5185094065tubereculosis in children(学习资料).ppt

Tuberculosis in children,Prof.Jianhua ZhouDept of PediatricsTongji Hospital,HUSTTel:83662684 e-mail:,Press Conference of the State Council 2004-6-29,4.5 million tuberculosis patients in China(0.35%),among them 1.5 million are infectious pulmonary tuberculosis patients.Each year about 1.45 million(0.12%)new cases and 130,000 death of tuberculosis.80%of pulmonary tuberculosis patients in rural areas.45%denied a break or interruption in the treatment of patients.,Return of Tuberculosis Tuberculosis,once a romantic 19th-century disease,has returned,reaching epidemic proportions worldwide.In New York Citys 1891 epidemic.Over one-third of the worlds population has latent tuberculosis;15 million Americans are infected with this highly contagious,airborne respiratory disease.TB chooses hosts indiscriminately;average middle-class Americans are not immunized agaist TB Reichman,director of National Tuberculosis Center,WHO Estimated Total Cases in 2000,TB in Children,WHO estimate of TB in children1.3 million annual cases450,000 deaths15%of TB in low-income countries children vs.6%in United States,Leading Infectious Disease Causes of Death,1998,3.5,2.3,2.2,1.5,1.1,0.9,WHO Report 2000,Mycobactrium tuberculosis,was first isolated from sputum of a patient by Koch in 1882Grow slowly，life cyclehr，p7.4O2mmg，low metabolismclassification：tuberculosis,bovis（）,africanumResistant to acid,alkali,live for years in gloomy damp room.,Mycobacterium tuberculosis infection of lung is shown with numerous red rods seen with acid fast staining,The single strand of the acid fast bacteria,mycobacterium tuberculosis,Drug resistance of Mycobacterium tuberculosis,Steiner reported 79 cases in 1974,more than one-third were resistant to one or more anti-TB drugsdrug-resistant strains grow under irregular use of drug or use in low dosage,Atypical Mycobacterium,Different biological characteristics,grow slightly faster,pigment-producing,pathogenic to human,similar clinical manifestations,drug resistance.cervical lymphadenitis in children low sensitive to PPD-S(purified protein derivative,PPD),but strong positive to PPD-F,PPD-Y,PPD-B,PPD-GCommon opportunistic infections in advanced AIDS,Epidemiology,Source of infection The major source of infection is the open pulmonary tuberculosis patients.,Transmission Transmission of Mycobacterium is person to person,usually by airborne mucus droplet nuclei.Transmission rarely occurs by direct contact with an infected discharge or a contaminated fomite(food-borne transmission,Susceptible population Poverty,over-crowding,malnutrition and low socioeconomic status contribute to higher incidence of TB.,Overview of TB pathogenesis,90%no sequellae,5%primary TB(within 2 years),5%reactivation(later in life),Primaryinfection(tuberculin positive),GET IN,STAY IN,GET OUT,WHY?,TB pathogenesis:two genomes do battle,M.tuberculosis,H.sapiens,Virulent vs.attenuated,Susceptible vs.resistant,TB infection(2 billion people),Active TB2-3 million deaths/year=tie for first place with HIV/AIDS,10%,90%,TB and AIDS:Epidemiology,Often high infection rates of bothMost notably sub-Saharan Africa,South-East AsiaM.tuberculosis accelerates progression of HIV infection to AIDSTB cause of death in about 25%AIDSHIV infection is single strongest risk factor for progression of TB infection to TB diseaseEvil synergy where resources most limited,Koch reaction,M.tuberculosis injected to healthy Guinea pig produce a lesion and cause death,to infected(small amount of M.tuberculosis)Guinea pigs cause strong inflammation and necrosis,but quickly recovered.allergy and immunity developed at the same time in initial infection existing.,Allergy of TB,T lymphocytes are sensitized after initial contact with M.tuberculosis,and transformed to release inflammatory lymphokine and skin reaction factor if contact again 2-10 weeks later,result in delayed allergic reaction in skin test,exudative pulmonary lesions,systemic reactions such as increased body temperature,general irritation and urticaria.,Immunity of TB,After exposure to TB again,sensitized lymphocytes transformed to lymphoblast to excrete chemokines,macrophage migration inhibitory factor and macrophage activating factor,etc.Macrophages aggregated and activated,most TB phagocytosed and killed,tuberculous nodules formed with epithelioid cells and Langerhans cells,lesions are limited.Activation of macrophages prevents tuberculous lesion progression and the exogenous reinfection of TB.when killed by macrophage,M.tuberculosis released a high concentration of tuberculin-like products which cause death of macrophage.,Genetics and susceptibility,HLA genotyping of 101 cases(36 tuberculous meningitis)in Beijing childrens Hospital demonstrated that HLA-BW35 and tuberculosis are closely associated,7.4 times relative risk of TB and 15.2 times risk of tuberculous,Pathology,Basic changes:exudation,proliferation and degenerationExudation seen in high allergic patients,exudate is made up of mononuclear cells and fibrin Proliferation seen in high immunity patients,tuberculous nodules and granuloma formed,main features of tuberculous inflammation.Degeneration is characterized by caseous necrosis,often occurs in the exudative lesions.good outcome of tuberculous inflammation is absorbing,fibrosis,calcification and ossification.,Epithelioid cells fused to form a giant cell,Langhans cell.,a golden example of a caseating granuloma,caseous necrosis in the center surrounded by a pale pink rim of epithelioid cells.,Nature progression of lung tuberculosis,Human tuberculosis:Natural History,Infection,Initial stay 95%,Early Progression-5%“Fast TB”,Tuberculosis:Transmission and Natural History,Infection,Initial stay 95%,Late Progression-5%“Reactivation TB”,Self-Cure 90%,Early Progression-5%“Fast TB”,Clinical Manifestations of TB,Generalfever,weight loss,weakness,“consumption”result from inflammatory responseOrgan specificpneumonia:cough,sputum+/-bloodscrofula:swollen lymph nodesgenitourinary:sterile pyuriabone:back pain,fracture,hump-back meningitis:headache,obtundationmiliary TB:no obvious source,Primary pulmonary tuberculosis,Primary pulmonary tuberculosis is the most common form of primary tuberculosis includes primary complex and tuberculosis of trachebronchial lymphnodes.,Primary complex includes the primary lesion in the pulmonary and the regional lymph nodes and lymphangitis.The hallmark of primary tuberculosis in the lung is the relatively large size of the regional lymphadenitis compared with the relatively small size of the initial lung focus.,Primary complex,The initial parenchymal inflammation usually is not visible on chest radiograph,or the initial parenchymal has resolved early,there is only the regional lymph,at this time it is called tuberculosis of trachebronchial lymphnodes.,tuberculosis of trachebronchial lymphnodes,Lesion in lung,Most of primary focus are in the basal part of upper lobes and superior part of lower lobes,near to subpleural.,Clinical manifestation,The symptoms and physical signs of pulmonary tuberculosis in children are surprisingly meager,considering the degree of radiographic changes often seen.,More than 50%of infants and children with radiographically moderate to severe pulmonary tuberculosis have no physical findings and are discovered only by contact tracing.,Infants are more likely to experience signs and symptom Nonproductive cough and mild dyspnea are the most common symptoms.Systemic complaints such as fever,night sweats,anorexia,and decreased activity less seen Some infants have difficulty gaining weight or develop a true failure-to-thrive syndrome,Peripheral lymph node enlarge in different degrees.Pulmonary signs are even less common.Some infants and young children with bronchial obstruction have localized wheezing or decreased breath sounds that may be accompanied by tachypnea or rarely,respiratory distress.,Chest radiograph of a girl with pulmonary tuberculosis.Note the significant hilar adenopathy in association with atelectasis,the so-called collapse-consolidation lesion,Clinical features in primary pulmonary tuberculosis,Severity variable,most without obvious symptoms Toxic symptoms:long-term low heat,weak,sweating,low appetite,and weight loss,meager oppressive symptoms:spasm coughing if bronchial oppression,hoarse sound if oppression of recurrent nerve by enlargement of lymph nodes highly allergic:erythema or blister corneal conjunctivitis,and joint swelling,Acute miliary tuberculosis,Primary lung TB caseous lesions ruptured to release a large number of TB into blood and disseminated to cause miliary tuberculosis more common in small or malnourished children initially infected within 3-6 months or after acute infectious diseases(such as measles,whooping cough,and so on),Clinical characteristics of acute miliary pulmonary tuberculosis in children,Most presented with acute onset,sudden high fever,cough,short of breath,pale,low appetite,toxic symptoms.There are also a few slow onset,characterized by low-heat,tuberculosis symptoms,often after the acute infectious diseases,weakness,night sweats,fatigue,chronic cough and other symptoms.50%children have superficial lymphadenopathy and hepatosplenomegaly,skin miliary rashes,choroidal tuberculous nodules,found around the central retinal artery branches,Diagnosis,History：of illness,exposure,infectious diseases and manifestation like cutaneous tuberculosis,positive PPD skin test symptom：obvious toxic TB symptoms but less pulmonary manifestationsign：enlarged cervical lymph nodes,Diagnosis（cont）,Mantoux test：replacing multipuncture testPathogen isolation：staining smear,culture,DNA probing,PCR of sputum and gastric aspiration Antibody Protein chip：Lam,16kd,38kd-sensitivity 76.74%,specificity 81.70%,Radiography：x-ray,CT,MRIPathology:tuberculous nodules and granulomasLymph node aspiration:lymphocytes,Thoracentesis:exudative effusion with a high protein,low glucose,lymphocyte,and an absence of mesothelial cellsOther：ESR,Flexible fiberoptic bronchoscopy,Mantoux test,A useful diagnostic tool:delayed-type hypersensitivity happens in most individuals infected with tubercle bacillusAlso called PPD skin test：intradermal injection of 5u PPD in 0.1ml，observe skin reaction by measuring induration 48-72hr later,Cut-off size for positive Mantoux test,Clinical significance of PPD skin test,5 points for positive result vaccination with Bacilli Calmette-Guerin Vaccination(BCG)previous infection if+positive but no clinical manifestation in older children,TB infection if positive in children 3 yr,not vaccinated with BCG,small ages is more likely to have active TB than old ages.,active TB disease is indicated for strong positive recent infection if transition from negative to positive,or the induration diameters become enlarged more than 6 mm,Differences between nature infection and BCG vaccination,Negative result,4 points for negative resultnot infected with TBtested too soon after breathing in the germs.It takes a number of weeks(4-8weeks)after becoming infected by the germ for the body to react to the skin test.If this happens,the test will have to be repeated again after 3 months.too weak or immunocompromised to react to the skin test although infected.（including malnutrition,immunosuppression by disease or drug,viral infections like measles,mumps,varicella,influenza;corticosteroid therapy）poor technique or lose efficacy of the reagent,Assesement of disease activity,According to the relations between age,exposure history and PPD skin testBody temperature：irregular fever in active tuberculosis Nutritional state and body weight：malnourished or underweight with unknown causes remind of active tuberculosisFast ESR with unknown causes Tubercle bacillus found in sputumActive lesions in radiography,Treatment,Firstly,to know the type,activity of tuberculosisSecondly,to note the nutritional state and liver and renal function Chemotherapy in the center of comprehensive thrapy,General treatment,Basis for comprehensive treatmentRational nutrition with foods rich in protein and vitamin A、D、CLiving environment:good ventilation and shiningStay on bed for exhausted patients and those with severe toxic symptoms,violent cough,Anti-TB chemotherapy,Depend on the replication of tubercle bacilli and penetrating and concentration of the drug tubercle bacilli can be killed only during replication tubercle bacilli in nonreplication can be obliterated slowly only through immunityNaturally resistant strain to anti-mycobacterial drug occur in 1 among 106 through gene mutationThe gene encoding for drug resistance located on a chromosome,dosnt transfer between organisms,The major biologic determinant of the success of Antituberculosis chemotherapy is the size of the bacillary population within the hostCavities or extensive infiltrates mean large population and shuld contain resistant strain,so require multi-drug therapyPoor adherence to or inadequate treatment lead to the development of drug resistant tuberculosis,Antimycobacterial drugs,Tubercle bacilli killing only when the drug tissue concentration reach 10 times of MICBactericidal drugs:isoniazid(异菸肼),rifampin(利福平)Semi-bactericidal drugs：streptomycin(链霉素)works on extra-cellular tubercle bacilli in neutral or alkali environment,Pyrazinamide(呲嗪酰胺)works on intra-cellular tubercle bacilli in acid environmentBacteriostatic drugs：Ethambutol(乙胺丁醇),Ethiomide(氨硫脲),aminoglucoside(氨基糖苷)、PAS(对氨基水杨酸钠),etc,Protocols,Normal course：INH、RFP and/orEMB for 9-12mTwo stages：3-4 bactericidal drugs for 3-4m，then 2（INH、RFP）for 12-18mShort course：3-4 bactericidal drugs for 2m，then 2（INH、RFP）for 4m,Corticosteroids,Beneficial when host inflammatory reaction contributes significantly to tissue damage or impairment of organ function,so lower toxic symptom,allergy and inflammation,collagen proleferation indication：beneficial order：pleural effusion or meningitis；extensive lung infiltrates；obvious toxic symptom and dyspnea in milliary；caseous pneumonia；tuberculosis of trachebronchial lymphnodes with dyspnea method：prednison at 1.5mg/kgfor 3-4 times，m/d,m for pleural effusion，m for others,Surgery,Mainly used for pulmonary segment,lobectomy or pneumonectomy,stripping of pleura.Indications:open lung cavity resistant to drugs.caseous foci or tumor-like tuberculosis resistant to drugs.hilar lymphadenopathy caused persistent bronchial stenosis and pulmonary atelectasis.hard and pulmonary fibrosis or calcification with recurrent hemoptysis.atelectasis caused by enlarged lymph nodes after the development of the bronchiectasis.,Prevention,1.Control the sources of infection:2.Bacilli Calmette-Guerin Vaccination(BCG):,Bacillus Calmette-Guerin(BCG)vaccine,a live,attenuated strain of Mycobacterium bovis introduced in 1922.the true efficacy of BCG is unknownEarly clinical trials in Europe showed up to 80%protection,but more recent trials in India and Africa showed little value.,Counterindication of BCG Vaccination,1.The patients of DiGeorge anormaly（congenital thymic aplasia）and severe combin