NWT TUBERCULOSIS MANUAL

JuneNovember 2014 2014 | www.hss.gov.nt.ca | www.hss.gov.nt.ca Table of Contents

Section 1: Purpose and Introduction 1-1 Purpose 1-2 Acknowledgements 1-2 Introduction 1-3 Section 2: Description of TB 2-1 Etiology 2-2 Pathogenesis 2-2 Primary TB (Early Disease Progression) 2-3 Latent TB Infection (LTBI) 2-3 Reinfection 2-3 Reactivation (Late Disease Progression) 2-4 Transmission 2-5 Factors that Increase the Risk of Transmission 2-7 Transmission Outcomes 2-8 Risk Factors 2-11 Section 3: Bacillus Calmette-Guérin (BCG) Vaccination 3-1 Description 3-2 Indications for Use 3-3 Infants in High Risk Communities 3-3 Travellers 3-3 Occupational Setting 3-4 Booster Doses and Revaccination 3-4 Administration Procedure 3-4 Safety 3-6 Contraindications 3-6 Adverse Reactions 3-7 Management of BCG Abscess 3-8 Important Considerations 3-9 BCG Vaccine Usage in Canada 3-9 Section 4: TB Screening 4-1 Components of Screening 4-2 The Tuberculin Skin Test (TST) 4-3 TST Technique 4-3 Special Considerations Using TST 4-13 Two-Step TST: Distinguishing Between the Booster Phenomenon and Conversion 4-14 Contraindications to TST 4-16 Precautions with TST 4-16 Interferon Gamma Release Assay (IGRA) 4-17

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 i Section 5: TB Assessment 5-1 Rationale 5-2 Signs and Symptoms 5-4 Baseline Investigations 5-5 Goals of Treatment 5-5 Section 6: Diagnosis of TB (Latent vs. Active Disease) 6-1 Latent TB 6-1 Diagnosis of Latent Tuberculosis Infection (LTBI) 6-2 Guidelines for Use: TST or IGRA 6-2 Tuberculin Skin Test (TST) 6-3 Chest Radiography 6-3 Active TB 6-6 Diagnosis of Active TB 6-6 Respiratory TB 6-6 Clinical Presentation 6-6 Microbacteria Testing: AFB Smear and Culture 6-9 Respiratory Specimen Collection 6-11 Non-respiratory TB 6-17 Clinical Presentations 6-17 Radiography 6-18 Section 7: Management of TB 7-1 Management of Suspect TB 7-2 Medical Transportation of a Confirmed or Suspected Case 7-3 Infection Control Measures in the Management of TB 7-7 Criteria for Discontinuing Airborne Precautions for TB 7-13 Direct Observed Treatment (DOT) 7-14 Discharge Planning 7-14 Section 8: Treatment for Tuberculosis 8-1 Latent TB 8-3 Indications and Objectives for Treatment 8-3 Treatment, Duration and Adherence 8-4 Special Considerations in the Treatment of LTBI 8-6 Monitoring Treatment of LTBI 8-7 Adverse Reactions/Treatment Induced Side Effects 8-9 Follow-Up after LTBI Treatment and Management Following Re-Exposure 8-12 Active TB 8-13 Objectives of Treatment 8-13 Principles of Treatment 8-13 Special Considerations in the Treatment of Active TB Disease 8-18 Anti-Tuberculosis Drugs 8-19 Monitoring of Treatment of Active TB 8-23 Adverse Reactions/Treatment Induced Side Effects 8-25 Completion of Treatment 8-30

iiNWT Tuberculosis Manual - JuneNovember 2014 2014 Surveillance 8-30 Drug-Resistant Tuberculosis 8-30 Multidrug-Resistant (MDR-TB) and Extensively Drug-Resistant (XDR-TB) Tuberculosis 8-34 Non-respiratory TB 8-36 Diagnosis of Non-respiratory TB 8-36 Treatment of Non-respiratory TB 8-36 Section 9: Contact Tracing 9-1 Contact Tracing Algorithms 9-2 Contact Tracing and Contact Investigations 9-5 Goals and Objectives of Contact Tracing 9-5 Factors Contributing to Transmission 9-5 Prioritization of Contact Follow-Up 9-6 Steps in a Contact Investigation 9-7 Evaluation of Contacts for the Presence of Active Disease and Evidence of Recent Infection 9-9 Organizing an Investigation: Identification and Interview of Contacts 9-10 Screening Contacts in a Contact Investigation 9-13 INH Preventive Treatment for Contacts 9-14 Evaluation of Contact Investigation 9-14 Section 10: Role of Public Health in TB Prevention and Control in the NWT 10-1 Notification and Reporting of Suspect and Confirmed Cases of TB 10-2 Directly Observed Treatment (DOT) and Directly Observed Preventive Treatment (DOPT) 10-4 Surveillance 10-5 Managing an Outbreak 10-7 Section 11: Pediatric TB 11-1 Pediatric Population 11-2 Transmission and Pathogenesis 11-2 Latent TB 11-3 Pediatric LTBI Treatment 11-3 Active TB 11-5 Pediatric Active TB Disease Treatment 11-5 Management and Treatment of Active Disease 11-6 Monitoring and Follow-up 11-10 Management of Children with Close Contact to Smear (-), Culture (+) TB 11-12 Management of Children wtih Close Contact to Smear (+) TB 11-13 Section 12: Populations at Risk 12-1 Overview of Screening Populations at Risk 12-2 Immigrant Screening in the Northwest Territories 12-3 Homeless Populations and Injection Drug Use 12-6 Institutionalized Population – Correctional Facilities 12-7 HIV and TB 12-8

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 iii Section 13: 13: Caring Caring for for the the Deceased Deceased with with TB TB 13-113-1 General Policy and Procedures 13-2 Section 14: 14: History History and and Epidemiology Epidemiology of TB of in TB the in NWT the NWT 14-114-1 NWT History 14-2 WWorldorld TB Day 14-4 Epidemiology of TB in the NWT 14-4 Global Occurrence of TB 14-7 Section 15: 15: A A Glossary Glossary of ofTerms Terms and and TB Classifications TB Classifications 15-115-1 Section 16: 16: Forms Forms 16-116-1 1. NWT TB Assessment Form 16-2 2. NWT LatentTB Initiation Tuberculosis Form Infection (LTBI) Treatment Initiation form 16-4 3. NWT TB Case LLTBITBI TX Completion Form 16-5 4. NWT LLTBITBI Tuberculosis Community Surveillance Form 16-6 5. NWT TTuberculosisuberculosis Surveillance & Screening Form 16-7 6. NWT TTuberculosisuberculosis Case and Contact Tracing Record 16-8 7. NWT Communicable Disease Passenger Declaration Form 16-9 8. NWT Latent TTuberculosisuberculosis Infection (LTBI) Drug Treatment & Progress Record 16-10 9. NWT Active TB Drug TTreatmentreatment & Progress Record 16-12 10. 10. AEFI Form 16-15 11. 11. Common Abbreviations in NWT TB Program 16-19 12. 12. Medication Information 16-21 Section 17: 17: Specimen Specimen Collection Collection Procedures Procedures 17-117-1 Section 18: 18: List List of of Figur Figureses 18-118-1 Section 19: 19: List List of of Tables Tables 19-119-1

iv NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 1: Purpose and Introduction

Section 1 Purpose and Introduction

Purpose 1-2 Acknowledgements 1-2 Introduction 1-3

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 1-1 Section 1: Purpose and Introduction

Purpose This manual provides the Northwest Territories (NWT) standards for the prevention, detection, and treatment of tuberculosis (TB) to health professionals. It will be updated at regular intervals to reflect new developments in TB prevention and control.

The purpose of this manual is to:

1 2 3 Provide education Provide individual Provide standards for and program and population-based diagnosing, treating, standards to prevent surveillance standards monitoring, and the spread of TB. to encourage early contact tracing for detection of TB. active TB disease and latent TB infection.

Acknowledgements The Department of Health and Social Services would like to thank all community, regional and departmental personnel who have contributed their expertise to the updating of the NWT Tuberculosis Manual 2014.

Especially: • Community Health Nurses • Members of the former Canadian TB Committee • Public Health Nurses • Regional and Territorial Public Health Officers • Public Health and Preventive Medicine Residents • Specialists at Stanton Territorial Hospital • TB Specialists from the University of Alberta

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Introduction This TB manual will serve as a resource guide to all Health Care Providers (HCPs) who provide clinical support, treatment and/or management to patients with tuberculosis in the Northwest Territories (NWT). Many HCPs in Canada have limited experience with tuberculosis management. This manual provides information and direction to: • Increase awareness among HCPs about TB in the NWT • Clarify roles and responsibilities of HCPs in public health management activities for TB • Familiarize HCPs about TB screening, disease prevention, treatment and community follow-up • Describe the TB prevention and control program in the NWT as required by the Public Health Act (2009) and related regulations • Provide references and resources for supplemental information on TB

The information in this manual is based on the recommendations of the Tuberculosis Committee of the Canadian Thoracic Society in the 7th edition of the Canadian Tuberculosis Standards (2013) as well as other relevant national and international standards in TB diagnosis, treatment and control. Tuberculosis remains an important global issue and has become more difficult to clinically manage. Many related issues contribute to its complexity, such as an increasing epidemic of people living with Human Immunodeficiency Virus (HIV) and TB disease. Canada is not considered a high burden TB country. However, subgroups of the Canadian population suffer from a higher burden of active TB or are at increased risk of being infected, leading to the spread of the disease in and outside these subgroups. One such subgroup is the Aboriginal peoples of Canada, who are disproportionately impacted by this disease. The NWT, with over half the population self-identifying as Aboriginal, does not escape the ongoing threat of TB. The NWT rate of TB is significantly higher than the national Canadian average. Whenever a diagnosis of TB is being considered, the Office of the Chief Public Health Officer (OCPHO) must be notified immediately in accordance with thePublic Health Act (2009). OCPHO staff will provide field staff with guidance and direction regarding disease investigation, control measures, and follow-up. TB has serious implications for a patient’s family and community. The management of TB is a high priority public health issue.

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THINK TB! In the NWT, THINK TB! In the NWT, THINK TB!

IF YOU SUSPECT A PATIENT HAS TB, CONTACT: The Office of the Chief Public Health Officer (OCPHO) Telephone (867) 920-8646 Fax (867) 873-0442 (Medical Confidential) And Your Regional Nursing Manager or Public Health Unit

Note: Three key colour schemes have been utilized in the NWT Tuberculosis Manual to facilitate identification of active, latent and non-respiratory TB within sections of the text.

1-4 NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 2 Description of TB

Etiology 2-2 Pathogenesis 2-2 Primary TB (Early Disease Progression) 2-3 Latent TB Infection (LTBI) 2-3 Reinfection 2-3 Reactivation (Late Disease Progression) 2-4 Transmission 2-5 Factors that Increase the Risk of Transmission 2-7 Transmission Outcomes 2-8 Risk Factors 2-11

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Etiology Tuberculosis is a mycobacterial disease resulting from infection with any species of the mycobacterium tuberculosis complex (MTBC). The species of this complex include: M. tuberculosis, M. bovis, M. bovis BCG, M. africanum, M. canetti, M. caprae, M. microti and M. pinnipedii. Among these species, M. tuberculosis (MTB) is the most common and important agent of human disease.

Figure 2.1: Mycobacterium Species

Image Credit: CDC Public Health Image Library/Dr. George P. Kubica

All species of mycobacteria that do not cause TB are referred to as non-tuberculous (or atypical) mycobacteria (NTM). They are commonly found in the environment and typically only cause human disease in people with weak immune systems (e.g. elderly). These mycobacteria have some similarities with M. tuberculosis. If someone has past exposure to NTM, it can cause a positive result in a screening test, such as the tuberculin skin test (TST). These NTM mycobacteria can include: M. avium complex, M. Kansaii, M. xenopi, M. marinum, M. abscessus, M. ulcerans, M. chelonae, M. fortuitum, M. malmoense, M. haemophilum. Transmission of non-tuberculosis mycobacterium (NTM) between people is believed to be extremely rare. As such, NTM is not reportable. Public Health case management is not required and treatment is not mandatory but rather determined on a case by case basis.

Pathogenesis The pathogenesis and transmission of TB are inter-related. M. tuberculosis is almost exclusively a human pathogen. How it interacts with the human host determines its survival. From the perspective of the bacterium, a successful host-pathogen interaction is one that results in pathogen transmission. Initial infection is usually self-limited and followed by a variable period of latency, which ultimately, in a proportion of those infected, results in infectious pulmonary TB. Transmission from a case of infectious pulmonary TB is by the airborne route in minute droplets of moisture that become increasingly reduced by evaporation, creating “droplet nuclei”.

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If the initial immune system response is not sufficient to clear the bacteria, the bacilli may spread from the initial lesion via the lymphatic and/or circulatory systems to other parts of the body. After a period lasting from 3 to 8 weeks the host develops specific immunity. This is known as cell-mediated immunity (CMI) and delayed-type hypersensitivity (DTH) to the bacilli. Individuals typically show positive results on the TST or interferon gamma release assay (IGRA). Clinical evidence of an initial infection may include a Ghon focus (a calcified granuloma in the lung), alone, or in combination, with a calcified focus in a draining lymph node (Ghon Complex). The Ghon Focus or Ghon Complex may be demonstrated on chest X-ray, but their absence does not imply absence of TB infection. In a small proportion of those infected, erythema nodosum (a cutaneous immunologic response to an extracutaneous TB infection) or phlyctenular conjunctivitis (a hypersensitivity reaction) may develop.

Primary TB (Early Disease Progression) For purposes of disease reporting, everyone with a diagnosis of TB made within 18–24 months of infection is considered to have “primary” disease (about 5% of those infected). Those newly infected people in whom TB does not develop within this period of time will either be left with latent TB infection (LTBI) and will never experience disease (about 90% of those infected) or, after a variable period of latency, they will show late disease progression (about 5% of those infected). A proportion of those infected with TB will go on to develop active disease within a matter of months. This is especially true in young children and the immunocompromised. A progressive Ghon focus, disseminated (miliary) disease and central nervous system disease may occur as early as 2 to 6 months after infection in infants and the severely immunocompromised. Lymph node disease (which may or may not include respiratory involvement) may also occur.

Latent TB Infection (LTBI) The majority of those infected will be classified as having a latent TB infection. This means MTB can survive in the granulomas for many years without causing symptoms of active disease. LTBI is usually identified by a positive TST or IGRA.

Reinfection Studies suggest it takes up to 18 months after the initial infection for cell mediated immunity to mature. During this time, a reinfection carries the same risk of disease as the initial infection, perhaps explaining why disease is much more common in newly infected close contacts of smear-positive cases than it is in newly infected close contacts of smear-negative cases – the former having a greater likelihood than the latter of repeated exposure and reinfection.

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Reactivation (Late Disease Progression) In Canada, most active TB is due to “reactivation” TB, i.e. occurring 24 months or more after the initial infection. In any population group, reactivation of LTBI, leading to active TB disease (reactivation TB), is much more likely to occur in people who are immunocompromised. People with a history of untreated or inadequately treated pulmonary TB or a “high-risk” lung scar (upper lung zone fibronodular abnormality) on chest radiograph are understood to have a higher TB burden than those without such a history/radiograph, and to be at increased risk of reactivation TB.

Table 2.1: Classification of a TB Case

The presence of active TB is based on positive bacteriology (culture). However in some cases, active TB is diagnosed on the basis of appropriate clinical and radiologic presentation New Active Case associated with a positive response to treatment. Active TB can be classified as respiratory or non-respiratory. No documented evidence or adequate history of previously active TB.

Reactivation The development of active disease after a period of latency or (previously referred to dormant infection (usually 18-24 months or longer). as Post Primary)

The recurrence of active disease in the same patient after Relapsed Case 6 months of inactivity after treatment, indicating a possible treatment failure.

The presence of Mycobacterium tuberculosis complex Laboratory Confirmed demonstrated by laboratory culture (i.e. not just AFB smear Case positive).

The presence of a positive TST result and significant clinical evidence of disease, such as: •Chest x-ray (CXR) compatible with active TB, including idiopathic pleurisy and pleural effusion; Clinical Case •History of contact with active TB; •Signs and symptoms consistent with TB disease; •Pathologic or post-mortem evidence of active TB; or •Clinical improvement of signs and symptoms with anti- tuberculous medications.

A patient in whom TB disease is suspected by the clinician, but who does not meet the criteria outlined for either lab confirmed or clinical cases. All efforts should be made to ensure that Suspect Case appropriate investigations are completed so that the patient can be classified as a lab confirmed or clinical case or a diagnosis of TB can be ruled out.

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Transmission Transmission of bacteria occurs most exclusively by airborne route via respiratory droplets containing small amounts of viable bacteria.

Figure 2.2: Expulsion of Respiratory Droplets

If the droplets containing the organism reach the trachea/bronchi, they can easily be inhaled. If the droplet nuclei are small enough (1-5 microns in size), they can be breathed into the lungs (i.e. alveoli) where infection is usually established in the host. Nearly all cases occur from exposure to human source, created via forceful expiratory efforts (i.e. coughing, sneezing). Certain procedures, for example, bronchoscopy, sputum induction, processing of specimens, autopsy and even irrigation or other manipulation of tuberculous abscesses, may also produce infectious aerosols. The droplets have an extremely slow settling rate (0.5mm per second or less), which permits their transport by air currents, duct systems or elevator shafts for significant distances from the source case. Large particles settle quickly and are either not inhaled by contacts or, if inhaled, are trapped in the mucus of the upper airway. If the organism reaches the trachea and bronchi it is usually swept back to the larynx by ciliary action and cough, and then swallowed. For practical purposes, only the droplet nuclei in the size range 1-5 microns reach the terminal air spaces or alveoli; each is understood to contain only a few bacteria. In most instances, only one such droplet nucleus is believed to be responsible for establishing infection in the host. Bacteria that are lodged on fomites (linen, furniture, books, and floors) do not constitute a significant source of infection: most die quickly through the action of drying, heat, or sunlight.

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Figure 2.3: TB Transmission

A person may be infected with tuberculosis if infectious droplets are inhaled. Transmission is facilitated by respiratory disease (coughing).

The body’s immune system encapsulates MTB in a granuloma for undetermined time period which is known as latent TB infection (LTBI).

Adapted from: http://www.pennmedicine.org/encyclopedia/em_ DisplayImage.aspx?gcid=19099&ptid=2&rgcid=000077&rptid=1

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Factors that Increase the Risk of Transmission • Infectiousness of person with TB: -Presence of acid fast bacilli (AFB) in sputum, cough, or cavitation on CXR (severity of disease) -TB disease affecting the lungs, larynx and/or lower airways -Failure to cover mouth and nose when coughing, laughing or singing (lack of infection control practices) -Any procedure that can induce coughing or cause aerosolization of tubercle bacilli (e.g. sputum induction, bronchoscopy or playing a wind instrument) -Delay of diagnosis and effective treatment

• Environment in which exposure occurred: -Exposure of susceptible persons to an infectious individual in a relatively small enclosed space (proximity) -Poor local or general ventilation (i.e. does not dilute infectious droplet nuclei) or recirculation of air

• Magnitude of exposure depends on: -Duration of exposure (e.g. time spent with infected person) -Prevalence of active, infectious TB in the community -Type of dwelling or facility in which exposure occurred (poor air circulation, home vs. arena, many people in a small, poorly ventilated space)

• Susceptibility of those exposed: -When the immune system is weakened, either from disease processes or medications, the body may not be able to control the replication and subsequently spread of tubercle bacilli

“High Risk Groups,” See Table 2.3 further in this section The risk of transition from LTBI to active TB, primary disease or reactivation, is largely dependent on the immune competence of the host. Age and sex appear to directly affect the immunologic response and the risk of disease: morbidity is greater among young children (<5 years of age, especially infants), among young adults (especially females), and among older adults (especially males). In high-burden countries, the population attributable fraction of under nutrition for TB is 27% according to the WHO. The seasonality of TB (with the highest incidence in spring and early summer) has been attributed to reduced sunlight and vitamin D deficiency during the winter months in some studies but not in others.

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Minimizing Transmission Treat persons with active TB using anti-TB drugs. This reduces the number and viability of tubercle bacilli in the sputum and reduces sputum production. People producing sputum samples that are smear positive and/or culture positive for AFB should be isolated for a minimum of two weeks after start of treatment, AND until they have three consecutive smear-negative sputa samples. The spread of tubercle bacilli can be controlled by mechanical means such as covering the nose and mouth, wearing a N95 mask while in transit, and remaining isolated in a facility with negative pressure ventilation. All TB isolation rooms in a facility are to meet Canadian Standards for airborne respiratory isolation (http://shop.csa.ca/en/canada/health-care-facility-engineering/cancsa-z3172-10/ invt/27013482010). Exhaust is to be vented to the outside, and air exchange is to be greater than 12 air exchanges per hour (http://www.hss.gov.nt.ca/sites/default/files/nwtinfectioncontrolmanual.pdf).

Transmission Outcomes After exposure to a source case, it can lead to one of three different outcomes:

1 2 3 The bacteria are Infection will lead Cell-mediated immunity destroyed by to primary disease and delayed-type phagocytic cells (i.e. active disease) hypersensitivity reactions of the immune usually in less than contain the infection at the system and cause no 24 months site of implantation (i.e. infection via encapsulation) and the bacteria remains dormant TST- / IGRA- (LTBI) TST+ / IGRA+

In the first situation, if bacteria are successfully cleared by the immune system, then test results will remain negative on the tuberculin skin test (TST) or interferon-gamma release assay (IGRA). In the latter situation, latent TB infection can stay dormant and never develop into active disease. This is the most probable occurrence. In less than 5% of cases and after a certain period of dormancy, the infection can progress to active disease during an individual’s lifetime. It has been observed that the Aboriginal population tend to develop primary tuberculosis disease at higher rates within the first 24 month period of infection. This alludes to a possible genetic variation in the cytokine/vitamin D response as witnessed in the Dene/Cree population.

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Figure 2.4: The Pathogenesis of Tuberculosis in the Infected Host (Adapted from the 7th Edition of the Canadian TB Standards)

Exposure to an Infectious Case of TB

No infection Initial Infection Hypersensitivity Reactions

5% 95%

Primary Disease Latent TB Infection (within 2 years)

The probability of primary disease is much 5% 95% greater than 5% in patients with severe immuno-compromising conditions, such as HIV/ AIDS. See Table 2.3 for risk factors. Reactivation TB No Disease

Respiratory Non-respiratory

New Infections

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Figure 2.5: Defense Against Respiratory Infection

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Table 2.2: Respiratory vs. Non-respiratory TB Disease

Respiratory Tuberculosis Disease Non-respiratory Tuberculosis Disease

•Lungs •Peripheral lymph nodes •Conducting airways •Genitourinary system •Pleura •Bone and joint •Intrathoracic lymph nodes •Intestines/Peritoneum/Mesenteric glands •Mediastinum •Brain/Meninges •Nasopharynx •Eye/Retina •Nose •Ear •Sinus •Thyroid •Adrenals •Liver •Spleen •Skin •Myocardium/Epicardium/Pericardium •Oesophagus

Those with reactivated TB disease (in the past referred to as post primary disease) will manifest as respiratory, non-respiratory disease or both in rare cases. The differentiation of both diseases is described in Table 2.2. Non-respiratory disease occurs when the immune system does not contain the bacteria and they gain access to the circulatory system and lymphatic system seeding other organ sites as a consequence. Non-respiratory tuberculosis involvement tends to increase in those with worsening immune compromise.

Risk Factors Specific risk factors have been identified for the development of active TB among persons who are infected with MTB. The lifetime cumulative risk to develop TB disease is 10% and these risk factors influence at various levels of the immune response as it diminishes, leading to the possibility of reactivation.

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Table 2.3: Risk Factors for the Development of Active TB Among People with a Positive Tuberculin Skin Test (Presumed Infected With Mycobacterium Tuberculosis)

Estimated risk factor for Risk Factor development of TB, relative to no known risk factor HIGH RISK Acquired immunodeficiency syndrome (AIDS) 110–170 Human immunodeficiency virus infection (HIV) 50–110 Transplantation (related to immune-suppressant therapy) 20–74 Silicosis 30 Chronic renal failure requiring hemodialysis 10–25 Carcinoma of head and neck 11.6 Recent TB infection (<2 years) 15.0 Abnormal chest x-ray – fibronodular disease 6-19 MODERATE RISK Tumour necrosis factor alpha inhibitors 1.5–4 Diabetes mellitus (all types) 2–3.6 Treatment with glucocorticoids (>15mg/d prednisone) 4.9 Young age when infected (0–4 years) 2.2–5 SLIGHTLY INCREASED RISK Heavy alcohol consumption (>3 drinks/day) 3–4 Underweight (<90% ideal body weight; for most people, this 2–3 is a body mass index <20) Cigarette smoker (1 pack/day) 1.8–3.5 Abnormal chest x-ray – granuloma 2 LOW RISK Person with positive TST, no known risk factor, normal chest 1 x-ray (“low risk reactor”) VERY LOW RISK Person with positive two-step TST (booster), no other known 1 risk factor and normal chest x-ray

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Other important considerations for the development of TB relate to social risk factors and/or more individual risk factors which increase exposure to infectious droplets or impair the host’s defense against infection leading to increased susceptibility to disease (Table 2.4)

Table 2.4: Other Factors for Disease Development

Social Risk Factors Proximal (Individual) Risk Factors

•Low socioeconomic status •Malnutrition •Vulnerable populations (e.g. prisoners, •Smoking tobacco homeless) •Alcohol abuse •Certain ethnic minorities •Wide range of chronic conditions •Immigrants from high endemic countries (e.g. Diabetes) •Aboriginal population •Malignancies •Immunosuppressive conditions i.e. HIV

The causal pathway is not well understood between all these factors and TB; nonetheless, each of these factors adds significantly to the risk of developing TB infection and/or disease.

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2-14NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 3: Bacillus Calmette-Guérin (BCG) Vaccination Section 3 Bacillus Calmette-Guérin (BCG) Vaccination

Description 3-2 Indications for Use 3-3 Infants in High Risk Communities 3-3 Travellers 3-3 Occupational Setting 3-4 Booster Doses and Revaccination 3-4 Administration Procedure 3-4 Safety 3-6 Contraindications 3-6 Adverse Reactions 3-7 Management of BCG Abscess 3-8 Important Considerations 3-9 BCG Vaccine Usage in Canada 3-9

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 3-1 Section 3: Bacillus Calmette-Guérin (BCG) Vaccination

Bacillus Calmette-Guérin vaccine (BCG) is a suspension of a live attenuated vaccine derived from Mycobacterium bovis. It is the only vaccine currently available against tuberculosis. BCG immunization is considered an important component of the TB prevention and control program in the NWT. It is used to prevent people from getting certain forms of TB. BCG vaccine has a documented protective effect against meningitis and disseminated TB in children. It does not prevent primary infection and, more importantly, does not prevent reactivation of latent pulmonary infection (LTBI), the principal source of bacillary spread in the community. (http://www.who.int/biologicals/areas/vaccines/bcg/en/). If infection does occur, it is widely accepted that BCG increases the resistance to uncontrolled multiplication and dissemination of M. tuberculosis from the primary focus of infection to other parts of the lung and body. BCG will not prevent the development of active TB in individuals who are already infected with M. tuberculosis. BCG vaccine efficacy is estimated to be about 51% in preventing any TB disease and up to 78% in protecting newborns from miliary (disseminated) or meningeal TB. (http://www.phac-aspc.gc.ca/publicat/cig-gci/p04-bcg-eng.php#effimm). The populations most affected by TB in Canada (i.e. Aboriginal and foreign born) represent the majority of cases in the NWT. Present TB rates in a number of NWT communities continue to fulfill international criteria for implementing a BCG vaccination program, therefore BCG immunization will continue to be an essential part of the NWT’s TB prevention and control program.

Description BCG vaccine is a lyophilized (i.e. affinity to fat),live attenuated vaccine. This implies that the mycobacterium in the vaccine has been modified. It still has the ability to grow and produce immunity but does not lead to illness. Mycobacterium bovis (Connaught substrain) is used in the vaccine preparation made by Sanofi Pasteur® and is available for use in Canada. In times of vaccine shortage, other manufacturers may be procured. It is imperative that all HCPs review the product monograph carefully, particularly if using an unfamiliar product.

Figure 3.1: BCG Vaccine

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Indications for Use

BCG is currently recommended in Canada. See Canadian Immunization Guide, BCG Chapter): • For infants in high-incidence (TB rates >30/100,000 total cases) settings and; • Travellers returning for extended stays to a high TB incidence country where BCG is routinely given. BCG is NOT recommended for adults, such as HCPs, before travel to high-incidence settings.

Infants in High Risk Communities Vaccination is recommended for infants in First Nations and Inuit communities and for groups of people with an: • average annual rate of smear-positive pulmonary TB greater than 15/100,000 population, or • annual rate of culture-positive pulmonary TB greater than 30/100,000 during the previous 3 years, or • annual risk of TB infection (ARI) greater than 0.1%, or • if early identification and treatment of LTBI are not available.

HIV testing of the infant’s mother must be negative, and there must be no evidence or known risk factors for immunodeficiency in the infant being vaccinated. Typically, BCG is given at birth, but if vaccination is delayed after birth, a TST test is recommended in those over 6 months of age to ensure that the vaccine is only given to TST-negative infants. For infants aged between 2 months and 6 months, an individual assessment of the risks and benefits of tuberculin skin testing before BCG vaccination is indicated. Before an infant receives the BCG vaccine: • The mother’s HIV status is negative • There is no risk or evidence of immunodeficiency in the infant being vaccinated • No history in immediate or extended family of immunodeficiency in the infant being vaccinated (i.e. history of neonatal or infant deaths, history of severe combined immunodeficiency syndrome (SCIDS) or unusual infections)

If any of these conditions cannot be guaranteed, the infant is excluded from receiving the BCG vaccine. A pediatrician should be consulted to help determine the suitability of any infants with questionable immune status.

Travellers Vaccination of travelers is recommended if planning extended stays in areas of high TB incidence, particularly when a program of serial TST and appropriate chemotherapy is not possible or where the prevalence of drug resistance, especially multidrug-resistant TB, is high.

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This recommendation largely pertains to infants born in Canada who will be moving to and/ or staying for extended periods of time in a country with high TB incidence and where BCG vaccination is still standard practice. In this situation, it is often more practical to recommend vaccination prior to arrival in the high-incidence country. For adults, such as health care practitioners, planning temporary travel to high-incidence countries, previous guidelines suggested that BCG vaccination should be considered. In the absence of evidence for the efficacy of BCG in such a situation, this is NO longer recommended. Infection can be monitored using serial skin testing.

Occupational Setting In general, workers do not need BCG vaccine. Appropriate personal protection, environmental controls, treatment of the source, and TB screening and preventative treatment of the exposed person as indicated are the typical approaches to TB control in workers.

Booster Doses and Revaccination Revaccination with BCG is not recommended as there is no evidence that it confers additional protection. Because there is no correlation between skin test reactivity and protection, the TST is not recommended as a method to evaluate immunogenicity.

Administration Procedure

Before administrating the BCG vaccine, the following must always be done:

• Explain risks and benefits of BCG vaccine because the risk of prior TB exposure to parents or individual is low and the sensitivity of the TST at • Obtain informed consent (according to detecting latent TB infection is unknown. your Regional Health and Social Services • If the infant is between 2 and 6 Authority’s policy) months of age: complete an individual • Assess general health and fitness to risk-benefit assessment because the immunize (i.e. HIV status AND past validity of TST in infants under 6 months diagnosis or family history of immune of age is unknown. disorder AND TB exposure) • Perform a one-step TST if infant is • Assure the individual has had a negative >6 months old; therefore plan for next 2-step tuberculin skin test (TST) before visit to read TST (48–72 hours later) and if getting the vaccine. Infants do not require negative give BCG vaccine a 2-step TST. • Wear personal protective equipment • If the infant is less than 2 months of (mask, gloves, and eyewear). age: give BCG vaccine without prior TST The dose in neonates is 0.05ml, half the usual dose of 0.1ml. The higher dose is recommended in children greater than 12 months of age, given intradermally.

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The BCG vaccine is administered as follows: 1. Freeze-dried BCG vaccine should be given, using a disposable syringe and a 26 or 27-gauge needle. 2. Wear protective goggles and gloves. Protective eyewear is required to ensure that an eye splash does not occur. 3. Cleanse the right deltoid area with an alcohol swab and let dry completely.

It is necessary to have two nurses available: one to hold the infant, the other to immunize.

4. Holding the syringe parallel to the skin surface, insert the needle (bevel upward) into the intradermal layer of skin in the upper right deltoid area and slowly inject the solution.

5. Record information required for documentation 1. Date given 2. Dose administered 3. Site of administration 4. Route of administration 5. Lot number of vaccine 6. Name of antigen, manufacturer

6. Advise the parent/guardian to contact clinic if there are any concerns about the reaction/site or patient’s health (see Section 3, Adverse Reactions) 7. Observe site at subsequent visits until healing is complete

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After receiving a BCG vaccine, it is expected that a local reaction occur at the site of injection. For 90–95% of cases, the area becomes red and tender, changes to a vesicle and develops into an ulcer in about 2–4 weeks. The ulcer will take 2–5 months to heal. The remaining lesion at the immunization site is a 2–10mm superficial scar. See Figures below for details.

Figure 3.2: Local Reaction (Progression) of BCG Vaccine at Site of Administration

Day 4 Day 7

Day 14 Day 21

Safety In the event of any exposure to the vaccine (i.e. on a mucous membrane or open wound), wash area thoroughly with saline or water. Contact the OCPHO at (867) 920-8646 for further advice on how to proceed with post-exposure treatment.

Contraindications BCG is a live vaccine. If BCG is given to a person diagnosed with certain immune compromising conditions, they are at high risk of developing disseminated TB disease (severe form of TB). The infant or individual should never receive the BCG vaccine when: • HIV status is positive or unknown • Has immune deficiency disorder or past family history of immune deficiency disorder (i.e. SCIDS) • Has active TB disease or recent TB exposure

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The following are subgroups of the population to whom BCG vaccine should never be given: • Person with a history of anaphylaxis after receiving a vaccine or to any component of the BCG vaccine or its container • Pregnant (deferred after delivery) or lactating women • Immunocompromised person including those with: congenital immunodeficiency, HIV infection, altered immune status because of cancer or transplant, secondary to treatment with corticosteroids, chemo treatment or radiation • Manifestations of extensive skin disease or burns

Maternal human T-cell lymphotrophic virus type 1 infection (HTLV-1) and possible neonatal HTLV-1 infection are not a contraindication to BCG, as neonatal HTLV-1 infection does not result in significant immune suppression in the infant.

After administration of the BCG vaccine, the following must always be done: • Educate parents or patient on expected local reaction and to seek medical attention if severe adverse reactions manifest. • Encourage patient or parents to inform health care providers on evolving healing process. Report all adverse reactions on an Adverse Events Form (AEFI) Following Immunization AEFI form, Section 16 and fax to OCPHO (867) 873-0442

Adverse Reactions Most adverse reactions are mild. Abscess formation and suppurative adenitis may be related to technique of administration, improper dilution or injecting too deeply.

Mild and Expected Reactions: -Erythema -Papule formation - Superficial ulceration three to six weeks after BCG -Scarring of site

Moderate Reactions: -Skin ulceration lasting up to three months, with a tendency to local spread -Regional lymphadenitis -Lipoid (ulcerative) reactions and keloid (scar) formation -Abscess formation

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Moderately Severe Reactions: - Suppurative adenitis (draining lymph nodes) (frequency 1:1000)

Severe Reactions:

-Disseminated BCG infection (frequency <1:1,000,000) which may be fatal

Table 3.1: Adverse Events Following BCG Vaccine and Suggested Management

Complication Management Common and Local Adverse Effects Keloid formation (scar that spreads beyond None; avoid injecting higher up in arm borders of original lesion) None (resolves spontaneously) or topical Local hypersensitivity reaction dressing Less Common And Serious Adverse Effects Conservative approach. Except if Regional lymphadenitis (inflammation suppurating and discharging, see section on causing enlarged axillary lymph nodes) management below Local abscess formation See section below Disseminated disease TB treatment

Management of BCG Abscess • DO NOT INCISE AND DRAIN. -Use warm water compresses over the injection site or suppurating lymph node(s) 4–5 times/day. -Observe and document the progress of the lesion on the monthly NWT Tuberculosis Surveillance and Screening form, Section 16 and on the client health record.

• Cover with dry (non-occlusive) dressing to keep clean. Swab for culture and sensitivity (C&S) only if secondary infection is suspected. • Antibiotic treatment, such as isoniazid (INH), is NOT routinely indicated. • Regional adenopathy in the absence of erythema or vesicle formation should be considered an expected reaction to the vaccine.

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Important Considerations • A TST is a screening test to help diagnose TB infection. The BCG vaccine may cause a positive result when a TST is given after infancy (12 months of age). • Depending on when the vaccine is given, it will influence the outcome of the TST differently. • For further information on how BCG vaccination can influence the TST, see Section 4, TB Screening.

BCG Vaccine Usage in Canada Not all jurisdictions in Canada have BCG vaccine as part of their vaccination programs. Many Aboriginal Canadians and persons born in Quebec and Newfoundland and Labrador were vaccinated between 1940 until the late 1970s. BCG vaccination of First Nations infants has now been discontinued in the Atlantic Provinces and British Columbia. In Alberta, the rationale for continued use of the BCG has been challenged, and a process of systematic withdrawal has begun. Elsewhere, on the prairies and in the territories, the benefits of BCG vaccination in preventing severe forms of TB in infants and young children outweigh any risks.

Table 3.2: BCG Vaccine Usage in Canada

Provinces and Territories Provinces and Territories who have discontinued using BCG who continue to use BCG vaccine*

•British Columbia •Alberta •New Brunswick •Manitoba •Newfoundland and Labrador •Northwest Territories •Nova Scotia •Nunavut •Prince Edward Island •Ontario •Quebec •Saskatchewan •Yukon

*BCG usage differs for different regions, usually according to local epidemiology

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3-10NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 4 TB Screening

Components of Screening 4-2 The Tuberculin Skin Test (TST) 4-3 TST Technique 4-3 Special Considerations Using TST 4-13 Two-Step TST: Distinguishing Between the Booster Phenomenon and Conversion 4-14 Contraindications to TST 4-16 Precautions with TST 4-16 Interferon Gamma Release Assay (IGRA) 4-17

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The use of targeted screening is part of the three basic strategies critical to the prevention and control of TB: 1. Identification of persons with active TB 2. Investigation of contacts of infectious TB 3. Investigation of populations at risk of LTBI and progression to TB disease

Screening and treatment for LTBI should only be undertaken if the local TB Control Program effectively manages active TB cases and contacts and if available infrastructure, resources and monitoring is in place to deliver safe and complete treatment.

Components of Screening • Education and community outreach • Informed consent • Relevant history taking: history of BCG vaccine, contact with active TB, results of previous TST and CXR, and concomitant immune compromising illness present • Clinical evaluation of clients who have a positive TST or are immunocompromised • Complete and accurate record keeping • Compilation of summary data to evaluate and assess the need for an ongoing screening program (including prevalence of active TB, latent infection and treatment rates)

Symptom screens and chest radiography are the primary screening tools when the focus is the identification of prevalent, undiagnosed active cases of infectious pulmonary TB (so as to treat and render them noninfectious). Subsequent microbiologic confirmation with sputum smear and culture or other suitable specimens is always recommended. When screening is focused on the detection of latent TB infection, the preferred screening test is a TST. TB screening activities should be targeting groups most at risk of TB. High risk groups may change over time; therefore, it is important to reassess their risk periodically.

Recommendations for Screening HCPs for LTBI • Baseline two-step TST for all HCPs upon starting work. An exception applies where documented results of a prior two-step TST exist, in which case a single-step TST should be given and prior TST results transcribed into the HCPs health record. • Annual TST for HCPs (with negative baseline TSTs) involved in intermediate-risk activities in health care settings not considered low risk and those involved in high-risk activities in all health care settings. • IGRA is not recommended for serial testing.

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• After 2 or more years of annual screening, if the annual risk of infection (based on TST conversion rate in those screened) is shown to be less than 0.5%, consultation should be made with the OCPHO to consider the possibility of reducing the frequency of screening and/or restricting annual screening to fewer workers who are at higher risk, and not testing the remaining workers except after exposure. Post-Exposure: • Single TST 8 weeks after exposure for TST-negative HCPs exposed without adequate protection to people with respiratory TB disease. -For previously TST-positive HCPs exposed to people with respiratory TB disease without adequate protection refer for medical evaluation and educate on signs and symptoms of active TB disease.

Employers have reported greater success in encouraging HCPs to participate in screening programs when they are performed in conjunction with some other required activity (e.g. orientation, Workplace Hazardous Materials Information System (WHMIS) training, employee updates, vaccination days).

The Tuberculin Skin Test (TST) The TST is the standard method of determining whether a person is infected with MTB and is the test of choice for serial screening purposes. It consists of an intradermal injection of a small amount of purified protein derivative (PPD), derived from Mycobacterium tuberculosis bacteria. These extracts are also referred to as tuberculins. Its components have antigenic properties triggering a cell-mediated delayed hypersensitivity response that the immune system recognizes due to its similarities with the tubercle bacilli causing infection. This reaction is limited to the site of injection. Epinephrine hydrochloride solution (1:1000) and other appropriate agents should be routinely available for immediate use in case an anaphylactic or other acute hypersensitivity reaction occurs. Health care providers should be familiar with the current recommendations of the National Advisory Committee on Immunization (NACI) on monitoring the patient for immediate reactions over a period of at least 15 minutes after inoculation and for the initial management of anaphylaxis in non-hospital settings.

TST Technique The TST is an intradermal test conducted in three stages: 1) Administration 2) Reading 3) Interpretation. All tests should be performed, measured and interpreted by a trained health care professional. A positive test should be confirmed by two people with experience in interpreting the TST.

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Administration of the TST • Tubersol® 5 tuberculin units (5-TU) of purified protein derivative – standard (PPD-S) is recommended in Canada. Store at 2° to 8° C, but do not freeze. Discard the solution if frozen. • Remove the tuberculin solution from the vial under aseptic conditions. A little more than 0.1ml of PPD solution should be drawn into the TB syringe. Hold the syringe upright and lightly tap out the air, then expel one drop. Check that a full 0.1ml remains in the syringe. • Do not transfer the solution from one container to another (the potency of the PPD may be diminished). • Draw up the solution just before injecting it. Do not preload syringes for later use as the potency of the PPD may be diminished. • The solution can be adversely affected by exposure to light. PPD should be stored in the dark except when doses are actually being withdrawn from the vial. • Discard the solution if the vial has been in use for longer than 1 month or for an undetermined amount of time (the potency of the solution may be diminished). • Use the solution within 1 month after opening. Label each bottle with the discard date when it is opened. • If the TST is accidentally given as a subcutaneous or an intramuscular injection, this should not pose a serious problem. It is possible that tuberculin-sensitive people would have localized inflammation, which should be self-limited. It would not be possible to take a measurement of or clinically interpret any such reaction, so the TST should be administered again but using proper intradermal technique on the volar surface of the forearm. This should be done immediately (as soon as it is realized that the injection was too deep).

1. Locate and clean injection site

• Avoid any areas with abrasions, swelling, visible veins or lesions • Use inner aspect of forearm about 10cm below elbow • Cleanse the area with an 10cm alcohol swab and let it dry

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2. Prepare Syringe

3. Inject Tuberculin

Insert slow intradermal injection, bevel up at 5–15° degrees

After injection, look for a tense, pale wheal at needle point

4. Record Information • Record all the information required for documentation: -Date of injection -Dose -Lot # -Manufacturer -Expiration date -Site of injection -Person administering the TST

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Reading of the TST The TST should be read 48–72 hours after administration as the reaction to tuberculin causes maximal induration at 48–72 hours and subsides over a period of days. After 72 hours it is difficult to interpret a reaction.

Reactions may persist for up to 1 week, but for as many as 21% of individuals with a positive reaction at 48 to 72 hours the reaction will be negative after 1 week. If the TST cannot be read within 72 hours because of unforeseen circumstances, it should be repeated at a location far enough from the previous test that the reactions do not overlap. No minimum wait is required before the repeat test.

1. Inspect Site

Erythema (redness) Do Not Measure

Visually inspect under appropriate lighting

Measure Induration (hard, dense, raised formation)

2. Palpate Induration

Use fingertips to find margins of induration

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3. Mark Induration

• Mark the border of induration by moving the tip of a pen at a 45° angle laterally toward the site of the injection • The tip will stop at the edge of induration if present.

4. Measure induration (not redness)

• Use a caliper ruler to measure the distance between the pen marks, reflecting the transverse diameter of the induration • Disregard the redness • Record no induration as “0mm”. • Do not round off the diameter of the induration to the 5. Record measurement of transverse nearest 5mm as this induration in mm. can interfere with • Record all the information required for determining whether documentation: TST conversion has occurred in the event -Date the induration was read of a future TST. If the -Transverse measurement of measurement falls induration in mm (this is recorded between demarcations as one number i.e. 18mm not 18mm on the rules, the smaller x15mm). All TST readings, whether of the two numbers negative or positive should be should be recorded. recorded numerically and NEVER recorded as “negative” or “positive” -Any adverse reactions -Name of individual reading the test -Provide a record of the TST result to the individual tested

*All test results should be recorded on the NWT Tuberculosis Surveillance form and reported to the OCPHO (as per Public Health Act (2009)

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Interpretation of the TST When a TST is performed, the final result reflects a biological response that is presented as a TST reaction at the site of TST testing. This reaction will help determine if an individual is possibly infected with TB. Many factors can influence how a TST is interpreted. This is discussed in the following sections. A negative test results occurs if: • No reaction at TST testing site • Induration is less than 5mm

There are some circumstances that cause a result to be a false negative. There are technical and host-related factors that can influence this to happen.

Figure 4.1: TST Interpretation

Negative TST result

True Negative False Negative

Technical reason Host-related reason

Technical-related factors that cause false negative TSTs include the following: • Tuberculin used • Poor technique • Reader variability -Improper storage -Injection of too little -Inexperienced reader -Improper dilution antigen -Error in recording -Chemical denaturation -Subcutaneous injection -Conscious or -Contamination -Delayed administration unconscious bias after drawing into -Adsorption syringe -Injection too close to other skin tests

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Host-related factors that have been shown to cause a false negative TST are mostly for biological reasons, and include the following: • Immunosuppression due to -Advanced age - Treatment with corticosteroids (≥15mg/day of prednisone or equivalent) -Cancer treatment agents -HIV infection (especially CD4 count <500 x 106/L) -Tumor necrosis factor (TNF)- alpha inhibitors

• Malnutrition (particularly if recent weight loss) • Severe illness (including active TB) • Major viral illness (including mononucleosis, mumps or measles) • Immunization with live vaccines within 4 weeks such as Measles, Mumps, Rubella, Varicella (chicken pox) or Yellow Fever • Very young age (less than 6 months)

Individuals with an impaired immune response are unable to react to a TST test. They are referred to having an anergic response. As described above, a negative TST does not exclude the possibility of having TB infection or disease due to the numerous factors that can cause this to happen.

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Size The first dimension is the size of the TST reaction. Three cut points have been established according to the sensitivity and the specificity of the TST test and the prevalence of tuberculosis in different groups.

Table 4.1: Tuberculin Skin Test Cut-points for Interpretation of the TST

TST Result Indication* 0–4mm In general this is considered negative and no treatment is indicated† Child less than 5 years of age and high risk of TB infection‡ ≥5mm HIV infection Contact with infectious TB within the past 2 years Fibronodular disease on chest x-ray (healed TB and not previously treated) Organ transplantation (related to immune suppressant therapy)** TNF alpha inhibitors Other immunosuppressive drugs, e.g. corticosteroids (equivalent of ≥15mg/day of prednisone for 1 month or more; risk of TB disease increases with higher dose and longer duration) End-stage renal disease

≥10mm TST conversion (within 2 years) Diabetes, malnutrition (<90% ideal body weight), cigarette smoking, daily alcohol consumption (>3 drinks/day) Silicosis End-stage renal disease Hematologic malignancies (leukemia, lymphoma) and certain carcinomas (e.g. head and neck)

*Age >35 years is not a contraindication to treatment of LTBI if the risk of progression to active TB disease is greater than the risk of serious adverse reactions to treatment. †Treatment with INH of people with HIV infection who were TST negative (0–4mm) and/or anergic was of no benefit in several randomized trials. Other authorities suggest this treatment may be considered in the presence of HIV infection of other cause of severe immunosuppression AND high risk of TB infection (contact with infectious TB, from high TB incidence country or abnormal chest x-ray consistent with prior TB infection). Hence any decision to give treatment should be individualized in consultation with a TB expert. ‡If first TST test is negative, begin treatment immediately. Repeat TST 8 weeks after exposure to infectious TB case ended. Treatment can be stopped in a healthy child if repeat TST is negative. In children <6 months of age the immune system may not be mature enough to produce a positive TST, even if the child is infected. See Section 9, Pediatric Tuberculosis. **LTBI therapy is often given to people in whom transplantation is planned but before the actual transplantation.

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Positive Predictive Value of TST Another consideration of the interpretation of the TST is the positive predictive value (PPV) of the TST. PPV is the likelihood a positive test, represents a true TB infection. The higher the PPV, the more confident you are in the positive test result of the TST. You can estimate what the PPV is by considering the following factors: the prevalence of TB where the patient is from and if the patient is exposed to anything that causes the TST result to be falsely positive. The PPV is influenced by the prevalence of TB in the population. Therefore the higher the prevalence of TB, the more confident you are in the positive result of the TST. There are two main reasons that would cause a false positive reaction decreasing the specificity of the TST and in turn decreasing the PPV. The first are non-tuberculosis mycobacteria or NTM, which do not cause tuberculosis. However, the similarities of NTM with M. tuberculosis cause a cross-reaction in people with past exposure to NTM leading to a small positive tuberculin reaction (5–9mm). NTM are not very common in Canada but prior NTM exposure should be considered in patients from tropical, subtropical, or warm temperate climates.

Positive Predictive Risk of developing Size Value of TST active disease

•Is the patient •Past exposure to •Are they among the immunocompromised? NTM? high, increased or •Has there been a •Previous vaccination low risk categories? recent exposure to an with BCG? active case? •Are they from a •Do they have an community with high/ abnormal CXR? low prevalence of TB?

The second reason is due to prior BCG vaccination. If vaccinated with BCG in the past, it can influence the result of the TST. People vaccinatedafter 12 months of age have a greater chance of causing this false TST reaction. Populations who may have received BCG include: • Persons born in developed countries or where TB is endemic • Aboriginal persons from communities with high rates of TB (in the NWT most infants vaccinated with BCG are vaccinated in infancy <12 months of age) • Older Canadian-born persons, particularly health care practitioners

BCG vaccination can be ignored as a cause of a positive TST under the following circumstances: • BCG vaccination was given in infancy, and the person tested is now aged 10 years or older • There is a high probability of TB infection: such as those persons who are close contacts of an infectious TB case, Aboriginal Canadians from a high-risk community or immigrants/visitors from a country with high TB incidence • There is high risk of progression from TB infection to disease

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BCG should be considered the likely cause of a positive TST under the following circumstances: • BCG vaccine was given after 12 months of age AND • There has been no known exposure to active TB disease or other risk factors AND • The person is either Canadian-born non-Aboriginal OR • An immigrant/visitor from a country with low TB incidence.

Figure 4.2: The BCG World Atlas

http://www.bcgatlas.org/

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Special Considerations Using TST Interpretation When Serial (Repeated) TST Is Performed Nonspecific Variation Because of differences in the technique of administering or reading the TST or because of biologic differences in response, there may be differences in the same individual from test to test of as much as 5mm in reaction size. Therefore, 6mm has been selected as the criterion to distinguish a real increase from nonspecific variation.

Conversion Conversion is defined as the development of a delayed hypersensivity reaction with a TST in individuals with no history of previous TB infection. Conversion occurs when exposed to M. tuberculosis, NTM or with BCG vaccination. People who have undergone skin test conversion may be referred to as converters or Conversion positive converters describing the increase in reaction size of July 2008 – 0mm 6–10mm or more within a 24 month period. (See example.) June 2010 – 10mm True TST converters are classified as having a new or recent infection. However, due to the booster phenomenon it can be mistaken as a true test conversion when it actually is not. The two-step TST can help discern between these root causes of TST reactions. The most helpful guide in distinguishing conversion from the booster effect described in the next section is the clinical situation. If there has been recent exposure, such as close contact with an active case or occupational TB exposure, conversion will be more likely than when there has been no exposure. Conversion is defined as a TST of 10mm or greater when an earlier test resulted in a reaction of less than 5mm. If the earlier result was between 5 and 9mm, the definition of conversion is more controversial. There are at least two criteria in use, although neither have strong supportive evidence: 1. An increase of 6mm or more – this is a more sensitive criterion, recommended for those who are immunocompromised, or in the context of an outbreak. 2. An increase of 10mm or more – this is a less sensitive but more specific criterion. In general, the larger the increase, the more likely that it is due to true conversion.

All available experimental and epidemiologic evidence consistently shows that TST conversion occurs within 8 weeks of exposure. Therefore, adopting 8 weeks as the maximum interval for conversion following exposure allows newly infected contacts to be identified a month sooner. It is also more practical for casual contacts, who can be tested once only after 8 weeks, and it results in fewer problems of interpretation because of the booster effect.

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Booster Phenomenon When individuals are sensitized to M. tuberculosis, it usually persists throughout life and should reflect in every subsequent TST test done. However, some people will experience a decrease in the size of the reaction to the point it disappears. For these people, there is waning of their immune response to TB over time. The booster phenomenon occurs when a person’s immune response has waned. They will have an increased TST reaction not caused by a new infection but by the stimulation of their immune response to the TST. Yet, it could be incorrectly interpreted as a recent conversion with TB. A careful risk (medical and social) assessment should be done with the client to determine whether the benefits of treatment of LTBI outweigh the risks of not treating. For clients who have had BCG vaccination after age one, consider testing with IGRA. The booster effect has been described in the following individuals: • Older adults • BCG vaccinated populations • Individuals with prior exposure to NTM

Reactor If a person has a history of being infected with TB but the positive Reactor TST result is undocumented or a negative TST result is documented 2005 0mm TST more than 2 years ago with a current positive TST result due to an 2013 17mm TST unknown history of exposure, they are referred to as a reactor.

Two-Step TST: Distinguishing Between the Booster Phenomenon and Conversion To help discern between the booster phenomenon and conversion reactions, a two-step TST can be done. It provides an accurate baseline for individuals who will have repeated testing or who may have exposure to an infectious TB case (e.g. health care practitioners). The two-step TST requires the administration of two TSTs using the same techniques described in previous sections. A two-step TST is appropriate for the following situations: • Subsequent skin testing will be done regularly (e.g. health care practitioners) • Residents in long term care facilities on admission, should have a two-step TST (if no previous 2 two-step) • Staff who might be working with TB positive patients or clients (e.g. staff in correctional facilities)

Two-step TSTs are: • Performed once and documented for future reference • Never repeated but subsequent one step TST can be done if appropriate • Never done during a contact investigation. See Section 10, Role of Public Health in TB Prevention and Control in the NWT.

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Figure 4.3: Description of Two-Step TST Testing

(First Test)

Baseline Skin Test

negative What is the positive reaction?

Person probably has positive Retest in 1–4 weeks TST, must perform TB Assessment, Section 5.

(Second Test)

negative What is the positive reaction?

Person does NOT The reaction is a booster have TB Infection reaction, must refer to OCPHO to determine appropriate clinical management

Repeat TST testing as per patient’s level of risk/exposure to TB

Adapted from CDC Core Curriculum on Tuberculosis, website: http://www.cdc.gov/tb/education/core- curr/pdf/chapter3.pdf

The results from the second test will assist in ruling out a booster phenomenon. All TSTs must be reported to OCPHO.

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Contraindications to TST A TST must not be conducted in persons with the following: • History of a severe reaction to a TST such as blistering, necrosis, or ulceration • Extensive eczema or burns at the TST testing site • Documented active TB or documented history of adequate treatment (i.e. TST does not distinguish between prior and recent infection, and will not yield any useful information in this case) • Diagnosed with major viral infections (e.g. mononucleosis, mumps) • Documented previous positive reaction read by a healthcare professional • Recent history of measles immunization within the past 4 weeks; although no data is available with other live vaccine – mumps, rubella, varicella, and yellow fever- there is a theoretical risk therefore prudent to follow the same 4 week guideline

A person can receive a TST if they: • Have a common cold • Are pregnant or breast-feeding • Are immunized with any vaccine the same day • Are immunized within the previous 4 weeks with vaccines different from what was listed earlier • Have a history of a positive TST reaction that is not documented (unless the patient recalls having a positive or blistering reaction in the past) • Are taking a low dose of systemic corticosteroids <15mg prednisone (or equivalent); it takes a steroid dose equivalent of ≥15mg prednisone daily for 2–4 weeks to suppress tuberculin reactivity

Precautions with TST There is a potential risk for an adverse allergic reaction with the use of Tubersol®. Nine reported cases in 14 million doses distributed in Canada (equivalent to a rate of 1 per million doses) led to serious allergic reactions and/or allergic-related symptoms temporally associated with tuberculin skin testing. The Canadian post-marketing surveillance system for vaccine associated adverse events noted that case reports included: • Anaphylaxis • Angioedema • Oedema • Urticaria and/or dyspnea • Throat swelling/tightness • Lip swelling • Hives

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These cases also included patients that did not have previous exposure to tuberculin. It is imperative that health care providers should have Epinephrine Hypochloride solution (1:1000) and other appropriate agents available for immediate use in the case of a hypersensitivity reaction. As per NACI, recommendations all patients must be monitored for 15 minutes after inoculation.

Interferon Gamma Release Assay (IGRA) Interferon gamma release assay (IGRA) is a blood test that has recently been introduced as another method to diagnose LTBI. Therefore, it can complement the TST in certain situations. In general, IGRAs are more specific than the TST in populations vaccinated with BCG, especially if BCG is given after infancy or multiple times. When a person is exposed to MTB it produces many immune cells, which produce various proteins. Among these proteins are interferon gamma or IFN-y. The interferon gamma release assay (IGRA) is a blood test that measures IFN-y. Therefore, if a person has been exposed and infected with TB, IFN-y can be detected with this test. There are two IGRA tests used in Canada, the T-SPOT.TB test and the QuantiFERON®-TB Gold test. Provincial Laboratory (ProvLab) Alberta uses QuantiFERON®-TB Gold (QFT) test in the NWT. Specimens must be received by the regional laboratory and incubated for 16–24 hours. This limits availability of this test in the NWT. IGRA can only be ordered through the Office of the Chief Public Health Officer and Stanton Regional Hospital Specialists who are involved in TB management and treatment. IGRAs require laboratories with adequate equipment and trained personnel to perform the assays. In addition, IGRAs require fresh blood samples: pre-analytical steps and transportation delays can affect test performance.

Table 4.2: QuantiFERON®-TB Gold (QFT) Assay

QuantiFERON®-TB Gold (QFT) assay

•Uses whole blood •Mixes blood + MTB antigen components •Measures amount of IFN-Y (concentration: IU/ml) •Possible Results: positive, negative or indeterminate

(Adapted from CDC fact sheet: http://www.cdc.gov/tb/publications/factsheets/testing/IGRA.pdf)

There can be difficulty in how to interpret disagreement between TST and IGRA tests results (positive TST and negative IGRA and vice versa). It makes interpretation and appropriate management difficult. More studies are required to understand these contradictions. Advantages and important limitations of IGRA tests are listed in the table on the following page.

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Table 4:3: Advantages and Disadvantages of IGRA Tests

Advantages Disadvantages

•Requires one visit to screen for TB •Blood samples are required (rather than 2 visits for TST) •Technical errors in collecting, •Does not cause a booster transporting or interpreting results phenomenon decreases the accuracy of the test •Prior BCG vaccination does not cause •Limited evidence on the use of IGRA a false positive result to predict those who will progress to having TB disease

(Adapted from CDC fact sheet http://www.cdc.gov/tb/publications/factsheets/testing/IGRA.pdf)

While both the TST and IGRA are acceptable alternatives for LTBI diagnosis, TST is the preferable choice in NWT due to transport constraints in the smaller communities for IGRA specimens. Indications and exceptions for the use of these screening tests are outlined below.

1. Situations in which neither TST nor IGRAs should be used for testing • Neither the TST nor the IGRA should be used for testing people who have a low risk of infection and a low risk that there will be progression to active TB disease if they are infected. However, low-risk individuals are commonly tested before exposure, when repeat testing is likely. In this situation TST is recommended (see 3 below); if the TST is positive then an IGRA may be useful to confirm a positive TST result to enhance specificity. • Neither TST nor IGRA should be used for active TB diagnosis in adults (for children, see 4). • Neither TST nor IGRA should be used for routine or mass screening for LTBI of all immigrants (adults and children). • Neither TST nor IGRAs are useful tools for monitoring anti-TB treatment response.

2. Situations in which IGRAs are preferred for testing but a TST is acceptable • People who have received BCG as a vaccine after infancy (1 year of age) and/or have received BCG vaccination more than once. • People from groups that historically have poor rates of return for TST reading.

3. Situations in which TST is recommended for testing but an IGRA is NOT acceptable • The TST is recommended whenever it is planned to repeat the test later to assess risk of new infection (i.e. conversions), such as repeat testing in a contact investigation, or serial testing of health care or other populations (e.g. corrections staff or prison inmates) with potential for ongoing exposure.

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4. Situations in which both tests can be used (sequentially, in any order) to enhance sensitivity • Although routine dual testing with both TST and IGRA is not recommended, there are situations in which the results from both tests may be helpful to enhance the overall sensitivity: -When the risk of infection, of progression to disease and of a poor outcome are high. -In children (under age 18 years) with suspected TB disease, IGRAs may be used as a supplementary diagnostic aid in combination with the TST and other investigations to help support a diagnosis of TB. However, IGRA should not be a substitute, or obviate the need, for appropriate specimen collection. A negative IGRA (or TST) does NOT rule out active TB at any age and especially not in young children. -In addition, repeating an IGRA or performing a TST might be useful when the initial IGRA result is indeterminate, borderline or invalid and a reason for testing persists. - IGRA testing can be used as a supplementary test to increase the specificity of the TST for those determined to have borderline positive TSTs.

Importance of Considering the Clinical Context The results of both TST and IGRA should be interpreted with other relevant clinical information, such as age, BCG status, history of contact with active TB and factors that increase the risk of progression to active disease. An online TST/IGRA algorithm (www.tstin3d.com) has been developed to facilitate the three-dimensional interpretation of these tests. All individuals with positive TST or IGRA results should undergo evaluation to determine whether they have LTBI or active TB disease and be managed accordingly.

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4-20NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 5 TB Assessment

Rationale 5-2 Signs and Symptoms 5-4 Baseline Investigations 5-5 Goals of Treatment 5-5

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 5-15-1 Section 5: TB Assessment

Once a TST result (or other screening test) is evaluated as positive (see Table 4.1, Section 4), a TB Assessment must be performed. The TB assessment will help determine the possibility of active TB disease (see NWT Tuberculosis Assessment Form). A thorough TB assessment includes: • Reviewing risk factors and co-morbidities for TB through history taking: -Advanced age, medical conditions, history of TB exposure, status of immune system

• Assessing presence of symptoms and looking for physical signs by examining the patient for: -Cough, night sweats, coughing up blood, loss of appetite, unexplained weight loss

• Investigating with a CXR and microbiological testing (i.e. sputum specimen): -CXR abnormalities typical of disease, acid-fast bacilli (AFB) staining and culture of sputa (or other samples) for MTB

These indicators will help determine if the TB case definition is fulfilled to confirm a case. All the information requested on the NWT Tuberculosis Assessment Form is required for the OCPHO to make an informed recommendation. Please answer all the questions on the form; sign and date the form; fax it to the OCPHO (867-873-0442).

Rationale • Untreated TB is easily transmitted especially to household members or other close contacts, particularly amongst children and to immunocompromised persons. • Early diagnosis and treatment is paramount to eliminating TB. • Tracing contacts and treating those with LTBI are important to reduce the emergence of new TB cases. • Other information can also serve as clues for the diagnosis of TB disease. The NWT Tuberculosis Assessment Form indicates all pertinent information that should be gathered when assessing a patient.

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Figure 5.1: Assessment of an Individual With a Positive TST Result

+ TST Result

Notify TB Program Coordinator (OCPHO) Must rule out active TB

NWT Tuberculosis Assessment Form to be completed: • Risk factors • Symptoms/signs • CXR • Sputa testing

• No risk factors • Patient history with risk factors • No symptoms/signs • Presence of symptoms/signs • CXR: as baseline - may show • CXR: abnormalities typical of TB evidence of TB infection disease (granuloma or Ghon complex) • Sputa tesing positive • Sputa testing negative (microscopy and/or culture)

Active TB disease ruled out Active TB disease ruled in

LTBI Control measures applied: treatment and isolation

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Signs and Symptoms Signs and symptoms of active TB disease can vary greatly and may depend upon: • Site of disease • Host immune response (e.g., presence of coexisting infections/conditions that impair immune function) • Severity of illness at the time of presentation • Ability and/or willingness of the individual to recognize and/or report symptoms/signs

Signs and symptoms suggestive of many forms of active TB disease include: • Fever and night sweats (may be absent in the very young and the elderly) • Fatigue/weakness • Anorexia (loss of appetite) • Weight loss • Hemoptysis

Symptoms consistent with active respiratory TB disease include: • Cough of at least two weeks duration (may start as dry cough but as disease progresses, cough becomes productive) • Chest pain (pleuritis)

Individuals who have active non-respiratory forms of TB disease may notice other, more specific symptoms and/or signs such as pain or dysfunction at the involved site(s). Many forms of active TB disease are non-respiratory, therefore it is important to remain alert for signs such as lymphadenopathy, pleural effusion, or abdominal, central nervous system, bone and joint involvement. This is particularly critical when examining infants, young children, and those who are immune-suppressed. These individuals are at increased risk of presenting with severe, non-respiratory forms of TB disease such as disseminated TB and TB meningitis. Delay in diagnosis may significantly contribute to morbidity and mortality from TB.

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Baseline Investigations • TST (unless previously positive test) • CXR • Three sputa for AFB (spontaneous or induced) • Gastric washings may be indicated for children less than 12 years old or elders who cannot expectorate (sputum induction may also be considered in these age groups) • Blood work: Erythrocyte Sedimentation Rate (ESR), Complete Blood Count (CBC), Platelets, Alanine Transferase (ALT), Blood Urea Nitrogen (BUN), Creatinine, Total Bilirubin • Urinalysis (routine and microscopy (R&M)) • HIV test and counseling (if applicable) • Uric acid (if Pyrazinamide (PZA) used during treatment) • Hearing test (if Streptomycin (SM) used during treatment) • Visual acuity test (if Ethambutol (EMB) used during treatment) • Hepatitis C in high risk populations (homeless and intravenous drug user IDU)

Goals of Treatment • To eliminate MTB from the individual with active TB • To reduce transmission of MTB • To eliminate MTB from the community • To prevent drug resistant TB by ensuring treatment completion and by never using monotreatment for treatment of active TB

For specific information on Treatment, seeSection 8, Treatment for Tuberculosis. If a patient does not show any evidence of active TB disease, this diagnosis can be ruled out. A recommendation for LTBI preventive treatment can be offered to those with risk of developing TB disease, see Table 2.3, Section 2 for various risk levels for progression of disease. If the patient is symptomatic or there are abnormalities in the CXR indicating TB disease, then further evaluation is warranted. Control measures are put into practice by isolating the patient and possibly giving empiric treatment until all investigations are completed. See Section 7, Management of TB and Section 8, Treatment for Tuberculosis.

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5-6NWT Tuberculosis Manual - JuneNovember 2014 2014 SectionSection 7 Bacillus 6 Calmette-GuérinDiagnosis of (BCG)TB (Latent vs.Vaccination Active Disease)

Latent TB Diagnosis of Latent Tuberculosis Infection (LTBI) 6-2 Guidelines for Use: TST or IGRA 6-2 Tuberculin Skin Test (TST) 6-3 Chest Radiography Sub Section 6-3

Active TB Diagnosis of Active TB 6-6 Respiratory TB 6-6 Clinical Presentation 6-6 Microbacteria Testing: AFB Smear and Culture 6-9 Respiratory Specimen Collection 6-11

Non-respiratory TB Non-respiratory TB 6-17 Clinical Presentations 6-17 Radiography 6-18

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 6-1 Section 6: Diagnosis of TB (Latent vs. Active Disease) Latent TB

Diagnosis of Latent Tuberculosis Infection (LTBI) LTBI is the presence of latent or dormant infection with Mycobacterium tuberculosis with no evidence of clinically active disease. The immunocompetent host generally has a lifetime risk of infection progressing to active disease (reactivation) in the range of 10%. Subjects deemed to have LTBI are by definitionnon-infectious . Depending on their contact history, age, chest radiographic findings, and associated medical conditions, they may be candidates for preventative treatment. It is important to consider treatment of LTBI to eliminate the seed pool of infection in a population.

Table 6.1: Latent TB Infection vs. Active Respiratory TB Disease

TB Infection (LTBI) Active TB Disease (pulmonary)

CXR usually normal CXR usually abnormal Sputum smears and/or cultures usually Sputum smears and cultures negative positive Symptoms such as cough, fever, weight No symptoms of disease loss Not infectious Often infectious before treatment Infected with TB germ (LTBI) BUT not an active An active case of TB case of TB

Guidelines for Use: TST or IGRA • Neither TST nor IGRA should be used for testing people who have a low risk of infection and a low risk that there will be progression to active TB disease if they are infected. Only those who would benefit from treatment should be tested, so a decision to test presupposes a decision to treat if the test is positive. • This means that screening for LTBI in people or groups who are healthy and at low risk of active disease development is discouraged, since the positive predictive value of TST or IGRA is low and the risks of treatment will often outweigh the potential benefits. TB screening programs should be focused on identifying those at risk for developing TB. • Moreover, screening for LTBI should be undertaken only when there is an a priori commitment to treatment or monitoring should test results be positive. • However, it commonly occurs that low-risk individuals are tested before exposure, when repeat testing is likely. In this situation TST is recommended; if the TST is positive then an IGRA may be ordered in consultation with OCPHO or Internal Medicine to confirm a positive result to enhance specificity. • Neither TST nor IGRA should be used for active TB diagnosis in adults or children. A negative TST or IGRA does not rule out active TB at any age and especially not in young children. • Neither TST nor IGRA should be used for routine or mass screening for LTBI of all immigrants (adults and children).

6-2 In the NWT, THINK TB! In the NWT, THINK TB! Latent TB Section 6: Diagnosis of TB (Latent vs. Active Disease)

• In a person who has received BCG as a vaccine after infancy (1 year of age) or has received more than one BCG vaccination, IGRA is preferred. • In those who have historically poor rates of return for TST readings; IGRA may be preferred. • The TST is recommended whenever it is planned to repeat the test later to assess risk of new infection (i.e. conversions), such as repeat testing in a contact investigation or serial testing of health care or other populations (e.g. corrections staff or prison inmates) with potential for ongoing exposure. In this scenario, a two-step TST is performed (see Section 4, TB Screening).

Tuberculin Skin Test (TST) The most commonly used tool for diagnosing LTBI is the TST. Testing for LTBI is indicated when there is a risk of an individual developing active TB disease, particularly for the following individuals: 1. Recent exposure to TB (highest risk is within 2 years of exposure) 2. Medical conditions or weakened immunity (i.e. HIV, cancer, etc.) See Table 2.3, Section 2 3. Radiological evidence of an old healed inactive TB lesion but no prior treatment given TST technique is described in Section 4, TB Screening.

Chest Radiography Although chest radiography is not used for diagnosing LTBI, if it has been done previously for other clinical purposes it can provide clues to previous TB infection. If a patient has a TST reaction size >5mm, the following signs on the CXR are indicative of previous TB infection (i.e. LTBI): • Granulomas that are or are not calcified hilar nodes • Costophrenic angle blunting See CXR examples in the following figures.

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 6-3 Section 6: Diagnosis of TB (Latent vs. Active Disease) Latent TB

Figure 6.1: Calcified Granulomas Indicated by Arrows (Image from Medscape)

Figure 6.2: Calcified Hilar Nodes Indicated by Lines

http://www.stanford.edu/dept/radiology/radiologysite/site51.html)

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Figure 6.3: Right Costophrenic Angle

BLUNTING (image from: http://radiologymasterclass.co.uk/tutorials/ chest/chest_pathology/chest_pathology_page6.html)

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Diagnosis of Active TB Proper diagnostic evaluation is essential before anticipating any treatment for active TB disease because the risk of unnecessary or inadequate treatment can lead to undue harm of the patient and encourage multidrug-resistant TB. The diagnosis of active TB disease involves: 1. Clinical presentation 2. Radiographic evidence 3. Diagnostic microbiology

A diagnosis of TB (respiratory and non-respiratory) should ALWAYS result in an HIV test.

Respiratory TB In Canada, respiratory TB includes primary TB, pulmonary TB, and tuberculous pleurisy (nonprimary) and TB of the intrathoracic lymph nodes, mediastinum, nasopharynx, nose (septum) and sinus (any nasal). Pulmonary TB refers to TB of the lungs and conducting airways, which includes tuberculous fibrosis of the lung, tuberculous bronchiectasis, tuberculous pneumonia, tuberculous pneumothorax, isolated tracheal or bronchial TB, and tuberculous laryngitis.

Clinical Presentation TB disease can cause systemic manifestations or more specific symptoms depending on the organ affected by the disease. Pulmonary TB disease can cause one or more of the following symptoms.

Table 6.2: Symptoms of Pulmonary TB Disease

Symptoms of Pulmonary TB Disease

• Cough lasting at least 2 weeks duration (i.e. dry at first then becomes productive) •Fever •Night sweats •Fatigue •Coughing up blood (i.e. hemoptysis) •Loss of appetite (i.e. anorexia) •Unexplained weight loss •Chest pain (pleurisy)

6-6NWT Tuberculosis Manual - JuneNovember 2014 2014 ActiveLatent TB SectionSection 6: 6: Diagnosis Diagnosis of of TB TB (Latent (Latent vs. vs. Active Active Disease) Disease)

The physical exam is unlikely to find any physical findings that are conclusive for a definite diagnosis of respiratory TB disease. This is the case even in advanced disease, since physical findings are not specific to just TB; however, it does give an overall impression of the status of the patient.

Infected children under the age of 5 have a high risk of progression to severe forms of TB such as pulmonary TB, TB meningitis or miliary disease. Older children and adolescents present with symptoms of adult-type disease. Thus, they may present with the classic triad of symptoms: fever, weight loss and night sweats.

Chest Radiography Chest radiography is a complimentary tool towards a diagnosis of pulmonary TB disease, and should be performed in any patient suspected of having pulmonary TB disease. It is important to be aware that chest radiography has substantial limitations in the diagnosis of pulmonary TB disease. Posterior-anterior [PA] and lateral radiographs are the standard views to see any chest abnormalities. Typical findings seen in individuals with a normal immune system, especially in reactivated TB, include: • Position – infiltrates in the apical-posterior segments of upper lobes or superior segment of lower lobes in 90% • Volume loss – this is a hallmark of TB disease because of its destructive and fibrotic nature • Cavitation – this is seen at a later stage and depends upon a vigorous immune response, therefore often not seen in immunocompromised individuals

Figure 6.4: Lung Cavitation in Left Upper Lobe

(Image from Medscape reference: http://img.medscape.com/pi/features/slideshow-slide/CXR/fig11.jpg)

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Figure 6.5: Chest Radiograph with Left Lower Lobe Cavity

(Image from: CDC (2011), reference guide for physicians)

In children, PA and lateral radiographs are required to detect hilar and paratracheal lymphadenopathy, the most common features of pediatric TB. Parenchymal lesions may be found anywhere in primary disease and are typically, but not always, in the upper lobes. Cavitation is rare in children but can be seen in children with adult-type disease or caseating pneumonia. In patients who are immunocompromised (e.g. HIV infection, corticosteroid use, other), there are specific features found on CXR: • Hilar and mediastinal adenopathy • Non-cavitary infiltrates and lower lobe involvement

Certain complications that may be diagnosed radiographically include: • Endobronchial spread of the disease (Tree in Bud appearance) • Pleural effusion • Pneumothorax

6-8NWT Tuberculosis Manual - JuneNovember 2014 2014 ActiveLatent TB SectionSection 6: 6: Diagnosis Diagnosis of of TB TB (Latent (Latent vs. vs. Active Active Disease) Disease)

Microbacteria Testing: AFB Smear and Culture The purpose of microbiological lab testing is to detect, isolate and identify the mycobacterial species and determine the drug susceptibilities of the organisms to anti-TB drugs.

Acid-Fast Bacilli (AFB) Staining and Microscopic Examination AFB stained smears are the first bacteriological evidence of mycobacteria in a clinical specimen, giving a quick and easy preliminary confirmation of the diagnosis. Essentially, the specimen is put on a microscope slide, stained and examined under the microscope. Mycobacteria are rod shaped and referred to as bacilli. There are two types of stains used regularly: Auramine Rhodamine (fluorescence microscopy) and Ziehl-Neelsen (or Kinyoun). The NWT uses fluorescence microscopy as the primary method of staining and detection. If mycobacteria are present they will retain the dye. The number of acid-fast bacilli can then be visualized and counted. An AFB smear result is reported within a 24 hour period from the time the specimen is received at the lab. AFB smears are ideal to identify mycobacteria but it is important to remember they do not differentiate between NTM and MTB. Therefore a positive AFB smear can be NTM or MTB and another test (culture and DNA probe) is necessary to tell the difference. A negative smear does not exclude an active TB diagnosis. Patients with active TB disease can have a negative smear. AFB smears are considered the first step in diagnosing TB disease.

Infectivity Smear Positive

Highly Infectious Less Infectious

Table 6.3: Infectivity Continuum Smear Positive TB Culture Positive TB (S-C+) Non-respiratory TB (S+C+) AFB seen under AFB not seen under direct microscopy but Blood, serum or microscope directly when placed on appropriate media, TB biopsy sample from a sputum sample organisms grown on culture Highly transmissible Less transmissible, but still infectious Rarely transmitted Usually symptomatic unless Localized or Symptomatic immunocompromised systemic symptoms

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AFB Smear Interpretation

Table 6.4: Number of Bacteria Seen on Microscopy and Laboratory Interpretation

Number Of AFB Seen By Staining Methods

Fuchsin stain (Ziehl-Neelsen) Fluorochrome Semi-quantitative grading (1,000-fold magnification) (250-fold magnification) system 0 in 300 fields 0 in 30 fields Negative

1–2 per 300 fields 1–2 per 30 fields Inconclusive, repeat

1–9 per 100 fields 1–9 per 10 fields 1+ (rare)

1–9 per 10 fields 1–9 per field 2+ (few)

1–9 per field 10–90 per field 3+ (moderate)

>9 per field >90 per field 4+ (numerous)

The infectiousness of a TB patient is directly related to the number of droplet nuclei carrying M. tuberculosis (tubercle bacilli) that are expelled into the air, through ways such as coughing.

Nucleic Acid Amplification Techniques (NAAT) Nucleic acid amplification tests (NAAT) amplify segments of DNA and RNA from the mycobacteria (i.e. genetic elements in the mycobacteria), to reliably identify the microorganisms. Results are usually available within 24 hours of receiving a positive AFB smear. They are recommended only for airway secretion specimens that are smear positive. Both NTM and MTB will stain AFB smear positive. NAAT is used to differentiate the two.

Mycobacterial Culture Mycobacterial culture is the gold standard for diagnosing active TB disease. It is also required to do drug susceptibility testing (DST) to direct therapy (see Section 8, Treatment for Tuberculosis). Cultures are performed on all specimens regardless of the AFB smear and NAAT results. Because mycobacteria are slow growing, it takes 6–8 weeks before obtaining a final result. Three sputum specimens are advised to increase the sensitivity of testing. Only 10–100 viable bacteria are necessary for a positive culture.

If the cultures are negative then the diagnosis of active TB disease must rely on the clinical presentation of the patient. It is also possible that mycobacteria are present in other body sites not examined or where specimens were not collected (see non-respiratory TB, this section). Cultures demonstrating AFB have DNA testing to identify MTB. If MTB is confirmed, drug susceptibility testing is done and reported so treatment can be tailored and any drug resistance (if present) is identified.

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Figure 6.6: Colonies of Mycobacterium Tuberculosis Grown in Culture

Respiratory Specimen Collection Due to the importance of lab testing in the diagnosis of active TB disease, collection and handling of specimens should be done carefully. When specimens are sent to the laboratory they must be collected in a leak proof container (laboratory approved). It must be accompanied with a requisition form and include the following information: • Patient demographic information (name, date of birth, address, health information number) • Submitting practitioner name • Date and time of collection • Specimen type and site • Specimen collection method

Sputa are the preferred method of detecting the presence of MTB in the lung(s). Relevant information on the patient’s status and initial diagnosis is advisable. Specimens should be collected before the start of anti-TB treatment: • Sputum collection is best done in the morning upon rising and can be repeated at a minimum of every hour thereafter (particularly in the hospital setting). • Three samples should be collected (if possible) to increase the sensitivity of testing. • Ideally, in the community setting, at least three consecutive early morning samples of sputum should be examined before a diagnosis of tuberculosis is excluded. The ideal sample contains 5–10ml of solid or purulent material. (Equivalent: 1–2 teaspoon). • Patient should NOT use antiseptic mouthwash or drink alcohol immediately prior to obtaining a sputum specimen.

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• Maximum yield of sputum is obtained from deep cough, and every effort should be made to obtain this type of specimen. Patients should be properly instructed regarding the importance and the appropriate technique of producing a good sputum sample (see Figure 6.7). • Some patients, particularly the elderly, may have difficulty in producing a good sputum sample; in these cases, chest percussion, taking a warm shower, using a cool mist humidifier, or deep breathing and coughing may help. • If the specimen cannot be at the lab within one hour of being collected then it must be stored at 4° Celsius and protected from light. • Twenty-four-hour collection is unacceptable because of lower sensitivity and significantly increased bacterial contamination.

Other techniques used when sputum is difficult to obtain include: • Induction of cough by warmed aerosol saline • Gastric wash (depending on presence of qualified personnel, may be done at health centre for adults but children are admitted to hospital under respiratory isolation) • Auger suction (done in hospital) • Bronchoscopy specimen (done in hospital) • Laryngeal swab

With smear-positive specimens, a positive culture will be obtained in well over 90 percent of cases.

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Figure 6.7: Sputum Collection Procedure

Go away from people – either outside or beside an open window – before collecting specimen

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Provider Safety: Minimizing Aerosolization Precautionary steps should be incorporated into collection of specimens, particularly for sputum inductions for mycobacteriology testing which includes: 1. Educating staff of the risks of the spread of M. tuberculosis through the air 2. Ensuring that the HCP and family members wear a N95 mask when in the same room 3. Making every attempt to have respiratory samples collected in airborne isolation rooms, airborne isolation tents, at home in well-ventilated areas, or outdoors 4. HCPs should not perform cough-inducing or aerosol-generating medical procedures on clients with suspected or confirmed infectious TB disease in the home or community, because recommended infection prevention and control measures will probably not be in place in the home

Induced Sputum Sputum induction should be done using airborne precautions. Some health facilities may have a specially-designed room or ISOPORT that ISOPORT Sputum can be used for this purpose, which has high levels of air exchanges Induction Hut per hour, air vented to the outdoors, and a door (as per Canadian available at Standards Association). Health facilities without such a room may Stanton Territorial consider administering the nebulized saline in a clinic room, and having Hospital. the patient produce the sputum sample outdoors. Alternatively, the nebulizer can be taken to the patient’s home and samples collected there.

Figure 6.8: Sputum Induction A nebulizer that can administer 5–6ml per minute over 15 minutes should be used. It is important that induced sputum be obtained using large volumes of 3% hypertonic saline. The requisition order should indicate that the sputum was induced, because the resulting specimen often appears watery. Using this method, virtually all patients will produce sputum.

Sputum induction may also be used for children. Children at least 2 years of age are able to do this procedure. For out-patient sputum inductions, Stanton Territorial Hospital is equipped with an ISOPORT™. This is a heavy-duty vinyl enclosure that encapsulates the patient and isolates them in a negative pressure setting. It has been CSA approved for sputum inductions. http://www.biologicalcontrols.com/isoport.shtml (Image adapted from: CDC, Core curriculum on tuberculosis: What clinicians should know, 2011)

6-14NWT Tuberculosis Manual - JuneNovember 2014 2014 ActiveLatent TB SectionSection 6: 6: Diagnosis Diagnosis of of TB TB (Latent (Latent vs. vs. Active Active Disease) Disease)

Figure 6.9: Sputum Induction Procedure

(Image adapted from: http://www2.medicine.wisc.edu/home/files/Sputinduc.jpg)

Bronchoscopy Bronchoscopy is performed in hospital by a specialist. Bronchoscopy is used when spontaneous or induced sputum collection cannot be done, or there is extensive lung disease suspected (e.g. lung cancer). A bronchoscope is passed through the mouth or nose into the lung where it is diseased. Sputum or lung tissue is removed for sampling. Post bronchoscopy sputum should be sent out for AFB testing as this has a yield similar to that of bronchial washings and lavage.

Figure 6.10: Bronchoscopy

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Gastric Aspirate/Gastric Lavage (Wash)

Gastric aspiration is a technique used for patients who cannot expectorate adequate amounts of sputum (e.g. children, elderly). A tube is inserted in the patient’s mouth or nose to get to the stomach. A sample of gastric secretions is taken presuming that sputum was coughed then swallowed. If nothing is found then a small amount of distilled water is instilled and aspirated afterwards (gastric lavage). Important points to consider before performing a gastric wash include the following: • It may be possible to obtain a specimen by inducing cough using warmed aerosol saline (humidified air). Auger suction is an alternative to gastric washing. • Gastric washings are specimens of sputum swallowed at night. There is no advantage to gastric washings if a patient can produce sputum.

Gastric wash must be added to buffer solution IMMEDIATELY to ensure viability of tubercle bacilli.

Gastric washings are most likely to yield AFB if obtained first thing after awakening, while still fasting. Once awake, normal peristalsis begins and the stomach empties. Gastric acid is toxic to tubercle bacilli and is neutralized by adding phosphate buffer immediately to the gastric solution. Containers that include phosphate buffer are available through the mycobacteriology laboratory at Stanton Territorial Hospital. As well, ensure laboratory requisition is clearly labeled “gastric washing for AFB”.

Laboratory Personnel Handling M. tuberculosis There are risks associated with handling M. tuberculosis in the laboratory that are not typically present in health care settings. Compared with the general population, laboratory HCPs have been found to have a greater risk of acquiring LTBI. Although this risk stems mainly from aerosol formation during specimen or isolate manipulation, other mechanisms of transmission have been described in this setting. The Public Health Agency of Canada (PHAC) has drafted a biosafety guideline that addresses prevention of laboratory-acquired M. tuberculosis complex. Recommendations on safe laboratory procedures, training programs, infection control plans, respiratory protection, TST screening for personnel and safe transportation of samples are also available from other sources.

6-16NWT Tuberculosis Manual - JuneNovember 2014 2014 Non-respiratoryLatent TB SectionSection 6: 6: Diagnosis Diagnosis of of TB TB (Latent (Latent vs. vs. Active Active Disease) Disease)

Non-respiratory TB Clinical Presentations Non-respiratory TB disease should always be considered in ill persons who have systemic symptoms, site-specific signs or symptoms, and who are at high risk for TB disease.

Table 6.5: Symptoms of Non-respiratory TB for Selected Sites

Constitutional symptoms (affects the body broadly) •Fever •Night sweats •Loss of appetite (anorexia) •Unexplained weight loss •Weakness/fatigue TB of lymph nodes (TB lymphadenitis) •Enlargement of lymph nodes* TB of the CNS† •Headache •Malaise •Fever •Personality changes •Meningismus (irritation of the brain and spinal cord) •Cranial nerve paralysis (i.e. palsy) •Confusion TB of the kidney (Genitourinary TB) •Blood in urine (hematuria) •Sterile pus in the urine (sterile pyuria) •Frequent urination (frequency) •Painful urination (dysuria) Miliary/Disseminated TB† •Fever of unknown origin and constitutional symptoms (as above) TB of bone and joint (Osteoarthritic TB)‡ •Bone Pain (depending on location of disease) Abdominal TB •Abdominal pain •Diarrhea Ocular TB (external and internal eye structure) •Decreased vision (decreased visual acuity)

* Almost all forms of TB involve regional lymphatics and nodes † Miliary TB and TB of the CNS (including TB meningitis, myelitis, and brain/meningeal tuberculoma – an abscess) are the most life threatening forms of TB

‡TB of the spine or vertebrae is referred to as Pott’s disease

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 6-17 Section 6: Diagnosis of TB (Latent vs. Active Disease) Non-respiratory TB

Radiography Radiography assists with the diagnosis of non-respiratory TB depending on the site of disease. Here are several examples where radiographic investigations are useful for certain types of non-respiratory TB diseases. In Figure 6.11, multiple fine nodular densities are distributed throughout the central and peripheral areas of both lungs. This nodular pattern is referred to as miliary pattern (millet seeds). In Figure 6.12, an irregular cavitation is seen in the lower pole calyx of the left kidney (seen on excretory urography: radiography of urinary tract with the use of contrast medium, indicated with arrow).

Figure 6.11: Miliary Tuberculosis

Figure 6.12: TB of the Kidney

(Image from: Medscape Reference Drug, Diseases and Procedures http://emedicine.medscape.com/article/381509-overview)

6-18NWT Tuberculosis Manual - JuneNovember 2014 2014 Non-respiratoryLatent TB SectionSection 6: 6: Diagnosis Diagnosis of of TB TB (Latent (Latent vs. vs. Active Active Disease) Disease)

6.13: TB of the Central Nervous System

MRI showing nodular lesions on meninges (arrows)

(Image from: NEJM website http://www.nejm.org/doi/ full/10.1056/NEJM199910143411605)

Mycobacteria Testing Non-respiratory TB disease can occur in various sites of the body, therefore a variety of clinical specimens can be submitted to the lab. These specimens can include: • Urine • Blood • Cerebrospinal fluid (CSF) • Tissue and other body fluids

All forms of non-respiratory TB are confirmed with specimens for mycobacteria such as AFB smear and culture as well as histopathology (i.e. testing of disease tissue). Drug susceptibility testing is also an important component of testing and is dependent on viable cultures. Although the specimens may be less straightforward to obtain, bacteriological testing is still as important for non-respiratory TB as it is for respiratory TB disease, in order to guide treatment.

Non-respiratory Specimen Collection Urine • Testing urine for AFB is expensive and requires specially-qualified lab personnel, and therefore is ONLY indicated in the investigation of miliary TB or when there are symptoms consistent with renal TB or a past history of renal TB. • Urine for R&M is required prior to proceeding with urine for AFB. • Only if R&M shows leukocytes, blood or high protein in the ABSENCE of bacteria will urine culture and sensitivity (C&S) for AFB be done. • Three consecutive early-morning midstream specimens should be collected at minimum.

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• A minimum of 40ml of urine per specimen is required for culture. • Twenty-four-hour urine collections are not acceptable for mycobacterial culture. • Antibiotics such as fluoroquinolones may compromise the lab’s ability to recover MTB in urine and should be stopped more than 48 hours prior to collection.

Other Specimens • Since TB may localize in almost any site in the body, a considerable variety of clinical material may be submitted (e.g. cerebrospinal fluid, body cavity fluids, bone marrow, tissues, etc.). • These specimens should be transferred to a sterile, screw-capped container. • Tissues should have a few drops of sterile saline added to keep them moist (do not immerse in formaldehyde). • Provide specific requests on requisitions that specimens be examined for presence of AFB and provide clinical symptomatology.

See Prov Lab for further information http://www.provlab.ab.ca/guide-to-services.pdf.

Transportation of Specimens • It is essential that the specimen be properly taken and then transported to the laboratory in leak proof containers at refrigerated temperatures. • Delays in transportation will lead to the overgrowth of normal flora in the specimen, which may lead to false negative results despite normal laboratory decontamination procedures. • The transportation of clinical material is governed by local and national regulations, and the referring laboratory should be consulted for details. • The referring laboratory customarily supplies appropriate transportation containers and laboratory requisition form. • Specimens are sent to Stanton Territorial Hospital (STH) Laboratory. STH Lab directly tests only samples received from Yellowknife and the hospital itself. All other specimens received are sorted and sent to DynaLife Laboratories or Provincial Laboratory or both for processing and reporting.

6-20NWT Tuberculosis Manual - JuneNovember 2014 2014 Non-Respiratory TB Section 7 Management of TB

Management of Suspect TB 7-2 Medical Transportation of a Confirmed or Suspected Case 7-3 Infection Control Measures in the Management of TB 7-7 Criteria for Discontinuing Airborne Precautions for TB 7-13 Direct Observed Treatment (DOT) 7-14 Discharge Planning 7-14

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Management of Suspect TB

Figure 7.1: Management of Suspect TB

Suspect Respiratory TB

Patient has abnormal CXR or presents with symptoms

Assess signs and symptoms and risk factors Perform TB assessment (see NWT Tuberculosis Assessment Form)

Consult with the OCPHO at (867) 920-8646 for recommendations and TB history

Complete diagnostics as applicable (TST, sputa for AFB x3, CXR)

Report findings and consult with OCPHO for further direction on management of patient

Diagnostics highly suspicious of Diagnostics confirm TB ruled out TB or TB confirmed

ADMIT

7-2 In the NWT, THINK TB! In the NWT, THINK TB! Section 7: Management of TB

Medical Transportation of a Confirmed or Suspected Case

Figure 7.2: Medical Transportation of a Confirmed or Suspected Case

Ensure the confirmed or suspected case of TB has been reported to the OCPHO Phone: (867) 920-8646

Is the patient acutely ill?

No Yes, requires oxygen

Send suspect case on scheduled Medevac flight with a medical escort See “medical escorts” in this section for details Contact regional Medical Travel Officer See “Transportation on Specific Airlines” in this section

Prepare the patient for travel See “Precaution for Flights” in this section for details If assistance or clarification is required for the transportation of a client with suspect or confirmed TB, please contact your Regional Public Health Officer or the OCPHO

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Transportation of patients with TB in the NWT Figure 7.3: N95 Mask presents unique risks and challenges. Many TB cases are identified in smaller communities, necessitating patient transportation over great distances to receive appropriate medical treatment. Generally, the patient is transported by air, requiring careful planning by the primary and receiving caregivers to reduce the risk of transmission of TB during travel. The final decision as to the acceptance of any air passenger with an infectious disease rests with the airline and captain of the flight. Asymptomatic or symptomatic TB patients, even if smear positive, can be safely transported by commercial (“scheduled”) flights. Symptomatic patients who are acutely ill should be transported by Medevac. World Health Organization (WHO) Tuberculosis and Air Travel Guidelines state ≥ 8 hours of travel with an active TB patient requires notification only to those travellers in close contact with and exposed to the index case. Using Precautions for Flights the risk to other passengers and operators/ attendants on airplanes or in ground transportation can be minimized. For transporting patients, the Medical Travel Officer must be informed that the patient must comply with wearing a N95 mask during transportation.

Precautions for Flights It is preferable that the patient wear a low-filtration (less than one micron) mask that is National Institute for Occupational Safety and Health (NIOSH) approved (e.g. N95), that provides a tight facial seal (<10% facial seal leak). Only NIOSH-certified respirators should be worn for TB protection. Although a surgical mask is not a respirator, it is acceptable only in the rare circumstance when an N95 respirator is not tolerated. It can only be used during a single patient medevac. The patient must have a container capable of tight closure, for the disposal of tissues where cough and sputum are involved. The patient may safely be situated in any seat; the pilot of a small plane may direct the patient to the “safest” seat, depending on the airflow in the plane. Other passengers may be seated ahead, behind, or across the aisle from the patient. It is preferable for the patient’s escort to occupy the adjacent seat. When an escort is advised; they will accept responsibility of assisting the patient with the instructed airborne precautions. No other special precautions need to be taken. Meals may be taken normally, except that the patient must use a paper tissue over the mouth if any coughing occurs during eating and use the container with tight-fitting lid for tissue disposal. There is no need for isolation procedures for any of the utensils or plates.

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Medical Escorts The OCPHO advises most cases of suspected or confirmed TB need to be accompanied by a medical escort on scheduled flights in order to ensure compliance of airborne precautions. For other reasons such as language and/ or cognitive barriers, the airline may also require that a non-medical person escort the patient. A medical escort is key in maintaining airborne isolation precautions. There may be a perceived social pressure for a patient to not appear “ill” in public, and therefore a temptation to remove their mask. The medical escort must be informed that an important part of their role is to ensure the patient exercises respiratory precautions. Using the Precautions for Flights and with a reliable medical escort, the risk of projecting droplet nuclei containing tubercle bacilli is minimal. The medical escort must be identified before scheduled departure. The HCP must ensure the medical escort: • Is committed to providing care for and advocating for the patient • Has a good understanding of the rationale and importance of maintaining respiratory isolation precautions • Has enough medical materials for the journey, given the possibility of delays (i.e. extra masks, tissues) • Is a reliable caregiver for both transporting and staying at the hospital, with the patient • Is medically/physically able to carry out the duties of an escort • Has photo ID for travel

Transportation on Specific Airlines Transportation policies of airlines for passengers with suspected or confirmed TB are presented below. These policies are subject to change. Arrangements for transportation are done between the Medical Travel Officer for each Regional Health and Social Services Authority and the head office of the airline.

Regional Airlines (Air Tindi, Kenn Borek, Northwright, etc.) • Attending health professional will provide requested information on the appropriate form to the Medical Travel Officer, as per medical travel guidelines. • Medical Travel Officer or attending health professional will complete theCommunicable Diseases Passenger Notification form and fax a copy to the air carrier’s head office and the health professional making the travel request (if applicable). • The air carrier will provide a copy of the completed and signed passenger declaration to the pilot.

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First Air • Medical Travel Officer or attending health professional will call First Air Reservations (1-800-267-1247) and inform them that they are arranging transportation of a passenger with or suspected to have an airborne disease. • Medical Travel Officer or attending health professional will complete the appropriate form specific to the airline and fax it to the First Air Reservations Office. • The Medical Director for First Air will review the form for medical clearance. A verbal reply will be given to the Reservations department stating acceptance or rejection of the patient’s travel. • Personnel from the Reservations Office will ensure the airline’s Medical Director’s decision is given to the Medical Travel Officer.

Air Canada • The patient is required to travel with an escort. • Patients who require oxygen will not be considered for transportation. • Medical Travel Officer or attending health professional (1-888-247-2262) will book flight with Air Canada reservations, and provide flight number and locator number to attending health care professional. • Attending healthcare professional will call Air Canada Medical Desk (MEDA) at 1-800-667-4732 to arrange clearance for their patient’s flight. They will be faxed a form which will require the following information: -Name of patient; -Date of travel; -Flight number and locator number; -Place of departure and destination; and -Patient diagnosis.

• The attending health care professional will complete the Air Canada medical clearance form and fax back to MEDA; MEDA will forward form to the Air Canada Medical Director for approval. • The healthcare professional will receive a verbal acceptance or rejection of their patient’s travel. This information will be sent via fax or phone to the booking agency or Medical Travel Officer.

Canadian North Canadian North declines to serve passengers who have suspected or confirmed TB.

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Infection Control Measures in the Management of TB Airborne Precautions Thorough infection control may prevent outbreaks in the community and nosocomial infection within facilities. Refer to the 2012 NWT Infection Prevention & Control Manual for detailed infection prevention control direction. TB is largely transmitted by aerosolized droplets, in minute droplets of airborne moisture, creating “droplet nuclei.” The droplet nuclei are extremely small, allowing them to remain suspended in the air or transported through air ducts or elevator shafts. They are not filtered by surgical masks or by covering the mouth when coughing. Personal protective equipment is part of the airborne precautions protocol. All patients with suspected or confirmed active (infectious) TB should be directly admitted to the health care facility, bypassing the ER and immediately be put on airborne precautions in a negative pressure airborne isolation room.

Infection Control Practitioner (ICP) Personnel designated as responsible for the facility’s infection control practices should receive timely notification whenever an individual with suspected or confirmed infectious TB is receiving treatment in the health care facility. The ICP designated will: • Educate HCPs about TB infection prevention and control measures at the time of hiring and periodically thereafter • Provide education for HCPs relevant to their duties. This should include awareness of epidemiologic and medical risk factors for TB, signs and symptoms of active TB disease (respiratory and non-respiratory) and mechanisms of transmission • Provide education for all HCPs, including orderlies, housekeeping and maintenance staff, with respect to signage and to understand the importance of administrative, environmental and personal protection controls in the prevention of transmission • Screen staff who have contact with TB patients with annual TST. The ICP will also screen staff if in contact with an active case • Encourage patients and health care provider adherence to airborne precautions • Ensure that occupational health personnel are notified so that contact follow-up of exposed HCPs may be initiated, and • Notify the OCPHO of any admissions for suspect TB or active TB

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Admission to Facility See Table 7.1 for risk assessment criteria for admission to a facility. The following isolation precautions should be implemented for patients with suspected or confirmed infectious TB admitted to a facility: • Directly admit patient (avoid assessment in ER) to the ward when there is a differential diagnosis of TB • Place patient in a negative pressure room as per CSA standards (see Figure 7.4) • Put signage on the door of the isolation room to alert other patients, visitors, and staff of the need for airborne precautions, including N95 respirators. Refer to 2012 NWT Infection Prevention and Control Manual for specific signage for airborne precautions • Ensure that the patient remains in the airborne isolation room (the patient should only leave the room for essential procedures) • The patient should wear a N95 mask if he/she must leave the isolation room • Keep the door and window to the isolation room closed to maintain negative pressure • Limit the number of people entering the room • Ensure that all persons entering the room wear a N95 mask • Instruct patients, visitors, and HCPs about the importance of adhering to TB isolation precautions • Equipment should be dedicated to patient use or disinfected afterwards, and • Staff should perform hand hygiene before and after contact with patient or patient’s environment

Figure 7.4: CSA Standard Criteria for Negative Pressure Rooms

Criteria for Negative Pressurized Room, as Recommended by the Canadian Standards Association (CSA):

• The room must have a door. • There must be negative pressure between room and corridor. • The room must have 12 air exchanges per hour. • Air must be discharged outside the building, away from public places. • Construction of new isolation rooms should comply with the principles outlined in the Canadian Ventilation Standards which includes an anteroom. • Air exhaust grills must be located at floor level. • Electronic monitoring must be established to provide continuous information about the efficacy of the inward directional airflow system and rate of air change. • An alarm system must be installed so activation will occur when airflow is not meeting ventilation standards.

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Table 7.1: Risk Assessment – Admission to Health Care Facility

High Risk Patient Medium Risk Low Risk TB patient

•TST converter (if known) •Positive TST •If known, positive TST >2 years •Recent contact with known •No recent contact with active •No recent contact with active active case case case •Cough greater than 2 weeks •Cough greater than 2 weeks •Cough lasts greater than 2 weeks •Other associated signs and •Some associated signs and symptoms c/w TB (weight loss, symptoms of TB but not •No associated signs and night sweats, fever, bloody primary diagnosis symptoms of TB sputum) •Abnormal CXR and other •Admitted or seen in ER/clinic •Abnormal CXR suggest TB as etiology for unrelated diagnosis primary diagnosis •At least 1 high risk group •CXR with no active disease •High risk groups below elevate factor for active TB •At least 2 high risk group probability for active TB but factors not a mandatory criteria for What to do this classification 1. Admit to private room if no What to do respiratory isolation room 1. No special precautions •Homeless or correctional available facilities 2. If recent TST status is not a. Use airborne precautions known, please test if possible •Health care practitioner including N95 mask for •Aboriginal visitors and patient 3. If TST negative, discontinue sputum collection •Immigrant from high TB- 2. Spontaneous sputum collection endemic area outdoors or in ISOPORT qhr x 3 4. Spontaneous sputum collection outdoors or in ISOPORT qhr x •Alcoholic, IDU or other 3. Discharge patient only if all 3 if patient is to be admitted. sputa are collected and are addictions If patient is seen in ER/clinic, negative •Elderly collect one spontaneous sputum OR •Chronic disease (diabetes, cancer, renal failure, 5. Sputum induction in ISOPORT autoimmune) x 1 •HIV or immunocompromised 6. May discharge patient from hospital/ER or clinic if TST •Malnourished negative OR •Pediatric population a. After 1 spontaneous sputum •Prior history of active TB collection and patient is able to submit remaining 2 What to do samples to Public Health OR 1. Admit to Negative Pressure Isolation Room ONLY b. May discharge after 1 sputum induction 2. Sputum collection Qhr x 3 in negative pressure c. Please notify Public Health for follow up & possible 3. Discharge patient only if all treatment 3 sputa are collected and all 3 smears are negative AND if cleared by Internal Medicine

Notes: 1. According to Health Canada’s definition, Stanton Territorial Hospital would be currently classified as a high-risk facility for TB transmission. “A facility is considered high risk if it has six or more individuals seen with active TB annually” 2. TB screening/ contact follow-up is done primarily on an outpatient basis with sputum induction in ISOPORT when needed. If done in ER/clinic, obtain one sputum with follow-up with Public Health 3. Sputum Induction for TB testing ALWAYS takes place in a negative pressure environment. When rooms are available, place patients in private room for low risk admissions and negative pressure rooms for intermediate risk admissions

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Special Considerations Intensive care unit (ICU): Every patient with suspected or confirmed respiratory TB disease who requires care in an ICU should be placed in an appropriately ventilated airborne isolation Room within the ICU. If this is not available, arrangements should be made to transfer the patient to a negative pressure isolation room with specialized one on one nursing care if applicable or moved to another facility with airborne infection isolation room (AIIR) ICU rooms. For patients requiring intubation and mechanical ventilation, an appropriate bacterial filter should be placed on the endotracheal tube to prevent contamination of the ventilator and the ambient air, when endotracheal suctioning is performed a closed suction apparatus should be used. Emergency department: A high index of suspicion for TB is required when assessing patients presenting with signs and symptoms of respiratory TB disease. Such patients should be immediately transferred to an AIIR. If such a room does not exist within the emergency department but exists elsewhere in the hospital, patients should be promptly transferred to this room until respiratory TB disease has been excluded. Surgery: Surgery should either be postponed (if feasible) until the TB patient is no longer considered infectious or scheduled to allow adequate ventilation of the room after surgery. Surgery is sometimes required in patients with multidrug-resistant or extensively drug-resistant TB, or to drain tuberculous abscesses. Because of the presence of infectious mycobacteria (and anaesthesia gases), the air supplied to the operating room should be exhausted to the outside and not exit the room to other patient care areas. HCPs should wear appropriate respirators (N95). Post-operative recovery of the patient with suspected or confirmed respiratory TB disease should take place in the operating room or in an AIIR.

Figure 7.5: Risk Categories for Activities Performed by HCPs

High-risk Activities Intermediate-risk Activities Low-risk Activities •Cough-inducing procedures •Work requiring regular •Work requiring minimal (such as sputum induction) direct patient contact on patient contact (such as •Autopsy units (such as emergency clerical, reception and departments) where administration) •Morbid anatomy and patients with respiratory TB pathology examination •Work on units where disease may be present* patients with respiratory TB •Bronchoscopy •Work in pediatric units disease are unlikely to be •Mycobacteriology where patients with TB may present‡ laboratory procedures, be admitted† especially handling cultures •Cleaning of patients’ rooms of M. tuberculosis with respiratory TB disease

* This includes work done by all HCPs in these units. † Pediatric patients with respiratory TB disease should be considered infectious until infectiousness is ruled out by radiography and negative acid-fast bacteria sputum smears in patient and caregivers. ‡ Classification of such units as low risk may be inaccurate if the population they are serving has a high incidence of TB (e.g. patients born or previously residing in countries with a high TB incidence or other at-risk populations). Some of the longest delays in diagnosis may occur in such settings.

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Undergoing Procedures For patients with suspected or confirmed infectious TB undergoing procedures, the following precautions should be implemented: • Ensure that procedures are performed in a treatment or procedure room with appropriate engineering controls. This is especially important when cough-inducing procedures (i.e. sputum induction, aerosol treatments and bronchoscopy) are being performed • Some facilities may use portable (ISOPORT) negative pressure closets to ensure procedures can be done safely • Instruct patients to cover mouth and nose with tissues when coughing or sneezing • Ensure that all persons present during the procedure wear a N95 mask • Ensure that people enter or leave the procedure room during the procedure only if absolutely necessary (keep the door to the procedure room closed) • Ensure that patients remain in the procedure room until coughing subsides, thereby limiting exposure of other individuals who are in the general waiting or recovery areas • Ensure that patient wears a N95 mask when leaving the procedure room • Allow one hour or a minimum of 12 air changes between patient procedures so the air will be free of droplet nuclei, or place a notice on the procedure room advising HCPs who must enter the room that N95 masks should be worn for specified time • Perform procedures at the end of the staff schedule, whenever possible to allow time for cleaning and ventilation of the procedure room • Alert environmental cleaning staff of the need for airborne precautions when cleaning

Table 7.2: Recommended Air Exchanges per Area (Health Care Facilities)

NUMBER OF RECOMMENDED AIR EXCHANGES PER HOUR AREA CTS* Direction of air (2013) movement Autopsy suite 12 Inward Bronchoscopy room 6–12 Inward Sputum induction/ pentamidine aerosol Emergency department (waiting rooms) 2 Inward Trauma Radiology waiting rooms 2 Inward Operating room or surgical room 15 Outward Airborne infection isolation rooms - Existing buildings 6 Inward - New buildings 9

General patient care/non-isolation rooms 2 N/A

* Canadian Tuberculosis Standards, 7th Edition

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Table 7.3: Time Needed (by Number of Air Changes per Hour) to Remove Airborne Microorganisms After Generation of Infectious Droplet Nuclei has Ceased Minutes required for removal of airborne Air changes per hour microorganisms CSA 99% removal 99.9% removal Standards 6 46 69 12 23 35

Patient Transport Patients on airborne precautions may be transported to ancillary departments for diagnostic or therapeutic procedures when medically indicated. The preparation and transportation of these patients is a multi-disciplinary responsibility which requires collaboration. The patient must wear a N95 mask when leaving their room and for the duration of the time outside of the room. However, a surgical mask is an acceptable alternative only in the rare circumstance that a N95 is not tolerated. • The individual requesting the test or procedure that requires the patient to leave his/ her room should indicate on the requisition that the patient is on airborne precautions • If the patient is being taken to surgery or the operating room, staff there must be alerted to use airborne precautions • The ICP should be consulted • Notification is the responsibility of nursing personnel prior to transport of the patient

Waste Removal Waste removal from the rooms of patients on airborne precautions is managed the same as for patients on routine precautions, in accordance with the hospital’s regulated and non- regulated waste policies.

Emergency Situations Evacuation of patients on airborne precautions during a fire or other emergency where there is an immediate threat to life or limb takes precedence over managing the isolation procedures. When evacuation has involved a patient on airborne precautions, notify the ICP as soon as it is practical to do so. Notify the staff as well if any follow-up needs to be done for patients and/ or personnel who may have been exposed to the case/patient during the evacuation. In managing medical emergencies for patients on airborne precautions for suspected or confirmed TB, all responding personnel should put on an N95 mask before entering the room. If a staff member acts hastily and forgets to put on a mask or respirator, the ICP should be consulted.

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Food and Nutrition Disposable dishware and trays are not required for patients on airborne precautions. Food service personnel are not to enter patient’s room. Nursing staff will deliver and remove meal trays and nourishments to patient’s room. In the rare event that dishes, utensils, or food trays are contaminated with blood or body drainage, return the items to Central Supply Room (CSR) for reprocessing, using the following procedure: • Place the items in a designated container • Place in a biohazard red container, and take to CSR for reprocessing

Criteria for Discontinuing Airborne Precautions for TB The Internal Medicine Specialist, Chief Public Health Officer, or the Infection Control Practitioner, may terminate airborne precautions when the following criteria for discontinuation of airborne precautions have been met:

Suspect TB Cases A patient admitted for suspect TB will remain on airborne isolation until: • Three successive sputum specimens (spontaneous or induced) are negative on smear unless TB is still strongly suspected and no other diagnosis has been made. Note: Specimens can be collected within 1 hour of each other on the same day, and early morning collection is not considered necessary, but is optimal to yield better sensitivity. In patients who are no longer able to spontaneously produce a sputum specimen, sputum induction is useful and appropriate.

Confirmed TB Cases

Although the degree and duration of infectiousness of patients after initiation of effective therapy remains unclear, it is known that effective therapy (i.e. therapy with two or more drugs to which the TB organisms are susceptible) will rapidly reduce cough and the number of viable bacteria in the sputum. Note: DST results are usually available within 3 weeks in either a smear-negative, culture- positive case or a smear-positive case and these susceptibilities will confirm the effectiveness of therapy. • A patient admitted for active TB determined to be culture positive but of confirmed negative smear status will remain on airborne precautions until: -Completion of minimum 14 days of daily anti-tuberculosis therapy by Directly Observed Treatment (DOT) -Three successive sputum specimens (spontaneous or induced) are negative on smear -There is evidence of clinical improvement

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• A patient who is admitted for active TB determined to be smear and culture positive will remain on airborne precautions until: -Completion of minimum 14 days of daily anti-tuberculosis therapy by DOT; and -Three successive sputum specimens (spontaneous or induced) are negative on smear; and -There is clinical evidence of improvement and -Drug susceptibilities are known and drug resistance is ruled out -After 14 days of daily treatment if sputum specimens are still smear positive, the patient must remain in airborne isolation until three successive sputum specimens (spontaneous or induced) are negative on smear on three separate days -Patients known to have active multidrug-resistant TB or mono-resistance to rifampin: These patients should be kept under airborne precautions for the duration of their hospital stay or until three consecutive sputum cultures (not smears) are negative after 6 weeks of incubation.

Discontinuation of isolation precautions should NEVER be based on a fixed interval of treatment (e.g. 2 weeks) but, rather, on evidence of clinical and bacteriologic improvement and evidence of the adequacy of the treatment regimes. In summary, isolation precautions should be continued until patients are highly likely to be non-infectious. See Section 8, Treatment for Tuberculosis, for further details.

Direct Observed Treatment (DOT) Nursing staff are responsible for Directly Observed Treatment (DOT) of the patient’s anti-TB medications, which includes: • documentation of directly observing ingestion of the medications; OR • documentation and reporting of any refused doses. Refused or missed doses must be reported immediately to the OCPHO and IM specialist.

• See Section 8, Treatment for Tuberculosis, for more details on DOT.

Discharge Planning Prior to discharging a patient back to his or her home community, it is imperative to assess for any social issues Discharge planning that may limit adherence to the long-term TB treatment. should include a referral Referrals for alcohol or drug rehabilitation programs to social services if or social incentives such as food vouchers or taxi tickets indicated. needed to assist with adherence, may need consideration. It is also imperative that there is sufficient capacity at the local health clinic to provide DOT on a daily or thrice weekly basis depending on the recommendation of treatment. Failure to deal with these issues at the initial admission may at times necessitate repeat admissions under Public Health Order requiring 24/7 security. This is a costly endeavor especially to the health care facility which incurs the costs. Regional Health and Social Services Authorities may need to consider added staffing for management of the TB Program and DOT in situations of outbreak or where numerous patients are on DOT.

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Clinical Monitoring All patients going on treatment should be fully informed of the benefits and side effects of their medication and specific, personalized case management and follow-up MUST be done on all patients. Clinical monitoring is necessary for all patients receiving treatment for active TB disease (at least monthly) until treatment has been discontinued or completed. The Internal Medicine Specialist and OCPHO should be advised immediately of any patient that, during the course of treatment: • Experiences recurrence or worsening of symptoms of active TB disease (including unexpected weight loss) • Develops symptoms/signs suggestive of drug toxicity or other adverse reaction to anti- tuberculosis medications • Becomes pregnant • Misses more than two consecutive doses of TB meds • Any other significant changes to their health status • See Section 8, Treatment for Tuberculosis, for more details on clinical monitoring of the patient on TB treatment

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7-16NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 8: Treatment for Tuberculosis Section 8 Treatment for Tuberculosis

Latent TB Indications and Objectives for Treatment 8-3 Treatment, Duration and Adherence 8-4 Special Considerations in the Treatment of LTBI 8-6 Monitoring Treatment of LTBI 8-7 Adverse Reactions/Treatment Induced Side Effects 8-9 Follow-Up after LTBI Treatment and Management Following Re-Exposure 8-12

Active TB

Objectives of Treatment 8-13 Principles of Treatment 8-13 Special Considerations in the Treatment of Active TB Disease 8-18 Anti-Tuberculosis Drugs 8-19 Monitoring of Treatment of Active TB 8-23 Adverse Reactions/Treatment Induced Side Effects 8-25 Completion of Treatment 8-30 Surveillance 8-30 Drug-Resistant Tuberculosis 8-30 Multidrug-Resistant (MDR-TB) and Extensively Drug-Resistant (XDR-TB) Tuberculosis 8-34

Non-respiratory TB Non-respiratory TB 8-36 Diagnosis of Non-respiratory TB 8-36 Treatment of Non-respiratory TB 8-36

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“Treatment of tuberculosis is not only a matter of individual health it is also a matter of public health”. This statement by Tuberculosis Coalition for Technical Assistance speaks to the public health responsibility of health care providers to ensure adequate treatment is provided and adherence to treatment regimens is ensured to protect the health of the patient and the public. All cases of active TB must be treated. The treating physician (usually the Internal Medicine/ Pediatrics or Infectious Disease Specialist) has the responsibility of prescribing an appropriate regimen ideally within 24 hours of diagnosis especially for an infectious case. To increase patient adherence to and completion of treatment, directly observed treatment (DOT) is a process by which a health care practitioner watches the patient swallow each dose of medication to help ensure higher treatment completion rates. DOT also has a component of patient specific case management which is carried out under the collaboration of the physician, TB Program Coordinator (OCPHO) and public or community health nurse. In the NWT, DOT is the primary process for administering TB medication for all active cases of TB, especially respiratory. Any deviation from this regimen would require approval of the OCPHO.

Treatment completion is a fundamental principle in TB control. The most common reason for treatment failure, relapse, and drug resistance is inadequate treatment.

When the treating practitioner does not have the expertise or extra training in respirology or infectious disease, they should consult with a TB Specialist or Internal Medicine Specialist for case management. These specialists should be involved in all cases of TB. Depending on social or medical circumstances, TB treatment regimens may need to be modified. Changes in drug regimens should be made by the attending physician in consultation with a designated TB Specialist and/or the CPHO. The OCPHO shall be kept informed of all changes in drug treatment and adverse effects. This information is maintained in the NWT TB Registry and provides patient drug profiles for future reference.

Treatment of active TB disease and LTBI are publicly funded in the NWT. This includes first-line, second-line drugs and pyridoxine (vitamin B6). TB antibiotics are supplied by the hospital pharmacist while the patient is an in-patient. The public health unit/health centre is responsible for providing all necessary TB medications free of charge when the patient is discharged from the hospital Under no circumstance should TB medication be dispensed by a pharmacist directly to a patient.

8-2 In the NWT, THINK TB! In the NWT, THINK TB! Latent TB SectionSection 8: Treatment 8: Treatment for forTuberculosis Tuberculosis

Treatment of LTBI

Indications and Objectives for Treatment

Definition Figure 8.1: Patient Receiving TB Preventive TB treatment is a regimen of anti-TB drugs Medication with the aim of preventing latent TB infection (LTBI) from developing into active disease.

Rationale The short term goal of LTBI treatment is to prevent progression to active TB. The long term goal of LTBI treatment is to reduce the rate of TB by eliminating the seed pool of infection in the general population. A person, otherwise healthy, infected with TB bacteria has a 10% risk of developing TB disease in their lifetime (see Section 2, Description of TB). This risk is increased depending on many factors such as age or the condition of their immune system. Treatment for LTBI is important to consider if there is an increased risk of progression to TB disease and can help prevent the development of active TB disease now or later in life. Treatment of LTBI is an important part of TB control and should be recommended when appropriate. Persons in whom LTBI treatment should be considered are: • Household members in close contact with smear-positive respiratory cases • All children and adults with a positive TST • Children <5 with a negative TST who are high risk contacts of infectious respiratory TB • Recent TST converter (within two years) • Those with a past history of LTBI documented by positive TST result • Those with a past history of positive TST with an abnormal CXR • Patients with a positive TST who have an increased risk of progression to active disease such as: corticosteroid treatment, immune suppressive treatment, HIV infection, or chronic debilitating disease such as hematologic malignancy, renal failure, collagen disease, diabetes or silicosis • Aboriginal persons with a positive TST. This population appears to be at increased risk for progression to active infection for unknown reasons

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 8-3 Section 8: Treatment for Tuberculosis Latent TB

Treatment, Duration and Adherence • The recommended drug for treatment of LTBI is isoniazid (INH) • The optimal duration of treatment is 9 months (270 daily doses or 78 twice weekly doses) • The daily treatment for an adult is with a dose of 5mg/kg to a maximum of 300mg daily • The twice weekly treatment for an adult is with a dose of 15mg/kg to a maximum 900mg per dose • If INH is not well tolerated, rifampin (RMP) can be used as an alternative. RMP is used for a period of 4 months of daily doses (five days per week DOPT)

The number of total doses taken is far more crucial than the length of treatment duration. Much more emphasis should be put on treatment adherence for best curative results. This can be accomplished by using directly observed preventive treatment (DOPT).

Direct Observed Preventive Treatment (DOPT) • Preventive treatment will be administered by direct observation. • DOPT requires the patient is observed swallowing each and every dose of medication. • DOPT may be carried out by a health professional or a reliable person selected by and reporting to the health professional.

The optimal prophylaxis regimen is given daily. However, it is often more practical for the patient or the HCP to administer preventative treatment on a twice-weekly basis.

Contraindications/Precautions for LTBI Treatment

Consideration for treatment of LTBI should not be given to individuals with: • Active TB disease. Mono-treatment does not provide sufficient amounts of medication to treat active disease. Treating active disease with one antibiotic will result in acquiring anti- tuberculosis drug resistance • Previous adverse reaction to INH • Acute or chronic liver disease of any etiology

Signs or symptoms that suggest illness or adverse drug effects should be reported to the attending physician and the OCPHO immediately.

LTBI Treatment Regimen for Adults Anti-TB treatment for adults can be offered in various ways, as described in Tables 8.1 and 8.2. Recommendations for LTBI treatment are made by an Internal Medicine Specialist, Pediatrician or Chief Public Health Officer (or Public Health Officer designate).

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Table 8.1: Regimes for Treatment of Latent TB Infection

Drug Duration Interval Number of doses

NWT Regimen INH* 9 months 2x / week (DOPT) 78 Daily (if authorized for self-administration must INH* 9 months 270 only give 1 month supply (at a time)

RMP 4 months Daily (DOPT)

* Vitamin B6 is given to prevent peripheral neuropathy † Dosing for RMP can be discussed with the pediatrician, IM specialist, CPHO or designate

Table 8.2: INH Protocol for Treatment of LTBI

INH PROTOCOL FOR DOPT LTBI in NWT

DOSAGE FORMS DAILY DOSE TWICE WEEKLY DOSE

INH Tablets: Child** Adult Child** Adult •100mg 10–15mg/kg 5mg/kg 20–30mg/kg 15mg/kg •300mg

INH Syrup: Max: 300mg Max: 300mg Max: 900mg Max: 900mg •10mg/ml

Vitamin B6* 12.5mg 25mg 25mg 50mg •25 or 50mg

Duration: 9 months– 78 doses Duration: 9 months– 270 doses DOPT

*Vitamin B6 is given to prevent peripheral neuropathy **Dose is for children who are younger than 12 years or who weigh less than 35kg. In the older child or adolescent who weigh between 35–60 kg, recommendations differ between use of adult versus child dosage. All pediatric dosing is done by the referring Pediatrician. Reasons for Vitamin B6 Supplementation INH binds with existing Vitamin B6 in the blood, which can deplete the body stores of Vitamin B6, causing nausea, vomiting, dizziness, slurred speech, blurred vision, dilated pupils, tachycardia, and sometimes urine retention, stupor, coma and seizures, which if not controlled, may lead to death from brain damage, aspiration or hypoxia.

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Vitamin B6 (pyridoxine), 25mg daily dose or 50mg twice or thrice weekly dose, is recommended for all patients. It is given to prevent the development of neuropathy. Patients that can benefit from taking vitamin B6 include those who are pregnant, are HIV co-infected, diabetic, uremic, and those who suffer from renal insufficiency, poor nutrition or substance addiction such as alcoholism.

Resistance to Isoniazid (INH) or Rifampin (RMP) or Both

If a person has been infected with INH resistant bacteria or has been in contact with someone with known INH resistance, a daily RMP regimen for 4 months is an acceptable alternative (DOPT weekdays). Strict adherence is required to avoid multidrug-resistance. When there is resistance against both INH and RMP, then a TB Specialist must be consulted to direct clinical management.

Special Considerations in the Treatment of LTBI Treatment of LTBI is managed differently in these patient populations:

Table 8.3: Special Considerations in the Treatment of LTBI

Specific patient Remarks population

•Standard regimen is recommended since both INH and RMP are Patients with renal metabolized in the liver and do not rise in the presence of renal failure or dialysis failure

•INH and RMP are considered safe in pregnancy, although the mother should be given vitamin B6 supplements. However, an increased risk of hepatotoxicity from INH has been reported in women treated during the first 3 months postpartum. Pregnancy •Treatment of LTBI should be deferred in pregnant women until 3 months postpartum unless they are at very high risk of disease (HIV-infected, close contacts, documented TST conversion). •Breastfeeding is considered safe for mothers taking INH or RMP, and they should also take vitamin B6 supplements.

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Special Attention Special attention is required for consideration of LTBI preventative treatment in these patients: • Concurrent use of other drugs (e.g. INH increases the potency of Dilantin) • Alcoholism or binge drinking (increased risk of INH toxicity) • Pregnancy (prudent to defer until 3 months postpartum unless high risk of active disease). Carefully review the risks and benefits of delayed treatment for LTBI, including concomitant factors such as HIV-infection, close contact of an active case or documented TST conversion. LTBI treatment is safe for breastfeeding women • Compliance with full duration of treatment • People over the age of 35 years have an increased risk of INH toxicity. It is imperative to weight the risk of progression to active TB against the risk of serious adverse reaction to treatment

Treatment Refusal or Interruption When a patient (considered to be at high risk of disease) refuses to take LTBI treatment or does not complete the full regimen, it is essential they be seen in follow-up every 6 months for 2 years. It is within these two years they are most at risk of developing TB disease. Ongoing surveillance or follow up after two years post contact or conversion is determined by risk. New reactors (with unknown contact of an infectious case) should be placed on surveillance depending upon their risk for progression to active disease. For example, those reactors with underlying immune compromising conditions should be considered at high risk for progression to active disease and TB surveillance should be carried out yearly. Healthy individuals who are immunocompetent with no underlying comorbidities or risk factors may only need surveillance every 3 years.

Monitoring Treatment of LTBI HCPs following patients under LTBI treatment should assure adequate monitoring for safe and efficacious treatment. Effective monitoring should involve regular assessment including: • Brief physical assessment for signs of hepatitis (including symptom inquiry) • Specific liver enzyme monitoring in patients at higher risk for hepatoxicity • Review of symptoms of possible side effects of medication • Assessment of adherence

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Table 8.4: Summary of Care for Patients Receiving Treatment for LTBI Base-line Required (before Parameter Observation/ Rationale Assessment starting treatment) Symptom •weekly for four weeks; then observe for symptoms of ü Inquiry •monthly or as required (PRN) adverse drug reaction as indicated by symptom Physical Exam ü as required inquiry* monthly only if pediatric patient dosage adjustment may be Weight ü or if significant weight loss/gain required concerns with compliance, Social ü at each clinic visit alcohol consumption, Monitoring housing, nutrition, etc. •those at high risk of liver disease monitor case by case basis (i.e. more frequently if as indicated by symptom needed) inquiry*. Risk of liver toxicity Transaminases •>35 years = monthly (if no risk increases after age 35. AST/ALT ü factors) Children rarely experience •15–34 years = @ 4 weeks, then liver toxicity. ALT is affected PRN (if symptomatic) by INH, RMP, PZA** •<15 years = PRN (only if symptomatic or at risk)

PRN – only if symptomatic as indicated by symptom Sputum for AFB ü during course of treatment inquiry*

•PRN – only if symptomatic during course of treatment CXR •at 3 mo. if post exposure/ as indicated by symptom ü contact of case inquiry* •upon completion if baseline CXR abnormal increased ESR is a sign of ESR ü baseline only infection Creatinine/ Uric ü N/A Acid Bilirubin (Total) ü N/A CBC/ Platelets ü Urinalysis ü N/A

*Symptoms of anorexia, lethargy, sleep disturbance, nausea or vomiting, yellow sclera, very dark colored urine, or other pertinent findings should be reported to the attending physician and the OCPHO immediately. **Only those who show signs and symptoms of liver dysfunction or have risk factors present, such as substance abuse or known Hepatitis B or C carriers need to be monitored more frequently.

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Adverse Reactions/Treatment Induced Side Effects Hepatitis has been associated with INH use. It is defined as liver enzyme (AST/ALT) levels to be 5 times the upper limit of normal without symptoms or 3 times the upper limit of normal with symptoms. If either of those parameters are met at any time during treatment, INH must be stopped and treating practitioner and OCPHO notified. Hepatitis occurs more frequently and is usually worse in elderly clients or those who consume alcohol daily. It can be reversible if the medication is stopped. Patients should be advised to watch for the following symptoms indicative of toxicity from the medication:

Table 8.5: Symptoms of Toxicity INH or RMP induced side-effects •Unexplained weight loss •Fatigue •Headache •Dizziness •Sleepiness or insomnia •Nausea •Anorexia •Jaundice •Gastrointestinal upset and/or abdominal pain •Joint pain •Bruising •Rash

Patients taking INH or RMP who experience possible adverse reactions should be advised to consult their health care provider immediately. If they cannot contact their health care provider, they should stop INH or RMP until they can be seen and assessed. Liver enzyme monitoring should occur on a monthly basis (or more frequently if deemed necessary by Internal Medicine or TB Specialist) for the following patients: • Pre-existing liver disease • Concomittant use of hepatotoxic drugs • History of, or current ethanol abuse • Prior INH hepatitis • >35 years • Pregnant or within 3 months of postpartum • Anyone exhibiting symptoms

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Risk of Drug Toxicity The risk of INH toxicity must be weighed against the risk of developing active TB. The most significant side effect is INH hepatitis, which usually occurs within the first three to six months of administration. (http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/ CPS-%20Monographs/CPS-%20(General%20Monographs-%20I)/ISONIAZID.html) Early signs of liver toxicity are nausea, anorexia and an elevation of alanine transferase (ALT). The patient should be advised to contact his or her healthcare provider immediately should he/ she have symptoms of liver failure such as jaundice, dark urine, light-coloured stools, bleeding tendency, pruritus, confusion, and coma. Liver toxicity is rare under the age of 20, but complicates INH treatment in: • 0.3% in the 20–34 age group • 1 to 2% in the 35–49 age group • 3% in the over 50 age group

Less serious, but more common side effects include erythematous itchy rash, lethargy, and arthralgia. Peripheral neuropathy is a more serious reaction. Patients 35 years and older receiving INH should be monitored with weekly symptom inquiry and ALT levels done monthly. Patients in the age range of 15–34 years of age should: • Have an initial baseline ALT level measured • Be rechecked one month after starting INH prophylaxis, and or/if side effects to anti TB meds is suspected • Symptom inquiry weekly

Patients 15 years or younger should have an ALT level measured at baseline and then only if signs and symptoms are indicative of liver toxicity. INH is toxic in large doses and should be dispensed with great caution. If there is any risk of overdosing, purposeful or otherwise, discretion should be used when dispensing any amount of INH.

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INH Drug Overdose The antidote to an INH overdose is injectable pyridoxine (vitamin B6). It is a must stock item in all pharmacies.

Table 8.6: INH Drug Overdose

INH Drug Overdose

Below is the recommended antidote for INH overdose. Consult with your on-call physician/ pediatrician IMMEDIATELY and initiate treatment.

Consider calling the PADIS – Poison and Drug Information Services, Alberta and Northwest Territories contact: 1-800-332-1414.

Management of INH overdose includes supportive care focusing on patient’s cardiovascular status, protecting the airway, abolishing seizure activity and correcting metabolic acidosis.

As soon as an overdose of INH has been recognized (even in the absence of symptoms), Pyridoxine IV should be administered to prevent neurotoxic effects.

The same dose of Pyridoxine (Vitamin B6) as the dose of INH ingested should be given intravenously.

•For example, a child who has ingested 3.0g of INH should be given 3.0g of pyridoxine. If the dose is not known, Pyridoxine should be given intravenously in a dose of 5g in adults or 70mg/kg (maximum dose 5g) in children, at a rate of 1g every 2–3 minutes (CP, 2013). •This dose of pyridoxine should be repeated in two hours if the response to treatment has been incomplete. A total dose of 25g may be required in the first 12 hours. •A single dose of activated charcoal should be considered at a dose of 1g/kg. •Diazepam IV with addition of Phenobarbital or Propofol may be used in addition to Pyridoxine to treat convulsions. •Diazepam (Valium) should be given to control seizures (2mg by rectum for babies over the age of six months, or 5–10mg intravenously for older children and adults). Phenytoin (Dilantin) should not be given as it increases levels of INH. Please note INH also increases serum levels (Dart, 2004). •Once the patient is stabilized, refer to an internal medical specialist or pediatrician for further medical treatment.

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Follow-Up after LTBI Treatment and Management Following Re-Exposure There is no need for routine follow-up after completion of LTBI treatment. If a patient refuses or does not complete therapy, then he or she should be instructed carefully regarding the principal symptoms of active TB and instructed to return for evaluation if those symptoms arise. Routine repeat chest radiography has very low yield and is not recommended. If patients are re-exposed through contact with a case of active infectious TB, there is no value in repeating the tests for LTBI infection (once positive = no longer useful). In immunocompetent people there is evidence that a first episode of TB infection provides approximately 80% protection against development of disease following re-exposure. This benefit is similar to that achieved with 9 months of INH therapy. Hence, a second course of LTBI treatment is not recommended, even if the re-exposure was close/intense and even if exposure was to a drug-resistant case. However, if there is uncertainty that a previous course of LTBI therapy was taken adequately, then it may be prudent to recommend the patient take a full course of LTBI therapy. In immunocompromised individuals, such as HIV-infected people or very young children (under 5), there may not be any effective immunity conferred by prior TB infection. Therefore, it is recommended that these individuals could be considered for a second course of LTBI treatment. However, this recommendation is not based on any published evidence that such treatment is effective, nor is there broad consensus on the benefits of retreatment of LTBI following re-exposure. Further considerations include how well the individual tolerated previous LTBI treatment, likely adherence to another course of treatment and probable public health consequences if active TB develops.

Documentation of Treatment of LTBI The drug, dosage, interval (daily, 2x/wk, 3x/wk), mode (directly observed or self-administered), start date, end date and total number of doses taken should be recorded on the NWT Latent Tuberculosis Infection (LTBI) Drug Treatment and Progress Record and once treatment is finished (or stopped for another reason) theNWT Latent Tuberculosis Infection (LTBI) Treatment Completion Form must be faxed to the OCPHO at 867-873-0442.

Program Indicators The ideal LTBI treatment delivery program will achieve, at a minimum, 80% acceptance of treatment among people with LTBI in whom treatment is indicated, and at least 80% of those starting will complete the required number of doses.

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Treatment of Active TB Treatment of active TB cases is the key component in controlling the spread of disease.

Objectives of Treatment There are three fundamental objectives of treatment of active TB. It is useful to understand these objectives, as each one is achieved by different TB drugs or combinations of drugs: 1. Rapid killing of TB bacilli, to produce rapid improvement in the clinical condition of the patient and thereby prevent complications (reduce morbidity), prevent death (reduce mortality) and prevent transmission (reduce infectiousness). 2. Prevent the emergence or worsening of drug resistance. 3. Prevent the relapse of disease after completion of therapy and achieve long-lasting cure.

Principles of Treatment Therapy is given in two phases: initial and continuation. In the initial phase multiple effective drugs are used in combination to achieve the first and second objective. On the basis of results of randomized trials, this phase should last 2 months, and the drugs should be given daily. The second objective is addressed by the continuation phase, during which only two drugs are usually given. The length of this phase is variable, depending on indicators of risk of relapse, on the drugs given in the initial phase and on the results of pre-treatment drug susceptibility testing. Therapy can be daily or intermittent. Optimal therapy to achieve all three treatment objectives for patients of all ages, with disease at any site, should be guided by the results of drug susceptibility testing. This reinforces the importance of microbiologic confirmation of the diagnosis of TB disease. Patients with suspected active TB should always have multiple specimens sent for microbiologic investigation before treatment is started. It is recommended that at least two effective drugs should be used at all times. If drug susceptibility testing results are pending then more drugs may be needed to ensure that at least two are likely to be effective. In the initial phase, particularly when bacillary load is high, three likely effective drugs should be used to prevent emergence of drug resistance.

Initiation Phase Continuation Phase • Drugs are used in combination to kill • Drugs are used to kill remaining most populations of M. tuberculosis replicating populations of M. tuberculosis • Leads to rapid sputum conversion from positve to negative, thereby • Helps to prevent TB disease reducing infectiousness reoccurence

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 8-13 Section 8: Treatment for Tuberculosis Active TB

Initial Phase (2 months) • This is the initial phase for any TB regimen • This phase is crucial for preventing drug resistance • The duration is 2 months or 8 weeks of daily therapy. If the patient is discharged from hospital, daily therapy can continue as 5 days per week DOT. Thrice weeky, vs. daily, treatment is also a consideration and will be determined in consultation with the Internal Medicine Specialist and OCPHO • Treatment of active TB should include 2 effective drugs at all times, and in the initial phase at least 3 effective drugs are recommended • Treatment should be guided by the results of drug sensitivity testing, which should be performed for all patients with culture-confirmed disease • All patients with active TB in Canada should be treated with an initial regimen of 4 drugs consisting of: isoniazid (INH), rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB) • If the isolate causing disease is fully susceptible to all first-line drugs, the EMB can be stopped. PZA should be given for the first 2 months if tolerable. PZA in the initial phase can shorten the overall length of TB treatment

Continuation Phase (4–7 months) • This is the phase that follows the initial phase • The duration can be from 4–7 months depending on the infectiousness of the case, drug sensitivity results and the type of TB the patient is being treated for • In the continuation phase, anti-tuberculosis medications are given thrice weekly until treatment completion, unless it is determined by the TB Internal Medicine Specialist or Pediatrician that continuation of daily therapy is more effective • The total treatment phase is 6 months for uncomplicated, drug-susceptible, non cavitary TB

Prolonging the Continuation Phase is Recommended for the Following Cases: • If PZA is not included in initial phase of treatment • If risk factors for relapse have been identified. These include: -having more extensive disease and/or cavities on a chest x-ray -being smear and/or culture positive after 2 months of therapy -having a cavity on chest x-ray at the end of treatment (5–6 months) -HIV coinfection

In patients with any of these risk factors, the continuation phase should be prolonged from 4–7 months, to provide a total of 9 months of therapy. Any regimen that does not include INH or RMP throughout its course should be extended to a minimum of 12–18 months.

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Duration of Treatment The duration of treatment will depend on the anti-TB drugs used, the patient’s response to treatment, DST results and, type and severity of TB disease. Most regimens are of 6 months duration but can also be longer depending on the circumstances. Duration of treatment will be set out at the onset of treatment but may change over the course of treatment depending on factors such as sputa and radiographic conversion, response to treatment, adverse reactions, and adherence or tolerance to medication regimen. Duration of treatment is reviewed at each TB Rounds.

Recommendations for Previously Treated Patients • DST at or before treatment is started must be done and results should guide treatment choice • Empirical regimen (i.e. in patients without major risk factors for drug resistance, INH, RMP, PZA, EMB) should be used while waiting for DST results • Likelihood of multidrug resistance can be higher in patients who have undergone TB treatment in the past, therefore more caution should be exercised in the event that second line treatment becomes necessary. In this case, consultation with an expert in the treatment of TB is recommended

Response to Treatment Response to treatment of respiratory TB is accomplished by sputum and smear examination. This applies to all patients undergoing treatment. Sputum should be collected at the end of the initial phase (8 weeks), which is at the second month of treatment for new TB patients. Recommendations for smear-negative patients at start of treatment: • Conduct sputum specimen collection and examination at the end of the initial phase • If sputa smears are negative at 2 months no further sputum monitoring is necessary • If sputa smears are positive follow recommendations for smear positive patients (below) Recommendations for smear-positive patients at start of treatment: • Conduct specimen collection and examination at the end of the initial phase • If smear or culture positive after 2 months, DST should be done. Repeat sputum examination after 4 months of treatment • If specimens are still smear-positive at the end of four months, sputum culture and DST should be performed again to ensure patient is not developing drug resistance to the current regimen

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Treatment Interruption During treatment, it is possible that a patient interrupts their regimen by missing anti-TB drug doses. When this occurs it is important to understand the reasons why the patient is missing treatment to help mitigate any barriers to treatment. Otherwise there are essential factors to take into account for managing a patient with interruption of their treatment including: • If the patient is smear or culture positive after interruption of treatment • If interruption occurred during the initial or continuation phase • The duration of the interruption • The patient’s medical condition (i.e. immunocompromised) • The patient’s response to treatment before interruption of treatment • If drug-resistant disease is present or suspected

Management of Non-adherence to Treatment Individuals who are unable or unwilling to take appropriate steps to take treatment for active TB (e.g. anyone who has missed more than two consecutive doses of TB medications) may pose a public health risk. These cases shall be referred to the OCPHO. Those who start but do not finish treatment for active TB or LTBI may develop drug-resistant MTB strains. A staged intervention must be used in dealing with such persons. Ensure that sensitive supportive case management is established for treatment and ongoing support, and follow these steps: 1. If a patient with active respiratory TB misses two consecutive doses of medication while on thrice weekly treatment (or the equivalent if on daily medication), notify the OCPHO immediately. 2. The CPHO or designate will determine if the patient is unwilling or unable to take the medication in consultation with local public health or health centre staff. 3. Through negotiation with the patient, the OCPHO or designate will attempt to re-establish the medication regimen. 4. The patient will be given a verbal warning. 5. If a third dose of the thrice weekly regime is missed, an “Apprehension Order” will be issued mandating admission to a designated facility. The client will be informed of the public health hazard he/she poses if the TB medicine is not restarted. 6. The individual will be apprehended by local RCMP and taken to a facility under guard of a Peace Officer for 72 hours. 7. After 72 hours, should the CPHO still determine the client is a public health threat, a court order will be requested to detain the individual up to a maximum of 4 months.

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Drug Management of Treatment Interruptions

Table 8.7: Management of Treatment Interruptions

Situation Guideline* During the initial phase Interruption <14 days Continue treatment Interruption ≥14 days Restart treatment from the beginning During the continuation phase Received 80% of doses AND sputum smear ≥ Further treatment may not be necessary negative on initial testing

Received ≥80% of doses AND sputum smear Continue treatment until all doses are positive on initial testing completed Continue treatment until all doses are completed Received ≤80% of doses AND interruption is <3 months If cannot be completed within recommended timeframe for regimen restart treatment from the beginning

Received ≤80% of doses AND interruption is Restart treatment from the beginning, new ≥3 months initial and continuation phase

* In all cases of treatment interruption, consultation with OCPHO and a TB Specialist is required

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Special Considerations in the Treatment of Active TB Disease

Table 8.8: Special Considerations in the Treatment of Active TB Disease Specific patient Remarks population TB patients with Due to the hepatotoxicity caused by INH, RMP and PZA regular hepatic disease monitoring is necessary if the patient has hepatic disease Patients with renal disease can tolerate usual doses of first line TB patients with treatment except for EMB which requires specific adjustments and serum renal disease levels monitored carefully. In patients in renal failure, PZA also needs to be adjusted TB patients with Dosing of medications is dependent on CD4 count levels; consult HIV/TB HIV infection Specialist for specific treatment •TB can be treated in pregnancy. Breast-feeding is not discouraged during treatment •1st line treatment is safe in pregnancy •The use of PZA must be consulted with a TB consultant TB in pregnancy •Other second line drugs that may be used in TB management, such as aminoglycosides (streptomycin, amikacin, and kanamycin) and polypeptide (capreomycin), are contra-indicated in pregnancy due to the effects on the fetus •Pyridoxine is recommended for pregnant and breastfeeding women receiving INH • Adjunctive corticosteroid treatment is beneficial in TB meningitis, TB patients and TB pericarditis, and in life threatening cases such as disseminated TB corticosteroids •Before using corticosteroids a TB Specialist must be consulted

Treatment of Active TB in Pregnancy The risk of untreated active TB to a pregnant woman and her fetus is far greater than the risk of toxic effects from the drugs used in its treatment. In a pregnant woman with active TB it is recommended effective therapy be administered promptly. TB is not an indication for the termination of pregnancy. INH, RMP, and EMB are considered safe in pregnancy, so all three should be used as initial treatment. Pyridoxine (Vitamin B6) should be given. PZA is recommended for use in pregnancy by the WHO, although there remains some uncertainty about the safety of PZA in pregnancy. To date there have been no reports of teratogenicity even though this drug has been given to millions of pregnant women world-wide. Hence PZA can be given in women with extensive disease and/or women who do not tolerate any of the other fluoroquinolones (FQN).

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Most second-line agents are not considered safe in pregnancy either because of known teratogenicity or inadequate data indicating safety. FQN are best avoided during pregnancy, and breast feeding. The use of injectables (streptomycin, amikacin, kanamycin, and capreomycin) is contraindicated because of the effects on the fetus, including eighth cranial nerve palsies, deafness, and teratogenicity. These drugs should only be considered for use in specific instances after consultation with a TB specialist.

Anti-Tuberculosis Drugs Anti-TB drugs are divided into two broad groups.

First-line drugs (FLD) Four drugs are classified as FLD in Canada, because all are effective, can be taken orally and are well tolerated (or at least better tolerated than the second-line drugs). The first line anti-TB treatments for which M. tuberculosis is susceptible are the following: • Isoniazid (INH) • Rifampin (RMP) Core standard treatment • Pyrazinamide (PZA) for active TB • Ethambutol (EMB)

The first line drugs are used to treat respiratory and non-respiratory tuberculosis, with several exceptions described in the following sections. FLD are administered orally unless required by means of nasogastric or feeding tube. If oral medication cannot be used, consultation with a TB Specialist is necessary. The tablets can be crushed and mixed with water, or suspensions of the medications can be prepared to make delivery easier.

Isoniazid (INH) INH was first introduced in 1952 and is still a cornerstone of modern TB therapy. It has very powerful early bactericidal activity, meaning that it is highly effective in rapid killing of bacteria in the first few days. Hence, the drug is important in achieving rapid killing of TB bacilli. It is also effective in preventing the emergence of resistance, although its role in preventing relapse is unclear. If INH is not given for the full duration of therapy, then therapy should be prolonged. If INH is not given at all, therapy should be for at least 12 months. Pyridoxine (vitamin B6) should routinely be added to all INH regimens. A pyridoxine daily dose of 25mg is sufficient; higher doses (50mg) may be used for intermittent therapy.

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Rifampin (RMP) This drug, introduced in 1968, is the most potent anti-TB drug available. Its use allows shortening of the regimen to a total of 9 months (or 6 months if PZA is also used). The drug has good bactericidal activity, prevents acquired drug resistance and is very important in preventing relapse. Current doses are based on studies performed in the 1960s, when the lowest effective dose was used because of the high cost of the drug. If RMP is not given for the full duration of therapy, then therapy should be prolonged. If RMP is not given at all, therapy should be for at least 18 months.

Pyrazinamide (PZA) This drug is also bactericidal but appears to provide benefit only in the first 2 months of therapy. In randomized trials, use of PZA in the continuation phase did not reduce relapse rates, and the drug appeared to offer no protection against the development of resistance. If PZA is not given for the entire first 2 months, the total duration of therapy should be 9 months.

Ethambutol (EMB) This is the least effective of the four FLD for bactericidal activity, or prevention of relapse, but it is effective in preventing the emergence of drug resistance. If a previously untreated patient has unrecognized INH resistance and is given only INH, RMP and PZA for the first 2 months then RMP resistance could emerge, given the inability of PZA to protect against the emergence of resistance. Hence, EMB is added in the initial phase empirically while the results of drug susceptibility testing (DST) are pending.

Second-line drugs (SLD) The SLD include the fluoroquinolones, all injectables and many “older” TB drugs that were used in the 1950s and 1960s but were abandoned because of relatively poor efficacy and/or greater toxicity.

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Drug Regime Options Below are the recommended drug regimen options for the treatment of fully sensitive TB:

Table 8.9: Recommended Drug Regime

Standard

Initial Phase (first 2 months) Continuation Phase

•INH RMP PZA EMB*† •INH RMP for 4–7 months Regime 1 •Daily (or 5 days/week) •Daily (or thrice weekly) •INH RMP EMB*† •INH RMP for 7 months Regime 2 •Daily (or 5 days/week) •Daily (or thrice weekly) •+/- 2nd line agent

Elderly (>65) or other risk factor for hepatotoxicity

•INH RMP EMB*† •INH RMP for 7 months •Daily (or 5 days/week) •Daily (or thrice weekly)

Pregnant

•INH RMP PZA EMB** †, or •INH RMP - for 7 months if PZA not used, and for 4 months if PZA •INH RMP EMB* used in first two months •Daily (or 5 days/week) •Daily (or thrice weekly)

*EMB can be stopped as soon as the DST are available and if pan sensitive. PZA should continue for the full 2 months of the initial phase. **Three times weekly preferred over twice weekly for programmatic reasons. If patients miss a single dose while receiving thrice weekly therapy they effectively receive twice weekly therapy, which is still adequate. If they miss a dose of twice weekly therapy they effectively receive once weekly therapy which is inadequate. † If the patient is smear negative, the TB Specialist or Internal Medicine Specialist may consider thrice weekly for the remainder of the initial phase and all of the continuation phase after the first two weeks of daily dosing (typically thrice weekly treatment is considered after discharge from hospital).

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Table 8.10: Recommended Drug Doses for Daily and Intermittent Therapy in Adolescents and Adults

Daily Thrice Weekly First line drugs By weight* Max (mg) By weight* Max (mg) INH 5mg/kg 300 10mg/kg 600 RMP 10mg/kg 600 10mg/kg 600 PZA 20–25mg/kg 2000 30–40mg/kg 4000 EMB 15–20mg/kg† 1600 25–40mg/kg 2400 Second line drugs Fluoroquinolones┼‡ - Moxifloxacin 400 # - Levofloxacin 750–1000 # 15mg/kg as a Injectables: Amikacint # single dose

* For doses for children see Section 11, Pediatric TB † EMB dosing: Optimal dosing is unclear. It is clear that eye toxicity is dose dependant and its risk is higher at 25mg/kg than at 15mg/kg. ‡ Fluoroquinolones: Gatifloxacin is not recommended in Canada because of dysglycemia problems. This drug has been used in recent trials and is still used in some countries.

tAmikacin: of the injectables, Amikacin is preferred for use in Canada because of the ready availability of the drug, familiarity with its use by clinicians, nurses and pharmacists, and the ability to measure serum drug concentration in many facilities. Streptomycin is not available in Canada, but may be preferred in some low and middle income countries as toxicity is similar and costs may be lower. #There is inadequate data from randomized trials on use of fluoroquinolones or injectables as part of intermittent regimens. If these drugs are needed, because of intolerance or resistance to first line drugs, daily therapy is suggested.

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Monitoring of Treatment of Active TB The decision by a healthcare provider to initiate treatment of active TB implies a commitment to ensure that all the recommended doses are taken without interruption. The goal of active TB treatment is to take 100% of prescribed doses. This is best done by providing a comprehensive, patient-centered treatment program. Close supervision and monitoring of medication is considered essential for all TB patients. It is mandatory that all regions have the capacity to provide DOT. This means not only careful monitoring of adherence and response to the treatment regimen but also providing multi- disciplinary support for all problems facing the patients. Key elements include use of incentives and enablers, nursing care, coordinating care for other medical problems, social service support such as for child care, housing assistance, referral for treatment of substance abuse and providing transportation where possible. An additional advantage of DOT is the closer monitoring of side effects for all patients. All patients must be monitored regularly during treatment. Continued assessment during patient treatment facilitates completion of treatment and identifies any adverse effects or the reappearance of TB-related symptoms. This can be done by keeping a record for all patients on TB medications with the following: • All medications given (NWT Active Tuberculosis Drug Treatment and Progress Record) • Adverse reactions to treatment see Section 8, Adverse Reactions/Treatment Induced Side Effects • Bacteriological response during treatment (i.e. conversion of sputa)

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Table 8.11: Summary of Care for Patients Receiving Treatment for Active TB

Required Baseline Case Observation/ Rationale Assessment •twice a week for two weeks; then Observe for symptoms of Symptom adverse drug reaction and ü •weekly for four weeks; then Inquiry indication of improvement •monthly or as required (PRN) with treatment as indicated by symptom Physical Exam ü PRN inquiry* weight loss may indicate Weight ü monthly worsening of TB disease concerns with compliance, Social ü at each clinic visit alcohol consumption, Monitoring housing, nutrition, etc. •those at high risk of liver disease monitor on case by case basis (i.e. more frequently if as indicated by symptom needed) inquiry. Risk of liver toxicity Transaminases increases after age 35. ü ALT/AST •>35 years = monthly & PRN Children rarely experience •15 –34 years = monthly & PRN liver toxicity. Affected by INH, RMP, PZA** •<15 years = PRN if symptomatic or at risk •for S-/C+ collect at end of initial phase. If sputa testing helps to negative collect at treatment completion. determine treatment •S-/C+ if positive at end of initial phase, repeat response and hence length again at 4 months of treatment and at of treatment required for ü treatment completion effective cure Sputa for AFB (at start of •S+/C+ collect at end of initial phase. If S-/C+, treatment) collect again at 4 months and at treatment completion. •S+/C+ if still smear or culture positive at 4 months of treatment consult TB specialist. •monthly, initially until improvement, then serial radiographs help every 3 months until completion determine response to CXR ü •PRN if symptomatic or poor radiographic treatment resolution of disease increased ESR is a sign of ESR ü baseline only infection Creatinine / PZA can cause ü monthly while on PZA Uric Acid nephrotoxicity every 3 months (Months 1, 4, and 7 while on Bilirubin ü treatment) CBC / every 3 months (Months 1, 4, and 7 while on RMP can cause blood ü Platelets treatment) dyscrasias Color Vision / baseline EMB can cause visual ü Visual Acuity monthly if ETOH use disturbances

*Symptoms of anorexia, lethargy, sleep disturbance, nausea or vomiting, yellow sclera, very dark colored urine, or other pertinent findings should be reported to the attending physician and the OCPHO. **Only those who show signs and symptoms of liver dysfunction or have risk factors present, such as substance abuse or known Hepatitis B or C carriers need to be monitored more frequently.

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Adverse Reactions/Treatment Induced Side Effects Recognition and appropriate management of adverse drug reactions is an essential part of the treatment program. Physicians and nurses responsible for the treatment of TB should be well acquainted with these reactions. Any possible adverse event should be carefully evaluated in order to identify other potential causes or to identify the responsible drug, which is not easy with multiple-drug regimens. It is very important to avoid unnecessary cessation of a first-line drug, as the efficacy of the treatment will be less, the duration longer and the toxicity of a replacement drug possibly worse than that of the drug that was stopped. Once a serious adverse reaction is clearly attributed to any anti-TB drug, the patient should not receive this agent again.

Table 8.12: Common Adverse Reactions with First Line Anti-Tuberculosis Drugs Rank for Uncommon but Rank for Common probability important adverse probability adverse events of events of rash hepatitis* First-line drugs Rash, hepatitis, CNS toxicity, INH 2 3 neuropathy anemia Hepatitis, Drug flu-like illness, RMP interactions, 3 1 neutropenia, rash thrombocytopenia

PZA Hepatitis, rash, Gout 1 2 arthralgia

EMB Eye toxicity Rash 4 4 Second-line drugs Tendonitis, tendon rupture, Fluoroquinolones Rash QT interval prolongation Nephrotoxicity, Amikacin ototoxicity CNS = central nervous system *1 = most likely / 4 = least likely

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INH INH may produce liver dysfunction ranging from asymptomatic, mild elevation of the serum transaminases to liver failure. Risk factors for hepatotoxicity include older age, daily alcohol consumption and pre-existing liver disease, particularly hepatitis C. INH may interfere with pyridoxine metabolism and cause peripheral neuropathy or other significant reactions (i.e. psychotic episodes). Rash may also occur, as may nausea and vomiting, especially with intermittent regimens administered in combination with RMP. Finally, patients may also note fatigue, drowsiness, headaches or mild hair loss.

RMP The most important adverse reactions with RMP are hypersensitivity reactions and drug interactions. Hypersensitivity reactions to RMP include skin rash, fever, abdominal pain, thrombocytopenia and a rare hypotensive reaction similar to anaphylactic shock. RMP induces hepatic microsomal enzymes and accelerates the clearance of many drugs metabolized by the liver. These include estrogens, coumadin, anticonvulsants, glucocorticoids, digoxin, antiarrhythmics, sulfonylureas, theophylline, cyclosporin, methadone and ketoconazole. Women using hormonal contraceptives should be advised to use alternative forms of birth control while receiving RMP. RMP alone is rarely hepatotoxic, but combined with INH there is a slightly increased incidence of liver toxicity than with either drug alone. Patients receiving RMP should be informed that their saliva and urine may become orange/red in color but that this is of no significance. Those wearing soft contact lenses should be advised that the drug may lead to permanent discoloration of the lenses from pigmented tears.

PZA PZA is the most common cause of drug-induced hepatotoxicity and rash in patients taking standard initial therapy. In up to 11% of people taking PZA arthralgias will develop; these can be very painful but are easily managed with non-steroidal anti-inflammatory drugs. Almost invariably PZA will cause elevation of serum uric acid levels, but acute gout is rarely seen except in patients with pre-existing gout. Gastrointestinal upset may also occur with PZA.

EMB Visual impairment manifested by decreases in visual acuity, visual fields or colour vision is the most significant adverse effect of EMB. Risk factors include higher doses (e.g. 25mg/kg), older age and renal impairment. Patients should be advised to report any change in vision immediately. Patients who will take EMB for longer than just the initial phase should be referred to an ophthalmologist for periodic assessment of visual acuity, colour vision and visual fields. Monthly nursing assessment of visual acuity and red-green colour discrimination is recommended. EMB-related optic neuritis is usually reversible if the drug is stopped promptly, although resolution can take several months. EMB should be used with caution in children who are too young for monitoring. Other side effects, such as rash may also occur.

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Suggested Management of Common Adverse Reactions Appropriate management of adverse reactions is complicated. If there is uncertainty, consultation with a TB specialist is recommended. All of the TB drugs may cause rash, although some cause rash more frequently than others. Mild itching or slight rash may be treated symptomatically without changing TB treatment. It is important to remember that failure and relapse rates are higher with alternative regimens; hence, any decision to stop the first-line drugs should never be made lightly. However, if the rash is generalized, particularly if associated with involvement of mucous membranes, wheezing, hypotension etc., then stop treatment and follow these recommendations: • Stop all current drugs, and immediately start at least two alternative TB medications: - A fluoroquinolone plus an injectable or an oral second-line agent

• Review the history carefully, especially with regard to other possible causes of rash, such as food allergies or other drugs taken, including over-the-counter and herbal remedies • When rash has resolved restart one TB drug. Give the drug judged least likely responsible but also one of the most effective TB drugs. If history is unclear (which is the norm) give INH • Wait 2–3 days to verify if rash recurs with INH before starting the second drug – RMP • If there is no rash after 2–3 days of RMP give EMB • If there is no rash with EMB, assume that the rash was due to PZA. The decision to rechallenge with PZA depends on the need for PZA and the severity of the initial allergic reaction • If the rash recurs with one agent, then discontinue that drug permanently and start all remaining drugs. Adjust the regimen according to which drug was permanently stopped

Interactions of TB Medications with Drugs and Food Significant interactions may occur between TB medications and other medications. The absorption of some TB drugs may be adversely affected by food. A list of significant interactions is available from the Heartland National TB Center, Texas. The most important cause of interactions with other medications is RMP. Most of these drug interactions can be managed by adjusting the dosage according to measured drug concentrations (e.g. phenytoin), by monitoring the clinical effect of these drugs (e.g. international normalized ratio for warfarin) or by substituting certain drugs (e.g. antiretroviral regimens). *Please refer to drug monograph for complete information on each drug.

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Management of Presumed TB Drug-Induced Hepatitis Drug-induced hepatitis can be caused by PZA, INH or RMP, in that order of probability Diagnosis may be difficult, as symptoms are nonspecific. A feeling of being unwell may be the first sign of impending hepatitis. If the serum transaminase level (aspartate aminotransferase or alanine aminotransferase) exceeds five times the upper limit of normal, signs and symptoms present or clinical jaundice develops then the following recommendations are suggested:

• Stop PZA, INH and RMP, and immediately start at least two alternative TB medications: a FQN plus an injectable, or a FQN plus an oral second-line agent • Review the history carefully, especially with regard to other possible causes of hepatotoxicity, such as alcohol or other drugs taken, including over-the-counter and herbal remedies. Check viral serologies (hepatitis A, B and C) • When transaminases have returned to normal restart one of the three TB drugs stopped earlier. Give RMP, as this drug is the least likely to be responsible and is the most effective TB drug • Wait 2 weeks to verify that transaminases remain normal with RMP before starting INH. If initial hepatotoxicity was very severe (ALT >1,000U/L) it may be wiser not to rechallenge with PZA or with INH; fatalities have been reported with INH rechallenge in this situation. This depends on the need for these two drugs. Consult with a TB specialist • If RMP and INH are restarted and transaminases remain normal, assume that the hepatitis is due to PZA. Do NOT rechallenge with PZA

If hepatitis recurs with one agent, then discontinue that drug permanently and start all remaining drugs. Adjust regimen according to which drug was permanently stopped.

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INH Drug Overdose

Table 8.13: INH Drug Overdose

INH Drug Overdose

Below is the recommended antidote for INH overdose. Consult with your on-call physician/ pediatrician IMMEDIATELY and initiate treatment.

Consider calling the PADIS – Poison and Drug Information Services, Alberta and Northwest Territories contact: 1-800-332-1414.

Management of INH overdose includes supportive care focusing on patient’s cardiovascular status, protecting the airway, abolishing seizure activity and correcting metabolic acidosis.

As soon as an overdose of INH has been recognized (even in the absence of symptoms), Pyridoxine IV should be administered to prevent neurotoxic effects.

The same dose of Pyridoxine (Vitamin B6) as the dose of INH ingested should be given intravenously.

•For example, a child who has ingested 3.0g of INH should be given 3.0g of pyridoxine. If the dose is not known, Pyridoxine should be given intravenously in a dose of 5g in adults or 70mg/kg (maximum dose 5g) in children, at a rate of 1g every 2–3 minutes (CP, 2013). •This dose of pyridoxine should be repeated in two hours if the response to treatment has been incomplete. A total dose of 25g may be required in the first 12 hours. •A single dose of activated charcoal should be considered at a dose of 1g/kg. •Diazepam IV with addition of Phenobarbital or Propofol may be used in addition to Pyridoxine to treat convulsions. •Diazepam (Valium) should be given to control seizures (2mg by rectum for babies over the age of six months, or 5–10mg intravenously for older children and adults). Phenytoin (Dilantin) should not be given as it increases levels of INH. Please note INH also increases serum levels (Dart, 2004). •Once the patient is stabilized, refer to an internal medical specialist or pediatrician for further medical treatment.

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Completion of Treatment The end of treatment occurs when the patient has ingested every dose of anti-TB drugs in accordance with the recommended standards in this TB manual and, in consultation with the Internal Medicine Specialist, TB Specialists and with the OCPHO. The completion of TB treatment for respiratory TB involves: • Thorough review of patient’s case and treatment, including compliance • Physical assessment • CXR at treatment completion • Three consecutive sputa for AFB at treatment completion • Complete NWT Active Tuberculosis Drug Treatment and Progress Record • For cases of non-respiratory TB follow-up after treatment is individualized and will be determined by the Internal Medicine Specialist If all signs and symptoms of TB have resolved, no follow-up is required if the patient is low-risk for re-infection and not living in a TB-endemic community. If treatment is considered inadequate, follow-up will be determined in consultation with the Internal Medicine Specialist and the OCPHO.

Surveillance Generally, all patients who have completed their treatment and are considered cured from their TB do not require follow-up or surveillance. Patients who require follow-up after treatment include the following: • Patients with inadequate regimens • Patients who were non-adherent to their regimen • Patients with multidrug or extensively drug resistant TB • Patients with HIV co-infection For these patients it is recommended to provide regular follow-up every 6 months or yearly for up to 3 years. If patients are reporting symptoms such as persistent cough, or fever, it may suggest TB disease relapse. Therefore these patients must be provided with a follow-up examination. All patients should be told to return at any time in the future for evaluation of symptoms that suggest disease relapse, such as persistent cough or fever, hemoptysis or unexplained weight loss.

Drug-Resistant Tuberculosis Globally, the rate of drug-resistant TB is increasing. In Canada, two systems are used to track drug-resistant TB: • The Canadian TB Reporting System and; • The Canadian TB Laboratory Surveillance System.

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The major risk factors for drug-resistant TB in Canada are previous treatment and foreign birth. Drug-resistant TB should be suspected in patients who have: • Previously been treated for active TB, • Originated from, resided in or travelled to a country where drug-resistant TB is highly prevalent or; • Been exposed to a person with infectious drug-resistant TB. A person is considered to have drug-resistant TB if the bacteria strain that caused their disease is resistant to one or more of four FLD used for TB treatment (i.e. INH, RMP, PZA, and EMB). In Canada, INH resistance is the most common pattern of first-line drug resistance. Drug-resistant TB cases, confirmed or suspected, are difficult to clinically manage and must be referred to a TB Specialist.

Table 8.14: Type of Drug Resistance Type of Resistance Description Tuberculosis due to bacteria resistant to one of the four first Mono-resistant TB line drugs (i.e. INH)

Tuberculosis due to bacteria resistant to two or more first line Polyresistant TB drugs (i.e. INH and RMP) Tuberculosis due to bacteria resistant to INH and RMP with Multidrug-resistant TB or without resistance to other first or second line drugs (MDR-TB) (described below) Tuberculosis due to bacteria resistant to at least INH and RMP PLUS Resistance to any fluoroquinolone (second line anti-TB drug; a Extensively drug- class of antibiotic) resistant TB (XDR-TB) AND Resistance to at least one of the three injectable second line drugs (including capreomycin, kanamycin, amikacin)

Previous treatment for TB is an important consideration in determining risk of drug resistance. If a patient has a history of previous TB treatment, it is important to note the following: •Patient has taken anti-TB medication(s) for one month or more at any time in the past but has not completed full treatment •Patient lived in a TB-endemic country where drug resistance is prevalent •Patient’s drug regimen did not include INH and RMP throughout its entire course and was less than 12 months in duration •DOT was not used, or patient reported missed doses •Patient was exposed to a person with infectious drug-resistant TB

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Prevention of drug-resistant TB can be achieved by doing the following: • Prescribe at least two anti-TB drugs to which the bacteria strain is susceptible • It is imperative to give TB drug regime by DOT • Never introduce a single drug to a failing regimen • Case management of all TB patients is necessary

Traditionally, drug resistance in TB has been classified into three types:

1. Primary Drug Resistance: When previously untreated patients are diagnosed to have drug-resistant organisms, presumably because they have been infected from an outside source of resistant bacteria. Primary drug resistance is uncommon in Canadian-born people unless they have travelled abroad to a country with a high prevalence of anti-TB drug resistance.

2. Acquired Drug Resistance: When patients who initially have drug-susceptible TB bacteria later become drug-resistant as a result of inadequate, inappropriate or irregular treatment or, more importantly, because of non adherence in drug taking. Acquired drug resistance is uncommon in Canadian-born people, perhaps because directly observed therapy (DOT) is frequently used to promote treatment adherence.

3. Initial Drug Resistance: When drug resistance occurs in patients who deny previous treatment but whose history of prior drug use cannot be verified. In reality it consists of true primary resistance and an unknown amount of undisclosed acquired resistance. These patients are classified as having initial rather than primary drug resistance.

Management of Drug-Resistant TB For the management of all drug-resistant TB cases the following is required: • Adequate drug-susceptibility testing • The appropriate use of first and second line anti-TB drugs according to drug susceptibility results • Access to experienced health care specialist who will direct the management of drug- resistant TB. This is a mandatory requirement.

Any patient with drug-resistance to INH and RMP must undergo drug susceptibility testing for second line anti-TB drugs.

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Second-Line Anti-Tuberculosis Treatment Treatment for drug-resistant TB is usually with a daily regimen (particularly the initial phase of treatment), under DOT. Otherwise there is a greater risk of inadequate treatment or treatment failure. Drug serum levels are also required if drug malabsorption is suspected. If an anti-TB drug regimen is changed because there is suspect of treatment failure, there must be a minimum of two new drugs added. The drug susceptibility of the added drugs must be confirmed or it must be known that the patient has never received the new added drugs. Refer to Canadian TB Standards, 7th Edition, for further information on treatment and drugs used for multidrug-resistant TB.

Recommendations for Treatment of INH Mono-resistant TB • All patients suspected of drug-resistant TB must be started on four first-line anti-TB drugs while awaiting drug susceptibility results • In the NWT DOT is used for all TB cases. It is especially important in patients with sputum smear-positive respiratory disease or co-infection with HIV • Regimens for the treatment for INH mono-resistant TB are:

Table 8.15: Regimens for the Treatment of INH Mono-resistant TB

Regimen Initial Phase Continuation Phase 4–7 months daily or thrice weekly 1 2 months daily (INH), RMP, PZA, EMB*† RMP, PZA, EMB 10 months daily or thrice weekly 2 2 months daily (INH), RMP, PZA, EMB*† RMP, EMB 4–7 months daily or thrice weekly 3 2 months daily (INH), FQN, RMP, PZA, EMB*‡ FQN/RMP/EMB

* If treatment was started with a standard 4-drug regime, INH can be stopped when resistance is documented. † If a patient has extensive disease a Fluoroquinolone (levofloxacin and not moxifloxacin) can be added to the regimen especially during the initial phase. ‡ PZA is recommended here but in most trials this drug was not included in the regime.

Recommendations for Treatment of RMP Mono-resistant TB RMP mono-resistant TB is uncommon except in HIV-infected patients. It is estimated RMP monoresistance occurs approximately 10% of the time. Therefore, 90% of time RMP resistance is accompanied by another drug-resistance, such as INH. RMP resistance should strongly signal suspicion for MDR-TB cases.

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Table 8.16: Regimens for the Treatment of RMP Mono-resistant TB

Regimens Initial Phase Continuation Phase 10–16 months daily or thrice 1 2 months daily INH, PZA, EMB, FQN* weekly INH, EMB, FQN 2 months daily INH, PZA, SM (or other 7 months daily or thrice weekly 2 aminoglycoside/polypeptide daily or INH, PZA, SM thrice weekly) 16 months daily or thrice weekly 3 2 months daily INH, PZA, EMB daily† INH, EMB

INH = isoniazid, PZA = pyrazinamide, EMB = ethambutol, FQN = levofloxacin or moxifloxacin, SM = streptomycin *For treatment in patients with extensive cavitary disease or to shorten the duration of treatment (e.g. 12 months), addition of an injectable agent for at least the first 2 months is recommended. † An injectable agent may strengthen the regimen in patients with extensive disease

Recommendations for Treatment of PZA or EMB Mono-resistant TB Monoresistance to PZA or EMB is rare. Isolated PZA resistance occurs with exposure and infection with M. bovis. Therefore it can serve as a critical tool for laboratories to differentiate between M. tuberculosis from M. bovis or M. bovis BCG. • Patients with mono-resistant TB to PZA should have their total duration of treatment as 9 months or more • Patients with mono-resistant TB to EMB, the standard regimens do not change

Multidrug-Resistant (MDR-TB) and Extensively Drug-Resistant (XDR-TB) Tuberculosis A patient with MDR-TB or XDR-TB will need treatment with second-line treatment. Second-line anti-TB drugs are considered less effective, require extended periods of treatment (20–24 months or more) and can cause more side effects than first-line drugs. When on treatment, these patients can be infectious for a longer period of time before improvements are seen.

When the drug susceptibility results are available, then the treatment regimen can be determined.

Surgery is considered in cases of MDR-TB/XDR-TB when the bacteria drug-resistance pattern shows a high probability of treatment failure. Removal of diseased lung by resection is an option for these patients to improve their chances of cure.

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Cure from MDR-TB is reached when five consecutive negative cultures are collected 30 days apart in the final 12 months of the treatment. Treatment is usually 18 months in duration after there is evidence of culture conversion. When treatment is completed, patients should be seen every 6 months for a minimum of 2 years. Clinical, radiologic and mycobacteriologic assessment is necessary at each follow up.

Historical TB Cases A review of old cases of active TB should be undertaken in every community. Inadequately treated TB increases the risk of relapse and outbreak in the community. Treatment regimens considered to be complete include: •INH and para-aminosalicylic acid (PAS) for 18 months (used in the 1950s and 1960s) •INH and EMB for 15 months (used in the 1970s)

If treatment regimens are uncertain or if treatment is determined to be inadequate, these patients require yearly follow-up consisting of: •Symptom Inquiry (see NWT Tuberculosis Assessment Form) •CXR •Sputa for AFB x 3

In situations where treatment falls short of the above requirements, and once active disease has been ruled out, individuals may be considered for further prophylaxis treatment. In cases where there has been a wide variety of treatment regimes, these will be assessed by the TB Specialist for treatment options.

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 8-35 Section 8: Treatment for Tuberculosis Non-respiratory TB

Non-respiratory TB TB can affect any organ or organ system (eye, brain, lymph, heart, etc.) of the body, including the skin, non-nodal glandular tissue (i.e. breast), great vessels and bone marrow. The terms non-respiratory TB and extra-pulmonary TB are often used interchangeably. In Canada, extra-pulmonary TB refers to everything but pulmonary TB. Non-respiratory tuberculosis accounted for 25% of cases of TB in Canada in 2010. Isolated non-respiratory TB is more commonly seen in females and foreign-born people. Disseminated disease (concurrent involvement of at least two non-contiguous organ sites of the body or the involvement of the blood or bone marrow) is associated with immunodeficiency.

Diagnosis of Non-respiratory TB A diagnosis of non-respiratory TB often requires biopsy of the affected organ, and samples must be sent for AFB smear and culture. The clinical specimens obtained for diagnostic purposes will depend upon the suspected anatomic site of involvement. In general, tissue biopsy yields positive culture results more often than fluid aspiration; both are superior to swabs. Biopsy material for mycobacterial culture should be submitted fresh or in a small amount of sterile saline. All suspected cases of non-respiratory TB should be assessed for concomitant respiratory TB to determine whether the case is infectious and to assist with diagnosis. Pulmonary involvement in patients with non-respiratory TB disease can range from 10% to 50%. A diagnosis of non-respiratory TB, as with all cases of respiratory TB, should prompt an HIV test.

Treatment of Non-respiratory TB The fundamental principles that apply to the treatment of respiratory TB are also applicable to non-respiratory TB. The same treatment regimens are used unless there is drug resistance to first line treatment. In some cases, longer therapies are used in specific sites of non-respiratory TB. Six months of standard anti-TB medical therapy is considered adequate for most forms of non-respiratory TB. Treatment for CNS TB (including TB meningitis, TB myelitis, or brain and meningeal TB) is highly effective when duration is at least 12 months. TB meningitis should be treated as a medical emergency; time is of the essence in achieving a good outcome, as the condition is frequently associated with devastating consequences: 25% morbidity (i.e. permanent neurologic deficit) and 15% to 40% mortality despite available treatment. In meningitis, empiric therapy with standard quadruple therapy should be initiated immediately on suspicion of the diagnosis to prevent complications. Corticosteroids might also be used to help reduce the risk of complications and death. If complications do happen, neurosurgery might be needed.

8-36NWT Tuberculosis Manual - JuneNovember 2014 2014 Non-respiratory TB SectionSection 8: 8: Treatment Treatment for for Tuberculosis Tuberculosis

Miliary TB/Disseminated TB implies there is widespread distribution of TB bacteria to most organs of the body. Longer treatment (12 months) is recommended especially for those who are: • Immunocompromised • Have a slow response to treatment • Have drug-resistant disease

Mortality from miliary TB is high (about 20%). The disease may manifest as a miliary pattern on the chest radiograph, which is characterized by 1–5mm nodules, or, among those without a miliary pattern on chest radiograph, as a bone marrow aspirate/biopsy or a blood culture positive for M. tuberculosis, or as generalized TB at postmortem examination. A significant proportion present with fever of unknown origin. Most often, the presentation is subacute or chronic, though acute fulminant presentations can occur, with shock and acute respiratory distress syndrome. The nonspecific and often variable presentation frequently leads to a delay or lack of diagnosis and thus the high mortality rate. Treatment regimens for bone and joint TB in complicated patients are more successful if longer regimens (12 months) are used.

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8-38NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 9: Contact Tracing Section 9 Contact Tracing

Contact Tracing Algorithms 9-2 Contact Tracing and Contact Investigations 9-5 Goals and Objectives of Contact Tracing 9-5 Factors Contributing to Transmission 9-5 Prioritization of Contact Follow-Up 9-6 Steps in a Contact Investigation 9-7 Evaluation of Contacts for the Presence of Active Disease and Evidence of Recent Infection 9-9 Organizing an Investigation: Identification and Interview of Contacts 9-10 Screening Contacts in a Contact Investigation 9-13 INH Preventive Treatment for Contacts 9-14 Evaluation of Contact Investigation 9-14

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Contact Tracing Algorithms

Figure 9.1: Contact Tracing for Active Respiratory TB

Active Respiratory TB

Interview case, close relatives, and friends to determine when the person became symptomatic (This determines time frame for exposure to contacts)

Initiate NWT Tuberculosis Case and Contact Tracing Record identifying contacts for investigation and report to OCPHO within 7 days

Screen high-priority contacts only (if case is smear negative respiratory TB). Add medium priority contacts if case is smear positive (more infectious). Report results to OCPHO within 3 weeks

If conversion in TSTs or evidence of infected persons, (i.e. +transmission), add low risk or casual contacts. Casual contacts can be screened once at 8 weeks after last exposure

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Figure 9.2: Management of TB Contacts (Negative TST History or No Previous TST Algorithm)

Contacts with negative TST history or no previous TST

Positive Do symptom Negative (>5mm in high risk inquiry and TST (less than 5mm) contacts or >10mm initially in all in average or low high priority risk contacts) contacts

Do: •CXR Positive Repeat TST in 8 weeks •Sputa x3 for AFB •Complete NWT (Children under five Tuberculosis years old who are Active TB Assessment Form contacts of a smear ruled in positive case should be given INH during the 8 weeks between tests) Consult OCPHO If active TB is ruled out, Admit offer INH (DOPT) as per OCPHO recommendation

Negative No Follow-up Accept Refuse

• CXR Notify at 6, 12, 18, OCPHO of • symptom inquiry • sputa for AFB 24 months start date and then • Follow-up yearly if surveillance as high risk necessary based on risk

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 9-3 Section 9: Contact Tracing

Figure 9.3: Management of TB Contacts (Previous Positive TST Algorithm)

Contacts with: • previous positive TST • CXR consistent with previous TB exposure; or • symptomatic (cough, weight loss)

Do this today: • symptom inquiry • sputa x3 for AFB • CXR

Positive Findings Negative Findings

• Consult OCPHO Repeat investigation in 8 Positive • Complete NWT Tuberculosis weeks (if high priority contact) Assessment Form

If negative, consider Active TB LTBI

Offer INH Yearly follow-up Consult Internal Consider INH Prophylaxis if if high risk and Medicine prophylaxis (DOPT no previous treatment not Specialist or as per OCPHO LTBI treatment, possible Pediatrician recommendations as per OCPHO if patient has recommendations not previously been treated prophylactically Admit for +TST. If yes, treat If previously treated DOPT (appropriately), no need to retreat LTBI.

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Contact Tracing and Contact Investigations Only respiratory TB, with limited exceptions, is infectious. Contact follow-up should be carried out for both sputum smear-negative and smear-positive cases. Contact tracing is the compilation of a list of people (contacts) by a nurse or public health worker about the people with whom a confirmed or suspect TB index case (first identified or presenting case) lives, works and socializes. An organized and systematic approach is used to discover people who may have contracted TB from the case. Contact tracing not only finds those who may have been infected by the index case, but also detects a possible source case. Definitions used in a contact investigation include: • Index case: the first case or initial active case from which the process of contact investigation begins • Source case: the person who was the original source of infection for secondary case(s) or contacts. The source case can be, but is not necessarily, the index case • Contact: a person identified as having been exposed to an active case of disease. The closeness and duration of exposure usually corresponds with the risk of becoming infected

Goals and Objectives of Contact Tracing The goal of contact tracing is to prevent the development of active TB disease and to identify new infections (latent or active) as soon as possible. Contact follow-up is the key to preventing or minimizing outbreaks. Staff from the Office of the CPHO, together with Health Centres and Public Health Units, direct the contact tracing of active cases as per Reportable Disease Control Regulations of the Public Health Act (2009). A contact investigation has three main objectives: 1. Identify and initiate treatment of secondary cases of active TB disease. 2. Identify and treat the source case who infected the index case, if the index case is >5 years old. 3. Identify contacts with LTBI in order to offer preventative treatment.

Factors Contributing to Transmission The level of advancement of disease in the source case is usually directly related to the degree of infectiousness. Highly infectious source cases are usually AFB sputum smear positive and have cavitary pulmonary TB or laryngeal TB. Cases of laryngeal TB are considered four to five times more infectious than smear-positive pulmonary cases, as they are likely to have a large number of bacteria due to extensive concurrent pulmonary disease. Transmission is dependent on the length of illness and severity of disease. In general, children under age 10 with TB are not considered infectious. However, in unusual circumstances, even very small children can transmit TB. Adolescents can be very effective transmitters of TB, partly because they can have extensive disease by the time it is diagnosed, and particularly because in high school they can have large numbers of contacts. It is recommended that any child presenting with adult-type pulmonary TB (cough, cavitation on

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chest x-ray, smear-positive sputum) should be considered infectious and contact investigation undertaken. The longer the shared airspace (exposure) between the source case and contacts is directly related to the possibility of transmission or contracting TB. For example, a crowded home would have more contaminated airspace than an outdoor soccer field or hockey rink. Transmission is rarely thought to occur outdoors; however, indoor environments that are poorly ventilated, dark and damp can lead to increased concentration and survival of M. tuberculosis. The vulnerability of the contacts is also a factor contributing to transmission of disease. Children and those with immune compromising diseases are more susceptible to contracting TB. Source-case identification/investigation is recommended for children under 5 years old with a diagnosis of active TB disease. In infected contacts that are vulnerable because of young age (under 5 years), HIV or other causes of significant immune suppression, infection may progress quickly to active disease. Therefore early diagnosis often depends on good contact follow-up.

Prioritization of Contact Follow-Up Prioritization of contact follow-up is recommended by the infectiousness of the source case, extent of exposure and immunologic vulnerability of those exposed. Thus, the greatest effort is put into reaching contacts who are most at risk of being infected and/or most at risk of developing active TB disease if infected. Interviews with the infectious case to identify contacts should include questions about locations/activities of potential exposure as well as specific named contacts. The classic concentric-circle approach to contact follow-up is no longer recommended. This approach does not take into account contacts who may have less extensive exposure but, if infected, are immunologically vulnerable to rapid development of active TB. It can lead to long delays in appropriate contact follow-up when the index case is already known to be highly infectious. A fundamental difficulty is that transmission can be very difficult to evaluate when the background rate of positive TST results is unknown or is high. Rather, the initial follow-up should include non-household contacts from the outset when case infectiousness and contact vulnerability warrants it. Contacts may be grouped as follows: • High priority – household contacts plus close non-household contacts who are immunologically vulnerable, such as children under 5 years • Medium priority – close non-household contacts with daily or almost daily exposure, including those at school and work • Low priority – casual contacts with lower amounts of exposure Cases that are sputum smear-positive or have cavitary disease on chest x-ray are significantly more infectious than smear-negative or non-cavitary cases. Coughing, sneezing and singing also increase the risk of transmission. Therefore, for smear-positive/cavitary/laryngeal TB, it is recommended that the initial contact follow-up include both high- and medium-priority contacts. If there is evidence of transmission within these two groups, consideration should be given to expanding contact follow up to casual contacts. For laryngeal TB, also consider including any casual contacts (social/recreational groups, etc.) from the outset.

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For smear-negative, non-cavitary pulmonary TB, the initial contact follow-up should be for high-priority contacts only. In both situations, contact investigation is iterative: it should be expanded if the initial follow-up results indicate that transmission has occurred. A single evaluation at least 8 weeks after the end of exposure (with TST and symptom assessment) is recommended in most non-household contact settings, in order to maximize participation and minimize over diagnosis of “conversion” related to boosting. Initial plus 8 week post-exposure TST is recommended for household and other high-priority contacts. Two-step TST is not recommended in the setting of a contact investigation. TST is no longer recommended as a primary assessment tool in the contact follow-up of elderly residents in long-term care, in whom it is less reliable and for many of whom the risks of treatment of LTBI in old age will outweigh any benefit. The focus for these individuals should be on early detection of secondary cases Contact investigation often demands considerable time, expertise and coordination. It is usually best carried out by public health/TB control personnel in collaboration with treating clinicians and other providers. Anxiety, stigma and lack of knowledge about TB among those exposed may be major issues. Provision of clear, credible and consistent information about TB and the contact follow-up plan is crucial for success.

Steps in a Contact Investigation Below are the steps in conducting a contact investigation:

Step 1: Confirm the diagnosis of the case • Provide appropriate medical evaluation (i.e. history for risk factors, clinical assessment, CXR, culture results)

Step 2: Determine infectiousness of case • Determine the type of TB (i.e. respiratory, miliary, laryngeal) • Consider associated risk factors for infectiousness (i.e. age, cough, etc.) • Obtain microbiological testing results

Step 3: Determine likely duration of infectiousness Cases of pulmonary TB are generally considered to become infectious at the time of onset of cough or worsening of a baseline cough. • If patient is coughing, estimate time of onset of infectiousness at time of onset of cough • If patient is not coughing but symptomatic or smear positive, estimate time of onset of infectiousness by the following: - Patient is infectious for 3 months prior to symptom onset OR since first positive finding consistent with TB disease – whichever comes first

• If patient is asymptomatic with negative smear and no cavities on CXR, estimate time of onset of infectiousness by the following: -Patient is infectious since 4 weeks before the date that TB was suspected

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Priority should always be given to contact tracing during the period when the TB patient was symptomatic

Step 4: Determine all possible settings where transmission of TB might have occurred

Step 5: Find contacts in those settings • Contacts include: Household, non-household or casual contacts • Determine name of contacts and assign priority on basis of likelihood of infection

Step 6: Investigate close contacts suspected of having TB • Investigation of close contacts strongly suspected of having TB must be completed regardless if confirmation tests of source case are not complete. • Especially in children, contacts with HIV infection, or contacts with any risk factors for progression to TB disease • Investigation of contacts can also be directed according to TB status of source case: • Casual contacts are only investigated after final confirmation of the diagnosis of source case and all high risk contacts have been prioritized and investigated.

Step 7: Determine TB status of contacts investigated and manage accordingly • Investigation of contacts involve interview of each contact on: -Type of contact with source case -Signs and symptoms of disease -Risk factors for progression to TB disease -History of TB treatment (call the TB Registry at 867-920-8646 for a TB history) (See section on assessment on positive TST) • If suspected of having active TB disease, investigate further with appropriate diagnostic tests (see Section 6, Diagnosis Of Active TB Disease) • If active TB excluded, do TST if applicable - If TST negative but performed in less than 8 weeks must repeat 8 weeks after contact with source case was broken -If TST negative and test done after 8 weeks contact with source case was known then consider contact TB negative and no other tests are required -If TST positive, consider LTBI preventive treatment (see Section 8, LTBI Treatment)

• See Table 9.1 for interpretation of TST in a contact investigation

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Table 9.1: TST in the Context of a Contact Investigation

Previous Test Result: Positive if:

No documented previous TST result TST 5mm or more on first test or @ 8 weeks after the last exposure to source case

TST <5mm (documented previously) TST 10mm or more on first test or @ 8 weeks after the last exposure to source case TST >10mm on first test or @ 8 weeks However TST 6mm increase from previous TST is accepted as positive if: •Source case highly infectious •Long exposure between contact and source case •Contact <5 years of age •Contact has impaired immunity

TST between 5–9mm and no history TST 6mm increase on initial TST or @ 8 weeks after of treatment of TB disease or LTBI the last exposure to source case (documented previously)

TST >10mm or history of treatment No TST required for TB disease or LTBI (documented Evaluation should include: previously) •Assessment of signs and symptoms of active TB disease •Additional investigation as necessary (see Section 8, Diagnosis of Active TB)

Evaluation of Contacts for the Presence of Active Disease and Evidence of Recent Infection All identified contacts should be interviewed systematically regarding their exposure to the case, presence of symptoms, risk factors for progression to active TB if infected and history of treatment of TB or LTBI. If there are any concerns, rapid evaluation to exclude active TB should be carried out. Once active disease has been excluded, contacts should receive a TST unless there is a history of prior treatment of TB or a documented prior positive TST result. The TST should be carried out and interpreted regardless of BCG vaccination status. A TST of 5mm or more is considered positive for contacts. Note that TB assessment of contacts may involve TST or an IGRA.

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A two-step TST is not recommended in the setting of a contact investigation. Skin test conversion can occur as early as 3 weeks after exposure, and it will generally be impossible to differentiate between true TST conversion and a boosted reaction in the setting of a contact investigation (see Section 4, TB Screening). This is another reason why only those with significant exposure should be considered contacts. Window treatment of LTBI for those most susceptible. Contacts who are at very high risk of progression to active disease if infected (children under 5 years; HIV positive or other immunosuppressed individuals) should receive window prophylaxis in the interval between a negative initial TST result and the definitive TST at least 8 weeks after the last day of exposure because of the high risk of progression to active TB if infected.

Organizing an Investigation: Identification and Interview of Contacts The interview of an infectious TB patient for contact tracing purposes is one of the most important parts of the investigation. It takes considerable skill and is most successful when done by staff with training and experience in public health interview techniques. Trust and rapport are important for full disclosure, and the initial interview can also lay the foundation for long-term adherence to TB treatment. Face-to-face interviewing, in privacy, is ideal. Most TB patients in Canada were born in countries with high TB incidence or in First Nations/ Inuit communities, so sensitivity to language and cultural perceptions about TB and health is very important. Interviews are best carried out in the language the patient is most comfortable with. It is recommended that a professional interpreter or an objective third party (not a family member) be used for interpretation if possible, either in person or participating by telephone. Interviewers should always be respectful and sensitive to patient concerns and beliefs about TB, should incorporate education about TB and stress the confidentiality of contact investigations. The first public health communication with a new infectious patient (and/or the health care providers if the patient is hospitalized) should ideally begin within 1 calendar day of the case being notified. The purpose of this brief initial communication is to achieve adequate airborne isolation, provide any urgent support, identify the household contacts and direct any who are ill to immediate TB assessment. Interviewing to determine the full set of contacts should be initiated within 3 working days. Interviewing is usually best extended over two (or more) sessions, a week or more apart, as the patient becomes more familiar with public health staff, and the initial stress and anxiety over the diagnosis are resolving. Proxy or supplemental interviews (ideally with patient permission) with family, close friends, coworkers, etc., may be helpful if patients are unable or unwilling to participate. It is important to include questions about the places where the case spends time regularly, not just names of individual people, and to get contact details whenever possible (name, alias/nickname, phone, address, email, age, nature of interaction). There are so many variables in TB transmission that it is very difficult to quantify the amount of exposure that constitutes a significant risk. In theory, there is no amount of exposure to infectious TB that is absolutely without risk; in practice, each case should be evaluated on its specific characteristics. Exposure in cramped, ill-ventilated spaces may lead to transmission in much shorter exposure times, and genetic fingerprinting has occasionally discovered apparent transmission following close but very brief exposure.

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• Interviews to identify contacts should include the following information: -Any contact with children and their ages -Any contact with immunosuppressed people (HIV positive, cancer patients, etc.)

• Whenever possible, initial assessment of the high-priority contacts should begin within 7 working days of their being identified as contacts and be completed within 1 month. High- priority contacts should ideally have both an initial and a second TST (at least 8 weeks from the last day of exposure) to identify conversion.

• Close household contacts: -Live in the same house or dwelling (jail, homeless shelter, etc.) sharing breathing space on a daily basis with the index case; may or may not be a family member, but share a living space (more than four hours per week).

• Close non-household contacts: -Have regular and prolonged contact with the index case, share breathing space daily, but do not share a household; may include sexual partners, close friends, or regular or frequent (overnight) guests(more than four hours per week).

• Casual contacts: -Spend less frequent time (2–4 hours per week) with the source case; may include classmates, officemates, members of a club or team, social circles (bingo, cards, sewing circles, church groups). Individuals who have only transient or occasional exposure are in this group. Casual contacts are low priority. It is generally recommended that the investigation be expanded to this group only if there is evidence of transmission or the case is considered to be extremely infectious. However, the specific circumstances should always be considered. For example, a choir group meeting once per week may pose significantly more risk than a weekly outdoor soccer game; children riding on long daily school bus routes in winter, when windows are usually closed, may have considerable exposure.

• Community contacts: -Living in the same community, or attending the same school or workplace.

Participation rates often drop significantly between initial and post-8-week screenings as the level of initial concern declines. Thus, in most non-household settings it is most practical to aim for a single round of screening after 8 weeks from the break in contact. In populations in which many people have prior exposure to TB or BCG vaccination (e.g. immigrants from high-incidence countries), this also avoids false TST “conversion” related to boosting. If casual contacts are investigated, only a single TST after 8 weeks from the last day of exposure is recommended. The highest priority contacts are those with the most exposure and those with the highest risk of progression to active TB if infected, as follows: • Household contacts, including those exposed as “household members” in congregate settings such as homeless shelters, jails and long-term care facilities (generally, room-mates or cell-mates).

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• Contacts who are close non-household or casual contacts AND who are at high risk of progression of LTBI to TB disease, e.g. age under 5 years, HIV, dialysis, transplant, silicosis contacts exposed (i.e. without an N95 mask) during bronchoscopy, sputum induction, autopsy or other aerosolizing medical procedures.

Social Networking and Location-Based Screening All cases should routinely be asked about the locations where they spend time. Particularly when infectious cases are unable or unwilling to name specific contacts, or when cases are occurring without identifiable exposure risks or sources. Identifying locations where the case spent time may be more productive than traditional name-based approaches. Epidemiologic links among cases can be enhanced when questions about common locations are included in case interviews. Social networks analysis examines the social relationships between cases and contacts to identify settings and behaviors that characterize transmission events. Social network analysis has been extensively studied in sexually transmitted infections and more recently in the study of TB outbreaks. Some populations are highly mobile and often live unconventional lifestyles. In these circumstances, consider additional options such as targeted screening in locations where the source case frequents such as shelters, drop-in centers, other homes, and common hang-out areas.

Expanding Contact Investigation Transmission is considered to have occurred if a secondary case is identified in any contact, if there are any TST converters, if the prevalence rate of TST ≥10mm among contacts is significantly higher than expected or if a child contact under age 5 years is infected without another probable source. When there is evidence of transmission, the contact investigation should first address any high-priority contacts who have not yet been assessed and investigate moderate-priority contacts if this has not already been done. Consideration should then be given to expanding to casual contacts. There is often pressure on a public health department or physician to initiate widespread contact investigation – e.g. to an entire school – from the outset. If this is done, however, it is often impossible to interpret the results of a positive TST result (or IGRA) in individual patients. Contacts may then be mistakenly identified as recently infected and the investigation expanded yet further. This can also lead to widespread concern about the risk of transmission to community contacts. If expansion of the investigation beyond high- and moderate-priority groups is considered, the decision should be based on evaluation of any evidence of transmission in the initial investigation, the probability of finding infected individuals among less exposed contacts and the likelihood that these casual contacts will follow up on screening and LTBI treatment recommendations. Contacts with less exposure have a positive TST prevalence rate that is usually four to eight times less than that among household contacts.

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Site-Base Screening and Congregate Settings In some settings, it is far more practical and feasible to carry out contact investigation for an entire group (such as a class at school or coworkers in a work setting) than attempt to identify the specific individuals who were most exposed. Practical factors, such as the ability to reliably measure the degree of exposure of different individuals in the setting, the administrative ability to provide efficient testing and TB education, and the ramifications of extending the investigation to a larger group later if it becomes necessary, should be taken into account in deciding on the extent and number of people to be tested. Similarly, in certain settings (e.g. shelters for the homeless) in which contacts may be difficult to identify or to find, it may be helpful to do wider testing from the outset. School, workplace and other congregate setting investigations are usually best carried out on site. This leads to higher participation rates among contacts, better communication and less anxiety; it is usually the most effective and efficient way of carrying out the investigation and obtaining the necessary information.

Screening Contacts in a Contact Investigation Contacts with No Record of Previous TB Treatment or Negative TST • Do a symptom inquiry • Perform a TST (see Section 4, Tuberculin Skin Testing) • Obtain CXR and sputa collection if person is symptomatic • Complete NWT Tuberculosis Assessment Form

If any of these investigations suggest clinical or laboratory evidence of tuberculosis, the contact is considered a case, and should be managed accordingly. If TST is positive and TB is ruled out, the contact may have latent TB infection (LTBI) and could be a candidate for preventive treatment. Notify the OCPHO. See Figure 9.2 Contacts with Documented Previous TB Diagnosis and/or Treatment or Previous Positive TST • Do NOT perform a TST • Do a symptom inquiry • Collect three consecutive sputa specimens (if the contact is unable to produce sputum, consult with the attending physician or OCPHO regarding alternatives) • Do PA and lateral CXR

If any of these investigations suggest clinical or laboratory evidence of tuberculosis, the contact is considered a case, and should be managed accordingly.

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If test results are negative on initial investigation but the contact has not previously received anti-tuberculosis treatment or preventive treatment, treatment for LTBI should be considered. Repeat the symptom inquiry, sputa collection and CXR in 8 weeks. If any of these investigations suggest clinical or laboratory evidence of tuberculosis, then the contact becomes a case, and should be managed accordingly. See Figure 9.3.

INH Preventive Treatment for Contacts INH preventive treatment should be prescribed in consultation with the OCPHO or Public Health Officer (PHO), designate for contacts confirmed not to have active TB disease. • The success of preventive treatment depends upon the patient’s understanding of the disease and his or her willingness and/or ability to receive it. • Persons who are unable or unwilling to take preventive medication for a full treatment period should have periodic screening at least every 6 months for the initial 24 months after contact with an active case, as this is a period of high risk for progression to active disease.

Primary Preventive Treatment for Contacts who are <5 years • Primary preventive treatment is an important consideration in children <5 years who were exposed to an infectious case of respiratory TB (sputum is smear positive for AFB). • Primary preventative treatment is started on a child <5 years old who has an initial TST between 0–4mm. -A repeat TST is performed 8 weeks after the last known exposure or after the initial assessment due to high risk. -If this second TST is less than 5mm of induration, preventative treatment may be discontinued. -If the repeat TST results have increased by 6mm or more, further investigation should be carried out to rule out active TB, and treatment should continue for the specified duration set out by the OCPHO or Pediatrician.

N.B. In situations where a case is highly infectious, preventative treatment may be - Pediatrician. prescribed for 8 weeks to high-risk contacts, especially children younger than five years of age even if the initial TST is negative. Children have a 40% risk of progression to active disease in the first 2 years after initial exposure to tuberculosis.

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Evaluation of Contact Investigation The results of each contact investigation should be reviewed as they become available, to guide expansion and/or additional follow-up efforts. In addition, program-wide outcomes should be reviewed annually. Along with qualitative assessment of successes and challenges, they are important elements for program evaluation and future planning. Key indicators should include the following: • Initial list of contacts for each infectious TB case, completed within 7 calendar days • Assessment of close contacts completed and LTBI treatment started, if indicated and not contraindicated or refused, within 28 calendar days • Proportion of contacts with a diagnosis of LTBI who begin treatment • Proportion of contacts beginning treatment for LTBI who complete treatment • Proportion of contacts completing LTBI treatment who show active TB disease within 2 years after completion

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9-16NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 10: Role of Public Health in TB Prevention and Control in the NWT Section 10 Role of Public Health in TB Prevention and Control in the NWT

Notification and Reporting of Suspect and Confirmed Cases of TB 10-2 Directly Observed Treatment (DOT) and Directly Observed Preventive Treatment (DOPT) 10-4 Surveillance 10-5 Managing an Outbreak 10-7

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Notification and Reporting of Suspect and Confirmed Cases of TB

TB is a reportable disease under the Public Health Act (2009) and must be reported to the OCPHO. Notification is to be made to the Chief Public Health Officer as soon as a case is identified or suspected by means of telephone, fax or e-mail followed by a written report, the NWT Tuberculosis Assessment Form within 24 hours. The NWT TB prevention and control program is based on international and national standards http://www.who.int/tb/publications/2006/istc/en/andhttp://www. respiratoryguidelines.ca/tb-standards-2013. These standards provide guidance to all jurisdictions in Canada on the implementation of appropriate policies and procedures for TB programs. The TB prevention and control program in the NWT has many components, involves many partners and different levels of government. The term Health Care Provider (HCP) refers to individuals in health care settings who provide health care or support services, such as physicians, nurses, nurse practitioners, paramedics, emergency first-responders, respiratory therapists, home support workers, home care workers, clinical instructors, students, volunteers, and housekeeping, dietary and maintenance staff. See Figure 10.1 for a better appreciation of the components of the TB program in NWT. The attending physician or HCP must fill out aNWT Tuberculosis Assessment Form on each TB case. Information requested by the OCPHO includes the following: • Personal information of patient • Diagnosis • Symptoms • Physical assessment • Medical history • Present/Past Treatment • Laboratory investigations performed • Social profile

The collection of personal health information does not require the consent of the patient in the context of the TB program. This information can also be disclosed without consent where permitted and required by law. All personal health information is collected and used with the utmost respect for the person and for the purposes of the TB program. All necessary information and investigation is kept private to ensure confidentiality of each person. http://www.justice.gov.nt.ca/PDF/ACTS/Public%20Health.pdf [PHA Part 6 and Part 7, section 50, subsections t), x), y)].

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Figure 10.1: Components of the TB Prevention and Control Program in the NWT

Office of the Regional Chief Public Hospital Health and Community Health Officer/ Services Social Services CDC Unit Authorities

CPHO and Specialists Nurse in charge Primary care Deputy CPHO (internists/ services pediatrician/TB specialitsts) Designated CD consultant/ PHN/CHN for TB Social support TB Program agencies Manager Laboratories & Diagnostics Pharmacy (Stanton/ProvLab) Epidemiologist Community Pharmacy Health Workers TB disease registry officer Infection control Home Support practitioner Workers

Hospitals

The Office of the Chief Public Health Officer (OCPHO) and the Communicable Disease Control (CDC) Unit leads the TB program in the NWT. The TB Program Manager in the CDC Unit coordinates the program and works in collaboration with all other HCPs involved in TB care and program delivery. The roles and responsibilities of each group are established by NWT legislation – The Public Health Act (2009). Each jurisdiction in Canada is obliged under legislation to report TB. The PHA through its regulations provides detail on specific roles and responsibilities in:

• Who is required to report TB cases • To whom TB cases must be reported • What information must be reported on each case of TB

These Disease Regulations under the PHA are listed below • Reportable Disease Control Regulations R-128-2009 (http://www.canlii.org/en/nt/laws/ regu/nwt-reg-128-2009/latest/nwt-reg-128-2009.html) • Disease Surveillance Regulations R-096-2009 (http://www.canlii.org/en/nt/laws/regu/nwt- reg-096-2009/latest/nwt-reg-096-2009.html)

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The Public Health Act (2009) and Regulations provide the power to collect information about TB and contributes to the ability to: • Detect outbreaks • Have timely follow-up of TB cases and to prevent further transmission of TB • Implement public health interventions rapidly • Target prevention programs to populations at risk and for effective use of resources • Evaluate the success of control measures Guidance for these activities is also provided by the regulations. They are listed in Table 10.1.

Table 10.1: Public Health Act Legislation and NWT Regulation for Public Health Activities for TB Control

Act/Regulation Sections* TB Program Operational Activities Disease Surveillance Regulations s.6 Public Health Act section 2 schedule 3 part 2 Public Health Act sections 25, 28, 29, 30 Public health orders Public Health Act Part 4 section 23 Reportable Disease Control Regulation section 4 Reporting requirements Disease Surveillance Regulations section 6–10 Public Health Act Part 1 section 7–8 Case finding and management Reportable Disease Control Regulation Isolation requirements section 13–17 Reportable Disease Control Regulations Public Health Act Part 1 section 7–8 under s.1 and 2 Public Health Act Part 1 section 7–8 Outbreak investigation

Public Health Act Part 1 section 7–8 and section 24 Surveillance and screening

*Please refer to actual legislation and regulations for more detailed information.

Directly Observed Treatment (DOT) and Directly Observed Preventive Treatment (DOPT) The challenges in adherence to treatment have been shown to be multidimensional. It can be dealt with if an individualized approach is applied. An indispensable component of the TB program is DOT and DOPT. Both involve a health care provider that watches the patient swallow each dose of medication to help ensure higher treatment completion rates. Both serve as a way to increase adherence to treatment, monitoring for adverse effects and assuring the success of completion of all doses of medication, hence the success of treatment and cure for the patient and the protection of the public from TB.

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In all NWT communities the standard of practice is to administer DOT/DOPT to all patients receiving TB treatment (active or latent) as ordered by the attending physician or CPHO. These drugs are to be dispensed and monitored by: • The Public Health Nurse (PHN) • The Community Health Nurse (CHN) • The Community Health Representative (CHR) or Prevention and Health Promotion Worker (PHPW) • Home Support Worker (HSW) • A qualified Lay Dispenser • Another carefully selected community member, if properly trained (with a reporting mechanism in place with the HCP responsible for the TB Control Program in the community)

In larger centers such as Fort Smith, Inuvik, Hay River, and Yellowknife, patients prescribed anti-tuberculosis drugs by their practitioner must be referred to the local Public Health Unit for DOT/DOPT. It is the responsibility of the HCP to ensure that the patient understands the disease and the treatment being proposed in order to improve compliance with the drug regime and that effective case management of all patients is implemented. DOT /DOPT is necessary for these reasons: • A large proportion of the NWT population lives in TB-endemic communities and is considered at risk for acquiring the disease • Risk factors for TB such as smoking, over-crowded living conditions, homelessness, alcohol and other substance abuse and co-morbidities are highly prevalent in this population • Treatment of those with LTBI prevents progression to active disease and thus further spread to others • DOT/DOPT promotes compliance to ensure cure and prevents development of drug resistance • DOT/DOPT allows for regular monitoring and early detection of drug toxicity or side effects, or treatment interruption

Rationale for Public Funding for TB Treatment It is the policy of the OCPHO that all residents undergoing treatment for active TB or LTBI shall be treated through the public health system. The NWT TB Program is publicly funded and, therefore treatment is free of charge to the patient.

Surveillance Surveillance in the context of the TB program implies an ongoing process of gathering, analyzing, interpreting, and distributing data on TB cases to guide all public health actions related to TB prevention and control.

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Surveillance is the on-going process of finding active cases. In this case, obtain history related to previous TB, TST, CXR, and/ or sputa testing for AFB in order to determine the relative risk of acquiring or transmitting TB within the community setting.

Goals of TB Surveillance Programs Include: • Early case finding • To decrease the transmission of TB • To strategically decrease the seed pool of infection by offering prophylaxis to those with LTBI • To identify and monitor those persons most susceptible to TB, referred to as high-risk population • To target TB screening programs to high risk groups (see Section 4, TB Screening) • To provide community health practitioners with community profiles to identify populations at risk • To eliminate TB in the NWT

The components of the surveillance system for the NWT TB program include the following:

Figure 10.2: Surveillance

Data collection: information on TB cases

Analysis: Action: who, when Investigations, and where are programs TB cases

Distribution: Interpretation: articles, reports trends and comparisons

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Surveillance is also done by the staff of the OCPHO. Abnormal CXR results are paired with previous TB histories for the purpose of early detection of those at risk of developing active TB disease. HCPs are notified when there appears to be an increased risk of TB and directed to do an investigation to rule out TB. In Health Centers and Public Health Units, old cases of TB are periodically reviewed to assess adequacy of treatment and if shown inadequate, follow-up testing and consideration of re-reatment is considered. An annual review of the indices of health care associated transmission should be done by each Regional Health and Social Services Authority. This includes: • Quality control measures related to occupational health screening, level of nosocomial exposures or contact tracing of staff around exposures

Data provided by HCPs to the OCPHO is collected in a Central TB Registry (867) 920-8646 and used on a regular basis to: • Guide health interventions • Estimate trends • Identify groups at risk • Monitor changes in patterns of transmission

A TB report is done periodically from the centralized data and published in EpiNorth (NWT epidemiological bulletin). In conjunction with World TB day on March 24th, TB related information is distributed to health care providers and the public to raise awareness about TB.

Managing an Outbreak Organization and Resources Given the scale and duration of most TB outbreaks, it is important that there be adequate staffing and resources for investigation and management from the onset of the response efforts. Assistance from outside the TB program may be necessary. Advice from experienced colleagues who have managed TB outbreaks elsewhere can be invaluable. The following components are recommended in any TB outbreak response: • an identified outbreak manager, appointed for the duration, with overall responsibility for management and coordination of the outbreak response • public health/TB control staff to register and case-manage patients with TB, define infectiousness, coordinate the investigation and provide consultation and communication with those in the field • sufficient field staff to carry out the contact investigation and follow-up; for outbreaks dispersed across remote communities, mobile specialized teams may be an effective strategy to support local staff • information technology (IT)/database and epidemiologic support • consistent, coordinated clinical and diagnostic supports with expertise in TB

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• prompt, local access to chest radiography of adequate quality • identified medical consultants with expertise in TB to review chest radiology, evaluate patients for TB, hospitalize if necessary, and manage suspected cases and contacts in a consistent manner, without delay; for remote communities telemedicine links (including review of digital radiology) can be extremely effective • hospital facilities that can offer airborne isolation rooms, diagnostic examinations and treatment without delay • links to public health laboratories for specialized supports (arrangements to handle larger numbers of specimens, DNA fingerprinting, etc.) • rapid and safe transportation of specimens and, if necessary, patients • sufficient case-management and DOT staff to provide supervision of the complete course of drug treatment for all active and latent cases – at least 1 year’s additional staffing after the outbreak is over may be required • communications personnel to provide regular updates to the media and community on the status of the investigation • staff and resources to carry out the evaluation of the contact investigation

Roles and Responsibilities It is crucial, from the onset of the investigation, that the roles of all those involved in the investigation and management are clearly defined. Establishing an outbreak coordinating group, including the key individuals from public health/TB control, clinical expert care, hospitals, laboratory, the affected community and communications, can be very helpful. Collaboration and regular feedback among all levels of health care are important. There should be clear agreement to be followed in the investigation and the management of suspected cases and contacts, and written protocols.

Communication with Health Care Providers Local health care providers, particularly those who are most likely to first see new cases of TB in the outbreak population (emergency room, primary care in the outbreak neighbourhood, etc.) are key partners. Presentation at medical rounds, written notification about the outbreak and other ongoing communication will help to raise the index of clinical suspicion for TB, provide up-to-date information about TB diagnosis and management, and help decrease barriers to care, including early hospitalization for suspected infectious cases when necessary.

Staff Training Given the scale of TB outbreaks and response, many staff involved may not be experienced in TB work. Training, education and participation in clinical rounds can be helpful.

Prompt Isolation and Treatment of Cases of Active Disease An outbreak should markedly raise the index of clinical suspicion for TB when anyone in the affected community presents with compatible symptoms, particularly for respiratory (i.e. infectious) TB. All suspected infectious cases should be promptly isolated – in hospital if necessary – and investigated to confirm the diagnosis and the degree of infectiousness. Suspect cases should not return to congregate settings until infectious TB has been ruled out.

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All suspect cases or confirmed active cases must be immediately reported to the OCPHO.

Case-Finding, Identification of Source Case, and Contact Investigation In outbreaks among homeless and other marginalized populations, outreach street nursing, primary care clinics on site at shelters or other homeless services, and other low-threshold types of care are often critical for early diagnosis. Shelter staff may be the first to identify an ill resident. Training about TB and infection control precautions, basic symptom screening on admission, and mechanisms to rapidly isolate and refer suspect TB cases for medical evaluation should be implemented.

If not apparent, the source case or cases should be identified through aggressive investigation of all symptomatic individuals in the at-risk community. Once the initial investigation is under way, a review of the history of TB in the community is important. Review of “old cases” by provincial/territorial and local public health/TB programs may identify previously inadequately treated cases. In some circumstances it may be helpful to locate and reassess previously identified high-risk contacts who were lost to follow-up or did not take or complete treatment for LTBI. Contact the OCPHO/Disease Registeries for a TB history (867) 920-8640. In small communities or in closed settings it may be more efficient to screen the entire community or those in the facility at baseline, especially as it may be difficult to determine the exact level of contact in a small, close-knit community. In some settings, especially if members are very mobile, offering on-site active case-finding (sputum and/or chest radiography as well as symptom screening) on an ongoing basis over an extended period of time may be the only way to ensure that most contacts are identified and screened. Many remote communities have members who travel back and forth frequently to other communities; tracking these individuals is particularly difficult, yet they can be a conduit to spread the outbreak to additional communities. Coordination and shared follow-up arrangements with TB programs in these other communities may be very helpful in the assessment and management of mobile contacts and cases. In populations in which treatment of LTBI is not realistic as a major outbreak control strategy, the primary emphasis should be on early detection and treatment-to-cure of active cases, rather than extensive efforts to do skin testing. Examples include elderly residents (over 65 years) in long-term care facilities and some homeless populations (e.g. older alcoholics). A heightened index of clinical suspicion and perhaps case finding efforts should be maintained for several years after the outbreak subsides, as there is usually a pool of recently infected people remaining in the community. It may be possible to follow infected contacts who refuse or are not eligible for treatment of LTBI in order to detect early TB disease (e.g. periodic clinical assessment for 2 years after exposure). Data management and epidemiologic support in a contact investigation and management of a TB outbreak is very data-heavy. Tracking hundreds of contacts, often through multiple sites and assessments, demands a good database and IT support. Rapid, thoughtful evaluation of the aggregate results as they become available requires a dedicated epidemiologist.

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Identify Fundamental Causes TB outbreaks mainly take place in settings where rapid transmission is possible – inadequate housing (overcrowding, inadequate ventilation) and prolonged infectiousness often related to limited health care access. A high prevalence of vulnerability factors among contacts accelerates the development of secondary cases: the presence of many young children, diabetes and other causes of immunosuppression, smoking, malnutrition, etc. In facility- based outbreaks (homeless shelters, hospitals, jails) a systematic assessment of conditions and practices, including ventilation, may identify areas for intervention. Individual cases can be treated and cured, but it is very difficult to contain outbreaks or reduce endemically high rates of TB without addressing the fundamental causes. These aspects, too, should be recognized, and when possible addressed in the outbreak response.

Community Outreach and Education TB outbreaks can be anxiety-provoking and stigmatizing. Often they take place in a context of limited or inaccurate information about TB and sometimes quite negative cultural/historical associations. All these can prolong the situation through delayed diagnosis if individuals either do not recognize the significance of their symptoms or are afraid to receive a diagnosis of TB. It is crucial to provide information about TB and the outbreak response to the affected community or setting as early as possible in the investigation of the outbreak, with regular updates for them and for the general local population. The information should be in a style and format that is accessible and takes into account the cultural and practical setting of those affected. Standard materials may need to be adapted, ideally with input from community members. Peer outreach may be very useful, particularly for hard-to-reach individuals. This will help reduce the level of anxiety and will likely lead to greater cooperation and adherence to recommendations.

Evaluate the Process and Outcome of the Outbreak Investigation Ongoing evaluation and a formal evaluation at the end of the outbreak, including both the process and outcome of the outbreak investigation, are crucial. DNA genotyping of isolates may be useful in identifying the presence of an outbreak, mapping its extent and evaluating the results of the outbreak investigation and control. Identification of key contributing factors, often social determinants of health, may point to future non-TB-specific interventions

10-10NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 11: Pediatric TB Section 11 Pediatric TB

Pediatric Population 11-2 Transmission and Pathogenesis 11-2 Pediatric LTBI Treatment 11-3 Pediatric Active TB Disease Treatment 11-5 Management and Treatment of Active Disease 11-6 Monitoring and Follow-up 11-10 Management of Children with Close Contact to Smear (-), Culture (+) TB 11-12 Management of Children wtih Close Contact to Smear (+) TB 11-13

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In Canada, pediatric TB is largely a disease of Canadian-born Aboriginal and foreign-born children. TB in children differs from that in adults in several ways: • Diagnosis in young children may be difficult, since signs and symptoms are often nonspecific and disease is often paucibacillary • TB disease in a very young child is often a sentinel event indicating recent transmission • In young children, especially infants, there is a high risk of progression from infection to disease • Disease is often more severe, can be disseminated and even fatal

Pediatric Population The World Health Organization (WHO) has defined pediatric TB as TB in personsless than 15 years of age. Pediatric TB classification is dependent on the stage of TB and anatomical location: • LTBI • Respiratory TB • Non-respiratory TB

BCG vaccine is used as a preventative measure and is routinely recommended for newborns born in the NWT, particularly those among high risk populations (see Section 3, BCG Vaccination)

Transmission and Pathogenesis Children inhale MTB from adults or adolescents with infectious respiratory TB. Inhaled bacteria are taken up by alveolar macrophages and, if not immediately destroyed, result in a primary infection that consists of a small parenchymal focus that spreads via local lymphatics to regional lymph nodes. Transmission almost always occurs from adult or adolescent to child. This is known as unidirectional transmission. Children usually do not transmit TB to others-often because of low bacillary load (paucibacillary disease) and ineffective cough. An unexpected finding of TB infection or disease in children is considered a signal indicating recent transmission from an active TB case in the community. In most cases the primary focus heals, and the bacteria continue to survive in a dormant state as latent infection. Similar to adults, children with LTBI and an immunocompromising condition are at increased risk of TB disease progression. Risk of progression from infection to disease varies by age (see Table 11.1). The distinction between infection and disease is not always easy and can be somewhat artificial, since infection and primary disease are parts of a continuum. Children, and especially infants, are at greater risk than adults for quickly progressing from LTBI to active TB disease.

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Table 11.1: Average Age-Specific Risk For Disease Development After Untreated Primary Infection

Age At Primary Manifestations Of Disease Risk Of Disease (%) Infection No disease 50 <12 months Pulmonary disease 30–40 TB meningitis or miliary disease 10–20 No disease 70–80 12–23 months Pulmonary disease 10–20 TB meningitis or miliary disease 2–5 No disease 95 2–4 years Pulmonary disease 5 TB meningitis or miliary disease 0.5 No disease 98 5–10 years Pulmonary disease 2 TB meningitis or miliary disease <0.5 No disease 80–90 >10 years Pulmonary disease 10–20 TB meningitis or miliary disease <0.5

Pediatric LTBI Treatment Treating children with LTBI requires the use of INH or RMP. The usual regimen involves INH with different intervals of treatment. In the case of INH resistance or intolerance, RMP is then used. Further detail is provided in Table 11.2.

Table 11.2: Regimes for Treatment of LTBI in Children

Drug Duration Dose Interval Number of doses Preferred NWT Regime 10–15mg/kg INH 9 months Daily 270 (MAX 300mg/day) Alternative Regime 20–30mg/kg INH 9 months 2x/week 78 (MAX 900mg/dose) INH Resistance Regime 10–20mg/kg RMP 4 months Daily (MAX 600mg/day)

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 11-3 Section 11: Pediatric TB Latent TB

Monitoring of LTBI Treatment and Side Effects For a summary of care for patients receiving LTBI treatment, see Table 8.4, Section 8. Patients and their parents should be informed of the side effects indicating hepatotoxicity and other drug toxicities and should be asked to recall these at each clinic visit. They should be provided with a clear plan of action, preferably written, including contact telephone numbers, should symptoms arise. Monthly monitoring is recommended for children being treated for LTBI. Each visit is an opportunity to explore possible side effects due to medication, symptoms of active TB and adherence to treatment. Monitor for Vitamin B6 depletion (INH binds with Vitamin B6 in the blood) - and INH overdose. For details of signs and symptoms of overdose, see INH overdose antidote treatment Table 11.5. Liver transaminases (AST/ALT) are not indicated during treatment for patients who are asymptomatic, who do not have a liver disease or who do not take any other hepatotoxic drugs. Parents and families should be educated on the symptoms of hepatotoxicity. Jaundice is often seen within days or weeks before other hepatitis-related symptoms arise such as malaise and nausea. Lastly, children taking medication for epilepsy must be monitored closely since INH and RMP can both affect the metabolism and blood levels of these drugs.

In addition to DOPT, children should be seen on a monthly basis by their HCP to: • Measure weight and adjust drug doses accordingly • Review of symptoms of possible hepatitis, drug interaction or of symptoms of active TB • Assess adherence to treatment • Verify blood levels of children taking anti-epileptic drugs • Follow-up with skin testing results of family members and other relevant contacts

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Pediatric Active TB Disease Treatment A small proportion of children or infants may exhibit nonspecific signs and symptoms of disease. In infants, hepatosplenomegaly, respiratory distress, fever, lymphadenopathy, abdominal distention, lethargy or irritability may be manifestations or early signs of disease. Failure to thrive may be the only presenting symptom. Older children and adolescents are more likely to experience adult-type disease and often present with the classic triad of fever, night sweats and weight loss. Those with pulmonary disease are also more likely to present with respiratory symptoms (cough, sputum and sometimes hemoptysis). Any non-respiratory site may be involved, most commonly extrathoracic lymph nodes. Miliary/ disseminated disease and CNS disease, the most life-threatening forms of TB, are more likely to occur in young children and the immunocompromised. Epidemiologic risk factors and/or a clinical picture compatible with TB should prompt appropriate testing.

Differential Diagnoses to Consider • Pneumonia • Asthma • Immune compromising diseases (HIV, etc.) • Foreign body or trauma in the airway (hemoptysis) • Failure to thrive • Neoplasm

The practitioner is advised to include TB as a differential diagnosis in any respiratory illness or unexplained weight loss in high risk groups including children.

Complications of Active TB in Children • Meningeal disease • Permanent lung damage • Growth and development impediments • Irreversible damage to affected organ (non-respiratory TB) • Death

Diagnosing Active TB in Children Typically, children with respiratory disease are often said to have paucibacillary disease (having few bacilli). In these cases it is often difficult to obtain enough bacilli in a specimen to culture and identify. Therefore, many, if not most, pediatric TB cases are diagnosed as clinical cases based on a positive TST or IGRA, abnormal CXR, history of contact with a case of infectious TB and compatible signs or symptoms. A negative TST or IGRA does not exclude active TB.

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• TST or IGRA: if not contraindicated (i.e. in the case of a previously positive TST). • Serial sputa: if the child is able to expectorate (often a gastric aspirate will be requested for infants and small children). Induced sputum may be done on older children but is a promising technique for the diagnosis of TB disease in young children. • CXR: children under 15 years old must have both a PA and lateral view to detect hilar and paratracheal lymphadenopathy, the most common features expected in pediatric TB. This may require referral to a regional centre depending upon the age of the child. • Weight and development milestones: should be checked regularly on all children with suspected or confirmed TB. • Lab: blood work and urine to ensure liver and kidney function is intact prior to treatment. • See NWT Tuberculosis Assessment Form.

Management and Treatment of Active Disease Treatment The patient can be infectious, although younger children are less so due to their relatively ineffective cough. There are several challenges when treating children with TB. Severe forms of TB disease after infection seem to affect those who are younger, especially those under 5 years of age. In addition, TB in infants and children younger than 5 years of age tend to disseminate. Therefore, treatment should start as soon as there is any indication (via lab tests or case definitions) of active TB disease. It is crucial that a clinician experienced in managing pediatric tuberculosis be consulted when treating children with active TB disease.

All children suspected (or confirmed) of having active TB should be managed by a Pediatrician with experience in pediatric tuberculosis.

Respiratory/Non-respiratory TB Respiratory and non-respiratory TB are managed with the same treatment regimens, with a few exceptions. These exceptions include: TB of CNS, disseminated TB, TB meningitis, bone and joint TB. They require longer duration of treatment from 9–12 months. Infants 0–3 months with respiratory TB should be treated with standard treatment for TB (see Table 11.3). Treatment should be adjusted to account for possible toxicity in this age group.

Drug Administration Children might present with some challenges to ingest the medication because of the formulation of the anti-TB drugs (i.e. tablet/capsule). For this reason it is recommended to ask the advice of a pharmacist and /or OCPHO on how to best administer the medication to children.

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Guidance for Treatment The choice of anti-TB drugs is usually guided by culture and drug susceptibility results. However, it is often difficult to obtain specimens for testing from children. It is recommended to use the culture and drug susceptibility results from the person identified as the source case of the child’s infection (if available and known). If the source case is unknown or drug resistance is suspected, it is recommended to get a specimen for testing by: 1) three morning gastric aspirations, 2) sputum induction, 3) bronchial lavage, 4) tissue biopsy or 5) other method as appropriate.

Use of Corticosteroids Corticosteroids are used as adjunctive therapy when the inflammatory response is threatening to cause a life-endangering complication. Corticosteroids may be added to the TB treatment for children, who are affected by the following: • TB meningitis • Pleural or pericardial effusions • Endobronchial disease • Abdominal TB

Corticosteroids must be accompanied with anti-TB medication. Dose tapering of corticosteroids is always done to complete treatment. The dose is generally decreased slowly by 1–2mg/kg daily of prednisone (maximum of 60mg/day) or its equivalent over 6–8 weeks.

Drugs Used for Treatment of Tuberculosis in Children NWT Pediatricians follow the dosage recommendations put forth by the Red Book where there is a discrepancy with the American Thoracic Society (ATS). See Table 11.3 and 11.4 for anti-tuberculosis drugs, dosing recommendations, side effects and acceptable regimens.

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Table 11.3: Doses of Anti-Tuberculosis Drugs for Children

Thrice weekly dose† Daily dose (range) Principal side effects (range) By Available By weight Max weight Max (mg) dosage (mg/kg) (mg) (mg/kg) forms •Mild liver 10mg/ml transaminase suspension 10mg/ml elevation suspension 100mg •Hepatitis INH 10 (10 –15)‡ 300 20–30 tablet 100mg tablet •Gastritis 300mg 300mg tablet tablet •Peripheral neuropathy •Hypersensitivity 10mg/ml •Orange suspension discoloration of 150mg secretions RMP 15 (10–20) 600 10–20 600 capsule •Vomiting 300mg •Hepatitis capsule •Flu-like illness •Hepatotoxicity 70 500mg PZA 35 (30–40) 2000 * •Hyperuricemia (60–80) scored tablet •Arthralgia •Optic neuritis with decreased visual acuity and 40 100mg tablet decreased red- EMB 20 (15–25)† ** *** (30–50) 400mg tablet green colour discrimination •Gastrointestinal disturbance Pyridoxine (used to 25mg tablet prevent INH 1mg/kg 25 •Few neuropathy: 50mg tablet has no anti- TB activity)

† Intermittent doses should be prescribed only when directly observed therapy is available. In general daily therapy is definitely preferred over intermittent regimens. ‡ Hepatotoxicity is greater when INH doses are more than 10–15mg/kg daily. For older children and adolescents, the optimal dosing of INH is an area of uncertainty * For PZA: 3000mg according to the American Thoracic Society (ATS), 2000mg according to the Red Book ** For EMB: 1600mg according to the ATS, 2500mg according to the Red Book *** For EMB: 2400mg according to the ATS, 2500mg according to the Red Book † Ethambutol at 15mg/kg daily presents a very low risk of optic neuritis but may sometimes result in subtherapeutic serum drug levels in young children. ‡ INH crushed into semisoft food (e.g. pudding, baby food, and yogurt) is acceptable and well tolerated. However avoid crushing into sugary liquids. RMP can be compounded into suspension by pharmacists but is only stable for at least one month

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Figure 11.1: DOT Note: Doses per weight is based on ideal body weight of the child All TB Medications Are To Be Administered By DOT. See Section 8, Treatment for Tuberculosis for more details

Table 11.4: Drug Regimes for Treating TB in Children

Regime: INH, RMP, PZA Type of TB Disease Initial Phase Continuation Phase Total 2 months: Respiratory and INH, RMP, PZA daily non-respiratory TB 4 months: OR (Except for TB INH and RMP daily meningitis, 2 weeks: OR 6 months disseminated TB, INH, RMP, PZA daily CNS TB, adult type 3x/week Followed by respiratory TB*) 6 weeks: INH, RMP, PZA 3x/week Regimen: INH, RMP, PZA + Aminoglycoside or Ethionamide

2 months: 7–10 months: INH, RMP, PZA and INH and RMP daily TB meningitis 9–12 months Aminoglycoside or OR Ethionamide daily 3x/week Regimen: INH, RMP, PZA, EMB Adult type respiratory TB*, disseminated TB, 2 months: 4 months: 6 months CNS TB, risk of INH, RMP, PZA, EMB‡ daily INH, RMP daily resistance to INH or HIV prevalence high 2 months: 10 months: Osteoarticular TB 12 months INH, RMP, PZA, EMB‡ daily INH, RMP daily

* Adult type respiratory TB is defined as upper lobe infiltration and cavitation associated with sputum production ‡ EMB can be used in children aged 5 years or more without taking more precautions than adults and even in younger children too young for routine eye testing (Trebucq A. Should Ethambutol be recommended for routine treatment of tuberculosis in children? A review of the literature, Int J Tuberc Lung Dis 1997; 1: 12–15)

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 11-9 SectionSection 11: 11: Pediatric Pediatric TB TB Active TB

Monitoring and Follow-up For a summary of care for patients receiving treatment for active disease, see Table 8.11, Section 8. Patients and their parents should be informed of the side effects indicating hepatotoxicity and other drug toxicities and should be asked to recall these at each clinic visit. They should be provided with a clear plan of action, preferably written, including contact telephone numbers, should symptoms arise. • Monitor for Vitamin B6 depletion (INH binds with Vitamin B6 in the blood) - and INH overdose. For details of signs and symptoms of overdose, see INH overdose antidote treatment (Table 11.5) • Special attention should be given to developmental milestones of patients under five years old • Once treatment is complete, the patient should return to screening as per risk group • Whenever administrating anti-TB drugs to children it is important to adjust the doses according to their weight. Children’s body weight must be monitored on a monthly basis to make any necessary changes to their drug doses when needed.

In the NWT, due to high levels of food insecurity and poor consumption of fruits and vegetables, vitamin B6 is supplied to all children at a daily dose of 12.5mg and twice weekly dose of 25mg.

Treatment Adherence Recognizing that adherence of treatment is an important issue for children; all children treated for active TB in NWT are to be under DOT. It is not the responsibility of the parent to supervise DOT. Here are several recommendations to help improve adherence and completion rates of TB treatment in children: • Use tablets crushed into semisoft foods to avoid stomach upset from the liquid preparation • Advise the family that the first couple of weeks of treatment will be challenging • Provide written education regarding reasons for treatment and symptoms of TB and toxicity • Develop a small dedicated and enthusiastic team of staff providers, nurse and interpreters • Develop systems to encourage adherence, such as having the child put a sticker on the calendar for each dose taken • Have convenient clinic hours and short waiting times or alternatively, provide DOT in the child’s home, or at school • Develop a patient alert system of following up patients who have missed appointments • Praise the family and child for good adherence and clinic attendance

11-10NWT Tuberculosis Manual - JuneNovember 2014 2014 Active TB SectionSection 11: 11: Pediatric Pediatric TB TB

Table 11.5: INH Drug Overdose

INH Drug Overdose

Below is the recommended antidote for INH overdose. Consult with your on-call physician/ pediatrician IMMEDIATELY and initiate treatment. Consider calling the Poison and Drug Information Services, Alberta and Northwest Territories contact: 1-800-332-1414.

Management of INH overdose includes supportive care focusing on patient’s cardiovascular status, protecting the airway, abolishing seizure activity and correcting metabolic acidosis. As soon as an overdose of INH has been recognized (even in the absence of symptoms), Pyridoxine IV should be administered to prevent neurotoxic effects. The same dose of Pyridoxine (Vitamin B6) as the dose of INH ingested should be given intravenously.

•For example, a child who has ingested 3.0g of INH should be given 3.0g of pyridoxine. If the dose is not known, Pyridoxine should be given intravenously in a dose of 5g in adults or 70mg/kg (maximum dose 5g) in children, at a rate of 1g every 2–3 minutes (CPS, 2010).

•This dose of pyridoxine should be repeated in two hours if the response to treatment has been incomplete. A total dose of 25g may be required in the first 12 hours.

•A single dose of activated charcoal should be considered at a dose of 1g/kg.

•Diazepam IV with addition of Phenobarbital or Propofol may be used in addition to Pyridoxine to treat convulsions.

•Diazepam (Valium) should be given to control seizures (2mg by rectum for babies over the age of six months, or 5–10mg intravenously for older children and adults). Phenytoin (Dilantin) should not be given as it increases levels of INH. Please note INH also increases Serum levels (Dart, 2004).

•Once the patient is stabilized, consult and refer to an internal medical specialist or pediatrician for further medical treatment.

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 11-11 SectionSection 11: 11: Pediatric Pediatric TB TB Active TB

Management of Children with Close Contact to Smear (-), Culture (+) TB

Figure 11.2: Management of Children with Close Contact to Smear Negative (Culture Positive) TB

TST <5mm TST >5mm

• Refer to OCPHO If <5mm and household • Complete NWT Tuberculosis contact– consider primary Assessment Form preventative treatment. • Pediatrician referral required (PEDS to determine) • Arrange for PA/lateral

CXR & blood work Diagnosis Positive Retest in 8 weeks TST >5mm Diagnosis

LTBI Active TB Offer preventative treatment TST <5mm in consultation with OCPHO and Pediatrician

Case Closed Admit to hospital for See Table 8.4, Section 8 for treatment summary of care for patients receiving treatment for LTBI

See Table 8.11, Section 8 for summary of care for patients receiving treatment for active TB

11-12NWT Tuberculosis Manual - JuneNovember 2014 2014 Active TB SectionSection 11: 11: Pediatric Pediatric TB TB

Management of Children with Close Contact to Smear (+) TB

Figure 11.3: Management of Children with Close Contact to Smear Positive TB

TST <5mm TST >5mm

If <5mm and household • Refer to OCPHO contact– give primary • Complete NWT Tuberculosis preventative treatment (PEDS Assessment Form to prescribe treatment) • Pediatrician referral • Arrange for PA/ lat CXR &

blood work Diagnosis

Positive Diagnosis Retest in 8 weeks TST >5mm

LTBI Active TB Offer preventative treatment in consultation TST <5mm with OCPHO and Pediatrician Stop previously prescribed preventative treatment Admit to hospital for See Table 8.4, Section 8 for treatment summary of care for patients Case Closed receiving treatment for LTBI

See Table 8.11, Section 8 for summary of care for patients receiving treatment for active TB

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 11-13 SectionSection 11: 11: Pediatric Pediatric TB TB Active TB

11-14NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 12: Populations at Risk Section 12 Populations at Risk

Overview of Screening Populations at Risk 12-2 Immigrant Screening in the Northwest Territories 12-3 Homeless Populations and Injection Drug Use 12-6 Institutionalized Population – Correctional Facilities 12-7 HIV and TB 12-8

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 12-1 Section 12: Populations at Risk

Overview of Screening Populations at Risk As a routine surveillance program outside of contact tracing in outbreak situations, screening for and treatment of LTBI should only be undertaken if the local TB control program already effectively manages active TB cases and their contacts. The selection of people for targeted LTBI screening and treatment is based on their risk of prior TB exposure and their risk of reactivation, balanced against the likelihood of safe completion of treatment, including the risk of hepatotoxicity, which increases with age. Special groups that will warrant targeted screening* include: • Immigrants (particularly those who have arrived in Canada within the previous 2 years) • People living with HIV • Those with immune suppression and other medical risk factors for TB • The homeless and injection drug use (IDU) population • Inmates/employees in correctional facilities • Long-term visitors to countries with higher TB incidence • Residents of long term care • Screening of healthcare workers is addressed in the chapter on Section 4, TB Screening as well as in the Infection Prevention and Control Manual • Foreign-born children up to age 20 should be offered LTBI screening and treatment as soon as possible after arrival • Population groups with increased prevalence of LTBI (such as the foreign-born from countries with high TB incidence) http://www.phac-aspc.gc.ca/tbpc-latb/itir-eng.php and with conditions presenting an increased risk of reactivation (i.e. refugee status) should be offered LTBI screening and treatment up until age 65 years • Everyone with conditions associated with a high risk of LTBI reactivation should be considered for screening • See Table 12.1 for further details

*For more information on risk and targeted screening see Section 4, TB Screening • Routine screening of people with a low prevalence of LTBI and medical risk factors with a low relative risk for LTBI reactivation (i.e. a relative risk of <2.0 compared with a healthy individual without known risk factors (see Table 2.3, Section 2) is not recommended.

12-2In NWT the Tuberculosis NWT, Manual - June THINK 2014 TB! In the NWT, THINK TB! Section 12: Populations at Risk

Immigrant Screening in the Northwest Territories Canada was built as a result of immigration. In 2001, 18% of the total population of the nation was born out of Canada. This is the highest proportion of foreign-born people since 1931. As well, international visitors number millions per year. Citizen and Immigration Canada (CIC) is responsible for the immigration process. All applicants of permanent residency in Canada, refugee claimants and certain applicants for temporary residency are required to undergo an Immigration Medical Examination (IME). With regards to tuberculosis, the IME objective is to detect active cases of tuberculosis, through chest radiography for all immigrants 12 years of age and older.

Management of TB in the Immigration Context TB screening is done by assigned CIC medical officers prior to the immigrant’s arrival to Canada. Applicants identified as havingactive TB are denied entry to Canada until proof of complete treatment is provided and includes: three negative sputum smears and cultures, and stable and/or improving CXRs taken over a minimum period of 3 months. Applicants identified as havinginactive respiratory TB (LTBI) are permitted to enter Canada but are placed under medical surveillance and referred to provincial/territorial public health authorities in the immigrant’s port of entry.

• Such individuals receive a Medical Surveillance Undertaking Form (IMM 0535B) and an informational handout that provides instructions relating to contact with provincial/ territorial public health authority within 30 days of entry. • The IMM 0535B Form is then referred from the Office of the Chief Public Health Officer to the respective public health unit or community health center, as indicated by the displayed address on the form. • The local public health unit/health center will report the immigrant’s compliance back to the CIC Medical Surveillance Program.

There is great variability in the risk of active disease among migrants according to region of origin, age at immigration, migrant type, time since immigration, referral for medical surveillance and socioeconomic status. Immigrants to Canada represent the largest risk group for non-respiratory TB disease in the country. Epidemiologic profiles are key components of targeted screening activities in this migrant population, which can be accessed through Public Health Agency of Canada, Tuberculosis Prevention and Control website at: http://www.phac-aspc.gc.ca/TBpc-laTB/itir-eng.php The NWT TB program needs to identify groups of foreign-born persons in a jurisdiction who are at high risk of TB disease. For instance, cases of TB that have been reported in the NWT among foreign born have included country of origin as: Philippines, Vietnam, China and Africa.

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 12-3 Section 12: Populations at Risk

Targeted Screening of Immigrant Populations Routine or mass screening for TB of all immigrants (adults and children) is not recommended. However, targeted screening for LTBI after arrival in Canada is recommended among foreign-born individuals and travelers (adults and children) with risk factors for reactivation of LTBI (these risk groups are listed below): • HIV infection • transplantation (related to immunosuppressant treatment) • silicosis • chronic renal failure requiring hemodialysis • carcinoma of head and neck • recent TB infection (≤2 years) • abnormal chest radiographic result– fibronodular disease or granuloma • treatment with glucocorticoids • treatment with tumor necrosis factor (TNF)-alpha inhibitors • diabetes mellitus (all types) • underweight (for TB purposes, this is a body mass index <20 for most persons) • cigarette smoker • persons who have lived in a country with high TB incidence, have immigrated within the past 2 years and have either been living with or in known contact with a TB case in the past or are at high risk of development of active TB

Incidentally, these risk factors apply to all Canadians, not specifically foreign-born Canadians. Screening Guide The main tool to diagnose LTBI is the TST. If the immigrant has a history of a previous positive TST, then proceed to symptom inquiry, CXR, and sputa collection. IGRA testing may be considered under specific circumstances. Each individual case should be discussed with the OCPHO or the Internal Medicine Specialist.

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Table 12.1: Recommendations of The Canadian Thoracic Society for Groups for Targeted LTBI Screening Age limit for Group at risk Group to be screened screening Close contacts of an active As soon as possible after diagnosis of the Any age case of pulmonary TB index case Immigrants from countries Fibronodular changes on chest x-ray with high TB incidence (usually in the context of Post-Landing Any age Surveillance) All children and adolescents as soon as Up to age 20 years possible after arrival Refugees

Immigrants and refugees with underlying 20–50 years medical comorbidities with the following risk of TB reactivation:* High risk Any age Moderate risk Up to 65 years Slightly increased risk Up to 50 years Medical comorbidities* All individuals regardless of prior TB exposure should be considered for screening if they have certain medical comorbidities that increase risk of TB reactivation* High risk Any age Moderate risk Up to 65 years Slightly increased risk Up to age 50 years Injection drug user OR the In the presence of underlying medical homeless † comorbidities with the following risk of TB reactivation* High risk Any age Moderate risk Up to 65 years Slightly increased risk Up to 50 years Travelers to countries with ≥ 1 month of travel with very high high TB incidence‡ risk contact, particularly direct patient contact in a hospital or indoor setting, but possibly including work in prisons, homeless shelters, refugee camps or Up to 50 years if inner city slums. single post-travel TST ≥ 3 months of travel to TB incidence country >400/100,000 population** Any age if ≥ 6 months of travel to TB incidence documented TST country 200– 399/100,000 population conversion ≥ 12 months of travel to TB incidence country 100– 199/100,000 population

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 12-5 Section 12: Populations at Risk

Age limit for Group at risk Group to be screened screening HIV positive Screening done immediately at time of Any age diagnosis Aboriginal peoples See TB screening Any age Health care practitioners, Baseline screening upon hire or employees of LTC or placement using two-step TST. correctional facilities Annual TST if employee’s results were Any age previously negative and agency provides care for people with infectious TB. Otherwise, annual TST is not necessary Residents of long-term Screening for LTBI not recommended for care facilities those age 65 years and greater. For all Age less than 65 others, facility risk assessment and local years epidemiology should inform decision Residents of correctional All inmates not previously screened Any age facilities * Risk of reactivation for different medical comorbidities is outlined in Table 2.3, † For those at high risk, strongly consider measures to enhance adherence, such as DOPT treatment with incentives. For all others only consider LTBI screening and treatment provided treatment completion and adequate follow-up for hepatotoxicity can be achieved. ‡ For those >50 years and at higher risk of prior TB exposure, i.e. foreign-born, current or previous IDU, Aboriginal people, health care practitioners or those with pre-existing liver disease, consider doing a pre- and post-travel TST to detect recent conversion. In this case, performance of two-step TST pre-travel would enhance the accuracy of testing after travel to detect true conversions from recent infection. For all other travelers, perform a single TST 2 months after return from travel. ** TB incidence expressed as all TB cases/100,000.

Homeless Populations and Injection Drug Use To improve the likelihood of safe completion of LTBI treatment in vulnerable groups, such as injection drug users and the homeless, it is suggested that patients be assessed to determine coexisting viral hepatitis in order to decrease the possibility of hepatotoxic effects of LTBI treatment. Those at highest risk of reactivation should be considered for special measures to enhance adherence, such as incentives and enablers. Employees/volunteers working in shelters or drop-in facilities should have baseline TB screening upon hire or placement using two-step TST and an annual TST if negative and risk is high locally.

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Institutionalized Population – Correctional Facilities Individuals entering Correctional facilities are screened by nursing staff for latent or active TB. The OCPHO must be consulted when a diagnosis of LTBI is made or active disease is suspected. Incarceration provides patients with excellent access to nursing care, and a period of time when they are less likely to consume alcohol. This makes it an optimal time to consider LTBI treatment, if the patient is willing to complete the treatment. In the event of an unforeseen release, early involvement with the local public health team can assist with continuity of care to help patients continue their LTBI treatment. Treatment of LTBI involves several months of oral medications, given by DOT either daily or twice weekly. Accepted regimens include (see Table 8.1): • Nine months of daily or twice weekly INH (preferred) if patient’s sentence allows treatment to be completed while incarcerated • Four months of daily RMP as an alternative for those patients with sentences of less than nine months or for those with INH intolerance or active liver disease

Monitoring of patients on LTBI treatment follows standard protocols depending on age and co-morbidities, and is performed by correctional facility nurses with the support of the OCPHO (see Table 8.4, Section 8).

Special considerations of incarcerated patients include: • Due to the high risk lifestyle of the offender population, HIV screening is recommended for patients being considered for LTBI treatment • Any HIV-positive patient entering correctional facility should have a full TB assessment and be reviewed at TB rounds, regardless of TST status • Some remanded offenders may be candidates for LTBI treatment, depending on court date, the seriousness of the offence committed, and eligibility for bail • Incarcerated patients who are started on medications for LTBI may become candidates for a temporary absence. In this case, options include: -administration of LTBI treatment under DOT by Public Health, possibly as part of the terms for the temporary absence -administration of LTBI treatment under DOT by supervisory staff at patient’s workplace, if it is out of town

In these cases, daily medication administration may not be feasible, and INH may need to be given twice weekly (dose adjusted) or RMP given five days per week (Mon-Fri) for the duration of the temporary absence. Release preparation and continuation of TB treatment plans need to be coordinated between correctional facility and community health care to facilitate continuation of treatment regime.

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 12-7 Section 12: Populations at Risk

HIV and TB The NWT has not as yet experienced an epidemic of HIV/ AIDS. Globally, the HIV epidemic has accelerated TB rates. This has decreased TB control in populations in which both infections are prevalent. HIV, in particular advanced HIV (AIDS), is the most potent risk factor ever identified for the progression of tuberculosis. Health care providers, administrators, and TB controllers should strive to promote coordinated care for patients with TB and HIV, and to improve information sharing between TB control programs and HIV/AIDS programs.

Important Considerations in a Patient with HIV and TB: • HIV/ AIDS is an immune-compromising condition allowing easier transmission of TB and progression from LTBI to active TB disease. • The incidence of HIV/ AIDS is increasing among Aboriginal people. • The incidence of HIV is increasing among those born in TB-endemic countries. In 2010, one- eighth of incident cases were co-infected with HIV, 82% of whom were in the African Region (WHO). • There is significant overlap between TB-endemic countries having both drug-resistant TB strains and drug-resistant HIV, making both difficult to treat. • Treatment of LTBI has been shown to reduce the risk of progression to active TB disease in patients with both infections. • The administration of BCG vaccine to HIV infected patients is contraindicated because of its potential to cause disseminated M. bovis disease. For this reason HIV status of the mother must be confirmed prior to administering BCG vaccine to the newborn (usually within 72 hours). • HIV infected patients should be advised that certain activities and occupations may increase the likelihood of exposure to TB. These include volunteer work or employment in health care facilities, correctional institutions, and shelters for the homeless, as well as travel to or living in TB endemic communities or countries. • There is no clear evidence that people infected with M. tuberculosis are more infectious if they are co-infected with HIV. However, there will often be rapid development of active TB disease, and HIV-related TB disease will often have atypical clinical manifestations, leading to delayed diagnosis. The increased risk of M. tuberculosis transmission by this population is related to the potential for delayed isolation if the index of suspicion for respiratory TB disease is low.

Screening for HIV in TB Patients and their Contacts

All patients with newly diagnosed TB should be strongly encouraged to undergo informed HIV serological testing.

• HIV testing of contacts of patients with infectious TB should be considered if the contacts are at risk of HIV or the index case of TB is HIV co-infected.

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• Health care providers caring for HIV positive people should maintain a high level of suspicion for TB. • Every patient with newly diagnosed HIV infection should be: -assessed for the presence of active TB at the time of diagnosis of HIV with a TST and symptom inquiry, NWT Tuberculosis Assessment Form -assessed for adequacy of treatment in patients who report that they have received treatment of active TB or LTBI in the past (call OCPHO/TB Registry 867-920-8646 for TB history) -offered a physical examination that includes examination of extra respiratory sites of disease, such as lymph nodes -offered a CXR, serial sputa, and a TST and/or IGRA if indicated

• TB screening with TST (all HIV positive patients should be offered a baseline two step TST) TST should be performed as soon as possible after HIV infection is diagnosed, because the reliability of the TST can diminish as the CD4 lymphocyte count declines. • Induration of >5mm on the TST should be considered positive or indicative of TB infection. • Additional information resources concerning HIV is available from: Canadian TB Standards, Chapter HIV. Treatment Considerations Active vs. Latent TB Except when there is a well-documented history of completed treatment of LTBI or active TB, treatment for LTBI should be strongly recommended for every HIV infected patient with a TST reaction >5mm, regardless of age or BCG vaccination status, after exclusion of an active TB diagnosis. Those TST negative HIV positive patients with evidence of old healed TB on the CXR, especially those with a history of TB exposure, once active TB has been excluded, may have TST repeated after institution of antiretroviral treatment and evidence of immune reconstitution. • Preventive treatment is recommended during pregnancy for HIV infected patients who have either a positive TST or a recent history of exposure to active TB, after active TB has been excluded. • HIV infected people who are candidates for, but who decline or do not receive TB preventive treatment should be assessed every 6 months for symptoms of active TB as part of their ongoing management of HIV infection. Clinicians should educate them about the symptoms of TB and advise them to seek medical attention promptly should such symptoms develop • DOT is required for treatment of LTBI and active TB. • Treatment regimens for LTBI must be discussed with the Internal Medicine Specialist and the patient’s HIV specialist. • Treatment of active TB in HIV infected patients should be guided by a physician with expertise in the management of both diseases or in close collaboration with a physician who is an expert in HIV care.

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Knowledge of the HIV status of TB patients may also influence the treatment of their TB. Even in those not receiving antiretroviral drugs there may be an increased risk of adverse reactions from anti-tuberculosis drugs. Because HIV infected people are at risk of peripheral neuropathy, co-administration of pyridoxine (B6) with INH may be prudent. For some HIV infected TB patients, malabsorption of their anti-tuberculosis drugs has been reported, so that measurement of serum drug levels may be necessary if there is a poor response to treatment.

The benefits of INH therapy will exceed the risks of toxicity at almost any age in an HIV-infected individual.

12-10NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 13: Care of the Deceased with TB Section 13 Caring for the Deceased with TB

General Policy and Procedures 13-2

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 13-1 Section 13: Care of the Deceased with TB

General Policy and Procedures The Infection Control Nurse for the Regional Health and Social Services Authority and the OCPHO should be notified when the death of an infectious patient occurs, whether active TB is confirmed or suspected. For more detail on process and procedure, please consult the 2012 NWT Infection Prevention and Control Manual Section - 11, Care of the Deceased.

13-2In NWT the Tuberculosis NWT, Manual - June THINK 2014 TB! In the NWT, THINK TB! Section 14: History of TB in the NWT Section 14 History and Epidemiology of TB in the NWT

NWT History 14-2 World TB Day 14-4 Epidemiology of TB in the NWT 14-4 Global Occurrence of TB 14-7

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 14-1 Section 14: History of TB in the NWT

NWT History Tuberculosis was not just a medical tragedy for Canada’s Aboriginal people, often it was a family tragedy. TB struck hard in the north in the 1950s and 60s and thousands of people went to southern Canada for treatment. Some were never seen again. Adults died of the disease and were buried without their family’s knowledge, while young children were sent from one hospital to the next without records or documentation of their whereabouts. In 1950, the coast guard ship C.D. Howe made its first voyage to the Arctic. It was specially designed to cruise through ice and was outfitted with a small hospital including an operating room, a sick bay, a dental office, x-ray machine, and darkroom. The ship made annual summer trips to Inuit settlements across the Arctic, taking x-ray surveys and removing TB patients who were sick enough to require treatment in a southern hospital.

Gradually, through immunization (BCG vaccine), Figure 14.1: Lutselk’e: a Doctor Giving early detection, contact tracing, and early treatment a Person a BCG Inoculation in the of infection and disease, there was a dramatic Hudson’s Bay Company Store 1955 decline in TB disease incidence. Given the insidious nature of tuberculosis infection, however, the need for vigilance continues. Though the overall morbidity and mortality has declined, there are still many people who, though clinically well, continue to carry viable tubercle bacilli in their lungs. This is known as latent TB infection, or LTBI. Such individuals, when older or when affected by other illness, can experience reactivation of their disease and become infectious to others (active TB disease). This explains the continued reappearance of community cluster outbreaks that have brought the NWT TB incidence level four times higher than the Canadian national average. Much of the progress worldwide in the control of tuberculosis has been because of improved social determinants of health: improved housing, healthier diets, decreased incidence of alcoholism, and higher income. However, the continued reemergence of TB highlights the need to continue promoting wellness and healthy living, and advocating for improved social determinants of health for all residents of the NWT.

14-2 In the NWT, THINK TB! In the NWT, THINK TB! Section 14: History of TB in the NWT

TB Program and Treatment Timeline in the NWT 1897: Canada’s first sanatorium opened in Ontario. The concept of sanatorium treatment (bed rest and fresh air) as an essential part of treatment of tuberculosis persisted until 1970s. Over 19,000 beds existed during peak use of sanatoriums in 1953. 1908: Tuberculin skin testing began. 1919: Pneumothorax treatment (collapse treatment) became standard treatment for TB. This approach was used to put the lung to rest, and may have prevented the spread of TB to other parts of the body. 1923: Traveling TB clinics began – to find cases for sanatorium treatment. 1925: BCG vaccine was developed using attenuated M. bovis. 1942: Streptomycin (SM) first given in the treatment of TB patients. 1947: Sanatoriums were in Aklavik and Fort Smith. However, many residents from the Northwest Territories stayed at the Charles Camsell Sanatorium in Edmonton, Alberta. 1950: Para-aminor-salicylic acid (PAS) was introduced as a treatment for TB. 1953: INH was introduced with great success in the treatment of TB. 1954: BCG vaccine was introduced in NWT. 1965: RMP was developed and in combination with INH achieved rapid sterilization of the TB bacillus. 1970: Aggressive programs were initiated in the NWT for early case finding and treatment of LTBI in the 1960s and 70s. This intervention lowered transmission of disease with results matching the TB rates of the rest of Canada. 1980: INH, RMP, PZA, EMB, and SM given for six months was assuring 100% cure, with no need for rest or sanatorium isolation. 1995: DOT was established in the NWT. 2001: NWT TB Action Plan to Strengthen TB Management and Control was implemented (based on the Fanning report). 2004: A review to strengthen tuberculosis management and control in the NWT was done to assess the impact of change in response to the 2001 review (Fanning report). 2013: National TB guidelines (Canadian Tuberculosis Standards, 7th edition) released by the Public Health Agency of Canada. 2014: Development and release of NWT Tuberculosis Manual, incorporating national guidelines.

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 14-3 Section 14: History of TB in the NWT

World TB Day On March 24, 1882, Dr. Robert Koch announced the discovery of Mycobacterium tuberculosis, the bacteria that cause tuberculosis. During this time, TB killed one out of every seven people living in the United States and Europe. Dr. Koch’s discovery was the most important step taken toward the control and elimination of this deadly disease. In 1982, a century after Dr. Koch’s announcement, the first World TB Day was sponsored by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD). The event was intended to educate the public about the devastating health and economic consequences of TB, its effect on developing countries, and its continued tragic impact on global health. Today, World TB Day (http://www.stoptb.org/events/world_tb_day/) is commemorated across the globe with activities as diverse as the locations in which they are held. However, more can be done to raise awareness about the effects of TB. Among infectious diseases, TB remains the second leading killer of adults in the world, with 1.3 million TB-related deaths in 2012. Until TB is controlled, World TB Day will not be a celebration. It is a valuable opportunity to educate the public about the devastation TB can spread and how it can be stopped. It is commemorated annually on March 24 and in the Northwest Territories it is an opportunity to increase TB awareness among those working in the health care system and the general population.

Epidemiology of TB in the NWT TB remains a concern in the NWT, with an incidence rate that is 7 times higher than the national rate, on average from 1999 to 2013. Figure 14.2 shows the number of cases and annual incidence rates in the NWT during this 15-year period; a total of 149 cases of active TB were diagnosed, giving a crude average annual incidence rate of 23.2 per 100,000 population.

Figure 14.2: Number and Crude Annual Incidence Rates of Active TB Cases Diagnosed in the NWT, 1999–2013

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The three-year running NWT average TB rate in Figure 14.3 shows a peak between 2007 and 2010, representing two outbreaks. The smear positivity rates are an indication of disease severity and ultimately the potential to infect many close contacts.

Figure 14.3: Three-year Moving Average Incidence Rates of Active TB Cases (n=149) and Sputum Smear Positive Cases (n=40), NWT, 1999–2013

The geographic distribution of TB across seven Health Authorities demonstrates that some regions have higher rates of TB than others (Table 14.1). Notably, the Tlicho and Sahtu regions had the highest incidence rates between 1999–2013, while the Yellowknife and the Tlicho health authorities had the highest number of cases diagnosed during this time period.

Table 14.1: Average Annual Incidence Rates of Active TB per 100,000, and Total Number of Cases by Regional Health and Social Services Authority, 1999–2013

Average annual Authority TB Cases incidence per 100,000 Tłicho 87.8 38 Sahtu 66.8 26 Dehcho 23.7 11 Yellowknife 16.4 50 Beaufort Delta 14.4 15 Hay River 9.6 6 Fort Smith 8.2 3

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Figure 14.4 shows the age and gender distribution of active TB cases reported between 1999 and 2013. The majority (62%) of cases were male. Four percent of cases were 15 years or younger, individuals aged 15 to 34 represented 2% of cases, persons aged 35 to 64 represented another 40% of cases, and 31% of cases were aged 65 years and older.

Figure 14.4: Three-year Moving Average Incidence Rates of Active TB cases (n=149) and Sputum Smear Positive Cases (n=40), NWT, 1999–2013

The majority of TB cases diagnosed in the NWT between 1999 and 2013 were of Dene ethnicity (82%). Non-Aboriginal patients represented 10% of total cases, and Inuit (5%) and Métis individuals (3%) comprised the rest (Figure 14.5).

Figure 14.5: Ethnicity of Active TB Cases, NWT, 1999–2013 (n=149)

14-6NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 14: History of TB in the NWT

Global Occurrence of TB TB is still a significant global problem. In 2012, World Health Organization (WHO) estimated there were 8.6 million incident cases of TB worldwide. 85% of the world’s TB cases are from Asia and Africa. As indicated in the Canadian Tuberculosis Standards, 7th edition (CTS 2013), TB has become more difficult to manage due to the spread of HIV and the emergence of multidrug-resistant (MDR-TB) strains of MTB. As a result, it is estimated 650 000 cases of MDR-TB exist worldwide, and this estimation is felt to be under represented. 1.0–1.2 million TB cases are estimated to be co-infected with HIV (13% of new cases for 2010). Additionally, a total of 58 countries have confirmed at least one case of extensive multidrug-resistant TB (MDR-TB) since 1994 to present. In 2006, a global TB control paradigm was implemented to substantially decrease transmission and reverse the incidence by 2015, as well as achieve TB elimination by 2050. The Global Plan to Stop TB is a global movement led by the STOP TB Partnership, which is linked to the TB-related Millennium Development Goals (MDG) and the global STOP TB strategy http://www.stoptb.org/. There are 22 countries that are highly prioritized as they account for 80% of TB cases in the world. Since 2009, WHO defines high TB incidence countries/ territories as having a rate of at least 30/100,000 (three year average) for all active TB cases. Data on Canadian TB cases are reported through the Canadian TB Reporting System (CTBRS) with the collaboration of all provinces and territories. It is a requirement of the OCPHO (Public Health Act (2009)) that all cases of TB are reported to the NWT TB Program. Provincial and territorial TB programs then voluntarily submit reports of TB cases that meet the case definition for national-level surveillance to the CTBRS. Every year an annual report of TB in Canada is released. In 2012, three quarters of cases reported to CTBRS were respiratory TB. Half of non-respiratory cases involved peripheral lymph nodes. Canada has one of the lowest TB rates in the world. Within Canada, however, there are certain groups (Canadian born Aboriginal, foreign born) who are disproportionately affected by high rates of TB that are comparable to TB endemic countries elsewhere in the world. Consequently, Canada is a committed partner in the Global Plan to Stop TB 2006–2015 strategy by achieving an average reduction rate of 4% to achieve the targeted goals for Canada.

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 14-7 Section 14: History of TB in the NWT

Figure 14.6: High Burden Countries Accounting for 80% of the World’s TB Cases (Stop TB Partnership http://www.stoptb.org/countries/tbdata.as)

High Burden Countries

1. Afghanistan 8. India 16. Russian Federation 2. Bangladesh 9. Indonesia 17. South Africa 3. Brazil 10. Kenya 18. United Republic of 4. Cambodia 11. Mozambique Tanzania 5. China 12. Myanmar 19. Thailand 6. Democratic Republic of 13. Nigeria 20. Uganda Congo 14. Pakistan 21. Viet Nam 7. Ethiopia 15. Philippines 22. Zimbabwe

14-8NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 15: A Glossary of Terms and TB Classifications Section 15

A Glossary of Terms and TB Classifications

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 15-1 Section 15: A Glossary of Terms and TB Classifications

Term Definition Bacterial microorganisms which, after staining, resist decolonization Acid Fast Bacilli with strong acids. Mycobacteria are a common group of acid-fast (AFB) bacilli. Often used interchangeably with compliance and most often refers to Adherence the strict adherence by the patient to the prescribed regimen of anti- tuberculosis drug treatment or preventive treatment. Small droplets of moisture that are exhaled or coughed up. In a patient with respiratory tuberculosis, they may contain Mycobacterium Aerosol tuberculosis bacteria that lead to the spread of infection. Patients with laryngeal and cavitary respiratory disease are the most likely to produce infectious aerosols.

Alanine A serum liver function enzyme (also called SGPT). ALT values increase Aminotransferase when liver cell damage has occurred. It is also one of the liver enzymes (ALT) often measured to assess hepatotoxicity from TB drug treatment. The failure of a subject to respond to skin test antigens of infectious Anergy agents to which they have had prior exposure. Anergy may be due to severe immunodeficiency, such as occurs with HIV infection. This denotes a specimen that is acid-fast bacilli, smear, and/ or culture Bacillary-Positive positive, suspected to be a bacteria belonging to the genus of Mycobacteria. A vaccine containing a suspension of a live attenuated strain of Mycobacterium bovis. BCG vaccine is used in the prevention of Bacillus Calmette- human tuberculosis. As with other vaccines, it does not confer 100% Guérin (BCG) protection, but may have some benefit in the prevention of pediatric tuberculosis meningitis, miliary TB and other forms of invasive infection. The presence of an initially negative response to the Purified Protein Derivative (PPD) used in the tuberculin skin test (TST) followed by a Booster positive response when repeated, usually within one to four weeks. Phenomenon The effect often occurs many years after infection, most notably in the (Effect) elderly. The initial negative response is based on the subject’s initial failure to immunologically “recall” a prior infection. Refers to evidence of lung destruction (i.e. evidence on chest radiograph, or pathology of cavities or cystic areas that communicate Cavitary Disease with a bronchus). Cavities generally harbor large numbers of bacilli and, as a result, patients with cavitary disease tend to be highly infectious and take longer to treat. An immune response that does not involve antibodies but rather involves the activation of phagocytes, natural killer cells (NK), antigen- Cell Mediated specific cytotoxic T-lymphocytes, and the release of various cytokines Immunity (CMI) in response to an antigen. The effective immune response against tuberculosis is primarily due to cell-mediated immunity.

15-2 In the NWT, THINK TB! In the NWT, THINK TB! Section 15: A Glossary of Terms and TB Classifications

Term Definition A person identified as having been exposed to an active case of TB Contact disease. The closeness and duration of exposure usually corresponds with the risk of becoming infected. Conversion is defined as the development of a delayed hypersensivity Conversion reaction with a TST in individuals with no history of previous TB infection. Someone with a positive TST result who had a documented negative Converter (reaction of less than 10mm) result in the previous two years. Culture-Positive The isolation (growth) of M. tuberculosis complex by culture in the Disease laboratory, from sputum, body secretions, or tissue. Delayed-type hypersensitivity responses in the skin have been used to assess CMI in vivo. An antigen (Ag) is introduced intradermally Delayed Type (ID), and induration at 48–72 hours post injection indicate a positive Hypersensitivity reaction. Positive responses require the subject’s exposure to the Ag at least 4–6 weeks prior to skin testing.

Direct Observed The process whereby the ingestion of every dose of treatment for Preventive latent TB disease is directly observed, by a healthcare worker or Treatment (DOPT) delegate. The process whereby the ingestion of every dose of treatment for Direct Observed active TB disease is directly observed by a healthcare worker or Treatment (DOT) delegate. Erythema nodosum is a type of skin inflammation disorder characterized by painful red nodules appearing mostly on the shins, thighs, and forearms. Erythema nodosum can be caused by treatable Erythema nodosum diseases such as tuberculosis, several fungal lung infections, leprosy, inflammatory bowel disease, and some potentially dangerous bacterial infections.

Also called “sed rate”, is a non-specific test which may be elevated in Erythrocyte many infections, acute or chronic inflammation, and malignancy. ESR Sedimentation can be useful in following the course of a disease such as tuberculosis, Rate (ESR) as ESR rates will often vary with the activity of the disease.

A TB infection whose isolates show resistance to at least isoniazid (INH) and Rifampin from among the first-line drugs plus resistance to Extensively-Drug any flouroquinolone and to at least one of three injectable second- Resistant TB (XDR line drugs (capreomycin, kanamycin and amikacin). Third-line drugs or XDR-TB) are used to treat XDR-TB, and they are more expensive, less effective, need to be given for longer periods and have more side effects than first- or second-line drugs. A tiny collection of immune cells known as macrophages. Granulomas Granuloma form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 15-3 Section 15: A Glossary of Terms and TB Classifications

Term Definition Individuals in health care settings who provide health care or support services , such as nurses, physicians, nurse practitioners, paramedics, Health Care emergency first responders, respiratory therapists, home care workers, Providers (HCPs) clinical instructors, students, volunteers, housekeeping, dietary and maintenance staff. The first case. The initial active case from which the process of contact Index Case investigation begins. The soft tissue swelling that is measured when determining the skin test response to tuberculin. It is to be distinguished from erythema, Induration which is not measured and does not constitute a measurable reaction to the antigen. The condition whereby the patient can transmit infection to others Infectious through the production of infectious aerosols (e.g. coughing). Those with cavitary and laryngeal disease are usually the most infectious. A blood test to detect an infection of Mycobacterium Tuberculosis like a TST, does not differentiate between infection and disease. The test finds M. tuberculosis specific proteins that are not found Interferon Gamma in the BCG vaccine; therefore, this test can differentiate between a Release Assays true LTBI and a reaction from a previous BCG vaccine, unlike the TST. (IGRA) Other mycobacteria such as M. kansasii, M. marinum, M. szulgai, and M. flavascens (not common and listed in approximate order of their frequency in Canada) could cause a false positive result. The presence of dormant TB infection with no evidence of clinically active disease is known as LTBI. The immunocompetent host generally Latent Tuberculosis has a lifetime risk of active disease in the range of 10%. Subjects Infection (LTBI) deemed to have LTBI infection are by definition non-infectious. Depending on their contact history, age, and associated medical conditions, they may be candidates for preventive treatment. TB infection due to bacteria resistant to INH and Rifampin with or without resistance to other first- or second- line drugs. MDR-TB Multidrug-resistant represents a grave threat to TB control. Second-line drugs are used to TB (MDR or MDR- treat MDR-TB, and they are more expensive, less effective, need to be TB) given for longer periods of time and have more side effects than first- line drugs. Mycobacterium Refers to a genetically closely related group of Mycobacterium species tuberculosis that can cause tuberculosis. complex (MTC) TB is a disease caused by a bacterium called Mycobacterium Mycobacterium tuberculosis. The bacteria usually attack the lungs, but TB bacteria can tuberculosis (MTB) attack any part of the body such as the kidney, spine, and brain. If not treated properly, TB disease can be fatal.

15-4NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 15: A Glossary of Terms and TB Classifications

Term Definition

Non-respiratory Although the lungs are the major site of damage caused by tuberculosis, tuberculosis, many other organs and tissues in the body may be (formerly known affected. The usual progression is for the disease to spread from the as extra-pulmonary lungs to locations outside the lungs (Non-respiratory sites). In some tuberculosis) cases, however, the first sign of disease appears outside the lungs.

Non-tuberculous Mycobacteria which do not cause tuberculosis or Hansen’s disease mycobacteria (also known as leprosy). Human disease is believed to be acquired (NTM) (also from environmental exposures, and unlike tuberculosis and leprosy, known as Atypical there has been no evidence of animal-to-human or human-to-human Mycobacterium) transmission.

Drug treatment to prevent tuberculosis disease. Most frequently Preventative given to individuals who have TST results suggesting tuberculosis Treatment infection, and who show no signs or symptoms of disease. (Also called “chemoprophylaxis” or “prophylaxis”).

Purified Protein A standardized preparation of purified tuberculin. The usual Derivative (PPD) tuberculin test uses 0.1ml of PPD standardized to 5 tuberculin units.

QuantiFERON®-TB QuantiFERON®-TB Gold (QFT) test is a type of Interferon Gamma Gold (QFT) test Release Assay (IGRA) test method (see above).

Someone with a positive TST test result, without a previous tuberculin Reactor skin test within the last two years. Respiratory TB affecting the lungs, nasopharynx, sinuses, conducting airways, Tuberculosis pleura, intrathoracic lymph nodes and mediastinum. The term used to describe the examination of body secretions under the microscope to determine the presence of acid-fast bacilli. A smear is usually used to determine infectiousness, but initially, before formal Smear culture confirmation, a positive result may be due to infection with mycobacteria other than M. tuberculosis. It therefore requires careful interpretation. The person who is the original source of infection for secondary case(s) or contacts. The case, usually highly infectious (sputum smear-positive), Source Case responsible for having infected others. The source case may or may not be the index case. A notifiable case of disease due to M. tuberculosis complex (excluding TB Case BCG strain). See Table 2.1, Section 2 for classification. A country, region, or community with >10% infectivity (active cases and LTBI) or total burden of untreated TB infection. Over 90% of communities in NWT are considered endemic for TB. TB-endemic countries include south and central African countries, the Philippines, TB-Endemic China, regions of Russia, and Ukraine. For more complete information on international rates, refer to the World Health Organization (WHO) website or the WHO Annual Global TB Report http://www.who.int/ whosis/en/.

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 15-5 Section 15: A Glossary of Terms and TB Classifications

Term Definition A second TST performed one to three weeks after the first test for the purpose of boosting cellular memory. The second TST is only done if TST, Two Step the first test was NEGATIVE. If a second test is done within 12 months of the first it can still be considered a two-step. Tuberculin Skin Test (TST) TST change from negative to positive (10mm or greater) within a two- Converter year period. (also known as Mantoux Converter) A skin test used to identify if a person has delayed type Tuberculin Skin hypersensitivity reaction to tuberculin antigens in the form of purified Test (TST) protein derivatives (PPD). A TST may be falsely positive or falsely negative. See Section 4, TB Screening for more detail.

A soluble cell substance prepared from the tubercle bacillus, which is used to determine the presence of tuberculosis infection. Among the Tuberculin types of tuberculin used are Koch’s original or Old Tuberculin (OT or TO) and tuberculin Purified Protein Derivative (PPD). (SeePurified Protein Derivative).

15-6NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 16: Forms Section 16 Forms

1. NWT TB Assessment Form 16-2 2. NWT TB Initiation Form 16-4 3. NWT TB Case LTBI TX Completion Form 16-5 4. NWT LTBI Tuberculosis Community Surveillance Form 16-6 5. NWT Tuberculosis Surveillance & Screening Form 16-7 6. NWT Tuberculosis Case and Contact Tracing Record 16-8 7. NWT Communicable Disease Passenger Declaration Form 16-9 8. NWT Latent Tuberculosis Infection (LTBI) Drug Treatment & Progress Record 16-10 9. NWT Active TB Drug Treatment & Progress Record 16-12 10. AEFI Form 16-15 11. Common Abbreviations in NWT TB Program 16-19 12. Medication Information 16-21

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 16-1 Section 16: Forms

16-22NWT Tuberculosis Manual - JuneNovember 2014 2014 NWT Tuberculosis Last Name: First Name: Assessment Form DOB: HCP: Community: Please fax completed form to: The Office of the Health Care Provider: Chief Public Health Officer (OCPHO) 867-873-0442

Immigration only Birthplace outside of Canada: Date of arrival in Canada: Port of entry:

Past occupation: Past workplace: Refugee camp ☐ Yes ☐ No

Is family presently in country of origin: ☐Yes ☐ No

Social Profile: Occupation: Employer/school: Ages of all people living in house: #of Bedrooms: Smoking (amount and duration): Substance abuse (alcohol, drugs, inhalants) amount and duration:

Risk Factors/Markers

HIV: Positive Negative Test refused Test not offered Unknown

If positive year of 1st positive test: If negative year of most recent test:

Contact of person with TB in the last 2 years: Yes No Unknown

Diabetes Mellitus type 1 or 2: Yes No Unknown End stage renal disease: Yes No Unknown Homelessness (at diagnosis or within previous 12 months): Yes No Unknown Living in correctional setting at time of diagnosis: Yes No Unknown Long term (< than 1 month) corticosteroid use (prednisone > 15mg/day or equivalent): Yes No Unknown Previous abnormal chest x-ray: Yes No Unknown Transplant related to immunosuppression: Yes No Unknown Travel to high incidence TB country in last 2 years (if Yes how many weeks away ______): Yes No Unknown Other if Yes specify: Yes No Unknown

Previous TB History TST history Date Size of induration BCG Date given Scar present Comment Current Yes: ☐ No: ☐ Yes: ☐ No: ☐ Past Yes: ☐ No: ☐ Yes: ☐ No: ☐

Page 1 of 2

Patient Last Name: First Name: Previous TB History (contd.) Is this person a contact of a known or suspect case? Yes: ☐ No: ☐ If Yes, Whom?

Has this person been hospitalized? Name of hospital: Admit date: Discharge Yes: ☐ No: ☐ Y/M/D date: Y/M/D

Previous History of TB or Drug Therapy TB Medication Duration of Treatment Active TB: Yes: ☐ No: ☐ Year: Latent TB: Yes: ☐ No: ☐ Year

Lab/Radiological Investigations Y/M/D Lab/Radiological Investigations Y/M/D Chest x-ray recent (attach copy of CXR report) ☐ ALT, BUN, Total Bili, Creatinine ☐ Chest x-ray previous (attach copy of CXR report) ☐ Urine (R&M) /Urine Culture ☐ Sputum (smear/culture) ☐ HIV (for active TB cases only) ☐ ESR (erythrocyte sedimentation rate), CBC ☐

Physical Assessment (please place a check mark in box if applicable) Abnormal breath sounds ☐ Red raised skin lesions ☐ Skin colour (look for pallor) ☐ Enlarged lymph nodes ☐ Signs of weight loss ☐ Weight:

Onset Onset Onset Symptom date/duration Symptom date/duration Symptom date/duration Y/M/D Y/M/D Y/M/D Fatigue ☐ General Malaise ☐ Chest Pain ☐ Cough ☐ Night Sweats ☐ Other ☐ Hemoptysis ☐ Fever ☐

Medication

All Current Medications:

Prophylaxis Offered: Yes No

Recommendations from the Office of the Chief Public Health Officer (OCPHO)

Signature: Date:

Page 2 of 2

Last Name: First Name: NWT Latent DOB: HCP: Tuberculosis Community: Infection (LTBI) Treatment Health Care Provider: Initiation Form

Please fax completed form to: The Office of the Chief Public Health Officer (OCPHO) 867-873-0442

Date of diagnosis: y/m/d

1: mg: Doses Medications: Choose an item (dosage) 2: Choose an item mg: Doses Medication Start Date: y/m/d

TB assessment completed: Y: N:

Person prescribing medication: Choose an item Signature person reporting: y/m/d

Community reporting: Choose an item

NovemberJune 2014 2014 NWT Latent Last Name: First Name:

Tuberculosis DOB: HCP:

Infection (LTBI) Community:

Treatment Health Care Provider: Completion Form

Please fax completed form to: To be filled out for all LTBI patients who The Office of the Chief Public Health complete or discontinue treatment Officer (OCPHO) 867-873-0442 Date of diagnosis: y/m/d

Amount in Number of Number of weeks Medications mg. doses completed

Choose an item

Choose an item

Choose an item

Choose an item

Choose an item

Choose an item Start date: End date:

Most recent sputum date: Result: Choose an item Latest chest x-ray date: Result: Choose an item Treatment completed Yes No Further follow up: No: Yes: If No explain: If Yes explain:

Signature person reporting: Date:

Community: Choose an item OCPHO recommendations for follow –up:

NovemberJune 2014 2014

Send in Monthly NWT LTBI Tuberculosis Surveillance (For positive TST- New and Historical) Reporting Unit: Month: Year: Person Reporting: Date: TST CXR Sputa DOB Last Name First Name HCP Result Result #1 #2 #3 Y/M/D Y/M/D Y/M/D (mm) N A Y/M/D N A Y/M/D N A Y/M/D N A ■ ■

Page 1 of 1 Fax to the Office of the Chief Public Health Officer (OCPHO) – 867-873-0442 NovemberJune 2014 2014

Please send in monthly • For TST Screening NWT Tuberculosis Surveillance & Screening • For those on DOPT Reporting Unit: For the month of: Nurse in Charge:

Last Name First Name DOB HCP BCG TST Drug Date # of doses Other information Started to date Adverse reaction, BCG/drug, blood Y N Date Result work, lab results

Page 1 of 1 Please Fax to the Office of the Chief Public Health Officer (OCPHO) 867-873-0442 NovemberMay 2014 2014

NWT Tuberculosis Case and Contact Tracing Record

Case Surname: Given Name: Diagnosis: Date of Diagnosis: y/m/d Date of Birth: y/m/d HCP: Sex: Bacterial Status: Please send in monthly • For TST Screening Community: Choose an item TB Drug Prescribed: INH______RMP______PZA______EMB______B6______CONTACTS • For those on DOPT NWT Tuberculosis Surveillance & Screening Current TST DOB Type of Risk BCG Date Previous TST X-Ray Date Sputa Date Remarks ReportingSurname Unit: Given Name(s) For the monthHCP of: Sex Nurse in Charge: Date Size Y/M/D Contact Level Y/M/D Date Size Y/M/D Y/M/D (results, symptoms, inquiry .etc.) mm 1.* 1.* 1.* 1. - 2.* 2.* 2.* Last Name First Name DOB HCP BCG TST Drug Date1.* # of doses 1.* Other information1.* 2. - Started2.* to date 2.* 2.* Adverse reaction, BCG/drug, blood Y N Date Result 1.* work,1.* lab results 1.* 3. - 2.* 2.* 2.* 1.* 1 1.* 4. - 2.* 2.* 2.* 1.* 1.* 1.* 5. - 2.* 2.* 2.*

1.* 1.* 1.* 6. - 2.* 2.* 2.* 1.* 1.* 1.* 7. - 2.* 2.* 2.*

1.* 1.* 1.* 8. - 2.* 2.* 2.*

Consult with the OCPHO for Contract Tracing: T 01.Spouse 05. In-laws 09. Neighbour 13. Caregiver 17. Son

Y 02. Parent 06. Household 10. Co-worker 14. Institutional Living 18. Daughter

P 03. Sibling 07. Intimate 11. Relative 15. Client 19. Grandchild E 04. Grandparent 08. Friend 12. Community 16. School

*1st round *2nd round

Page 1 of 1 Please Fax to the Office Faxof theResults Chief To: The Public Office Healthof the Chief Officer Public Health (OCPHO) Officer 867(OCPHO)-873 (867)-0442 873- 0442 May 2014 Copy 1 – to OCPHO Copy 3 – to Health Centre MayNovember 2014 2014 NWT Communicable Disease Passenger Declaration

Date: Date of Travel: Y: M: D: Y: M: D: Name of Patient: Surname: First Name: Name of Escort: Surname: First Name: Traveling From: Traveling To:

Air Carrier: Flight:

As per the guidelines recommended by the Canadian Thoracic Society, the following precautions have been taken to ensure there should be no risk of airborne infections:

The patient will be accompanied by an escort, and will wear a a CSA approved respiratory mask at all times. All of these precautions have been explained to the patient and escort, and the patient fully understands. The escort will be carrying a container with a tight fitting lid for disposal of any tissue or sputum. The Pilot in command of the aircraft will decide on appropriate seating, dependent on the type of aircraft configuration and airflow.

Regional Medical Health Officer Notified: Name: Receiving Physician: Treatment Facility

Ground Transportation and Destination:

Medical Travel Officer: Date:

Y: M: D:

NovemberMay 2014 2014

NWT Latent Last Name: First Name: Tuberculosis Infection DOB: HCP: Community: Gender: (LTBI) Drug Treatment Health Care Provider: & Progress Record

Diagnosis: Contact Of: Comments: Date Diagnosed: Last TST: Result: Allergies:

Medications Duration Date Initiated (y/m/d) Completion Date (y/m/d) 1. 2. 3. 4. 5. 6. 7. Ordered By:

Key: X = missed dose \= End of Month HCP Initial = DOPT taken (√) = Dose Self-Administered *Indicates First Dose

Mth 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Monthly Weekly Daily Total

.

Jan

Feb.

Mar.

April

May

June

July

Aug.

Sept.

Oct.

Nov.

Dec.

Page 1 of 2 Fax completed form to NovemberJune 2014 The Office of the Chief Public Health Officer 867-873-0442

See NWT TB Manual Baseline Date Month Month Month Month Month Month Month Month Completion of 2014 for Details (All Clients) 2 3 4 5 6 7 8 9 Treatment Date Symptom Inquiry y/m/d

Result Date Weight (kg) y/m/d Result Date Sputum for AFB y/m/d Result Date

CXR y/m/d Result Date

ESR y/m/d Result Date y/m/d CBC + Platelets Result Date

AST/ALT y/m/d

Result Date y/m/d Serum Bilirubin Result

Date

BUN & Creatinine y/m/d Result Date y/m/d Urinalysis Result Date y/m/d Creatinine/Uric Acid Result

Date y/m/d Audiometry Result Date y/m/d Visual Acuity/Colour Result Date y/m/d Other: Result

Page 2 of 2 Fax completed form to NovemberJune 20142014 The Office of the Chief Public Health Officer 867-873-0442

Surname: Sex: NWT Active TB DRUG Given Name: HCP: Address: TREATMENT &PROGRESS Phone: 867- DOB (y/m/d): Primary Care Provider: RECORD

Diagnosis: Contact Of: Comments: Date Diagnosed(y/m/d): Last TST(y/m/d): Result: Allergies: Ordered By:

Medications Initiation Phase Dose Route Frequency Date Initiated (y/m/d) Completion Date (y/m/d)

Continuation Phase

Person Reporting: Date (y/m/d):

Page 1 of 3 Fax completed form to NovemberJune 2014 2014 The Office of the Chief Public Health Officer 867-873-0442

Surname: Sex: NWT Active TB DRUG Given Name: HCP: Address: TREATMENT &PROGRESS Phone: 867- DOB: Primary Care Provider: RECORD

Weeks Doses Total MTH 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9

1

2

3

4

5

6

7

8

9

10

11

12

Key: X = Missed Dose \ = End of Month HCP Initial = DOPT taken (√) = Dose Self-Administered *Indicates First Dose

Page 2 of 3 Fax completed form to NovemberJune 2014 2014 The Office of the Chief Public Health Officer 867-873-0442

Baseline Date Month Month Month Month Month Month Month Month Month Completion See NWT TB Manual 2014 for Details of (All 1 2 3 4 5 6 7 8 9 Treatment Clients)

Date Symptom Inquiry y/m/d Result

Date Weight (kg) y/m/d Result

Date Sputum for y/m/d AFB Result

Date CXR y/m/d Result

Date ESR y/m/d Result

Date CBC + Platelets y/m/d Result

Date ALT/AST y/m/d Result Date Serum y/m/d Bilirubin Result Date BUN & Creatinine Result Date Urinalysis y/m/d Result Creatinine/Uric Date Acid y/m/d Result Date Audiometry y/m/d Result

Visual Date Acuity/Colour y/m/d Result Date Other: y/m/d Result

Page of Fax completed form to 3 3 NovemberJune 2014 2014 The Office of the Chief Public Health Officer

867-873-0442 REPORT OF ADVERSE EVENTS FOLLOWING IMMUNIZATION (AEFI)

INSTRUCTIONS: For more complete instructions and definitions, refer to the user guide at: www.phac-aspc.gc.ca/im/aefi-form-eng.php

Report events which have a temporal association with a vaccine and which cannot be clearly attributed to other causes. A causal relationship does not need to be proven, and submitting a report does not imply causality. Of particular interest are those AEFIs which: a) Meet one or more of the seriousness criteria b) Are unexpected regardless of seriousness Refer to the user guide, Background Information and for additional clarification.

Note: • the numbers below correspond to the numbered sections of the form. • All dates should be captured in the following format: YYYY / MM / DD. • When reporting an AeFI, check one of the boxes on the top right hand corner of the first page of the AeFI form to indicate whether it is an INITIAL or FOLLOW UP report. For all follow up reports, please specify the UNIqUE EPISODE NUMBER.

1a) The UNIqUE EPISODE NUMBER is assigned by the Province/Territory. Leave it blank unless authorized to assign it. 1b) The REGION NUMBER is a number that corresponds to a given health unit. Leave it blank if it doesn’t apply to your locale. 2) The IMPACT LIN is assigned by IMPACT nurse monitors (LIN: Local Inventory Number). 3) The information provided in this section is confidential and should not be sent to the Public Health Agency of Canada. 4a) Indicate the Province/Territory where the vaccine was administered, abbreviations may be used. 4c) Provide all information as requested in the table. For the “Dose #”, provide the number in series (1, 2, 3, 4, or 5) if known. For the Influenza vaccine, unless a patient receives two doses in one season, the “Dose #” should be recorded as “1”. 7a) Indicate the highest impact of the AEFI on the patient’s daily activities as assessed by the patient or the parent/caregiver. 7c) Provide details of any investigations or treatments in section 10. If the patient was already in hospital when immunized and the immunization resulted in a longer hospital stay, indicate “Resulted in prolongation of existing hospitalization” and provide the number of days by which the patient’s hospital stay was prolonged. For all hospitalizations, indicate the date of admission and discharge. 8) MOH/MHO: Medical Officer of Health, MD: Medical Doctor, RN: Registered Nurse. 9) Choose, from section 9 (AEFI details), the description that best fits the AEFI being reported. Make sure to record the time of onset and duration of signs/symptoms using the most appropriate time unit: Days, Hours or Minutes. Provide additional details of any investigation, therapy, and other information as appropriate in section 10. 11) This section is to be completed by the MOH/MHO, MD, RN or their designate who are assigned to provide public health recommendations according to the P/T best practices. 12) Information in this section is not collected by all P/Ts.

RETURN COMPLETED FORM TO yOUR LOCAL PUBLIC hEALTh UNIT ADDRESS AT:

Alberta (AB) Northwest Territories (NT) Quebec (QC) British Columbia (BC) Nova Scotia (NS) Saskatchewan (SK) Manitoba (MB) Nunavut (NU) Yukon (YT) New Brunswick (NB) Ontario (ON) Canadian Forces Health Services (CFHS) Newfoundland and Labrador (NL) Prince Edward Island (PE) Public Health Agency of Canada (PHAC)

PHAC 08/2011 2 | PUBLIC hEALTh AGENCy OF CANADA

Initial report REPORT OF ADVERSE EVENTS FOLLOWING IMMUNIZATION (AEFI) Follow up report (Unique episode number) 1a) UNIqUE EPISODE NUMBER: 1b) REGION NUMBER: 2) IMPACT LIN:

3) PATIENT IDENTIFICATION

First name: Last name: Health number:

Address of usual residence:

Province/Territory: Postal code: Phone: ( ) (ext. )

Information Source: First name: Last name: Relation to patient:

Contact info, if different:

4) INFORMATION AT TIME OF IMMUNIZATION AND AEFI ONSET

4a) At time of immunization 4b) Medical history (up to the time of AEFI onset) Province/Territory of immunization: ______(Check all that apply and provide details in section 10)

Date vaccine administered (Y / M / D): —– —– —– —– | —– —– | —– —– (hr: ___ am / pm) Concomitant medication(s) Date of birth (Y / M / D): —– —– —– —– | —– —– | —– —– Age: ______Known medical conditions/allergies Sex: Male Female Other Acute illness/injury

4c) Immunizing agent Trade name Manufacturer Lot number Dose # Dosage/unit Route Site

/

/

/

/

/

5) IMMUNIZATION ERRORS 6) PREVIOUS AEFI

Did this AEFI follow an incorrect immunization? No Unknown Yes Did an AEFI follow a previous dose of any of the above immunizing (If Yes, choose all that apply and provide details in section 10) agents (Table 4c)? (Choose one of the following)

Given outside the recommended age limits Product expired Incorrect route No Yes (Provide details in section 10) Wrong vaccine given Dose exceeded that recommended for age Unknown Not applicable (no prior doses) Other, specify:

7) IMPACT OF AEFI, OUTCOME, AND LEVEL OF CARE OBTAINED

7a) highest impact of AEFI: (Choose one of the following) 7b) Outcome at time of report: † Did not interfere with daily activities Death Date (Y / M / D): —– —– —– —– | —– —– | —– —– Interfered with but did not prevent daily activities Permanent disability/incapacity† Not yet recovered† Prevented daily activities Fully recovered Unknown †(Provide details in section 10)

7c) highest level of care obtained: (Choose one of the following) Unknown None Telephone advice from a health professional Non-urgent visit Emergency visit Required hospitalization ( ______days) OR Resulted in prolongation of existing hospitalization (by ______days)

Date of hospital admission: (Y / M / D): —– —– —– —– | —– —– | —– —– Date of hospital discharge: (Y / M / D): —– —– —– —– | —– —– | —– —–

7d) Treatment received: No Unknown Yes (Provide details of all treatments including self treatment, in section 10)

8) REPORTER INFORMATION

Setting: Physician office Public health hospital Other, specify:

Name: Phone: ( ) (ext. ) Fax: ( )

Address: City:

Province/Territory: Postal code: Date reported: (Y / M / D): —– —– —– —– | —– —– | —– —–

Signature: MD RN IMPACT Other, specify:

NOTE: Discuss with patient or his/her parent/caregiver reason for reporting and confidentiality of information. 3 | PUBLIC hEALTh AGENCy OF CANADA

REPORT OF ADVERSE EVENTS FOLLOWING IMMUNIZATION (AEFI)

UNIqUE EPISODE NUMBER: REGION NUMBER: IMPACT LIN:

9) AEFI DETAILS: Complete all sections as appropriate; for each, check all signs/symptoms that apply. Item(s) with asterisk (*) should be diagnosed by a physician. If not, provide sufficient information to support the selected item(s). Use SECTION 10 for additional information including, clinical details and test results.

9a) Local reaction at or Interval:  ____ Min ____ Hrs ____ Days from immunization to onset of 1st symptom or sign near vaccination site Duration:  ____ Min ____ Hrs ____ Days from onset of 1st symptom/sign to resolution of all symptoms/signs

Infected abscess Sterile abscess Cellulitis Nodule Reaction crosses joint Lymphadenitis Other, specify:

For any vaccination site reaction indicated above, check all that apply below and provide details in section 10: Swelling Pain Tenderness Erythema Warmth Induration Rash Largest diameter of vaccination site reaction: ____ cm Site(s) of reaction ______(e.g. LA, RA) Palpable fluctuance Fluid collection shown by imaging technique (e.g. MRI, CT, ultrasound) Spontaneous/surgical drainage Microbial results Lymphangitic streaking Regional lymphadenopathy

Interval:  ____ Min ____ Hrs ____ Days from immunization to onset of 1st symptom or sign 9b) Allergic and Allergic-like events Duration:  ____ Min ____ Hrs ____ Days from onset of 1st symptom/sign to resolution of all symptoms/signs

Chose one of the following: Anaphylaxis Oculo-Respiratory Syndrome (ORS) Other allergic events

Urticaria Erythema Pruritus Prickle sensation Rash (For these events, specify site of reaction)

Skin/mucosal Angioedema: Tongue Throat Uvula Larynx Lip Eye(s): Red bilateral Eyelids Face Limbs Other, specify: Red unilateral Itchy

Measured hypotension  central pulse volume Capillary refill time >3 sec Tachycardia Cardio-vascular  or loss of consciousness (Duration):

Sneezing Rhinorrhea Hoarse voice Sensation of throat closure Stridor Dry cough Respiratory Tachypnea Wheezing Indrawing/retractions Grunting Cyanosis Sore throat Difficulty swallowing Difficulty breathing Chest tightness

Gastrointestinal Diarrhea Abdominal pain Nausea Vomiting

Interval:  ____ Min ____ Hrs ____ Days from immunization to onset of 1st symptom or sign 9c) Neurologic events Duration:  ____ Min ____ Hrs ____ Days from onset of 1st symptom/sign to resolution of all symptoms/signs

Meningitis* Encephalopathy/Encephalitis* Guillain-Barré Syndrome (GBS)* Bell’s Palsy* Other paralysis* Seizure Other neurologic diagnosis*, specify:

Depressed/altered level of consciousness Lethargy Personality change lasting ≥24hrs Focal or multifocal neurologic sign(s) Fever (≥38.0°C) CSF abnormality EEG abnormality EMG abnormality Neuroimaging abnormality Brain/spinal cord histopathologic abnormality Seizure details: Witnessed by healthcare professional Ye s No Unknown Sudden loss of consciousness Ye s No Unknown Generalized (Specify: Tonic Clonic Tonic-clonic Atonic Absence Myoclonic) OR Partial Previous history of seizures (Specify: Febrile Afebrile Unknown type)

Interval:  ____ Min ____ Hrs ____ Days from immunization to onset of 1st symptom or sign 9d) Other events Duration:  ____ Min ____ Hrs ____ Days from onset of 1st symptom/sign to resolution of all symptoms/signs

hypotonic-hyporesponsive Episode (age <2 years) Rash (Non-allergic) Generalized Localized (Site) Limpness Pallor/cyanosis  responsiveness/unresponsiveness Thrombocytopenia* Platelet count <150x109/L Petechial rash Persistent crying (Continuous and unaltered crying for ≥3 hours) Other clinical evidence of bleeding

Intussusception* Anaesthesia/Paraesthesia Numbness Tingling Burning Formication Other, specify: Arthritis Joint redness Joint warm to touch Joint swelling Generalized Localized (Site) Inflammatory changes in synovial fluid Fever ≥38.0°C (Note: report ONLY if fever occurs in conjunction with Parotitis (Parotid gland swelling with pain and/or tenderness) a reportable event. For fever in a neurological event, use Section 9c)

Other serious or unexpected event(s) not listed in the form (Specify and provide details in Section 10) 4 | PUBLIC hEALTh AGENCy OF CANADA

REPORT OF ADVERSE EVENTS FOLLOWING IMMUNIZATION (AEFI)

UNIqUE EPISODE NUMBER: REGION NUMBER: IMPACT LIN:

10) SUPPLEMENTARy INFORMATION (Please indicate the section number when providing details. Please provide details of any investigation or treatment for the recorded AEFI). If not, provide sufficient information to support the selected item(s).

11) RECOMMENDATIONS FOR FURThER IMMUNIZATION (Provide comments, use section 10 if extra space needed)

No change to immunization schedule Controlled setting for next immunization Other, specify: Expert referral, specify: No further immunizations with: ______, specify: Determine protective antibody level Active follow up for AEFI recurrence after next vaccine

Name: Professional status: MOH/MHO MD RN Other, specify:

COMMENTS:

Phone: ( ) (ext. ) Date: (Y / M / D): —– —– —– —– | —– —– | —– —– Signature:

12) FOLLOW UP INFORMATION FOR A SUBSEqUENT DOSE OF SAME VACCINE(S) (Provide details in section 10)

Vaccine administered without AEFI Vaccine administered with recurrence of AEFI Vaccine administered, other AEFI observed Vaccine administered without information on AEFI Vaccine not administered Common Abbreviations in the NWT TB Program

AAP CTS American Academy of Pediatrics Canadian Tuberculosis Standards AEFI CXR Adverse Events Following Immunization Chest X-ray AFB DOPT Acid Fast Bacilli Direct Observed Preventative Treatment ARI DOT Annual Risk of Infection Directly Observed Therapy ART DST Antiretroviral Therapy Drug Susceptibility Testing AIDS DTH Acquired Immune Deficiency Syndrome Delayed-type hypersensitivity ALT EMB Alanine Aminotransferase Ethambutol AST FDA Aspartate Aminotransferase Food and Drug Administration ATS FLD American Thoracic Society First Line Drugs BCG FQN Bacille Calmette-Guérin Fluoroquinolone BID HCP Twice Daily Health Care Provider CDC HIV Communicable Disease Control Human Immunodeficiency Virus CHN HSW Community Health Nurse Home Support Worker CT ICU Computed Tomography Intensive Care Unit CHR IGRA Community Health Representative Interferon-gamma release assay CIC IFN-γ Citizen and Immigration Canada Interferon-gamma CMI IME Cell-mediated immunity Immigration Medical Examination CSA INH Canadian Standards Association Isoniazid CSR 9 INH Central Supply Room 9 months Isoniazid CTBRS IUATLD Canadian TB Reporting System

Page 1 of 2 Common Abbreviations in the NWT TB Program

International Union against Tuberculosis Pyrazinamide and Lung Disease QFT-GIT ISOPORT QuantiFERON®-TB Gold In-tube Portable Isolation Induction Hut RHA LTBI Regional Health Authorities Latent TB Infection RMP LFT Rifampin Liver Function Test 4 RMP MDG 4 Months Rifampin Millennium Development Goals SCIDS MDR TB Severe Combined Immunodeficiency Multidrug-Resistant Tuberculosis SI MMWR Sputum Induction Morbidity and Mortality Weekly Report SLD MTB Second Line Drugs Mycobacterium Tuberculosis SOB MTBC Shortness of Breath Mycobacterium Tuberculosis Complex SM NTM Streptomycin Nontuberculous Mycobacteria Also Known TB As Atypical Mycobacterium tuberculosis NWT TID Northwest Territories Thrice Daily OCPHO TNF Office of the Chief Public Health Officer Tumor necrosis factor OD TNF-α Once Daily tumor necrosis factor-alpha PA TST Posterior/Anterior tuberculin skin test PAS UVGI para-Aminosalicylic acid Ultra Violet Germicidal Irradiation PHA WHO Public Health Act World Health Organization PHN XDR-TB Public Health Nurse Extensive Drug Resistant TB PHPW Prevention and Health Promotion Worker PPD Purified protein derivative PZA

Page 2 of 2 What You Should Know TB medicines are usually safe. Very few people have side effects. If you have About Taking Tuberculosis any of the problems listed below, you must call Medications or see your health care worker right away.

• Vomiting • Loss of appetite • Stomach pain See NWT TB Manual Baseline Date Month Month Month• MonthDizziness Month Month Month Month Completion of 2014 for Details (All Clients) 2 3 4 5 6 7 8 Nausea9 Treatment Date Symptom Inquiry y/m/d • Yellowing of your • Bleeding easily-

Result eyes or skin Bruising easily Date Weight (kg) y/m/d • Tingling numbness • Tingling in your Result around your mouth fingers or toes Date Sputum for AFB y/m/d • Fever for more than • Blurred or change

Taking medicinesResult to kill TB germs can cure 3 days in your vision Date

CXRTB disease. y/m/d • Aching joints • Skin rash TB germs are strong.Result You need to take medicine Date

ESRfor many months (upy/m/d to 9 months) to be sure all Result If you are taking Rifampin , you should of the TB germs areDate dead. Follow your health y/m/d know that: CBC care + Platelets provider’s directions for taking your pills.. Result • Your urine, saliva, or tears can become Your health care workerDate will talk to you about

AST/ALT y/m/d orange in color. Directly Observed ResultTherapy (DOT). DOT is when • Your soft contact lenses may get a health care workerDate is with you when you take y/m/d stained t his can happen Serumyour Bilirubin TB pills. very quickly! Result Do not wear soft contact lenses when Date

y/m/d taking Rifampin. BUN & Creatinine . Do not stop takingResult your pills too soon • Your skin may become more sensitive Even though you mightDate start to feel better in y/m/d to the sun. Use sunscreen and cover Urinalysisfew weeks, TB can come back. You can again Result skin that might be exposed to the sun. spread TB to others.Date y/m/d • Some birth control methods do not Creatinine/Uric Acid Result work as well when you are taking Remember the followingDate when taking your y/m/d Rifampin . Women should use a back-up Audiometry TB pills: Result form of birth control, such as condoms, Tell your health careDate worker if you are tak ing y/m/d while taking Rifampin . Visual Acuity/Colour any other medicines.Result This includes medicine, vitamins and herbsDate that you buy without a y/m/d Other: If you have questions about medication, prescription. Avoid Resultdrinking beer, wine or liquor contact your Health Care Provider. while taking TB medicines. Tell your health care

provider if you are pregnant, breastfeeding or Adapted from: taking birth control pills. Tell your health care worker if you have any health problems other Virginia Department of Health Division of TB than TB.

Common TB medicines include: Protect yourself, your family and friends from TB. • Isoniazid (INH) • Rifampin (RMP) Finish your TB treatment! • Pyrazinamide (PZA) • Ethambutol (EMB)

Page 2 of 2 Fax completed form to June 2014 The Office of the Chief Public Health Officer 867-873-0442

November 2014

Section 17 Specimen Collection Procedures

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 17-1 Section 17: Specimen Collection Procedures

Table 17.1: Specimens

Specimen Unacceptable Specimen Type Special Instructions Requirements Specimens Abscess Place in sterile Cleanse skin with alcohol Dry swab contents, container and allow skin to dry before aspirated fluid aspirating sample. Collect specimen on swab, and place in transport medium only if volume is insufficient for aspiration by needle and syringe Blood 5ml inoculated Disinfect site as for routine Blood collected directly into liquid blood culture in EDTA will media greatly inhibit NOTE: AFB- mycobacterial specific blood growth even in culture bottle trace amounts must be used. Coagulated blood unacceptable. Effect of prolonged transit time has not been well studied Body fluids As much as possible Disinfect site with alcohol (pleural, (10 to 15ml if collecting by needle and Pericardial, minimum) in sterile syringe peritoneal, etc.) container Bone Bone in sterile Specimen container without submitted in fixative or formalin preservative Bone marrow Collect in sterile Collect aseptically container or directly on a Lowenstein-Jensen (LJ) medium

Bronchoalveolar ≥ 5ml in sterile Avoid contaminating lavage or container bronchoscope with tap water. bronchial Saprophytic mycobacteria may washings produce false-positive culture or smear results

17-2 In the NWT, THINK TB! In the NWT, THINK TB! Specimen Unacceptable Specimen Type Special Instructions Requirements Specimens Cerebrospinal >2ml in sterile Use maximum volume fluid container submitted Gastric lavage • ≥ 5–10ml in •Collect fasting early- Non-neutralized fluid sterile container morning specimen on 3 specimens that •Collect in the consecutive days do not arrive in morning soon •Use sterile, non- laboratory after patient bacteriostatic saline Within 4 hours awakens in order •Adjust to neutral pH with or for which no to obtain sputum 100mg of sodium carbonate collection time is swallowed immediately following noted during sleep collection •Non-neutralized samples should be identified as such (on the requisition and the container) and must be submitted to the laboratory within 4 hours of collection •Collection time must also be noted on the requisition and container Lymph node Node or portion in •Collect aseptically to avoid Specimen sterile container indigenous microorganisms. submitted in without fixative or Select caseous portion if formalin preservative available •Do not wrap in gauze •Freezing decreases yield Skin lesion Submit biopsy •Swabs in transport medium Dry swab material in specimen sterile are acceptable only if Specimen container without biopsy sample or aspirate is submitted in fixative or not obtainable formalin preservative •For cutaneous ulcer, collect biopsy sample from periphery of lesion, or aspirate material from under margin of lesion. Physician communication with the laboratory is important if patient originates from or has traveled to foreign countries

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 17-3 Section 17: Specimen Collection Procedures

Specimen Unacceptable Specimen Type Special Instructions Requirements Specimens Smear on slides Smear specimen • Heat fixes smears. Transport (e.g., M. leprae over 1.5cm by in slide container taped disease) 1.5cm area of clear closed and labeled slide BIOHAZARD Sputum •5–10ml in sterile •For induced sputum, use Pooled specimens; plastic disposable sterile, non-bacteriostatic, saliva container hypertonic (10–15 percent) •Collect an saline early-morning •Avoid sputum specimen from contamination with deep, productive nebulizer reservoir water cough • Saprophytic (environmental) •Samples may be mycobacteria in tab water collected 1 hour may produce false-positive apart with at culture or smear results least one early •Indicate on requisition morning sample if specimen is induced •Do not pool sputum, as these watery specimens specimens resemble saliva and risk being rejected as inadequate Stool >1g in sterile, •Collect specimen directly Frozen specimen plastic, disposable into container, or transfer container from bedpan or plastic wrap stretched over toilet bowl •Refrigerate immediately •Do not freeze specimen Tissue biopsy 1g of tissue, •Collect aseptically to avoid Specimen sample if possible, in indigenous microorganisms submitted in sterile container •Select caseous portion if formalin without fixative or available preservative •Do not wrap in gauze •Freezing decreases yield Transtracheal Sterile container aspirater

17-4NWT Tuberculosis Manual - JuneNovember 2014 2014 Specimen Unacceptable Specimen Type Special Instructions Requirements Specimens Urine •40–50ml of • Collect first morning 24-hour pooled first morning specimen on 3 consecutive specimens urine specimen days- only one specimen/ from catheter •Obtained by day bag specimens catheterization •Organisms accumulate in of <40ml unless, or midstream bladder overnight so first larger volume is clean catch in morning void provides best not obtainable sterile container yield •Specimens collected at other times are dilute and are not optimal Wound material See biopsy or •Swabs are acceptable only if Dry swab aspirate biopsy or •Aspirate is not obtainable. If used, they must be placed in transport medium

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 17-5 Section 17: Specimen Collection Procedures

17-6NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 18: List of Figures Section 18 List of Figures

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 18-1 Section 18: List of Figures

List of Figures Figure 2.1: Mycobacterium Species 2-2 Figure 2.2: Expulsion of Respiratory Droplets 2-5 Figure 2.3: TB Transmission 2-6 Figure 2.4: The Pathogenesis of Tuberculosis in the Infected Host (Adapted from the 6th Edition of the Canadian TB Standards) 2-9 Figure 2.5: Defense Against Respiratory Infection 2-10 Figure 3.1: BCG Vaccine 3-2 Figure 3.2: Local Reaction (Progression) of BCG Vaccine at Site of Administration 3-6 Figure 4.1: TST Interpretation 4-8 Figure 4.2: The BCG World Atlas 4-12 Figure 4.3: Description of Two-Step TST Testing 4-15 Figure 6.1: Calcified Granulomas Indicated by Arrows (Image from Medscape) 6-4 Figure 6.2: Calcified Hilar Nodes Indicated by Lines 6-4 Figure 6.3: Right Costophrenic Angle 6-5 Figure 6.4: Lung Cavitation in Left Upper Lobe 6-7 Figure 6.5: Chest Radiograph with Left Lower Lobe Cavity 6-8 Figure 6.6: Colonies of Mycobacterium Tuberculosis Grown in Culture 6-11 Figure 6.7: Sputum Collection Procedure 6-13 Figure 6.8: Sputum Induction 6-14 Figure 6.9: Sputum Induction Procedure 6-15 Figure 6.10: Bronchoscopy 6-15 Figure 6.11: Miliary Tuberculosis 6-18 Figure 6.12: TB of the Kidney 6-18 Figure 6.13: TB of the Central Nervous System 6-19 Figure 7.1: Management of Suspect TB 7-2 Figure 7.2: Medical Transportation of a Confirmed or Suspected Case 7-3 Figure 7.3: N95 Mask 7-4 Figure 7.4: CSA Standard Criteria for Negative Pressure Rooms 7-8 Figure 7.5: Risk Categories for Activities Performed by HCPs 7-10 Figure 8.1: Patient Receiving TB Medication 8-3 Figure 9.1: Contact Tracing for Active Respiratory TB 9-2

18-2 In the NWT, THINK TB! In the NWT, THINK TB! Section 18: List of Figures

Figure 9.2: Management of TB Contacts (Negative TST History or No Previous TST Algorithm) 9-3 Figure 9.3: Management of TB Contacts (Previous Positive TST Algorithm) 9-4 Figure 10.1: Components of the TB Prevention and Control Program in the NWT 10-3 Figure 10.2: Surveillance 10-6 Figure 11.1: DOT 11-9 Figure 11.2: Management of Children with Close Contact to Smear Negative (Culture Positive) TB 11-12 Figure 11.3: Management of Children with Close Contact to Smear Positive TB 11-13 Figure 14.1: Lutselk’e: a Doctor Giving a Person a BCG Inoculation in the Hudson’s Bay Company Store 1955 14-2 Figure 14.2: Number and Crude Annual Incidence Rates of Active TB Cases Diagnosed in the NWT, 1999–2013 14-4 Figure 14.3: Three-year Moving Average Incidence Rates of Active TB Cases (n=149) and Sputum Smear Positive Cases (n=40), NWT, 1999–2013 14-5 Figure 14.4: Three-year Moving Average Incidence Rates of Active TB cases (n=149) and Sputum Smear Positive Cases (n=40), NWT, 1999–2013 14-6 Figure 14.5: Ethnicity of Active TB Cases, NWT, 1999–2013 (n=149) 14-6 Figure 14.6: High Burden Countries Accounting for 80% of the World’s TB Cases (Stop TB Partnership http://www.stoptb.org/countries/tbdata.asp) 14-8

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 18-3 Section 18: List of Figures

18-4NWT Tuberculosis Manual - JuneNovember 2014 2014 Section 19: List of Tables Section 19 List of Tables

NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 19-1 Section 19: List of Tables

List of Tables Table 2.1: Classification of a TB Case 2-4 Table 2.2: Respiratory vs. Non-respiratory TB Disease 2-11 Table 2.3: Risk Factors for the Development of Active TB Among People with a Positive Tuberculin Skin Test (Presumed Infected With Mycobacterium Tuberculosis) 2-12 Table 2.4: Other Factors for Disease Development 2-13 Table 3.1: Adverse Events Following BCG Vaccine and Suggested Management 3-8 Table 3.2: BCG Vaccine Usage in Canada 3-9 Table 4.1: Tuberculin Skin Test Cut-points for Interpretation of the TST 4-10 Table 4.2: QuantiFERON®-TB Gold (QFT) Assay 4-17 Table 4:3: Advantages and Disadvantages of IGRA Tests 4-18 Table 6.1: Latent TB Infection Versus Active Respiratory TB Disease 6-2 Table 6.2: Symptoms of Pulmonary TB Disease 6-6 Table 6.3: Infectivity Continuum 6-9 Table 6.4: Number of Bacteria Seen on Microscopy and Laboratory Interpretation 6-10 Table 6.5: Symptoms of Non-respiratory TB for Selected Sites 6-17 Table 7.1: Risk Assessment – Admission to Health Care Facility 7-9 Table 7.2: Recommended Air Exchanges per Area (Health Care Facilities) 7-11 Table 7.3: Time Needed (by Number of Air Changes per Hour) to Remove Airborne Microorganisms After Generation of Infectious Droplet Nuclei has Ceased 7-12 Table 8.1: Regimes for Treatment of Latent TB Infection 8-5 Table 8.2: INH Protocol for Treatment of LTBI 8-5 Table 8.3: Special Considerations in the Treatment of LTBI 8-6 Table 8.4: Summary of Care for Patients Receiving Treatment for LTBI 8-8 Table 8.5: Symptoms of Toxicity 8-9 Table 8.6: INH Drug Overdose 8-11 Table 8.7: Management of Treatment Interruptions 8-17 Table 8.8: Special Considerations in the Treatment of Active TB Disease 8-18 Table 8.9: Recommended Drug Regime 8-21 Table 8.10: Recommended Drug Doses for Daily and Intermittent Therapy in Adolescents and Adults 8-22

19-2 In the NWT, THINK TB! In the NWT, THINK TB! Section 19: List of Tables

Table 8.11: Summary of Care for Patients Receiving Treatment for Active TB 8-24 Table 8.12: Common Adverse Reactions with First Line Anti-Tuberculosis Drugs 8-25 Table 8.13: INH Drug Overdose 8-29 Table 8.14: Type of Drug Resistance 8-31 Table 8.15: Regimens for the Treatment of INH Mono-resistant TB 8-33 Table 8.16: Regimens for the Treatment of RMP Mono-resistant TB 8-34 Table 9.1: TST in the Context of a Contact Investigation 9-9 Table 10.1: PHA Legislation and NWT Regulation for Public Health Activities for TB Control 10-4 Table 11.1: Average Age-Specific Risk For Disease Development After Untreated Primary Infection 11-3 Table 11.2: Regimes for Treatment of LTBI in Children 11-3 Table 11.3: Doses of Anti-Tuberculosis Drugs for Children 11-8

Table 11.4: Drug Regimes for Treating TB in Children 11-9 Table 11.5: INH Drug Overdose 11-11 Table 12.1: Recommendations of The Canadian Thoracic Society for Groups for Targeted LTBI Screening 12-5 Table 14.1: Average Annual Incidence Rates of Active TB per 100,000, and Total Number of Cases by Regional Health and Social Services Authority 1999–2013 14-5 Table 17.1: Specimens 17-2

In the NWT, THINK TB! In the NWT, THINK TB! NWT TuberculosisNWT Tuberculosis Manual Manual - November - June 2014 19-3