Tuberculosis Management in Children

Transcription

1 Tuberculosis Management in Children Ministry of Public Health and Sanitation Division of Leprosy, Tuberculosis and Lung Disease November, Division of Leprosy, Tuberculosis and Lung Disease i

2 Table of Contents Table of Contents...ii Forward iv Acknowledgement... v Chapter 1: Introduction and Definitions Introduction Definitions and Distinctions Rationale for Pediatric TB guideline... 4 Chapter 2: Diagnosis of Tuberculosis in Children Careful History Clinical Presentation of Pulmonary TB (PTB) Extra Pulmonary Tuberculosis (EPTB) Score Charts/ Diagnostic Criteria Chapter 3: Treatment of Tuberculosis Classification of TB in Children Recommended Treatment Regimens Additional Management Decisions Follow-up of a Child on anti-tb Therapy Poor Response to Treatment Treatment Interruptions Chapter 4: TB and HIV Co-infection Diagnosis Treatment Prevention Differential Diagnosis in HIV infected Child with Chronic Respiratory Symptoms Antiretroviral Therapy in HIV Infected Children with Tuberculosis Co-trimoxazole Preventive Therapy (CPT) Isoniazid Prophylactic Therapy (IPT) in Children Chapter 5: Tuberculosis in special circumstances Tuberculous Meningitis (TBM) Management of a Newborn born to a Mother with PTB Drug Resistant TB Chapter 6: TB Prevention Screening for Child Contacts of Known TB Cases Management of Child exposed to PTB ii

3 6.3 Tracing of TB Source BCG Vaccination in Children TB Infection Control Chapter 7: Roles and Responsibility Level 1: (family, patient, CHW, CHEW, community) Level 2 and 3: Dispensary and Health Centre Level 4, 5 and 6: District, Provincial and Referral Hospitals Follow-up Health education Case recording and reporting for childhood TB Annex 1: Tuberculin Skin Test (Mantoux test) Annex 2: Sputum Collection Annex 3: Seven Steps for Patient Management to prevent transmission of TB in Community and health care settings ANNEX 4: Interim recommendations for intensive phase using dispersible FDC tablets of RHZ and single INH tablets Annex 5: Interim recommendation for intensive phase using dispersible FDC tablets of RHZ 60/30/150 mg and additional RH 60/60 mg ANNEX 6: Child Tuberculosis Monitoring Card ANNEX 7: Second-line anti-tb drugs for treatment of MDR-TB in children iii

4 Forward Treatment of tuberculosis has over the years focused more on adults leaving children unattended appropriately as medical practitioners considered children of little epidemiologic significance. Available data indicate that more than 11% of TB cases notified in Kenya are children below 15 years. This is thought to be an under estimate considering the challenges faced in diagnosing TB in children. With the emergence of MDR TB, children are victims of contacts and poor case control of adult TB cases. This pool of cases will defeat the ultimate aim of eliminating TB. Kenya has pioneered interest in TB control amongst children by defining the epidemiologic parameters for children in age groups 0 4, 5 9 and years. Since children are born without TB and they are an important segment of the society for they signify the future, these guidelines seek to provide guidance to the management of TB in children. It seeks to demystify TB diagnosis in children especially with the coming of new diagnostic methods expected to revolutionalize TB diagnosis and management. The guideline is specifically designed for general health care workers readership and is therefore expected to stimulate interest in pediatric TB treatment and how to protect the children from getting infected. This guideline will also act as a reference material for medical students, researchers and the community. Dr. S. K. Sharif, MBS, MBChB, M. Med. DLSHTM, MSc. Director of Public health and Sanitation Ministry of Public Health and Sanitation iv

5 Acknowledgement The Division of Leprosy, Tuberculosis and Lung Disease is indebted to support received from the Ministries of Public Health and Sanitation and Ministry of Medical Services including health care workers in both Ministries of health in the implementation of TB control activities in the country. The Division specifically, acknowledges the support received from the following officers who worked tirelessly and sometimes worked late into the night in developing this guideline: Dr. Joel Kangangi WHO Mr. Hillary Kipruto WHO Dr. Joseph Odhiambo CDC Dr. Nicholas Wambua CDC Dr Maurice Maina USAID-Kenya Dr. Joseph Sitienei DLTLD Dr. Tsegaye Sentayehu TBCARE1 Dr. Herman Weyenga DLTLD Dr. Bernard Langat DLTLD Dr. Kamene Kimenye DLTLD Dr. Hajara El Busaidy PTLC Coast Dr. Immaculate Kathure PTLC Nairobi Dr. Shobha Vakil NASCOP Prof. Elizabeth Maleche Obimbo University of Nairobi Dr. Evans Amukoye KEMRI Dr. Agnes Langat CDC Dr. Francis Ogaro MTRH The Divison registers appreciation to the International Union against TB and Lung Diseases and specifically Prof Steve Graham and Penny Enarson for sharing and allowing the use of the WHO/IUATLD Paediatric TB Deskguide as a template in the development of our own Kenyan Paediatric TB Guideline. The division is indebted to USAID for providing funds for printing of this guideline. Dr. Joseph Sitienei Head, DLTLD v

6 List of Abbreviations AFB Acid Fast Bacilli ART Antiretroviral therapy BCG Bacille Calmette Guerin CXR Chest X-ray DLTLD Division of Leprosy Tuberculosis and Lung Disease DOT Directly observed therapy DST Drug Susceptibility Testing HIV Human Immunodeficiency Virus IPT Isoniazid Preventive Therapy MDR TB Multi-drug resistant NNRTI NonNucleoside Reverse Transcriptase Inhibitor NRTI Nucleoside Reverse Transcriptase Inhibitor PPD Purified protein derivative PTB Pulmonary Tuberculosis TB Tuberculosis TST Tuberculin Skin Test WHO World Health Organization XDR-TB Extensively Resistant Tuberculosis vi

7 Chapter 1: Introduction and Definitions 1.1 Introduction It is estimated that one third of the world s population is infected with Mycobacterium tuberculosis (the bacterium that causes tuberculosis (TB)), and that each year, about 9 million people develop TB, of whom about 2 million die. Of the 9 million annual TB cases, about 15% occur in children (under 15 years of age). Kenya is among the 22 TB high burden countries in the world and is among the top 5 from sub Saharan Africa. 75% of these childhood cases occur annually in these 22 high-burden countries that together account for 80% of the world s estimated incident cases. In 2009 Kenya reported a total of 110,065 cases of all forms of TB (case notification rate of 326/100,000). Paediatric age group of less than 15 years constituted 11% of all cases notified which is a significant proportion requiring special attention. In the last 5 years, Kenya has reported annual decline in the number of reported TB cases at a rate of 1% possibly due to effective control interventions coupled with the declining HIV prevalence in the population. Infection with M. tuberculosis usually results from inhalation of infected droplets produced by a patient who has pulmonary TB. The source of infection for most children is an infectious adult in their close environment (usually the household). This exposure leads to the development of a primary parenchymal lesion (Ghon focus) in the lung with spread to the regional lymph nodes. The immune response (delayed hypersensitivity and cellular immunity) develops about 4 6 weeks after the primary infection. In most cases, the immune response stops the multiplication of M. tuberculosis bacilli at this stage. However, a few dormant bacilli may persist. A positive tuberculin skin test (TST) where available would be the only evidence of infection. In some cases, the immune response is not strong enough to contain the infection and disease occurs within a few months. Risk of progression to disease and development of disseminated TB is increased in the very young (0-4 years), immuno-compromized and malnourished. In vast majority of children who 1

8 develop disease usually do so within 2 years following exposure and infection. Children can present with TB at any age, but the most common age is between 1 and 4 years. HIV infected children have a lifelong risk of developing TB. TB in young children and in the HIV infected is often disseminated and rapidly progressive 1.2 Definitions and Distinctions Infection with Mycobacterium tuberculosis usually results from inhalation of infected droplets produced by someone who has PTB and who is coughing. The most infectious source cases are those with sputum smear-positive disease. The closer the contact is to the source case, the greater the exposure and the greater the risk of getting infected with tuberculosis. TB infection is when a person carries the Mycobacterium tuberculosis bacteria inside the body. Many people have TB infection and are well. A positive TST indicates infection - but a negative TST does not exclude the possibility of infection. TB disease occurs in someone with TB infection when the bacteria inside the body start to multiply and become numerous enough to damage one or more organs of the body. This damage causes clinical symptoms and signs and is referred to as tuberculosis or active disease. Pulmonary TB sputum smear positive The criteria are. Two or more initial sputum smear examinations positive for AFBs or One sputum smear positive for AFB plus CXR abnormalities consistent with active PTB, as determined by the clinician or One sputum smear examination positive for AFB plus sputum culture positive for M. Tuberculosis. Adolescents or children of any age with complicated intrathoracic disease are more likely to have smear positive PTB. 2

9 Pulmonary TB sputum smear negative. A case of PTB that does not meet the above criteria for smear positive PTB: The Criteria are; At three sputum specimens negative for AFB, and Radiological abnormality consistent with active PTB, and No response to a course of broad spectrum antibiotics and Decision by clinician to treat with a full course of anti- TB chemotherapy. Such cases include cases without smear results, which is a common phenomenon in children. Extra pulmonary TB Children with EPTB should be classified under the same definition. Those with both PTB and EPTB should be classified as PTB Drug Resistant TB This is a laboratory diagnosis, however Drug resistant TB should be suspected if. 1. Features in the source case that are suggestive of drug resistant TB, Contact with known case of drug resistant TB. Remains sputum smear positive after 3 months of treatment, History of previously treated TB, History of treatment interruption. 2. Features of a child suspected of having drug resistant TB. Contact with a known case of drug resistant TB, Not responding to the anti- TB treatment regimen. Recurrence of TB after adherence to treatment The diagnosis and treatment of drug resistant TB in children is complex and should be carried out at referral centre, Source Case: Usually an adult with smear positive pulmonary TB. Close contact is defined as living in the same household as, or in frequent contact with (e.g. child minder, school staff), a source case with PTB. 3

10 Children refer to the 0 to 14 year age group Infant is a child of less than 1 year of age (0-12 month age group) 1.3 Rationale for Pediatric TB guideline The TB control program has in the past paid less attention on pediatric TB mainly due to the fact that children with TB rarely transmit the infection. However children contribute a significant proportion of the disease burden and suffer severe tuberculosis related morbidity and mortality, particularly in the endemic areas. The diagnosis of TB in children is particularly difficulty, more so in resource constrained settings like in Kenya with poor laboratory and X-ray services and high TB/HIV co infection rates. Hence there is need for pediatric TB management guidelines that will enhance early and accurate case identification and treatment as well as contact screening and management. 4

11 Chapter 2: Diagnosis of Tuberculosis in Children The diagnosis of TB in children relies on a careful and thorough history and physical examination as well as any relevant investigations e.g. TST, CXR and sputum smear microscopy. Even though microbiological diagnosis is not always feasible, all efforts should be made to do sputum microscopy where possible in children with suspected pulmonary tuberculosis. A trial treatment with anti- TB drugs is not recommended as a method of diagnosing TB in children. There are no clinical features that are diagnostic of TB in children as such. 2.1 Careful History a. Contact. Close contact is defined as living in the same household as or in frequent contact with smear positive PTB case. Smear negative but culture positive source cases are also infectious, but to a much lesser degree. All children who are symptomatic must be screened for TB. When any child is diagnosed with TB all efforts should be made to detect the source case. Children with smear positive TB or cavitary TB on CXR are infectious, their child contacts must be sought and screened for TB. If no source case is identified, always ask about anyone in the household with chronic cough- if present request assessment of that person for possible TB. Most children will develop TB within two years of exposure b. Symptoms. The commonest symptoms associated with TB. Include the following. Progressive and non-remitting cough for more than 2 weeks. Fever for more than 2 weeks, (usually low grade fever 38c) after common causes such as pneumonia, Malaria and Typhoid have been excluded. Fatigue, reduced playfulness, less active Failure to thrive. Weight loss, no or poor weight gain following nutritional rehabilitation. 5

12 The diagnosis of TB in children relies on a careful and thorough history and physical examination 2.2 Clinical Presentation of Pulmonary TB (PTB) Respiratory system May have increased respiratory rate May have signs of respiratory distress Auscultation and percussion: usually normal but may have abnormal sounds (e.g. crackles, bronchial breathing) or pleural effusion (dullness and reduced breath sounds) Atypical clinical presentations of PTB Acute severe pneumonia o Presents with fast breathing and chest in-drawing o Occurs especially in infants and HIV-infected children o Suspect PTB if response to antibiotic therapy is poor o If HIV infected also suspect other HIV-related lung disease e.g. PCP Wheeze o Asymmetrical and persistent wheeze can be caused by airway compression due to enlarged tuberculous hilar lymph nodes o Suspect PTB when wheeze is asymmetrical, persistent and non responsive to bronchodilator therapy PTB can also present acutely as bronchopneumonia in children with tachypnoea, respiratory distress and crackles. A normal respiratory clinical finding does not rule out PTB either 6

13 2.3 Investigations After history and physical examination, if investigations are available in the facility or nearby, attempt should be made to investigate every child suspected to have TB as follows: 1 Tuberculin Skin Test (Mantoux test) A positive TST is evidence that one is infected with M. Tuberculosis, but doesn t necessarily indicate disease. Mantoux test is the recommended test. Correct technique of administering the TST reagent, reading and interpretation of mantoux text is very important. Appendix 1 TST is regarded as positive if the induration is. More than 10 mm in all other children, whether they received BCG vaccine or not. More than 5mm in HIV infected, immunocompromised, or severely malnourished. Sometimes it is useful to repeat TST test once the nutritional status has improved. A positive mantoux test in the absence of symptoms or signs does not necessarily indicate active disease. Causes of false positive and false negative Mantoux test are listed in table 1 7

14 Table 1: Causes of false-negative and false- positive tuberculin skin tests (TST) Causes of false negative TST Incorrect administration or interpretation of test HIV infection Improper storage of tuberculin Viral infections (e.g. measles, varicella) Vaccinated with live viral vaccines (within 6 weeks) Malnutrition Bacterial infections (e.g. typhoid, leprosy, pertussis) Immunosuppressive medications (e.g. corticosteroids) Neonatal patient Primary immunodeficiencies Diseases of lymphoid tissue (e.g. Hodgkin disease, lymphoma, leukemia, sarcoidosis) Low protein states Severe TB Causes of false positive TST Incorrect interpretation of tests BCG vaccination Infection with non-tuberculous mycobacterium A negative mantoux test does not rule out TB 2. Bacteriological diagnosis Bacteriological confirmation is particularly important for children with Suspected drug resistant TB, Severe and complicated disease, HIV infected Diagnostic uncertainties. As much as possible appropriate specimen (sputum, CSF, gastric aspirate, lymph node biopsy etc) should be obtained for Microscopy for mycobacterium TB culture where possible (liquid and solid culture) 8

15 Histopathology depending on specimen Xpert MTB/RIF (to be used only with sputum and sputum sediments) Line Probe Assays (LIPA)` Expectoration, gastric aspirate or sputum induction can been used to obtain sputum depending on the age of the child. Sputum induction should be conducted in outdoor or in specially designed rooms with negative pressure and UV light for purposes of infection control. Appendix 2 and 3 3. Chest X-Ray This is particularly important in children with suspected PTB. Radiological features suggestive of PTB will include, Persistent lung opacification especially if focal Enlarged hilar or subcarinal lymph nodes, Diffuse micronodular infiltrates (miliary pattern) Pleural effusions with apical infiltrates and cavities especially in adolescents. The finding of marked abnormality on CXR in a child with no signs of respiratory distress (no fast breathing or chest in-drawing) is highly supportive of TB 9

16 CXR Pictures suggestive of Pulmonary TB Right perihilar lymph node enlargement with opacity in the right mid zone Left upper lobe opacification with narrowing and shift of left main bronchus Lateral CXR showing enlarged hilar lymph nodes ( doughnut sign ) Miliary TB - Typical bilateral diffuse micronodular pattern. Note differences to LIP X-ray above 10

17 Lymphoid interstitial pneumonitis: typical features are bilateral, diffuse reticulonodular infiltration with bilateral perihilar lymph node enlargement Bronchiectasis: focal opacification in right lower zone with thickening of bronchial walls and honeycomb appearance TB pleural effusion: large right-sided effusion. Pleural tap to differentiate from emphysema Spinal TB: collapse of thoracic vertebra causing angulation 11

18 Pericardial TB: enlarged cardiac shadow. Ultrasound to differentiate from other causes of cardiac failure 4. Other Tests. A number of other tests have been used in the diagnosis of TB. Examples include Serological tests, Nucleic acid amplification tests, Gamma interferon assays PCR Gene Xpert Most of these tests have not been adequately studied and evaluated for use in children and especially in TB endemic set ups. CT scan and bronchoscope are useful but not recommended for routine diagnosis of TB in children, except in special situations. 5. HIV test All children with suspected TB should be tested for HIV 2.4 Differential Diagnosis for child with Chronic Cough /Respiratory Symptoms Other conditions to consider, in a child with chronic cough /chronic respiratory symptoms who does not fulfil the classical clinical picture of PTB includes: (Table 2) 12

19 TABLE 2: Common causes of chronic cough/ respiratory symptoms in children Possible diagnosis Clinical Presentation Asthma Recurrent wheeze/cough responds to bronchodilators. Usually associated with other allergies such as eczema, rhinitis Upper airway conditions Recurrent/persistent runny nose and/or nasal Allergic rhinitis blockage and snoring Adenoid hypertrophy Seasonal pattern Triggers Foreign Body Inhalation Usually sudden onset in previously well child May have history of choking Persistent cough One sided respiratory signs inspiratory stridor, wheeze Gastro-esophageal Reflux Recurrent cough/wheeze Disease Onset in early infancy +/- hoarse voice Bronchiectasis Severe persistent cough, much sputum (often infected green or yellow in colour). Finger clubbing CXR shows reticular or honey-comb pattern Congenital Heart Disease Easily fatigueability, breathlessness, Onset early infancy Acquired heart disease Older children, palpitations, easy fatigueability, dyspnoea on exertion. +/- oedema Congenital respiratory Onset early infancy disorders Commonly premature baby Noisy breathing during inspiration not responding to bronchodilators 2.5 Extra Pulmonary Tuberculosis (EPTB) Extra pulmonary TB is common in children and presentation varies with age. Table lists typical clinical features for various forms of EPTB and suggested investigations for each category. Symptoms are usually persistent and progressive. The most common form of EPTB is TB lymphadenitis 13

20 Table 3 Extra Pulmonary Tuberculosis in Children Site of EPTB TB lymphadenitis Pleural TB Typical clinical presentation - Asymmetrical, painless, non-tender lymph node enlargement for more than one month +/- discharging sinus - Most commonly in neck area Dullness on percussion and reduced breath sounds +/-chest pain Headache, irritability/abnormal behaviour, lethargic/reduced level TB meningitis of consciousness, convulsions, neck stiffness, bulging fontanelle, cranial nerve palsies Miliary TB Non-specific, lethargic, fever, wasted Abdominal TB Spinal TB Pericardial TB TB bone and joint Painless abdominal swelling with ascites Painless deformity of spine May have lower limb weakness/paralysis Cardiac failure Distant heart sounds Apex beat difficult to palpate Painless, non-tender swelling end of long bones with limitation of movement Painless, non-tender unilateral effusion of usually knee or hip Investigation Fine needle aspiration when possible Mantoux CXR Pleural tap 1 Lumbar puncture obtain CSF 1 CXR CT scan Comment Treat if axillary node enlargement on same side as BCG in HIVpositive infant, consider BCG disease and refer Treat if pus in pleural tap, consider empyema and refer Hospitalise for TB treatment 2 CXR Treat and refer where appropriate Ascitic tap Refer where Ultra-sound appropriate Mantoux test X-ray spine Refer where appropriate 2 CXR Cardiac ultrasound Pericardial tap X-ray of affected bone and/or joint Joint tap Refer where appropriate Refer where appropriate 14

21 1. Require 5ml of CSF. 2. Typical findings: straw coloured fluid, exudates with high protein, white blood cells especially lymphocytes 3. Referral may be necessary for investigation procedure and laboratory support as well as clinical care. If referral is difficult or not readily available, start anti-tb treatment. The above table highlights the more common forms of EPTB; however TB may infect other organs. 4. Abdominal ultra-sound shows complex ascites +/- septation All specimens (FNA, CSF, aspirates etc) should be sent for AFB microscopy and TB culture where visible Clinical assessment in all cases of EPTB should consider: Time lapse from exposure to disease presentation can be quite variable shorter for young children with disseminated disease, longer for other forms that present in school-aged children Common symptoms present in most cases of EPTB include fever, weight loss/poor weight gain, and lethargy/reduced play lasting > 2weeks. Symptoms and signs specific to the site of EPTB as shown in the table below Investigations for TB as appropriate according to site of infection (see table 2) 2.6 Score Charts/ Diagnostic Criteria Due to the numerous challenges associated with the diagnosis of TB in children a number of scoring criteria have been suggested and used for TB diagnosis in children, best example is Keith Jones Criteria. Unfortunately most of them have not been evaluated and validated against a gold standard. They perform poorly in suspected PTB in children and even worse in TB/HIV co infected. Currently they are at best used as screening tools and not as a means of making a firm diagnosis. For the purposes of our National TB program the clinical diagnosis of PTB in children shall be based on the following. The approach to a child with suspected PTB is Shawn in the algorithm/ flow chart below Presence of 2 or more of the following symptoms Cough > 2weeks Weight loss or poor weight gain Persistent fever and/or night sweats > 2 weeks Fatigue, reduced playfulness, less active PLUS Presence of 2 or more of the following: Positive contact history Respiratory signs CXR suggestive of PTB (where available) Positive Mantoux test (where available Then PTB is likely, and treatment is justified 15

22 Figure 1: Approach to Pulmonary TB diagnosis in Children TB suspected based on two or more typical symptoms (Cough, fever, poor weight gain, fatigue > 2 weeks) Sputum No Sputum or Negative for AFB Smear-positive Clinical Diagnosis Positive contact history Respiratory signs CXR suggestive of PTB (where available) Positive Mantoux test (where available) TREAT FOR TB If only one or none of the features are present Make a diagnosis of TB if two or more of these features are present If child sick, admit to hospital for further management If child not very sick, give 7 days antibiotics then review after 1-2 weeks If child improves, complete the treatment and discharge and continue routine follow up If child improves, complete the treatment and continue routine follow up If no improvement, re-evaluate for TB (may need CXR, Mantoux test etc) If suspected, start TB treatment, continue regular follow up and complete the treatment Notes: 1. All children should be tested for HIV 2. Mantoux test should be regarded as positive as follows: >5 mm diameter of induration in high-risk children (includes HIV-infected children and severely malnourished children >10 mm diameter of induration in all other children (whether they have received a BCG vaccination or not) 3. Please note that a mantoux may be negative despite the child having TB, especially in severe disseminated TB, malnutrition and HIV disease. 16

23 Chapter 3: Treatment of Tuberculosis The main objectives of anti- TB treatment in children are to. 1. Cure the child of TB by rapidly eliminating most of the bacilli. 2. Prevent death from active TB or its late effects 3. Prevent TB relapse by eliminating the dormant bacilli 4. Prevent the development of drug resistance by using a combination of drugs 5. Decrease TB transmission to others. Some of the important points to note about TB treatment in children are. Children usually have pauci- bacillary (low organism numbers) pulmonary disease, cavitating disease is rare and EPTB is common. Severe and disseminated TB occurs especially in young children (less than 4years) and in HIV infected. Both the bacillary load and type of disease may influence the treatment regimens. Treatment outcomes in children are generally good even in the HIV infected provided treatment is started promptly. Children generally tolerate the anti- TB drugs better than adults. 3.1 Classification of TB in Children Table 4: TB Classification in children 1. Non Severe TB Pulmonary TB without extensive parenchymal lung disease TB lymphadenitis TB pleural effusion 2. Severe TB PTB with extensive parenchymal lung disease Miliary TB All other forms of extra-pulmonary TB including: o TB bone or joint o TB meningitis o Pericardial TB o Abdominal TB etc. 3. Retreatment 4. Multi-drug resistant TB TB is also classified as either pulmonary tuberculosis (PTB) or extra- pulmonary tuberculosis (EPTB) Standard Operating Procedures for Treatment Classify the case of child TB before starting treatment into non-severe or severe, pulmonary or extra-pulmonary, or retreatment. For extra-pulmonary forms, specify the site. Treatment regimens by disease category are listed in treatment table below Record the TB diagnostic category, treatment regimen and date anti-tb treatment was started on road-to-health book as well as on TB treatment card 17

24 A caregiver should be identified as the DOT provider for all ages including older children educate them on anti-tb regimen and adherence Record weight at each visit. Calculate drug dosages at every visit according to the child s current weight (note that children gain weight while receiving anti-tb treatment) Once treatment is started it must be completed; trial of TB treatment should never be used as a diagnostic tool 3.2 Recommended Treatment Regimens Table 5 below shows the treatment regimens currently in use in 2011 as recommended by the National TB program in Note that treatment is according to classification of severity and site of TB infection (pulmonary versus extra-pulmonary), and if patient is a newly diagnosed case, or for re-treatment. Table 5A: Kenya Paediatric TB Treatment Regimen (in use until 2012) Diagnostic Category III TB Cases NON SEVERE TB -Pulmonary TB without extensive parenchymal lung disease -TB lymphadenitis -TB pleural effusion 2HRZ Intensive Phase Regimen* Continuation Phase HR I a SEVERE TB (excluding TB meningitis) - Pulmonary TB with extensive parenchymal Involvement - New smear positive PTB - Extra-pulmonary TB (miliary TB, spinal TB, abdominal TB, bone and joint TB, etc) - Severe concurrent HIV disease 2HRZE 4HR I b SEVERE TB: TB Meningitis 2RHZS* 4HR II RETREATMENT - relapse - treatment after interruption/default - treatment failure 2HRZES/ 1HRZE 5HR IV Multi-drug resistant (MDR) TB Refer to TB specialist centre *Numeral refers to number of months of the regimen. H= Isoniazid R= Rifampicin Z= Pyrazinamide E= Ethambutol 2 HRZE refers to two months of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol 18

25 Table 5B below shows the NEW WHO recommended TB treatment regimens which shall be implemented in Kenya during 2012 when new four drug paediatric formulations of RHZE become available. The following changes are recommended: Use of four drugs during intensive phase for all children living in HIV endemic areas such as Kenya, adding ethambutol as a fourth drug for children of all ages. Treatment of TB meningitis and TB bone to be extended to a total of 12 months (2 months intensive phase, and 10 months continuation phase) In TB meningitis, ethambutol to replace streptomycin during intensive phase (RHZE) due to poor penetration of streptomycin across the blood brain barrier as well as toxicity. Table 5B: New WHO Recommended Treatment Regimen (for implementation 2012 when paediatric RHZE formulations become available) TB disease category Recommended regimen* Intensive phase All forms of PTB and EPTB except TB meningitis and osteoarticular TB 2 HRZE 4 HR TB meningitis Osteoarticular TB 2 HRZE 10 HR Continuation phase *Numeral refers to number of months of the regimen. H= Isoniazid R= Rifampicin Z= Pyrazinamide E= Ethambutol 2 HRZE refers to two months of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol Table 6; Dosage of Individual anti-tb drugs according to body weight Drug Recommendations Average dose in mg/kg Range mg/kg in Maximum Dose Isoniazid mg Rifampicin mg Pyrazinamide g Ethambutol g Other important observations to note include Treatment regimens are the same for HIV-infected and HIV-uninfected children Response to treatment in HIV infected may be slower. Register all children receiving anti-tb treatment with the National TB Program TB drugs are very well tolerated in almost all children. Side-effects are unusual and the most important is hepatotoxicity. Ethambutol can be safely used in all ages of children at recommended dosages of 20 mg/kg or as per the drug dosage chart. 19

26 3.3 Additional Management Decisions Hospitalization: The following categories of children with TB should be treated as inpatients o Severe forms of PTB and EPTB (e.g. Spinal TB) for further investigation and initial management. o TB meningitis o Severe malnutrition for nutritional rehabilitation o Signs of severe pneumonia (i.e. chest in-drawing) o Other co-morbidities e.g. severe anaemia o Social or logistic reasons to ensure adherence o Severe adverse reactions such as hepatotoxicity Steroid therapy: This should be given in the following situations: o TB meningitis, o PTB with respiratory distress, o PTB with airway obstruction by hilar lymph nodes. o Severe Miliary TB, o pericardial effusion, Give prednisone at 2mg/kg once daily for 4 weeks, and then taper down over 2 weeks (1mg/kg for 7 days, then 0.5mg/kg for 7 days) For all HIV-infected children o Commence Cotrimoxazole prophylaxis (25 30mg/kg of CTX once daily, or see appendix for dose in weight bands) o Commence antiretroviral therapy within 2 8 weeks of starting anti-tb therapy o Conduct family-based care/screening Immune re-constitution inflammatory syndrome (IRIS) - This is a paradoxical deterioration after initial improvement following treatment initiation. o Seen during the initial weeks of TB treatment with initial worsening of symptoms due to immune re-constitution. o IRIS is commonly seen in the severely immuno-compromised TB/HIV coinfected child after initiating ARV treatment o Management: Continue anti-tb therapy; give non steroidal antiinflammatory drugs or/and prednisone until severe symptoms subside. Referral of children with TB should be considered if o Diagnosis is uncertain o Necessity for HIV-related care e.g. to commence ART o Failure to respond to treatment despite good adherence Pyridoxine 5 10 mg once daily should be given to. o All malnourished children throughout the anti-tb therapy. o HIV infected children o Breast feeding infants. 20

27 o Pregnant Adolescents 3.4 Follow-up of a Child on anti-tb Therapy Patients visit the health facility 2 weekly during intensive phase and monthly during continuation phase and should be assessed for. o Drug adherence. o Drug toxicity. o Weight gain. o Symptom assessment. o Sputum for AFBs at two months for those who were smear positive at the beginning of treatment. This is a critical part of effective TB treatment requiring a clear management plan. The following should be done at each visit Weigh the child at each visit, document and adjust dosage if necessary Address Adherence issues o Explain and emphasize to care-giver and child why they must take the full course of treatment even if they are feeling better o Note risk factors for poor adherence such as distance/transport; orphan (especially if mother has died) or primary care-giver unwell; adolescents o Education and adherence support especially TB/HIV Explain that anti-tb drugs in children are well tolerated and safe. CXR is not required in follow-up if the child is responding well to anti-tb treatment At end of treatment, all children who had abnormal X-rays at baseline should have a repeat x-ray. The most important side-effect is hepatitis which usually presents with nausea, vomiting. Presence of abdominal pain, jaundice and tender enlarged liver suggest severe hepatotoxicity. Stop the anti-tb drugs immediately and refer to hospital 3.5 Poor Response to Treatment Most children with TB will start to show signs of improvement within 4 8 weeks of anti-tb treatment. Weight gain is a sensitive indicator of good response to treatment Potential causes of poor response to treatment include: Poor adherence; this should be evaluated and problems addressed. HIV infection Wrong diagnosis Other concurrent chronic lung diseases Under dosage of drugs Resistant form of TB Unusual Complications Consider treatment failure if child is receiving anti-tb treatment and: 21

28 No symptom resolution or symptoms getting worse Continued weight loss If smear positive at baseline and remains smear positive at 5 months Refer children with suspected treatment failure for further assessment 3.6 Treatment Interruptions If a child interrupts anti-tb treatment for a period less than 1 month, then restart them on first-line anti-tb therapy. If the child interrupts anti-tb therapy for a period longer than 1 month, then put them on a re-treatment regimen (Table 5). 22

29 Chapter 4: TB and HIV Co-infection Human Immunodeficiency Virus (HIV) infection is one of the risk factors associated with development of Tuberculosis in children. HIV influences TB in several ways, some of which include: Reactivation of Latent TB infection. Rapid progression of new TB infection to TB disease. Recurrence of TB after successful treatment. Increased risk of adverse reactions to anti-tb drugs Increased risk of death Increased risk of other infectious diseases including invasive pneumococcal disease. HIV infected children may have multiple and concurrent opportunistic lung infections that clinically present like TB, thus making the diagnosis of TB in an HIV infected child more difficulty. The ARVs and anti-tb drugs have potentially significant drug-drug interactions as well as overlapping toxicities that pose additional challenges Therefore comprehensive approach to management of both TB and HIV is critical. 4.1 Diagnosis Approach to diagnosis of TB in HIV infected children is similar as for HIV uninfected children, History of contact with TB is extremely important in pointing to possibility of TB disease in the HIV infected child The clinical presentation of TB is similar in those in early stages of HIV disease, however for those with advanced HIV disease they may not have the typical TB clinical features, and chronic respiratory symptoms may be due to other causes (differential diagnosis see table below) HIV test is indicated in all children with suspected TB TST reaction of 5mm is interpreted as positive in HIV. The TST (Mantoux Test) may be negative due to depressed immune response, this does not rule out TB CXR may be not show typical changes, and therefore may be difficult to interpret. 4.2 Treatment TB in HIV infected children should be treated with a 6 month regimen as in HIVuninfected children. Response to TB treatment may be slow All children with TB/HIV should receive co-trimoxazole prophylaxis All children with TB/HIV should receive antiretroviral therapy. Nutritional support is often needed for children with TB/HIV The management of children with TB/HIV should be integrated so that all family members are counselled and tested for HIV and screened for TB ARVs to be initiated within 2-8 weeks of starting anti-tb therapy 23

30 4.3 Prevention All HIV-infected children need to be screened for TB All HIV infected children exposed to sputum smear positive TB case should be evaluated for TB disease and treated if active disease present. If no active TB disease they should be offered isoniazid preventive therapy (IPT) at 10mg/kg for 6 months All TB infected children should be offered counselling and testing for HIV infection Known HIV infected children should minimize their exposure to other patients with chronic cough (e.g. separate waiting area, or fast track). The specific needs of each family need to be determined and a plan of action developed to ensure that the family receives comprehensive care using all available services Deliberate efforts be made to expand the prevention of mother to child transmission of HIV BCG vaccine to be given to all new born babies except those with symptoms of HIV infection or those on IPT 4.4 Differential Diagnosis in HIV infected Child with Chronic Respiratory Symptoms The diagnosis of PTB can be particularly challenging in the HIV-infected child because of clinical and radiological overlap with other HIV-related lung disease. The respiratory system is a common site for many opportunistic infections in HIV infected children. Often there is co-infection with other microbes as well, which further complicates the diagnosis. Other possible causes of chronic lung disease in HIV infected children are shown in the table 7. 24

31 Table 7: Causes of chronic respiratory symptoms in HIV infected children Differential Diagnosis Recurrent pneumonia Lymphoid interstitial pneumonia (LIP) Tuberculosis Bronchiectasis Pneumocystic jirovecci pneumia (PCP) Mixed infection Kaposi sarcoma Clinical features Recurrent episodes of cough, fever and fast breathing that usually respond to antibiotics Slow onset cough associated with generalised symmetrical lymphadenopathy, finger clubbing, parotid enlargement, sometimes with breathlessness, andmild hypoxia CXR: diffuse reticulonodular pattern and bilateral perihilar adenopathy Persistent respiratory symptoms not responding to antibiotics. Often poor nutritional status; positive TB contact especially in younger children CXR: Perihilar adenopathy, miliary, lobar consolidations or effusions (older child) Cough productive of purulent sputum, halitosis (foul breath), finger clubbing, seen in older children. CXR: honeycombing usually of lower lobes Complicates recurrent bacterial pneumonia, LIP or TB Common cause of acute severe pneumonia, severe hypoxia especially in infants. Unusual after 1 year. CXR: diffuse interstitial infiltrates, hyperinflation Common problem: LIP, bacterial pneumonia, TB Consider when poor response to first-line empiric management Uncommon Characteristic lesions on skin or palate 4.5 Antiretroviral Therapy in HIV Infected Children with Tuberculosis Tuberculosis is an increasingly common opportunistic infection in HIV-infected children. HIV infection increases a child s risk of progressive primary tuberculosis and reactivation of latent TB in the older child. The pill burden in treating TB/HIV co-infection is large. Intensive adherence support and monitoring should be offered. The risk of adverse drug reactions is increased during concomitant therapy. Perform a full clinical evaluation at every clinic visit and if there are symptoms suggestive of adverse drug reactions, particularly liver toxicity, do the appropriate laboratory tests. If significant problems are experienced, either severe drug intolerance, or erratic adherence, continue the anti-tb, but consider interrupting anti-retroviral therapy (ART). Resume after the problem has been adequately addressed (may occasionally have to wait until completion of anti-tb therapy). 25

32 The principles of treatment of tuberculosis in HIV-infected children are similar to those in HIV-negative children, and the same regimens should be used as those used in HIV negative children. Recent data suggest that early initiation of ART early in TB treatment reduces TB morbidity and mortality, without excess adverse events. Any child with active tuberculosis should begin TB treatment immediately; and begin ART as soon as the TB treatment is tolerated; i.e. no nausea or vomiting and no on-going or evolving adverse drug events, usually 2 to 8 weeks into TB therapy The HIV/TB co-infected child has not only diagnostic but also drug management challenges due to potential for drug-drug interactions and overlapping toxicity between the ARVs and anti-tb medications, and a high pill burden. However children generally appear to tolerate these drugs well, and experience side effects less frequently than adults. Rifampicin interacts with both PIs and NNRTIs, reducing their blood levels, therefore reducing their effectiveness, therefore when treating TB and giving concurrent ART the ART regimen may require adjustment. ART options with rifampicin are recommended as follows in Kenyan paediatric ART guidelines. Two nucleoside reverse transcriptase inhibitors (NRTIs) plus efavirenz (EFV) e.g. ABC or AZT + 3TC + EFV (children above 3 years only). Two NRTIs plus super boosted LPV/r (add ritonavir to standard LPV/r dose to achieve lopinavir:ritonavir at ratio 1:1) during TB treatment and revert to the normal LPV/r dosing after completion of TB treatment. Triple NRTI (e.g. ABC + AZT + 3TC). This is a weak ART combination and should be used only when other options are not possibleor not tolerated. After completion of anti-tb with triple NRTI regimen, it is ideal to do a viral load and ensure viral suppression before reverting to the standard first line ART regimen. Scenario A: Child develops TB before Initiating ART Start anti-tb treatment as soon as possible and ART within 2 8 weeks of starting anti- TB therapy. o a child who is severely ill needs to be started on ART sooner (within 2 weeks) o a child who is less severely ill may be started on ART within 2-8 weeks. o The ART options are as shown below: 26

33 Table 8: Initiation of ART in a Child 2 8 weeks after starting anti-tb Therapy Nevirapine exposed Irrespective of age and weight Preferred option: ABC/AZT + 3TC + LPV/r + RTV (add extra dose of RTV to make the LPV/RTV ratio 1:1 - super boosted LPV) NOT Nevirapine exposed < 3years and <10kg > 3 years and >10 kg Preferred option: ABC/AZT + 3TC + LPV/r + RTV (add extra dose of RTV to make the LPV/RTV ratio 1:1 - super boosted LPV) ABC/AZT+3TC+EFV Alternative Option: ABC+3TC+AZT Alternative Option: ABC + 3TC + AZT (If RTV formulation not available, or cannot tolerate LPV/r + R) Alternative option: ABC + 3TC + AZT (if cannot tolerate EFV) Scenario B: Child develops TB during the first 6 months of first-line ART Start TB treatment immediately and also change ART regimen IF indicated below. Table 9: Recommended ART regimens in a Child who Develops TB while already on First Line ART NVP exposed NVP non- exposed Irrespective of age and weight < 3years and <10kg > 3 years and >10 kg Preferred option: ABC/AZT + 3TC + LPV/r + RTV(add extra dose of RTV to make the LPV/RTV ratio 1:1-super boosted LPV) Alternative Option: ABC+3TC+AZT Change ART to AZT +3TC+ LPV/r after completion of TB treatment Preferred option: ABC/AZT + 3TC + LPV/r + RTV (add extra dose of RTV to make the LPV/RTV ratio 1:1-super boosted LPV) After completion of the TB treatment, child can be restarted on original 1 st line i.e. ABC/AZT+3TC+NVP Alternative Option: ABC+3TC+AZT (If RTV formulation not available, or cannot tolerate LPV/r + R) Preferred Option: ABC/AZT+3TC+EFV Alternative Option: ABC + 3TC + AZT (if cannot tolerate EFV) 27

34 Scenario C: Child develops TB while on 1st line ART for more than 6 months There is the possibility that this new episode of TB is an indication of poor response to ART due to non-adherence or of ARV treatment failure or both. Manage as follows: 1. Initiate anti-tb treatment immediately. 2. Evaluate for treatment failure for all. 3. Evaluate adherence to ART and ensure that any problems in adherence have been addressed before embarking on any change in ART regimen. 4. If there is good adherence, and viral load is suppressed, they should continue on first line ART regimen, using the guidelines in table 9 above. 5. If there is poor adherence and/or evidence of treatment failure (high viral load), adherence must first be addressed before modifying the ART regimen. This child s further ART should be managed in consultation with a paediatrician experienced in HIV treatment. REFER OR CONSULT! Scenario D. Child develops TB while on 2 nd line ART regimen 1. Anti-TB therapy should be started immediately. 2. Evaluate for failure of 2 nd line ART (do viral load and CD4 count). There is the possibility that this new episode of TB is an indication of poor response to ART due to non-adherence, or of ARV treatment failure, or both. 3. REFER! If treatment failure is confirmed, do not discontinue ART, continue with their existing regimen, and refer to a consultant with expertise in the management of HIV infection and the National HIV Therapeutics Committee. 4.6 Co-trimoxazole Preventive Therapy (CPT) Cotrixamozole has been shown to reduce mortality among TB children infected with HIV. All HIV/TB co-infected children should be offered CPT and it should be started as soon as possible. The duration of treatment is usually indefinite with a once daily dosing. The children should be monitored for side effects which include skin rashes and GI disturbances. Severe adverse reactions are uncommon and usually include extensive exfoliative rash, Steven Johnson syndrome or severe anemia / pancytopenia. CPT should be discontinued if a child develops severe adverse reactions. Table 10: Recommended doses for cotrimoxazole Weight in Kg Suspension 5mlsyrup of (200mg/40m g) Child Tablet (100mg/20mg) Single strength adult tablet (400mg/80mg) <5 2.5 ml One Tablet ¼ tablet ml Two tablets ½ tablet - Double strength adult tablet (800mg/160mg) ml Four tablets One tablet ½ tablet 28

35 > Two tablets One tablet 29

36 4.7 Isoniazid Prophylactic Therapy (IPT) in Children Children living with HIV who are more than 12 months of age and who are unlikely to have active TB on symptom-based screening, and have no contact with a TB case should receive six months of IPT (10 mg/kg/ day) as part of a comprehensive package of HIV prevention and care services. In children living with HIV who are less than 12 months of age, only those who have contact with a TB case and who are evaluated for TB (using investigations) should receive six months of IPT if the evaluation shows no TB disease Dose and duration of INH for IPT in children INH 10 mg/kg/day for 6 months (maximum 300 mg/day).plus Pyridoxine 25 mg/day Table 11 Dose of isoniazid for Prophylaxis (IPT) Weight Dose in mg/day Number of 100 mg, INH tablets <5 50 ½ ½ ½ ½ - >25 and adults Number of 300 mg (Adult) tablets 30

37 Chapter 5: Tuberculosis in special circumstances 3.7 Tuberculous Meningitis (TBM) TB meningitis is common in young children and is associated with high morbidity and mortality particularly if the diagnosis is delayed. It is therefore important to consider a diagnosis of TBM in young children as early as possible, especially in children who have a history of contact with an adult with infectious TB. Miliary or haematogenously disseminated TB has a high risk (60 70%) of meningeal involvement and should therefore be managed same way as TB meningitis. For this reason, all children with miliary TB (or suspected of having miliary TB) should undergo a lumbar puncture to exclude TB meningitis. Clinical presentation of TBM is usually insidious (subtle) and one must have a high index of suspicion (refer to chapter 2, table 3 for clinical features and investigation of TBM). Treatment Children with TB meningitis or miliary TB should be hospitalized, preferably for at least the first 2 months or until they have clinically stabilized. TB meningitis is one of the severe forms of TB and therefore four anti-tb drugs are recommended for the intensive phase. Ethambutol has poor CNS penetration and Streptomycin is currently used as the fourth drug. Isoniazid and Rifampicin are used for the continuation phase. Corticosteroids (usually prednisone) are recommended for all children with TB meningitis in a dose of 2 mg/kg daily for 4 weeks. The dose should then be gradually reduced (tapered) over 1 2 weeks before stopping. 3.8 Management of a Newborn born to a Mother with PTB Once a pregnant woman has been on anti- TB treatment for at least 4 weeks before delivery she is generally no longer infectious and is therefore unlikely that her baby will become infected. A newborn infant has a high risk of infection/ disease from a mother with smear-positive pulmonary TB if the mother is diagnosed at delivery or soon thereafter. If the mother is diagnosed with TB shortly before delivery, then the baby and possibly the placenta should be investigated for evidence of congenital TB 31