1. Tuberculosis Prof.Dr.Reha Cengizlier 7.1.2014

2. More than one third of the world's population is infected with Mycobacterium tuberculosis More than one third of the world's population is infected with Mycobacterium tuberculosis Almost 1.3 million cases and 450,000 deaths occur in children each year Almost 1.3 million cases and 450,000 deaths occur in children each year

4. There are five closely related mycobacteria in the Mycobacterium tuberculosis complex: There are five closely related mycobacteria in the Mycobacterium tuberculosis complex: – M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canetti – M. tuberculosis is the most important cause of tuberculosis disease in humans The tubercle bacilli are non–spore-forming, nonmotile, pleomorphic, weakly Gram-positive curved rods 2–4 μm long The tubercle bacilli are non–spore-forming, nonmotile, pleomorphic, weakly Gram-positive curved rods 2–4 μm long

7. Transmission Person to person, usually by airborne mucus droplet Person to person, usually by airborne mucus droplet Rarely by direct contact with an infected discharge Rarely by direct contact with an infected discharge Children and adolescents with adult-type pulmonary tuberculosis can transmit the organism Children and adolescents with adult-type pulmonary tuberculosis can transmit the organism Airborne transmission of M. bovis and M. africanum can also occur Airborne transmission of M. bovis and M. africanum can also occur

8. Pathogenesis The lung is the portal of entry in over 98% of cases The lung is the portal of entry in over 98% of cases The tubercle bacilli multiply initially within alveoli and alveolar ducts. Most of the bacilli are killed, but some survive within nonactivated macrophages, which carry them through lymphatic vessels to the regional lymph nodes The tubercle bacilli multiply initially within alveoli and alveolar ducts. Most of the bacilli are killed, but some survive within nonactivated macrophages, which carry them through lymphatic vessels to the regional lymph nodes When the primary infection is in the lung, the hilar lymph nodes usually are involved, although an upper lobe focus may drain into paratracheal nodes When the primary infection is in the lung, the hilar lymph nodes usually are involved, although an upper lobe focus may drain into paratracheal nodes

9. Pathogenesis The parenchymal portion of the primary complex often heals completely by fibrosis or calcification after undergoing caseous necrosis and encapsulation The parenchymal portion of the primary complex often heals completely by fibrosis or calcification after undergoing caseous necrosis and encapsulation If caseation is intense, the center of the lesion liquefies and empties into the associated bronchus, leaving a residual cavity If caseation is intense, the center of the lesion liquefies and empties into the associated bronchus, leaving a residual cavity

18. Pathogenesis The time between initial infection and clinically apparent disease is variable The time between initial infection and clinically apparent disease is variable – Disseminated and meningeal tuberculosis often occurring within 2–6 mo. – Clinically significant lymph node or endobronchial tuberculosis 3–9 mo. – Bones and joints take several years – Renal lesions may become decades after

19. Pathogenesis Pulmonary tuberculosis that occurs more than a year after the primary infection is usually caused by endogenous regrowth of bacilli persisting in partially encapsulated lesions Pulmonary tuberculosis that occurs more than a year after the primary infection is usually caused by endogenous regrowth of bacilli persisting in partially encapsulated lesions This reactivation tuberculosis is rare in children but is common among adolescents and young adults This reactivation tuberculosis is rare in children but is common among adolescents and young adults The most common form is an infiltrate or cavity in the apex of the upper lobes, where oxygen tension and blood flow are great The most common form is an infiltrate or cavity in the apex of the upper lobes, where oxygen tension and blood flow are great

20. Immunity Cell-mediated immunity develops 2–12 wk after infection, along with tissue hypersensitivity Cell-mediated immunity develops 2–12 wk after infection, along with tissue hypersensitivity Development of specific cellular immunity prevents progression of the initial infection in most individuals Development of specific cellular immunity prevents progression of the initial infection in most individuals

21. Tuberculin skin testing The Mantoux tuberculin skin test is the intradermal injection of 0.1 mL containing 5 tuberculin units (TU) of purified protein derivative (PPD) stabilized with Tween 80. The Mantoux tuberculin skin test is the intradermal injection of 0.1 mL containing 5 tuberculin units (TU) of purified protein derivative (PPD) stabilized with Tween 80. The amount of induration in response to the test should be measured by a trained person 48–72 hr after administration The amount of induration in response to the test should be measured by a trained person 48–72 hr after administration

23. Tuberculin skin testing Host-related factors, including very young age, malnutrition, immunosuppression by disease or drugs, viral infections (e.g., measles, mumps, varicella, influenza), vaccination with live-virus vaccines, and overwhelming tuberculosis can depress the skin test reaction in a child infected with M. Tuberculosis Host-related factors, including very young age, malnutrition, immunosuppression by disease or drugs, viral infections (e.g., measles, mumps, varicella, influenza), vaccination with live-virus vaccines, and overwhelming tuberculosis can depress the skin test reaction in a child infected with M. Tuberculosis Corticosteroid therapy may decrease the reaction to tuberculin, but the effect is variable Corticosteroid therapy may decrease the reaction to tuberculin, but the effect is variable The most common reasons for a false- negative skin test are poor technique or misreading of the results The most common reasons for a false- negative skin test are poor technique or misreading of the results

24. Prior vaccination with BCG is never a contraindication to tuberculin testing Prior vaccination with BCG is never a contraindication to tuberculin testing

25. Definition of a Positive Tuberculin Skin Test INDURATION ≥5 mm INDURATION ≥5 mm – Close contacts of known or suspected case of tuberculosis disease – Children having clinical or radiographic findings of tuberculosis disease – Children with immunosuppressive conditions, including HIV and organ transplantation – Patients receiving immunosuppressive therapy, including immunosuppressive doses of corticosteroids

26. INDURATION ≥10 mm INDURATION ≥10 mm – infants and children ≤4 yr of age – Children with underlying medical conditions or behaviors that increase risk (renal disease, hematologic disorders, diabetes mellitus, malnutrition, injection drug use) – Birth or recent immigration (<5 yr) from a high- prevalence country – Children with travel to or exposure to visitors from high- prevalence countries INDURATION ≥15 mm INDURATION ≥15 mm – Children >4 yr of age and older without any risk factors

27. Clinical Manifestations The majority of children with tuberculosis infection develop no signs or symptoms at any time The majority of children with tuberculosis infection develop no signs or symptoms at any time Occasionally, infection is marked by low-grade fever and mild cough, and rarely by high fever, cough, malaise, and flu-like symptoms that resolve within a week Occasionally, infection is marked by low-grade fever and mild cough, and rarely by high fever, cough, malaise, and flu-like symptoms that resolve within a week About 25–30% of children and 15% of adult tuberculosis cases are extrapulmonary About 25–30% of children and 15% of adult tuberculosis cases are extrapulmonary

28. Diagnosis The most specific confirmation of pulmonary tuberculosis is isolation of M. tuberculosis The most specific confirmation of pulmonary tuberculosis is isolation of M. tuberculosis Sputum specimens for culture should be collected from adolescents and older children who are capable to expectorate Sputum specimens for culture should be collected from adolescents and older children who are capable to expectorate The best culture specimen in young children is the early morning gastric acid obtained before the child has arisen and peristalsis has emptied the stomach of the pooled secretions that have been swallowed overnight The best culture specimen in young children is the early morning gastric acid obtained before the child has arisen and peristalsis has emptied the stomach of the pooled secretions that have been swallowed overnight Even under optimal conditions, though, three consecutive morning gastric aspirates yield the organisms in <50% of cases Even under optimal conditions, though, three consecutive morning gastric aspirates yield the organisms in <50% of cases

30. Treatment Tubercle bacilli can be killed only during replication Tubercle bacilli can be killed only during replication Several drugs are used to effect a relatively rapid cure and prevent the emergence of secondary drug resistance during therapy Several drugs are used to effect a relatively rapid cure and prevent the emergence of secondary drug resistance during therapy

31. Most Commonly Used Antituberculosis Drugs Drug Daily Dose (mg/kg/24 hr) Twice-Weekly Dose (mg/kg/dose) Maximum Dose Isoniazid ** 10–1520–30Daily: 300 mg; twice weekly: 900 mg Rifampin ** 10–20 600 mg Pyrazinamide ** 20–4040–602 g Streptomycin (IM)20–40 1 g Ethambutol15–2525–502.5 g Ethionamide15–20 (1–3 divided doses) —1 g Cycloserine10–20 (1–2 divided doses) —1 g Kanamycin or capreomycin (IM) 15–30 1 g Amikacin (IV)15–30 1 g IM = intramuscular; IV = intravenous. *Isoniazid (150 mg) and rifampin (300 mg) are combined in one preparation called Rifamate. Isoniazid (50 mg), rifampin

32. The standard therapy of intrathoracic tuberculosis (pulmonary disease and/or hilar lymphadenopathy) in children, recommended by the CDC and AAP, is a 6 mo regimen of INH and RIF supplemented in the first 2 mo of treatment by PZA The standard therapy of intrathoracic tuberculosis (pulmonary disease and/or hilar lymphadenopathy) in children, recommended by the CDC and AAP, is a 6 mo regimen of INH and RIF supplemented in the first 2 mo of treatment by PZA A regimen of INH and RIF for 9 mo is also highly effective for drug-susceptible tuberculosis, but the necessary length of treatment, the need for good adherence by the patient, and the relative lack of protection against possible initial drug resistance have led to the use of shorter regimens A regimen of INH and RIF for 9 mo is also highly effective for drug-susceptible tuberculosis, but the necessary length of treatment, the need for good adherence by the patient, and the relative lack of protection against possible initial drug resistance have led to the use of shorter regimens When directly observed therapy is used, intermittent (twice-weekly) administration of drugs after an initial period as short as 2 wk of daily therapy is as effective in children as daily therapy for the entire course When directly observed therapy is used, intermittent (twice-weekly) administration of drugs after an initial period as short as 2 wk of daily therapy is as effective in children as daily therapy for the entire course

33. Bone and joint, disseminated, and CNS tuberculosis for which there are inadequate data to recommend 6-mo therapy; these cases usually are treated for 9–12 mo. Bone and joint, disseminated, and CNS tuberculosis for which there are inadequate data to recommend 6-mo therapy; these cases usually are treated for 9–12 mo. Surgical debridement in bone and joint disease and ventriculoperitoneal shunting in CNS disease are frequently necessary Surgical debridement in bone and joint disease and ventriculoperitoneal shunting in CNS disease are frequently necessary

34. DRUG-RESISTANT TUBERCULOSIS Primary resistance occurs when an individual is infected with M. tuberculosis that is already resistant to a particular drug Primary resistance occurs when an individual is infected with M. tuberculosis that is already resistant to a particular drug The major causes of secondary drug resistance are poor adherence with the medication by the patient or inadequate treatment regimens prescribed by the physician The major causes of secondary drug resistance are poor adherence with the medication by the patient or inadequate treatment regimens prescribed by the physician The treatment of drug-resistant tuberculosis in children always should be undertaken by a clinician with specific expertise in the treatment of tuberculosis The treatment of drug-resistant tuberculosis in children always should be undertaken by a clinician with specific expertise in the treatment of tuberculosis

35. CORTICOSTEROIDS There is convincing evidence that corticosteroids decrease mortality rates and long-term neurologic sequelae in some patients with tuberculous meningitis by reducing vasculitis, inflammation, and ultimately, intracranial pressure There is convincing evidence that corticosteroids decrease mortality rates and long-term neurologic sequelae in some patients with tuberculous meningitis by reducing vasculitis, inflammation, and ultimately, intracranial pressure Short courses of corticosteroids also may be effective for children with endobronchial tuberculosis that causes respiratory distress, localized emphysema, or segmental pulmonary lesions. Short courses of corticosteroids also may be effective for children with endobronchial tuberculosis that causes respiratory distress, localized emphysema, or segmental pulmonary lesions. Treatment of pericardial effusion, pleural effusion and shift of the mediastinum, alveolocapillary block insevere miliary tuberculosis Treatment of pericardial effusion, pleural effusion and shift of the mediastinum, alveolocapillary block insevere miliary tuberculosis

36. TREATMENT OF LATENT TUBERCULOSIS INFECTION INH therapy should be given to any child with a positive tuberculin skin test but no clinical or radiographic evidence of disease INH therapy should be given to any child with a positive tuberculin skin test but no clinical or radiographic evidence of disease The currently recommended regimen is 9 mo of daily INH therapy. INH can be given twice weekly under direct observation if adherence with daily treatment is likely to be poor The currently recommended regimen is 9 mo of daily INH therapy. INH can be given twice weekly under direct observation if adherence with daily treatment is likely to be poor INH therapy also should be started for children <6 yr of age with a negative tuberculin skin test who have had recent exposure to an adult with infectious tuberculosis, including infants born to mothers who have tuberculosis. These children may already be infected with M. tuberculosis but have not yet developed delayed hypersensitivity INH therapy also should be started for children <6 yr of age with a negative tuberculin skin test who have had recent exposure to an adult with infectious tuberculosis, including infants born to mothers who have tuberculosis. These children may already be infected with M. tuberculosis but have not yet developed delayed hypersensitivity

37. In exposed children, tuberculin skin testing is repeated 3 mo after contact with the adult source case In exposed children, tuberculin skin testing is repeated 3 mo after contact with the adult source case – If the repeat tuberculin skin test is negative, INH can be discontinued; – If the second skin test is reactive (≥5 mm), the child has tuberculosis infection and a full course of INH therapy can be administered – Children with HIV infection or other causes of immune suppression should receive 12 mo of treatment

38. Prevention On average, 30–50% of household contacts to infectious cases will be tuberculin skin test positive, and 1% of contacts already have overt disease On average, 30–50% of household contacts to infectious cases will be tuberculin skin test positive, and 1% of contacts already have overt disease

39. BACILLE CALMETTE-GUÉRIN VACCINATION The only available vaccine against tuberculosis is the BCG, named for the two French investigators responsible for its development. The original vaccine organism was a strain of M. bovis attenuated by subculture every 3 wk for 13 yr The only available vaccine against tuberculosis is the BCG, named for the two French investigators responsible for its development. The original vaccine organism was a strain of M. bovis attenuated by subculture every 3 wk for 13 yr The official recommendation of the WHO is a single dose administered during infancy The official recommendation of the WHO is a single dose administered during infancy Recommended vaccine schedules vary widely among countries Recommended vaccine schedules vary widely among countries The BCG vaccines are extremely safe in immunocompetent hosts. Local ulceration and regional suppurative adenitis occur in 0.1–1% of vaccine recipients The BCG vaccines are extremely safe in immunocompetent hosts. Local ulceration and regional suppurative adenitis occur in 0.1–1% of vaccine recipients

40. Profoundly immunocompromised patients may develop disseminated BCG infection after vaccination Profoundly immunocompromised patients may develop disseminated BCG infection after vaccination BCG is 50% effective in preventing pulmonary tuberculosis in adults and children BCG is 50% effective in preventing pulmonary tuberculosis in adults and children The protective effect for disseminated and meningeal tuberculosis is 50–80% The protective effect for disseminated and meningeal tuberculosis is 50–80%

41. The best use of BCG vaccination appears to be prevention of life- threatening forms of tuberculosis in infants and young children The best use of BCG vaccination appears to be prevention of life- threatening forms of tuberculosis in infants and young children

42. PERINATAL TUBERCULOSIS If the mother has suspected tuberculosis at the time of delivery, the newborn should be separated from the mother until the chest radiograph is obtained If the mother has suspected tuberculosis at the time of delivery, the newborn should be separated from the mother until the chest radiograph is obtained If the mother's chest radiograph is abnormal, separation should be maintained until the mother has been evaluated thoroughly, including examination of the sputum If the mother's chest radiograph is abnormal, separation should be maintained until the mother has been evaluated thoroughly, including examination of the sputum

43. PERINATAL TUBERCULOSIS Symptoms of congenital tuberculosis may be present at birth but more commonly begin by the 2nd or 3rd wk of life Symptoms of congenital tuberculosis may be present at birth but more commonly begin by the 2nd or 3rd wk of life The signs and symptoms are nonspecific The signs and symptoms are nonspecific Many infants have an abnormal chest radiograph, most often a miliary pattern Many infants have an abnormal chest radiograph, most often a miliary pattern Hilar and mediastinal lymphadenopathy and lung infiltrates are common. Generalized lymphadenopathy and meningitis occur in 30–50% of patients Hilar and mediastinal lymphadenopathy and lung infiltrates are common. Generalized lymphadenopathy and meningitis occur in 30–50% of patients

44. Although INH is not thought to be teratogenic, the treatment of pregnant women with asymptomatic tuberculosis infection is often deferred until after delivery Although INH is not thought to be teratogenic, the treatment of pregnant women with asymptomatic tuberculosis infection is often deferred until after delivery