The guidance for the diagnosis and treatment of tuberculosis in children of the Republic of Tajikistan

Transcription

1 Ministry of Health and Social Protection of Population Republic of Tajikistan The guidance for the diagnosis and treatment of tuberculosis in children of the Republic of Tajikistan 2 nd Updated Edition 2014

2 The second completed edition of Guidance for diagnosis and treatment of tuberculosis in children of the Republic of Tajikistan, 2011 was updated by the working group of the specialists from the Ministry of Health and Social Protection of Population of the Republic of Tajikistan and Médecins Sans Frontièrs (MSF) mission in Tajikistan: Bobokhodjayev O.I, Doctor of Medical Sciences, Director of the Republican Tuberculosis Centre, Yusupdzhanova Dzh.M., Candidate of Medical Sciences, TB specialist at the Republican Tuberculosis Centre, Abdulloyev Z.Kh, the Deputy Director of the Republican Tuberculosis Centre, Sirodzhidinova U.Yu., Doctor of Medical Sciences, Professor, Head of Department of Paediatric Tuberculosis of State Medical University of Tajikistan named after Abuali ibni Sino, Dusmatova Z.Sh., Candidate of Medical Sciences, Coordinator of paediatric DR TB programme, Makhmudova M, country project manager, KNCV in Tajikistan Philipp du Cros, MSF, Sebastian Dietrich, MSF, Charles Ssonko, MSF, Christoph Hoehn, MSF, Beatrice Lau, MSF, Ann Akesson, MSF, Krzysztof Herboczek, MSF This guideline is meant for the undergraduate students, postgraduate students and clinical physicians of the State Medical University of Tajikistan named after Abuali ibni Sino, the postgraduate medical doctors in the Republic of Tajikistan and for the daily practice of TB specialists, paediatricians, pulmonologists and family physicians. The guideline was confirmed by the order of the Ministry of Health and Social Protection of Population of the Republic of Tajikistan 394 dated This guideline was printed with support from the organization Médecins Sans Frontières (MSF) in Tajikistan 2

3 Table of Contents Abbreviations... 1 Preface... 3 Introduction... 5 Chapter 1:... 8 Standard case definitions of TB in children Classification based on anatomical site of disease: Pulmonary TB, smear positive Pulmonary TB, smear-negative Extrapulmonary TB Classification based on history of previous TB treatment (patient registration group) Classification based on HIV status Classification based on drug resistance TB diagnostic algorithms Algorithm II: Diagnosis through clinical suspicion (no known contact) Annex 1A: Differential Diagnosis for Pulmonary TB Annex 1B: Extrapulmonary TB Annex 1C: Sputum induction Annex 1D: Expectoration Annex 1E: Gastric Aspirate Procedure Annex 1F: Tuberculin Skin Test Chapter 2: Treatment of TB in children Drug susceptible TB treatment Drug resistant TB treatment Dosing of DRTB drugs and side effects Hospitalisation Annex 2A: DS, mono and poly-drug resistant TB regimen choice Annex 2B: MDR, Pre-XDR and XDR TB regimen choice Annex 2C: Management of specific side effects Annex 2D: MDR TB drug dosages table Annex 2E: Dosage table for adults and adolescents weighing above 30 kg Annex 2F: Management of Side Effects of DR TB Treatment Annex 2G: TB Meningitis in children Annex 2H: Treatment monitoring chart Annex 2I: Management of TB medications used for treatment of children with TB and MDR- TB Chapter 3: Follow-up and monitoring of TB patients DS TB Treatment failure Outcome Definitions for DS and DRTB Chapter 4: Children with TB who are co infected with HIV

4 Cotrimoxazole prophylaxis Antiretroviral therapy Timing of ART Recommended ART regimens for children initiating ART while on TB treatment Immune reconstitution inflammatory syndrome Prevention Chapter 5: Contact screening and management Special circumstances Child contacts of infectious MDRTB cases Managing child contacts within the NTP Chapter 6: Roles and responsibilities Levels of care Chapter 7: Recording and reporting Chapter 8: BCG Vaccination in children

5 Abbreviations ALT Alanine transaminase Am - Amikacin Amx/Clv - Amoxicillin/Clavulanate AP - Anteroposterior ART - Antiretroviral therapy AST Aspartate transaminase BCG - Bacille Calmette Guérin vaccine Cfz - Clofazimine Clr - Clarithromycin Cm - Capreomycin Cs - Cycloserine CSF - Cerebrospinal Fluid CPT - Cotrimoxazole Preventive Therapy CXR - Chest X-ray DOT - Directly Observed Therapy DOTS - Directly observed therapy short course- internationally recommended strategy for TB control DR TB - Drug Resistant Tuberculosis DS TB - Drug Susceptible Tuberculosis DST - Drug Susceptibility Testing E - Ethambutol EP - Extrapulmonary Eto - Ethionamide ETR - Empirical (MDR TB) Treatment FDC - Fixed Dose Combination FNA - Fine Needle Aspiration Fq - Fluoroquinolone GA - Gastric Aspiration GI - Gastro Intestinal H - Isoniazid HdH - High Dose of Izoniazid HIV - Human Immunodeficiency Virus IC - Infection Control IGRA - Interferon Gamma Release Assays IS - Induced Sputum ITR - Individual (MDR-TB) treatment regimen Km - Kanamycin Lzd - Linezolid 1

6 Lfx - Levofloxacin MDG - Millennium Development Goal MDI - Meter Dosing Inhalator MDR - Multidrug resistance MGIT - Mycobacteria Growth Indicator Tube Mfx - Moxifloxacin ND - Not Determinable NTP - National Tuberculosis Control Programme Ofx - Ofloxacin PPD - Purified Protein Derivative PTB - Pulmonary Tuberculosis Pto - Prothionamide PAS - Para-aminosalicylic acid PDR - Polydrug resistance PHC - Primary Health Care QA - Quality Assurance R - Rifampicin S - Streptomycin SE - Side Effect SI - Sputum Induction SMX - Sulfamethoxazole SNL - Supranational Laboratory TB - Tuberculosis TBM - TB meningitis TMP - Trimethoprim TST - Tuberculin Skin Test TU - Tuberculin Unit USS - Ultrasound Sonography WHO - World Health Organisation XDR - Extensive Drug Resistance Z - Pyrazinamide ZN - Ziehl Neelsen stain 2

7 Preface With the development of the new WHO Stop TB Strategy and the launch of the Global Plan to Stop TB, (setting out the steps to implement the Strategy worldwide), 2006 is likely to be regarded in future as a turning point in the global campaign to stop tuberculosis (TB). The aim of the Stop TB Strategy is to "ensure equitable access to care of international standards for all TB patients infectious and non-infectious, adults and children, with and without HIV [human immunodeficiency virus], with and without drug-resistant TB" (The Stop TB Strategy. Geneva, W o r l d H e a l t h Organization, 2006). The strategy thus explicitly aims to redress the chronic neglect of childhood TB. Guidance for national TB programmes (NTPs) on managing TB in children is therefore timely in responding to the call for equitable access to care of international standards for all children with TB. The revision of the document has mainly concentrated on the integration of the diagnosis and management Drug Sensitive and Drug resistant tuberculosis by inclusion of chapters on DRTB within the existing guideline, acknowledging previous important policy changes. Firstly, NTPs should record and report three age groups for children (0 4 years, 5 14 years and years) using the quarterly reporting form. Routine reporting of these three age groups has considerable benefits. Enumerating children with TB is a key step in bringing their management into the mainstream of the Stop TB Strategy as part of routine NTP activities for in the Republic of Tajikistan. This age breakdown is crucial in ordering drugs (since child-friendly formulations are particularly important in children aged 0 4 years) and in monitoring of trends in these distinct age groups (since children aged 0 4 years are the most vulnerable and infection at these early ages indicates recent transmission). In addition, routine NTP data collection will provide valuable and sustainable information on market needs concerning child-friendly formulations of anti-tb drugs. Secondly, the revised recommended dose of ethambutol is now 20 mg/kg (range mg/kg) daily. Although ethambutol was previously often omitted from treatment regimens for children, due in part to concerns about toxicity (particularly optic neuritis), a literature review indicates that it is safe in children at this dose. Other key recommendations in this document include the following: All children should be managed under the Stop TB Strategy as part of routine NTP operations; Basic tools for diagnosis should be available, including chest X-ray and tuberculin skin tests; Additional tests for DRTB such as Xpert/MTB and culture should be routinely used; Children who are close contacts of smear-positive DR TB cases should have contact investigations; The diagnosis and treatment of TB in children infected with HIV merits special consideration, thus all children with TB should be offered HIV testing and counselling, and HIV-infected children should be offered the full range of available HIV services; Special care is needed in the diagnosis and management of children with drug-resistant TB; In line with the Expanded Programme on Immunization, single dose of bacille Calmette Guérin vaccination should be given to all neonates in countries with a high TB prevalence. 3

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9 Introduction It is estimated that one third of the world s population is infected with Mycobacterium tuberculosis (the bacterium that causes tuberculosis), and that each year, about 9 million people develop TB, of whom about 2 million die. Of the 9 million annual TB cases, about 1 million (11%) occur in children (under 15 years of age). Of these childhood cases, 75% occur annually in 22 high-burden countries that together account for 80% of the world s estimated incident cases. In countries worldwide, the reported percentage of all TB cases occurring in children varies from 3% to more than 25%. Infection with M. tuberculosis usually results from inhalation into the lungs of infected droplets produced by someone who has pulmonary TB and who is coughing. The source of infection of 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 node(s). 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) 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 is increased when primary infection occurs before adolescence (less than 10 years of age) particularly in the very young (0 4 years) and in immunocompromised children. Progression of disease occurs by: (i) extension of the primary focus with or without cavitation, (ii) the effects of pathological processes caused by the enlarging lymph nodes, or (iii) lymphatic and/or haematogenous spread. Children who develop disease usually do so within 2 years following exposure and infection, i.e. they develop primary TB. A small proportion of children with TB (generally older children) develop post-primary TB either due to reactivation, after a latent period, of dormant bacilli acquired from a primary infection or by reinfection. Children can present with TB at any age, but the most common age is between 1 and 4 years. Case notifications of childhood TB depend on the intensity of the epidemic, the age structure of the population, the available diagnostic tools, and the extent of routine contact tracing. The Stop TB Strategy, which builds on the DOTS strategy developed by the World Health Organization (WHO) and the International Union Against TB and Lung Disease, has a critical role in reducing the worldwide burden of disease and thus in protecting children from infection and disease (Box 1). The management of children with TB should be in line with the Stop TB Strategy, taking into consideration the particular epidemiology and clinical presentation of TB in children. 5

10 Box 1 Vision Goal Objectives The Stop TB Strategy A world free of TB To dramatically reduce the global burden of TB by 2015 in line with the Millennium Development Goals (MDGs) and the Stop TB Partnership targets Achieve universal access to high-quality diagnosis and patientcentred treatment Reduce the human suffering and socioeconomic burden associated with TB Protect poor and vulnerable populations from TB, TB/human immunodeficiency virus (HIV) and multidrug-resistant TB (MDR-TB) Support development of new tools and enable their timely and effective use Targets MDG 6, Target 8: "halted by 2015 and begun to reverse the incidence" [of TB] Targets linked to the MDGs and endorsed by Stop TB Partnership By 2005: detect at least 70% of new sputum smear-positive TB cases and cure at least 85% of these cases By 2015: reduce prevalence of and deaths due to TB by 50% relative to 1990 By 2050: eliminate TB as a public health problem (<1 case per million population) Components of the strategy and implementation approaches 1. Pursue high-quality DOTS 1 expansion and enhancement Political commitment with increased and sustained financing Case detection through quality-assured bacteriology Standardized treatment with supervision and patient support An effective drug supply and management system Monitoring and evaluation system, and impact measurement 2. Address TB/HIV, MDR-TB and other challenges Implement collaborative TB/HIV activities Prevent and control MDR -TB Address prisoners, refugees and other high-risk groups and special situations 3. Contribute to health system strengthening Actively participate in efforts to improve system -wide policy, human resources, financing, management, service delivery and information systems Share innovations that strengthen systems, including the Practical approach 1 The international recommended strategy for TB control. It was launched in 1994 and later named DOTS. 6

11 to lung health Adapt innovations from other fields 4. Engage all care providers Public public and public private mix approaches International standards for tuberculosis care 5. Empower people with TB, and communities Advocacy, communication and social mobilization Community participation in TB care Patients' charter for tuberculosis care 6. Enable and promote research Programme-based operational research Research to develop new diagnostics, drugs and vaccines The international standards for TB care, WHO s TB treatment guidelines and TB/HIV clinical manual are relevant for patients of all ages. The guidance presented here is designed not only to complement current national and international guidelines on the implementation of the Stop TB Strategy but also to fill existing gaps, to ensure that children with TB infection and disease are identified early and managed effectively. For national TB programmes (NTPs) to successfully manage TB in children, standardized approaches based on the best available evidence are required. The engagement of all who provide care to children (including paediatricians and other clinicians) is crucial. These standardized approaches need to be incorporated into existing guidelines and strategies that have been developed by NTPs. Reducing the burden of TB in children will require changing and improving many existing practices, such as those that relate to contact investigations. The HIV pandemic threatens TB control efforts, particularly in Africa. The HIV-infected children are at risk of TB. This guidance thus includes recommendations for HIVinfected children. This guidance is based on the best available evidence. However, epidemiological data on TB in children in high-burden countries are scarce. Children with TB differ from adults in their immunological and pathophysiological response in ways that may have important implications for the prevention, diagnosis and treatment of TB in children. Critical areas for further research include a better understanding of the epidemiology of childhood TB, vaccine development, the development of better diagnostic techniques, new drug development, and the optimal formulations and dosing of first- and second-line anti-tb medications in children. This guideline shall provide guidance to medical personnel involved in comprehensive pediatric TB care. All aspects of pediatric TB are compiled in one document. The guideline is developed specifically for Tajikistan taking into consideration the context of the country and set up of health care system. It will support the health professionals to fully comprehend all aspects of pediatric TB. 7

12 Chapter 1: The diagnosis of TB in children relies on careful and thorough assessment of all the evidence derived from a careful history, clinical examination and relevant investigations (see box 2 below). Most children with TB have pulmonary TB although extra-pulmonary TB is more common in children than adults. Although bacteriological confirmation of TB is not always feasible, it should be sought whenever possible, e.g. by sputum microscopy for children with suspected pulmonary TB (spontaneous expectoration particularly for older children or sputum induction sampling for younger children). A trial of treatment with anti-tb medications is not recommended as a method to diagnose TB in children. The decision to treat a child should be carefully considered and once such a decision is made, the child should be treated with a full course of TB therapy. Box 2: Practical steps in assessing paediatric TB suspects 1. Careful history (including history of TB contact and symptoms consistent with TB) 2. Clinical examination (including growth assessment) 3. Tuberculin skin testing (e.g Mantoux) 4. Bacteriological confirmation whenever possible (spontaneous or induced sputum for microscopy, molecular-xpert MTB/RIF or microbiological-culture tests). 5. Investigations relevant for suspected pulmonary and extrapulmonary TB (chest x-ray; lumbar puncture, Fine needle aspiration, ascitic and pleural aspirate if relevant) 6. HIV testing 7. Laboratory tests (complete blood count, biochemistry, urine) After the above steps have been taken, the decision to treat a child for TB or not is based on: either confirmation of active TB through molecular and microbiological tests Or a combination of key features suggestive of active TB. In most children, TB presents with symptoms of a chronic disease after they have been in contact with an infectious source case. The recognized risk factors are outline in box 3 below; 8

13 Box 3: Key risk factors for TB Sharing a household with a newly diagnosed smear-positive household member age less than 5 years having HIV infection Severe malnutrition. The presentation in infants may be more acute, resembling acute severe pneumonia and should be suspected when there is a poor response to antibiotics. Wheeze that is asymmetrical, persistent, and not responsive to bronchodilator therapy and associated with other typical features of TB below, might also be an atypical presentation. In such situations, there may often be an identifiable source case, usually the mother. Box 4: Key features suggestive of active TB The presence of three or more of the following should strongly suggest a diagnosis of TB: chronic symptoms suggestive of TB physical signs highly suggestive of TB a positive tuberculin skin test chest X-ray suggestive of TB The persistence of symptoms and signs suggestive of TB in a child with confirmed TB infection by TST and/or highly suspected of TB infection by having a close positive PTB contact can also be considered to have active TB disease. Recommended approach to diagnose TB in children 1. Careful history (including history of TB contact and symptoms consistent with TB) Close contact Defined as living in the same household as or in frequent contact with a source case (e.g. the child s caregiver) with sputum smear-positive pulmonary TB. The following points concerning contact are of importance for diagnosing TB in children. All children aged 0 4 years and children aged 5 years and above who are symptomatic, who have been in close contact with a TB case, must be screened for TB (see Algorithm 1). When any child (aged less than 15 years) is diagnosed with TB, an effort should be made to detect the source case (usually an adult with sputum smear-positive pulmonary TB) and any other undiagnosed cases in the household. If a child presents with infectious TB, child contacts must be sought and screened, as for any smear-positive source case. Children should be regarded as infectious if they have sputum smear-positive pulmonary TB or cavitary TB on CXR. 9

14 Symptoms suggestive of TB include; Cough Unremitting cough for at least 14 days Fever Body temperature of >38 C for 14 days, after common causes such as pneumonia have been excluded or prolonged subfebrile states. Weight loss or failure to thrive evidenced from the growth charts (WHO growth charts). 2. Physical signs highly suggestive of TB These are mostly suggestive of extra-pulmonary TB such a gibbus of recent onset suggesting vertebral TB (TB spine) and non-painful enlarged cervical lymph nodes with fistula formation suggestive of TB lymphadenopathy (adenitis). Documented weight loss or failure to gain weight despite adequate nutritional therapy are good indicators of chronic disease in children and thus may suggest TB. Other signs requiring investigation for EPTB include: meningitis, pleural and cardiac effusions, ascites, abdominal distension, non-painful enlarged lymph nodes even without fistula, nonpainful enlarged joints and signs of tuberculin hypersensitivity. 3. Tuberculin skin test (Mantoux) According to the existing national protocol in Tajikistan a TST is regarded as positive if >5 mm diameter of induration in all children (whether they have received BCG vaccination or not, including those from in high-risk (HIV-infected and severely malnourished, i.e. those with clinical evidence of marasmus or kwashiorkor). WHO recommends the diameter >5mm of as positive for children in high risk (HIV-infected, severely malnourished; >10 mm in all other children (whether they have received BCG vaccination or not). A positive TST is confirmation of TB infection and not necessarily active TB disease. Also note that a negative TST does not rule out TB infection as there are many causes of a falsenegative result; 15-25% of active TB cases may fall in this category. TST may be repeated after 2-3 months after improvement in nutritional or clinical status and health care workers must be trained (See Annex 1E). 4. Chest x-ray CXR remains an important tool for diagnosis of PTB in children who are sputum smear negative or who cannot produce sputum. Before interpreting a chest x-ray, ensure that a good viewing box, all previous radiographs and both AP and lateral views are available. The quality of the radiograph should also be assessed by establishing the rotation, penetration and inspiration. 10

15 The following abnormalities on CXR are suggestive of TB: Enlarged hilar or subcarinal lymph nodes and opacification in the lung tissue Enlarged paratracheal lymph nodes and segmental/lobar densities Miliary mottling in lung tissue Cavitations or adult type picture (tends to occur in older children) Pleural or pericardial effusion though seen on CXR are forms of extra pulmonary TB that tend to occur in older children The finding of marked abnormality on CXR in a child with no signs of respiratory distress (no fast breathing or chest indrawing) is supportive of TB. However, CXR alone cannot be used as the only tool to diagnose TB. 5. Biological confirmation of TB It is always advisable to confirm diagnosis of TB in a child using whatever specimens and laboratory facilities available. Appropriate specimens from the suspected sites of involvement should be obtained for microscopy, molecular testing and culture (and also histopathological examination). Appropriate clinical samples include sputum, gastric aspirates and certain other material (e.g. lymph node biopsy). Fine-needle aspiration of enlarged lymph glands for staining of acid-fast bacilli, culture and cytology has been shown to be a useful investigation, with a high bacteriological yield. Three sputum samples 2ml each will be required per patient. The first for Xpert MTB/RIF and microscopy, the second for culture +/- DST, and the last for a repeat Xpert MTB/RIF if the first was negative ml of sterile extrapulmonary samples including CSF, FNA, pleural, ascitic and synovial fluids should be inoculated directly in an MGIT tube. Non sterile samples e.g. pus could also be sent for culture in a sputum container. Xpert MTB/RIF can be can be also performed on the following samples: pus, gastric aspirate, fine needle aspirates, pleural aspirate, CSF. Obtaining samples Expectoration: Sputum should always be obtained in older children (10 years of age or older) who are pulmonary TB suspects. Among younger children, especially children under 5 years of age, sputum is difficult to obtain and most children are sputum smear-negative. Bacterial yields are higher in older children (more than 5 years of age) and adolescents, and in children of all ages with severe disease. Since most children will be diagnosed in the hospital setting, 3-4 early morning sputums under direct supervision should be collected. If a child cannot be referred to the hospital take 1 spot sample and 1 early morning sputum sample, or for children unable to produce sputum refer for sputum induction. Induced sputum: Sputum induction has been found to be safe and effective in children of all ages. Therefore all children including those presenting with extrapulmonary TB signs should undergo sputum induction if they cannot spontaneously expectorate. Up to three IS procedures at least 2 hours apart (maximum of 2 per day) may be required to collect the minimum sample quantity (6ml). This procedure requires trained personnel with all the required material to ensure patient safety and success. Strict infection control measures should be implemented as IS produces 11

16 aerosols which may have high concentrations of bacilli. The IC requirements, procedure and material for IS is detailed in Annex 1C. Gastric aspiration: GA using a nasogastric feeding tube can be performed in young children who are unable or unwilling to expectorate sputum. A gastric aspirate should be obtained on each of two consecutive mornings and should be sent for smear microscopy, Xpert MTB/RIF and mycobacterial culture. (See Annex 1E) Laboratory confirmation procedures Microscopy: ZN or fluorescent microscopy can be done on sputum and other samples although the sensitivity is low and specificity for GA samples is low as well. This will be conducted in the TB hospital lab. Molecular tests: Rapid molecular tests have been shown to be cost effective and improve TB treatment outcomes. Xpert MTB/RIF which provides results confirming the presence or not of MTB +/- Rifampicin resistance within 2 hours is the method of choice. If available, Hain could be used to identify H and R monoresistance patients early. Culture and DST: Machiton Laboratory performs cultures with DST with a quality assessment procedures with Gauting Laboratory in Germany.. HIV testing HIV counselling and testing is recommended for all TB patients as part of their routine management. Standard case definitions of TB in children The diagnosis of TB refers to the recognition of an active case, i.e. a patient with symptomatic disease (due to M. tuberculosis infection). Beyond the diagnosis of TB disease, the type of TB case should also be defined to enable appropriate treatment to be given and the outcome of treatment evaluated. The case definition is determined by the: (i) site of disease, (ii) result of any bacteriological tests, (iii) severity of TB disease, and (iv) history of previous anti- TB treatment. All children with TB should be registered with the NTP as smear-positive pulmonary, smear-negative pulmonary TB or extrapulmonary TB, and as a new case or a previously treated case. Standard case definitions are provided below. - bacteriologically confirmed TB case is one from whom a biological specimen is positive by smear microscopy, culture or WHO-approved rapid diagnostics (such as Xpert MTB/RIF). All such cases should be notified, regardless of whether TB treatment has started. - clinically diagnosed TB case is one who does not fulfil the criteria for bacteriological confirmation but has been diagnosed with active TB by a clinician or other medical practitioner who has decided to give the patient a full course of TB treatment. This definition includes cases diagnosed on the basis of X-ray abnormalities or suggestive histology and extrapulmonary cases without laboratory confirmation. Clinically diagnosed cases subsequently found to be bacteriologically positive (before or after starting treatment) should be reclassified as bacteriologically confirmed. 12

17 Bacteriologically confirmed or clinically diagnosed cases of TB are also classified according to: - anatomical site of disease; - history of previous treatment; - drug resistance; - HIV status. Classification based on anatomical site of disease: Pulmonary TB, smear positive The criteria include the following; Two or more initial sputum smear examinations positive for acid-fast bacilli; or One sputum smear examination positive for acid-fast bacilli plus CXR abnormalities consistent with active pulmonary TB, as determined by a clinician; or One sputum s mear examination positive for acid-fast bacilli plus sputum culture positive for M. tuberculosis Adolescents, or children of any age with complicated intrathoracic disease, are more likely to have sputum smear-positive pulmonary TB. Pulmonary TB, smear-negative A case of pulmonary TB that does not meet the above definition for smear-positive pulmonary TB, Such cases include cases without smear results, which should be exceptional in adults but relatively more frequent in children. In keeping with good clinical and public health practice, diagnostic criteria for sputum smearnegative pulmonary TB should include: At least three sputum specimens negative for acid-fast bacilli; and Radiological abnormalities consistent with active pulmonary TB; and No response to a course of broad-spectrum antibiotics; and Decision by a clinician to treat with a full course of anti-tb chemotherapy. Extrapulmonary TB Children with only extrapulmonary TB should be classified under this case definition. Children who have both pulmonary and extrapulmonary TB should be classified under the case definition of pulmonary TB. Classification based on history of previous TB treatment (patient registration group) They focus only on history of previous treatment and are independent of bacteriological confirmation or site of disease. New patients have never been treated for TB or have taken anti-tb drugs for less than 1 month. 13

18 Previously treated patients have received 1 month or more of anti-tb drugs in the past. They are further classified by the outcome of their most recent course of treatment Relapse patients have previously been treated for TB, were declared cured or treatment completed at the end of their most recent course of treatment, and are now diagnosed with a recurrent episode of TB (either a true relapse or a new episode of TB caused by reinfection). Treatment after failure patients are those who have previously been treated for TB and whose treatment failed at the end of their most recent course of treatment. Treatment after loss to follow-up patients have previously been treated for TB and were declared lost to follow-up at the end of their most recent course of treatment. (These were previously known as treatment after default patients.) Other previously treated patients are those who have previously been treated for TB but whose outcome after their most recent course of treatment is unknown or undocumented. Patients with unknown previous TB treatment history do not fit into any of the categories listed above. Classification based on HIV status HIV-positive TB patients HIV-negative TB patients HIV status unknown TB patients Classification based on drug resistance Cases are classified in categories based on drug susceptibility testing (DST) of clinical isolates confirmed to be M. tuberculosis: Monoresistance- resistance to one first-line anti-tb drug only. Polydrug resistance- resistance to more than one first-line anti-tb drug (other than both isoniazid and rifampicin). Multidrug resistance- resistance to at least both isoniazid and rifampicin. Extensive drug resistance- resistance to any fluoroquinolone and to at least one of three secondline injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance. Rifampicin resistance- resistance to rifampicin detected using phenotypic or genotypic methods, with or without resistance to other anti-tb drugs. It includes any resistance to rifampicin, whether monoresistance, multidrug resistance, polydrug resistance or extensive drug resistance. These categories are not all mutually exclusive. When enumerating rifampicin-resistant TB (RR- TB), for instance, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are also included. There are no clinical or radiological differences between drug-susceptible and drug-resistant TB in children except that a child with drug-resistant TB is more likely to have a history of close contact with a source case of drug-resistant TB. Confirmed drug-resistant TB is a laboratory diagnosis. 14

19 Drug resistant TB is suspected when there is close contact with a drug-resistant confirmed or suspected index case; or poor response to treatment in the patient or index case. The majority of children have culture negative TB thus drug susceptibility testing results are not available to confirm the diagnosis. Under these circumstances, drug-resistant TB should be suspected in the following cases: A child who is a close contact (household or other frequent contact e.g. caregiver or grandparents) of an infectious drug-resistant/mdr-tb case. A child who is a close contact of a TB patient who died while on treatment and there are reasons to suspect the patient had drug-resistant/mdr-tb Children with bacteriologically proven TB or probable TB not responding to first-line anti- TB treatment where adherence to therapy is ensured. The initial case finding strategy for paediatric DR TB will be: Intense search for TB bacteriological confirmation and DST for all children on admission to the paediatric TB hospital and Machinton hospital if not done before, Household contact tracing of all adult patients diagnosed with MDR TB. All children will undergo full diagnostic algorithm in order to diagnose DR TB as early as possible (see Algorithm I ) even if the symptom screening does not reveal TB suspects (symptoms may appear later) ; those below 5 years will also have a TST and CXR. Training of TB doctors in the suspicion of MDR TB in children to increase the rate of such children being referred from the oblast and rayon TB hospitals. As the programme expands, case finding strategy will include: Support to increased access to culture and DST in adults (especially in non-pilot rayons) as the potential paediatric DR TB index cases. Implementation of sputum induction and use of Xpert MTB/RIF in the Oblast TB hospitals. Support to increased TB case finding through diagnostic algorithms implementation in PHC facilities. TB diagnostic algorithms The use of adapted algorithms (I & II) is a practical way to arrive at decisions while following the approach summarized above in Box A and looking for both the key features suggestive of active TB and confirmatory tests. The approach in the diagnosis of children can either be through recognition of signs and symptoms suggestive of TB presented by the child or screening of a contact after an adult in the household or a sibling has been diagnosed with TB. 15

20 Algorithm I: Diagnosis through contact screening Contact of a TB case? a Yes No Refer to diagnosis through clinical suspicion algorithm Does the child have signs and symptoms suggestive of TB? Cough and/or Poor weight gain / weight loss b and/or Fever c Perform Chest Xray Yes Has signs or symptoms or CXR suggestive of TB 1. Antibiotics d, nutritional support or other treatment according to clinical findings 2. TST 3. Sputum for microbiology and molecular testing e 4. HIV counselling and testing 5. If clinically obvious TB, start TB treatment ASAP* 6. For all others: review at or before 1 WEEK No Child still symptomatic after completing a course of antibiotics d? No Yes CXR normal and smear (-) and Gene Xpert (-) and culture (-) And/Or CXR suggestive of TB f And/Or microbiology/molecular test positivity Presumed index case has DS TB: Give IPT if: < 6 years of age or HIV+ Presumed index case has DR TB: Do not give any prophylaxis Clinical follow up 3 monthly over a 2yr period Treat for DS-TB If presumed index case has DS TB: Start category I treatment (see chapter 2) Treat for DR-TB If presumed index case has DR TB or microbiological results show DRTB: Start DRTB treatment (see chapter 2) 16

21 Algorithm II: Diagnosis through clinical suspicion (no known contact) Does the child have signs and symptoms suggestive of TB?: Cough and/or Poor weight gain / weight loss b and/or Fever c Yes Contact of a TB case a? No Yes Refer to diagnosis through contact screening algorithm Antibiotics d, nutritional support or other treatment according to clinical findings Sputum or FNA (if lymphadenopathy suggestive of TB) for microbiology and molecular testing e CXR TST HIV counseling and testing Smear and/or Xpert MTB/RIF and/or Hain positive No Yes Still symptomatic after finishing antibiotics d? R and/or H resistance? Yes No No Yes CXR suggestive of TB f? Start DS-TB treatment Start DR-TB treatment No Yes CXR normal? TST positive? Yes Start DS-TB treatment No Yes No Consider alternative diagnosis Review regimen after full DST results or if no improvement 17 Active TB unlikely

22 Notes a Contact = living in the same household, or in close and regular contact with any known or suspected TB case in the last 12 months b W/A Z-score < -2 or weight loss or growth curve flattening c Temperature > 37.5 C (per axilla) either directly measured, or reliably reported by the caregiver d Cough may be due to a variety of causes including asthma, viral or bacterial infections. Clinicians should provide treatment accordingly. If pneumonia is diagnosed, the recommended treatment is: Non severe cases: Amoxicillin PO: 80 mg/kg/day in 3 divided doses for 7 days treat as outpatients: Advise carer to return with the child if no improvement after 48 hours of antibiotics If HIV exposed or infected consider adding: Cotrimoxazole PO: 40/8 mg/kg/dose 3 times per day for 21 days * Severe cases ** : Ceftriaxone IV or IM: 80mg/kg once daily (OD) +/- Cloxacillin IV or IM: 100 mg/kg/day in 3 divided doses (if S.aureus suspected) If HIV exposed or infected consider adding: Cotrimoxazole PO or IV(preferred): 40/8 mg/kg/dose 3 times per day for 21 days + If improvement after 3-5 days of parenteral treatment, switch to oral drugs to complete 7-10 days of antibiotics Prednisolone PO: 1mg/kg/dose twice per day for 5 days, then 1mg/kg OD for 5 days, then 0.5mg/kg OD for 5 days * * PCP treatment should be given presumptively to children < 1 year of age, and any older child with severe immune suppression and not on CTX prophylaxis. For all others, it should be considered if there is poor response to standard treatment after 48 hours. **Signs of severity: Cyanosis, hypoxemia SaO2 < 90%, nasal flaring, chest indrawing, grunting, tachypnoea, feeding difficulties in infants For non severe cases Clinical response to broad spectrum antibiotic does not rule out TB. Carer should be informed to consult if symptoms re-occur e Sputum may be obtained in older children able to expectorate spontaneously. For young children, sputum induction (+/- gastric aspiration) should be conducted by trained staff in a safe room with adequate infection control measures. f Enlarged hilar lymph nodes and opacification in the lung tissue, miliary mottling in lung tissue, cavitation (tends to occur in older children), pleural or pericardial effusion though seen on CXR are forms of extra pulmonary TB that tend to occur in older children. 18

23 Annex 1A: Differential Diagnosis for Pulmonary TB Disease Comment Bacterial Pneumonia Usually more acute and shorter in duration. High fever often present X-ray appearance can mimic TB but a lobar consolidation may suggest bacterial pneumonia. Response to broad spectrum antibiotics that have no anti- TB activity may suggest bacterial pneumonia. Viral pneumonia Air trapping with wheezing clinically More common in infants than older children Diffuse interstitial infiltration, hyperinflation Bronchiectasis A complication of successive and poorly treated bronchopulmonary infections. Haemoptysis, while usually mild can be present. Previous TB infection can also result in chronic bronchectasis. Pneumocystis pneumonia Occurs in HIV infected patients with CD4 less than 200 It can also occur in other immucompromised patients including those on corticosteroids and cancer chemotherapy agents. CXR: Diffuse interstitial infiltration or hyperinflation Lymphoid Interstitial Pneumonitis Older children with HIV An immune respone to EBV virus Slow onset, cough and mild hypoxia with generalised lymphadenopathy, parotid enlargement and finger clubbing Marked wheezing in a clinically stable child Diffuse reticulonodular pattern + lymph node enlargement Treat with antiretrovirals and in some cases requires corticosteroids. Pulmonary echinococcosis Also known as (hydatid disease or echinococcal disease. It occurs in only certain areas of the world. Lung involvement can lead chronic cough sometimes with accompanying hemoptysis. The cysts can mimic TB cavities. Involvement of cysts can occur in other organs. Other less common Strongyloidiasis, whooping cough. 19

24 Annex 1B: Extrapulmonary TB Extrapulmonary TB is common in children and presentation varies with age. The table below lists typical clinical features of forms of EPTB and suggested investigations for each category. Symptoms vary depending on site of disease and characteristically are persistent, progressive and may be associated with weight loss or poor weight gain. Clinical assessment in all cases should consider: Site of EPTB Typical clinical presentation Investigation Comment TB adenitis Asymmetrical, painless, non-tender lymph node enlargement for more than one month +/- discharging sinus Most commonly in neck area Fine needle aspiration when possible for culture and histology TST usually positive not necessary for diagnosis Treat If axillary node enlargement on same side as BCG, consider BCG disease Pleural TB Dullness on percussion and reduced breath sounds +/- chest pain CXR Pleural tap# Treat If pus in pleural tap, consider empyema Usually young (< 5 years) with disseminated disease and severely ill TB meningitis Subacute developing over days or weeks. Headache, irritability/ change in behaviour, vomiting (without diarrhoea), reduced feeding lethargic/reduced level of consciousness, convulsions, neck stiffness, bulging fontanelle, cranial nerve palsies Lumbar puncture obtain CSF # CXR Hospitalise for TB treatment Add corticoids Notice prolonged DS TB treatment Miliary TB Non-specific, lethargic, fever, wasted. High risk of meningeal involvement in children (60-70%) CXR Lumbar puncture Treat Usually 5 years and older Abdominal TB Abdominal swelling with ascites or abdominal Masses Ascitic tap # USS abdomen Treat 20

25 Site of EPTB Typical clinical presentation Investigation Comment Spinal TB Deformity of spine May have lower limb weakness/paralysis/unable to walk X-ray spine Treat Notice prolonged DS TB treatment Pericardial TB May cause cardiac failure Distant heart sounds Apex beat difficult to palpate CXR Cardiac ultrasound Pericardial tap # Treat Add corticoids TB bone and joint Swelling end of long bones with limitation of movement Unilateral effusion of usually knee or hip X-ray bone/joint Joint tap # Treat Notice prolonged DS TB treatment # typical findings: straw colored fluid, exudate with high protein, white blood cells predominantly lymphocytes on microscopy 2HREZ/10HR if meningeal or osteoarticular involvement 21

26 Procedures for obtaining clinical samples for smear microscopy, Molecular tests and Culture. Annex 1C: Sputum induction The child should undergo a thorough clinical examination before nebulisation and should have been fasting for at least 3 hours. Explain the procedure to the child and/or the accompanying adult and obtain consent The following should be examined and recorded: Observations: respiratory rate (rate per minute) and other signs of respiratory distress such as inter-or subcostal recession, nasal flaring or central cyanosis Heart rate (beats per minute) Oxygen saturation (through pulse oxymetry) Auscultation bilateral: to examine for reduced air entry, presence of stridor, wheeze Perform complete blood count Assess level of consciousness Exclusion criteria for induced sputum 1. Inadequate fasting: Child not fasting for at least 3 hours 2. Severe respiratory distress: RR > 50 c/min, severe coughing, lower airway obstruction (wheezing), moderate or severe; non-responsive to 2x MDI (metered dose inhaler) salbutamol before procedure, Stridor, Hypoxia: O2 saturation <92%, overt cyanosis, HR > 120 beats per minute, haemoptysis, large pleural effusions. 3. Low platelet count, bleeding tendency, severe epistaxis 4. Reduced level of consciousness. Staff and parent should wear protective masks (N95), goggles and non-sterile latex gloves during the procedure and stand behind the patient. All adverse events should be recorded in the hospital folder. How to perform the induced sputum Sputum is induced through the inhalation of hypertonic saline and physiotherapy techniques. The induced sputum is then either expectorated if possible or suction from the nasopharynx of a child. 22

27 Bronchodilation prior to procedure 1. Provide Salbutamol by metered dose inhaler (MDI 100 ug/puff) with a spacer (Aero chamber) and facemask, to prevent bronchoconstriction. Two puffs (200ug) of the MDI will be given via the spacer at a rate of 1 puff every 10 seconds. 2. After the nebulization, the child will be examined again. The RR, HR and O2 saturation will be recorded. If the O2 saturation is less than 90% for at least 20 seconds, an increase in respiratory rate of more than 30% from baseline or development of signs of lower airway obstruction, or a severe increase in coughing or frank epistaxis during nebulisation, the procedure should be aborted. Hypertonic saline nebulization Wait for up to ten minutes after bronchodilator administration. Nebulise the child with 5 mls of sterile hypertonic saline [6% NaCI] solution, via the ultrasonic nebuliser attached to an oxygen concentrator at a flow rate of3l/min. Continue the nebulisation for maximum 15 minutes or until all the solution is nebulised, whichever occurs first. If the child starts to cough productively before this, stop the procedure and obtain a sample immediately. Physiotherapy Physiotherapy will be performed on the child's chest to optimise mobilisation of secretions. The left and right chest over the anterior and posterior lung fields will be percussed and vibrated. If the child is under 6 months old, she/he will be held steadily over the ribs and gently shaken. Obtaining the induced sputum 1. Lay the child on the side, facing away from the operator. Swaddling may be necessary to immobilize the child during suctioning. 2. Suction the nasal passages using a sterile catheter of size 6 or 8 french gauge, to clear them of nasal secretions 3. Attach the suction tubing to a sterile mucus trap and the suction after that in serial Estimate the distance to insert the suction tubing by measuring the distance from the outer nostril to the tragus of the ear. 5. Suction the nasopharynx using a new sterile suction catheter attached to the aspirate bottle with thick tubing. The specimen obtained should be at least 2mls. 6. The suction tubing and catheter should be flushed with approximately 1 ml of normal saline to ensure optimal collection and volume of the nasopharyngeal aspirate. 7. Children able to cough (usually older than 5 years) will be instructed to expectorate (cough up) the induced sputum (see Annex 1D). The colour, density and origin of suctioned material should be noted. 2 If mechanical suction is not available, fit a suction catheter to a 50-ml syringe which acts both as suction and mucus trap. When inserting and withdrawing the catheter, pull on the plunger of the syringe to create suction. 23

28 If the child's respiratory status deteriorates, the procedure will be terminated and the child given salbutamol 200μg via an MDI-spacer and oxygen if necessary. The child should be observed for respiratory distress and the procedure should be stopped at any time if the child develops severe cough or wheeze either prior to or during nebulisation (see exclusion criteria). If oxygen saturations drop below 92%, give oxygen Possible adverse effects to anticipate Coughing spells (40%) If severe, stop the procedure and administer Salbutamol via the holding chamber. Oxygen should be available and can be administered in severe cases. Nosebleeds (8%) Stop the procedure and apply constant pressure to the mid portion of the nose until the bleeding stops. It is very common to see blood in the specimen collected (>80% of specimens). This in itself is not an adverse effect. Mild wheezing (<1%) Monitor the child closely. Stop the procedure if wheeze increases. Administer Salbutamol via the holding chamber and Oxygen if severe. Vomiting (<1%) Stop the procedure and observe the child closely until the vomiting stops. Further logistics Jar lids will be tightly closed and all specimen jars labelled. All sputum specimens (together with all documentation clearly completed) will be kept in the ward refrigerator until transported to the microbiology laboratory. If not possible, specimens should be placed in the fridge until collected Specimens will be transported on the same day on which they are obtained, within 4 hours of completing the procedure. Any adverse events will be recorded on the recording sheet and reported to the medical officer if serious. All biological waste will be discarded according to hospital infectious control guidelines. Mucus trap will only be used once, but the masks, spacers, nebulizer and tubing that connect the mucus trap to the wall suction will be re-used and disinfected. Between patients: The mask and Aero chamber spacer will be washed in soap and water and left in the sun for 3-4 hours to air-dry, after which they will be wiped down with chlorhexidine in 70% alcohol and the alcohol allowed to evaporate. The tubing and nebulizer will be sent for sterilization. 24

29 Infection control measures Management of materials Spacer devices (holding chambers) Either sterilize after each patient (preferred) or disinfect after each patient by soaking in hexanios for at least 15 minutes then rinse, then soak again in a new bath of hexanios for 15 minutes. Rinse well and then wipe dry All masks, tubing, suction catheters and syringes should be disinfected with 2% chlorine and then discarded Antibacterial filters should be fitted and changed for each patient to protect the nebulizer, oxygen cylinder (if used), and any aspiration device (if used) Management of the environment The room must be left unused with the windows open, or extraction fan on for a least 30mins after the procedure to allow adequate replacement of air in the room. A fan may be necessary to facilitate this. No one should enter this room during the period without a respirator. A sign should be placed on the door saying No Entry Without a Respirator until the minimum period has passed Description of physiotherapy techniques Percussion and vibrations The left and right chest over the anterior and posterior lung fields will be percussed and vibrated. Percussion will be done with a cupped hand on the chest wall of the child in alternate side lying positions, for 2 minutes on each side. Children under 6 months and very ill children (see under exclusion criteria) will only receive vibration. Vibration to loosen secretions will be performed on all children. Five vibrations will be performed on either side of the chest wall, alternately. Contra-indication for percussion (physiotherapy) Age younger than 6 months (gently shaken instead of vibrations) Severe respiratory distress Pleural effusion or empyema Annex 1D: Expectoration Background All sputum specimens produced by children should be sent for smear microscopy, molecular testing and, where available, mycobacterial culture. Children who can produce a sputum specimen may be infectious, so, as with adults, they should be asked to do this outside and not in enclosed spaces (such as toilets) unless there is a room especially equipped for this purpose. Three sputum specimens should be obtained: an on-the-spot specimen (at first evaluation), an early morning specimen and a second on- the-spot specimen (at follow-up visit). 25

30 Procedure (adapted from Laboratory services in tuberculosis control. Part II. Microscopy (1)) Give the child confidence by explaining to him or her (and any family members) the reason for sputum collection. Instruct the child to rinse his or her mouth with water before producing the specimen. This will help to remove food and any contaminating bacteria in the mouth. Instruct the child to take two deep breaths, holding the breath for a few seconds after each inhalation and then exhaling slowly. Ask him or her to breathe in a third time and then forcefully blow the air out. Ask him or her to breathe in again and then cough. This should produce sputum from deep in the lungs. Ask the child to hold the sputum container close to the lips and to spit into it gently after a productive cough. If the amount of sputum is insufficient, encourage the patient to cough again until a satisfactory specimen is obtained. Remember that many patients cannot produce sputum from deep in the respiratory track in only a few minutes. Give the child sufficient time to produce an expectoration which he or she feels is produced by a deep cough. If there is no expectoration, consider the container used and dispose of it in the appropriate manner. 26

31 Annex 1E: Gastric Aspirate Procedure Gastric aspirates should be performed early in the morning (around 7 am) by the ward staff, while the child is still recumbent and gastric secretions have not been lost through peristalsis. Children will have early morning gastric lavages / aspirates done on two consecutive mornings. Children less than 5 or unable to get sample by induced sputum Exclusion criteria Children not fasting for at least 4 hours Low platelet count, bleeding tendency Procedure The procedure will be done after an overnight fast. The procedure will be done first thing in the morning when the child wakes up but is not yet active. Infants will be kept nil by mouth for at least 3-4 hours before the procedure. A size 8-nasogastric tube will be inserted into the stomach and the gastric contents withdrawn mls of sterile normal saline will be instilled into the stomach through the tube and left for 2-3 minutes. The gastric contents will be withdrawn and at least 20 millilitres collected into a special sodium carbonate containing green- topped tube. If enough aspirates cannot be obtained, continue injecting 5-10 ml normal saline aliquots down the naso-gastric tube and aspirating until at least 20mls is obtained. After the procedure The (acidic) gastric specimen will be buffered/neutralized with phosphate buffer (prepared as described) immediately after specimen collection. This should be added in a 2:1 sample to buffer ratio, e.g. 2 ml of aspirate plus 1 ml of buffer. Addition of buffer prevents the degradation of the bacilli by stomach acid. The sample and buffer should be well-mixed on buffer addition. Wipe the specimen container with alcohol/chlorhexidine to prevent cross infection and label it. - The container with the aspirate will be labelled as follows: child's name, name of hospital, date. - The specimen must reach the laboratory within 4 hours for processing. If not possible, specimens should be placed in the fridge and stored at 4-8ºC until transport. - Samples will undergo the following: direct smear and microscopy for AFB s, Xpert MTB/RIF and culture. - The usual milk or other feed will be given to the child. 27

32 Laboratory Splitting and Processing Gastric Aspirates and Induced Sputum Specimens need to reach the microbiology laboratory within four hours after being obtained. If this is not possible, specimens should be stored in a refrigerator until transport. All gastric aspirates have to be neutralized with phosphate buffer immediately after collection, as described below. In the laboratory, samples will be split and processed. Gastric aspirates, sputum and induced sputum will be analysed by direct smear (microscopy for acid-fast bacilli; Ziehl- Nielsen test), Xpert MTB/RIF and cultures will be done. NALC-NaOH Specimen Processing To each homogenized and split specimen: Add an equal volume of 0.5% NALC/4% NaOH (2% NaOH final). Vortex and incubate for 15 minutes at room temperature. At the end of the incubation period, add phosphate buffer solution (PBS) to a final volume of 50 ml. Vortex specimens well, place in centrifuge, and concentrate the material by centrifugation at 3,000 g for 15 minutes at 4C. Decant supernatant completely into a splash-proof container, leaving only the sample pellet in the tube; resuspend with a few drops of PBS. Resuspend the sediment by vortexing. Spread one drop of the sediment onto the circle on the pre-etched glass slide for acid fast staining - label slide accordingly. Subject the remaining sediment to cultural analysis: transfer 0.5 ml to a MGIT culture vial or BACTEC bottle, supplemented with OADC and PANTA, and transfer 2-3 drops to an L-J slant. 28

33 Phosphate buffer for Gastric Aspiration 70 g di-sodium hydrogen phosphate dodecahydrate (Na2HPO4 * 12 H2O, Merck ) Dissolve in 100 ml boiling water until the solution is clear fill 1-2 ml of the hot solution in ml tubes The buffer crystallizes at room temperature. Store at room temperature up to 12 months. Or: When using Merck Number Description di-sodium hydrogen phosphate anhydrous for analysis, particle size about 0.2-1mm (~18-80 mesh ASTM) EMSURE, i.e. SLASZNL0118 DISODIUM HYDROGEN PHOSPHATE, powder, 500 grams Dissolve 0.4 g per ml of boiling water. Use 1 ml of phosphate buffer solution per 2 ml of aspirate. 29

34 Annex 1F: Tuberculin Skin Test The TST is given by using a single dose disposable syringe that injects 2 international units (IU) of tuberculin intradermally (between the layers of the skin) on the ventral surface (side of arm exposed with palm facing up) of the forearm. The test is read by a trained health care worker, 48 to 72 hours after the injection. The reaction is the area of induration (swelling that can be felt) around the injection. The diameter is measured with a ruler in millimetres across the forearm. The erythema (redness) around the indurated area is not measured, because the presence of redness does not indicate a reaction. Adverse reactions: Mild itching, swelling, or irritation are more common and are not a contraindication to future testing. Individuals should be instructed to avoid scratching or scrubbing the site, to keep the site clean and dry, and to avoid putting lotions or adhesive bandages on it. A cold compress may be helpful. Positive TST: A TST is considered as positive in Tajikistan if induration of 5 mm in all adults or children (BCG vaccinated or not). WHO recommends the diameter >5mm of as positive for children in high risk (HIV-infected, severely malnourished; >10 mm in all other children (whether they have received BCG vaccination or not). A reaction that appears several minutes or several hours after injection (occasionally even after 24 hours) but which disappears on the day after its appearance is of no significance. Hyperergic reaction-17mm in children, 21mm in adults. Moreover, the reaction is considered positive regardless of the size of the induration in the presence of: necrosis, vesicles or lymphangitis. In practice TST has less value as a diagnostic tool when the annual rate of infection (ARI) and BCG vaccine coverage are high. It can be used as one of several components in an algorithm to assess patients. 30

35 A highly positive (induration > 17 mm) or severe skin reaction should be considered as an argument in favour of active TB, but insufficient in itself for deciding on treatment. A topical corticosteroid (1% hydrocortisone) may be considered in severe local reactions that are at risk for ulceration. What Are False-Positive Reactions? Some persons may react to the TST even though they are not infected with M. tuberculosis. The causes of these false-positive reactions may include the following: Infection with nontuberculosis mycobacteria Previous BCG vaccination Incorrect method of TST administration Incorrect interpretation of reaction Incorrect bottle of antigen used What Are False-Negative Reactions? Some persons may not react to the TST even though they are infected with M. tuberculosis. The reasons for these false-negative reactions may include, but are not limited to, the following: Recent TB infection (within 8-10 weeks of exposure) Very old TB infection (many years) Very young age (less than 6 months old) Recent live-virus vaccination (e.g., measles) Recent viral (influenza, measles) or bacterial (whooping cough) infections. Poor general condition (malnutrition) Overwhelming TB disease Some viral illnesses (e.g., measles and chicken pox) Incorrect method of TST administration Incorrect interpretation of reaction Approximately 30% of children with active TB have false- negative or doubtful TST when diagnosed. In general once a patient tests positive with a TST, repeated tests are not indicated 31

36 Chapter 2: Treatment of TB in children After a decision to treat a child with TB has been reached, the choice of starting DS or DR TB treatment will initially be based on presence of R resistance on Xpert MTB/RIF and/or history of DR TB close contact as illustrated in figure 2.1 below. The treatment will then be individualised oznce the full DST results of the patient or a close contact are available, following guidance in Annexes 2A and 2B. Figure 2.1: initial treatment decisions Expectorated or induced sputum tested by Xpert MTB/RIF MTB+ Rif MTB- Follow diagnostic algorithms I and II. Treat for TB? MTB+ Rif + Contact DR-TB contact? Commence DS TB treatment 2 HREZ / 4 HR # No Yes Commence MDR TB treatment Z-Cm-Lfx-Pto-Cs-PAS The main objectives of anti-tb treatment are to: cure the patient of TB (by rapidly eliminating most of the bacilli); prevent death from active TB; prevent relapse of TB (by eliminating the dormant bacilli); prevent the development of drug resistance (by using a combination of drugs); decrease TB transmission to others. Drug susceptible TB treatment Children usually have paucibacillary pulmonary disease, as cavitating disease is relatively rare (about 6% of cases or fewer) in those under 13 years of age. In contrast, children develop extrapulmonary TB more often than adults do. Severe and disseminated TB (e.g. TB meningitis and miliary TB) occur especially in young children (less than 3 years old). Both the bacillary load and the type of disease may influence the effectiveness of treatment regimens. Treatment outcomes in children are generally good, even in young and immunocompromised children who are at higher risk of disease progression and disseminated disease. Treatment 32