlate clinically. 24
Picture 3.2: Algorithm on sending Xpert MTBRIF Ultra 25
Picture 3.3: Continuation of Algorithm on sending Xpert MTBRIF Ultra 26
Sputum LPA LPA (Line probe assay) is another molecular method and relatively fast in determining Isoniazid and Rifampicin resistant. The suggested indication for sputum LPA are as below: • Persistant smear positive despite after 2month of effective regime, • Prior to MDR regime initiation (to determine Inh-A and/or katG mutation), or • Newly diagnose PTB smear positive patient with positive contact with Isoniazid resistant index. Extrapulmonary TB (EPTB) Investigations for extrapulmonary TB will depend on suspected site of infection. Attending clinician should aim for microbiological confirmation and/or histology to make diagnosis. 27
Table 3.8: Suggested investigations for EPTB *in selected cases, tissue for MTB PCR may be considered after discussion with pathologist or microbiologist 28 Organ involved Investigations CNS (e.g. meningeal) 1) Contrasted CT brain 2) Lumbar puncture • Xpert MTBRIF Ultra • AFB • MTB C&S Spine 1) CT/MRI spine 2) Tissue for • HPE MTB C&S 3) Pus • MTB C&S • AFB Pericardium 1) Echocardiography 2) Pericardial tapping • AFB • MTB C&S • Xpert MTBRIF Ultra Abdomen (Liver, Gut, peritoneal) 1) Ultrasound abdomen 2) CECT if needed 3) Colonoscopy 4) Tissue for HPE & MTB C&S Lymph node 1) Lymph node FNAC and/or biopsy • HPE & MTB C&S Pleural • Pleural Fluid ADA (>30 IU/L) • Pleural biopsy & MTB C&S
Key points • Diagnosis of TB should be based on symptoms, radiology and microbiology. • MTB C&S (depending on site of infection) should be sent. • All baseline investigations should be send prior to initiation of ATT. 29
Chapter 4 : Treatment of TB in Adults Dr Lo Shan Min This section describes the revised definitions of TB cases, their classification and the treatment outcome categories. 30
Table 4.1: Classification based on history of previous TB treatment New patients Have never been treated for TB or have taken antiTB drugs for less than 1 month. Previously treated patients Relapse patient Previously been treated for TB, were declared cured or treatment completed as the end of their most recent course of treatment, and are now diagnosed with a recurrent episode of TB. Treatment after failure patients Previously been treated for TB, and whose treatment failed at the end of their most recent course of treatment. Treatment after loss to follow-up patients Previously been treated for TB, and were declared lost to follow-up at the end of their most recent course of treatment. Other previously treated patients Previously been treated for TB but whose outcome after their most recent course of treatment is unknown or undocumented. 31
Table 4.2: Treatment outcomes for TB patients (excluding patients treated for RR-TB or MRD-TB) Cured A pulmonary TB patient with bacteriologically confirmed TB at the beginning of treatment who was smear- or culture-negative in the last month of treatment and on at least one previous occasion. Treatment completed A TB patient who completed treatment without evidence of failure BUT with no record to show that sputum smear or culture results in the last month of treatment and on at least one previous occasion were negative, either because tests were not done or because results are unavailable. Treatment failed A TB patient whose sputum smear or culture is positive at month 5 or later during treatment. Died A TB patient who dies for any reason before starting or during the course of treatment. Lost to follow-up A TB patient who did not start treatment or whose treatment was interrupted for 2 consecutive months or more. Not evaluated A TB patient for whom no treatment outcome is assigned. This includes cases “transferred out” to another treatment unit as well as cases for whom the treatment outcome is unknown to the reporting unit. Treatment success The sum of cured and treatment completed. 32
Treatment for New Case If no contraindication present, six-month regimen consisting of two months of daily EHRZ* (2EHRZ) followed by four months of daily HR* (4HR) is recommended for newly-diagnosed PTB . Table 4.3: Dosage of first line ATT and formulation After measuring latest body weight, attending clinician should round ATT dosage to nearest available preparation (highest range is preferred for H & R). Example: Table 4.4: Example ATT calculation for patient with body weight of 45kg. *if no contraindications 33 ATT Dosage range Rounded dosage Isoniazid 235-282mg 250mg / 300mg* Rifampicin 470-564mg 600mg Ethambutol 705-1175mg 1000mg/ 1200mg* Pyrazinamide 940-1410mg 1250mg ATT Preparation available Minimum available preparation Dosage Maximum dosage Isoniazid (H) Tablet, 100mg & 400mg 50mg 5-6mg/kg/ daily single dose 300mg Rifampicin (R) Capsule 150mg & 300mg 150mg 10-12 mg/ kg/daily single dose 600mg Ethambutol (E) Tablet 400mg 200mg 15-25 mg/ kg/daily single dose 1600mg Pyrazinamide (Z) Tablet 500mg 250mg 20-30 mg/ kg/daily single dose 2000mg
FDC (Fixed dose combination) Akurit-4 & Forecox are the most common FDC used in Sabah. Table 4.5: The recommended dosage for FDC * If body weight less than 38kg, we recommend using loose tablet ATT Attending clinician should consider adding additional Rifampicin and/or Isoniazid on top of prescribed FDC if dosage of drug per body weight are not met. Example: For patient with body weight of 52kg Table 4.6: Suggested additional dosage of ATT on top of FDC Body weight Dosage 30-37kg 2 Tablets daily 38-54kg 3 Tablets daily 55-70kg 4 Tablets daily >70kg 5 Tablets daily (3 tablets) Actual FDC dosage Dosage Range per body weight Suggested Additional dosage Rifampicin 450mg 520-600mg 150mg Isoniazid 225mg 260-300mg 50mg 34
Prolongation of Treatment Expert opinion, suggest a total of 9 months treatment in high risk group for treatment failure and relapse. High risk group include: • cavitation or far advance TB on an initial chest radiograph, • at least one cavity on a follow-up radiograph, or • positive smear following two months of ATT once drug resistance has been rule out. *All cases that require prolongation of ATT should be discuss with respiratory team Treatment for Previously Treated Patient (Retreatment Group) Globally, all TB guidelines are moving away from injectable drugs. A regime that is previously used for retreatment group (2 SEHRZ+ 1 EHRZ + 5 REH) are no longer recommended. After succesfully ruling out R-R by Xpert MTBRIF Ultra, it is recommended to start EHRZ based on body weight. We recommend to give EHRZ for the whole 6 month regime (6EHRZ) if no contraindication present. Close monitoring eg. monthly review with blood investigations & eye asessment is necessary. 35
Extrapulmonary TB Treatment (EPTB) All EPTB cases in Sabah should be referred to Infectious Disease (ID) team for optimum regime & duration of treatment. An exception with pleural TB as it usually presented together with PTB. Table 4.7: Suggested duration of ATT in EPTB *Prolongation of treatment may be considered on case to case basis Corticosteroid Corticosteroid plays an important role in severe TB meningitis & pericarditis. It can improve symptom and survival. Table 4.8: Suggested steroid regime for TB meningitis 36 Organ involved Suggested Duration CNS (eg meningeal) 12 months Spine 9 months* Pericardium 6 months* Abdomen (Liver, Gut, peritoneal) 6 months* Pleural & Lymph node 6 months Disease severity Regimen Grade 1 disease Week 1: IV dexamethasone sodium phosphate 0.3 mg/kg/day Week 2: 0.2 mg/kg/day Week 3: Oral dexamethasone 0.1 mg/kg/day Week 4: Oral dexamethasone a total of 3 mg/day, decreasing by 1 mg each week Grade II & III disease Week 1: IV dexamethasone sodium phosphate 0.4 mg/kg/day Week 2: 0.3 mg/kg/day Week 3: 0.2 mg/kg/day Week 4: 0.1 mg/kg/day, then oral dexamethasone for 4 weeks, decreasing by 1 mg each week
Table 4.9: Suggested steroid regime for TB pericarditis *IV hydrocortisone can be used if patients cannot take orally: IV hydrocortisone 300 mg bolus, then 100 mg daily for 1 - 2 weeks, continued with oral prednisolone as above High Dose Rifampicin In confirmed PTB cases, clinicians can consider giving high dose Rifampicin (20mg/kg/day) in patients who are having cavitation and/or advanced PTB changes on CXR. It should be given during intensive phase and patient should receive normal dose of rifampicin (10-12mg/kg/day) during maintanence phase. Careful asessment should be made prior and after giving high dose rifampicin to ensure no adverse drug reactions. Consultation to a specialist is necessary prior to initiation. Directly observe therapy (DOT) Every clinician managing TB should ensure all TB patient that on ATT treatment need to undergo DOT to optimised management of TB. Pathway for DOT defaulter will be discussed in chapter 9. eDOT in TB Management eDOT is the use of electronic technologies to remotely monitor TB patients ingesting their medication, either in real-time. However, eDOT is not a complete replacement for in-person DOT. 37 Week Regimen 1-4 Oral prednisolone 60 mg daily 5-8 Oral prednisolone 30 mg daily 9-10 Oral prednisolone 15 mg daily 11 Oral prednisolone 5 mg daily
Picture 4.1: Algorithm for implementation of eDOTS *Patient who does not meet the criteria along the way can be assign back to inperson DOTS 38
Table 4.10: Inclusion & exclusion criteria for eDOT Key points • Standard TB treatment is 2EHRZ + 4HR. • Duration of ATT will depend on severity or site of infection. • Addition of Rifampicin and/or Isoniazid on top of FDC may be required if dosage per body weight is not met. • Retreatment regime (2SEHRZ + 1 EHRZ + 5REH) is no longer recommended. • Steroid is required for TB meningitis and TB pericarditis. Inclusion criteria Exclusion criteria • Has been on in-person DOT for at least 2 weeks with good adherence • Motivated patient (as determined by case manager) • Demonstrated adherence to treatment • Ability to effectively communicate with the healthcare worker • Drug-susceptible disease • No current alcohol or substance abuse • Proficient in using a smartphone or other technology • Able to accurately identify each medication • Adherence issues • Language barriers • Drug resistance (MDR-TB or XDR-TB) • Minors (less than 18 years old) without accompanying adult • Immunocompromised • Patient experiences adverse reactions • Patients at risk for hepatic complications while receiving Anti-TB medications • Patients with disabilities that prevent full participation in eDOT such as hearing or vision disabilities, or physically challenged 39
Chapter 5 : Latent TB Infection in Adults Dr Kunji Kannan Latent tuberculosis infection (LTBI) is defined as a state of persistent immune response to stimulation by M. tuberculosis antigens with no evidence of clinical manifestation of active TB. • ¼ of the world population is infected with TB. • TB preventive treatment (TPT) is one of the key interventions recommended by the WHO to achieve the EndTB Strategy targets. • There is no “gold standard” test for TB infection. • 5-10% of those infected will develop active TB disease over the course of their lives, usually within the first 5 years after initial infection. The risk is particularly elevated among children under the age of 5 years and among people with compromised immunity. 40
Table 5.1: Phases & action plan in LTBI management No. PHASE PLAN OF ACTION 1 Identification of population for LTBI testing and criteria to receive TB preventive treatment (TPT) 1. Adults and adolescents living with HIV Criteria to receive TPT (Irrespective of degree of immunosuppression, even if LTBI testing unavailable): • No active TB • Those on antiretroviral treatment (ART) • Pregnant women • Those previously been treated for TB 2. Household or close contact of pulmonary TB (Refer table 5.6: Definition of TB contact) Criteria to receive TPT: • No active TB. *for children, please refer to pediatric TB manual/ paediatrician 3. Contacts of Multidrug-resistant tuberculosis patients Criteria to receive TPT: • In high-risk household contacts, TPT may be considered based on individualized risk assessment and clinical justification (Refer respiratory physician) 4. Other people at risk Should be systematically tested and treated for LTBI: • Patients initiating anti-TNF treatment • Patients receiving dialysis • Preparing for organ or haematological transplant • Patients with silicosis 41
Table 5.2: Phases & action plan in LTBI management (cont.) 42 No. PHASE PLAN OF ACTION May consider systematic LTBI testing and treatment: • Healthcare workers • Prisoners & prison staff • Immigrants from countries with high TB burden • People who use illicit drug 2 Diagnosing LTBI Critical to EXCLUDE ACTIVE PTB & EPTB before initiating TPT: 1. No symptoms to suggest active disease: Current cough, weight loss, night sweats or fever in adults/adolescents 2. Normal CXR or static CXR findings (over a period of at least 6 months) 3. Smear/culture negative on sputum or bronchoalveolar lavage for Mycobacterium tuberculosis (if collected). Induced sputum or bronchoalveolar lavage should be considered in those with abnormal CXR findings *In certain situation, clinician may consider additional investigations eg. CT scan or biopsy to exclude EPTB
Table 5.3: Phases & suggested action plan in LTBI management (cont.) No. PHASE PLAN OF ACTION 3 Testing for LTBI (Refer Picture 5.1) Tuberculin skin test (TST) and IGRA are both of similar sensitivity and specificity. 1. Tuberculin skin test (TST) (Refer Table 5.7) 2. Interferon-gamma release assay (IGRA) Criteria for IGRA (MOH) A. Contact of smear positive PTB • Household contact or close contact AND • HIV negative AND • Exposed to case index minimum for 2 months AND • Age ≥ 5 years B. Contact of TB confirmed bacteriology cluster (SAFB or culture or Xpert MTBRIF Ultra) • HIV negative AND • Exposed to case index minimum for 2 months C. Healthcare workers • Pre-placement testing within 6 months of reporting for duty • One year prior to retirement (from the date of retirement) • Transfer to a new workplace: -Within 6 months if never been tested with IGRA OR -2 years from the date of last IGRA test There is no role for repeat LTBI testing if patient has re-exposure again after TPT completed. 43
Table 5.4: Phases & suggested action plan in LTBI management (cont.) *H: Isoniazid, R: Rifampicin, P: Rifapentine 44 No. PHASE PLAN OF ACTION 4 TPT options (Refer table 5.8) Counselling for TPT needs to be done prior to starting TPT 1. Two types of TPT: i. Combination Treatment regimens containing a rifamycin (rifampicin/ rifapentine) and Isoniazid (Refer Table 5.8: Recommended dosages of medicine for TB preventive treatment): a) 3HR or 3HP* regimens should be the first-line regimen unless contraindicated ii. Monotherapy with isoniazid or Rifampicin a) 4R may be used for patients who cannot tolerate or are contraindicated for INH- based regime b) 6H or 9H may be used for patients who cannot tolerate or are contraindicated for rifamycin based regimen 2. Preventive treatment for MDR-TB • Fluoroquinolones (e.g. moxifloxacin, levofloxacin) with or without other agents (e.g. ethambutol, ethionamide) • Duration: limited evidence *Primary care team to refer to respiratory physician for MDR-TB preventive treatment
Table 5.5: Phases & suggested action plan in LTBI management (cont.) 45 No. PHASE PLAN OF ACTION 5 Monitoring • HIV testing if having risk factor. • Additional blood test according to patient’s underlying risk factors/condition on caseto-case basis. • Treatment do not require strict DOTS. • Patient can be given medications monthly and reviewed every 1-2 months if patient is stable. • If patient develops active TB in the future and patient has undergone TPT (regardless of completion), drug resistance testing should be performed. TB treatment should be started first while awaiting results of resistance testing.
Justification & Evidence 1. Adults and adolescents living with HIV • TB is the most frequent cause of AIDS-related deaths worldwide, despite progress in access to ART. • TB represents about 1/3 of all HIV deaths. • About 20 times more likely to develop active TB than those without HIV infection. • TPT reduced overall risk for active TB by 33%. For those who were TST positive, the reduction increased to 64%. • Protective effect: > 5 years. 2. Household contact of pulmonary TB • All household contacts, regardless of their age or LTBI status, were nevertheless at a substantially higher risk for progression to active TB than the general population. • There is significantly higher risk of infants and young children < 5 years to develop active TB. • The disease can develop rapidly in young children and they are at greatest risk of severe and disseminated disease, associated with high morbidity and mortality. • Please refer to table 5.6 for definition of TB contact. 3. Systematic LTBI testing and treatment • It is not recommended for people with diabetes, people who engage in the harmful use of alcohol, tobacco smokers and underweight people. 4. Symptoms • Symptoms such as cough, weight loss, night sweats and fever had a sensitivity of 79%, a specificity of 50% and negative predictive value of 97.7%. 46
Table 5.6: Definition of TB contact TB contact An individual who has been exposed to TB index case. Household contact Any individual who lived in the same household as a TB patient for ≥ 1 month before the index case was started on treatment. Close / family contact Any individual who has a close relationship or are family members of an index case, and is exposed to the index case within an enclosed environment for duration of ≥ 1 month before the index case was started on treatment (including room mate / house mate / relative / baby sitter who is in an enclosed space with index case for ≥ 1 month). Workplace contact Any individual who has contact with index case in their work place for a reasonable amount of time (more than 40 hours/week or 8 Hours/ day). Social contact Any individual who has contact with index case on frequent and repeated basis for social activities (i.e. prayers at mosque, community service/works, sporting activities, etc), Travelling / flight contact Passengers who are exposed to someone who can or is at risk of spreading TB disease with travel duration of 8 hours or more passengers who are in the same row, within 2 rows in front and behind, or within 2 meter radius from the index case. Institutional contact An individual who is frequently exposed to the index case for a reasonable duration of time (more than 40 hours/week or 8 hours/day) within an institution (i.e. prison, pusat serenti, immigration detention centre, police lockup, boarding school, elderly care centre, dialysis centre, CCRC, etc). 47
5. CXR • Addition of abnormal CXR increased the negative predictive value by only 0.2%. • Static CXR: If abnormal findings are found on CXR, there should be no changes seen on repeat CXR over a period of at least six months. However, if CXR shows progressive changes, patient needs to be re-investigated. • Healed lesions are often characterised by nodules and fibrotic lesions that are well-demarcated. • Calcified nodular lesions (calcified granulomas) and apical or basal pleural thickening pose a lower risk for future progression to active TB. 6. LTBI testing • TST and IGRA can lead to false-negative results, particularly for young children and immunocompromised individuals. Table 5.7: Positive TST for LTBI 48 Positive TST reaction Type of individuals ≥5mm • PLHIV • Organ transplant recepients • Person who are immunosuppressed for other reasons (such as those taking the equivalent of >15mg prednisolone for >1month or taking TNF-α antagonist ≥15mm • Individuals from countries low incidence of TB ≥10mm • All other high risk individuals
7. TB preventive treatment (TPT) Table 5.8: Recommended dosage for TPT *Add Pyridoxine 20mg OD for TPT containing isoniazid component. H: Isoniazid, R: Rifampicin, P: Rifapentine 49 Drug Durations Interval Dosage H 6 or 9 month Daily 5mg/kg, max 300mg H & R 3 month Daily H: 5mg/kg, max 300mg R: 10mg/kg, max 600mg H & P 3 month Weekly H: 15mg/kg, max 300mg P: <50kg, 750mg (5 tablets) >50kg, 900mg (6 tablets) R 4 month Daily 10mg/kg, max 600mg
Picture 5.1: Algorithm for LTBI testing and TB preventive treatment in individuals at risk 50