Tuberculosis

Tuberculosis YANG YUXIA The third afflicated hospital of zhengzhou university

summary Tuberculosis(TB) is a chronic infectious disease that caused by Mycobacterium tuberculosis. It usually affects the lung , but it can affect any organs in the body. Such as digestive system 、 skin.

World TB Day 24 March 2001

"DOTS - TB cure for All " "DOTS : un traitement antituberculeux pour tous"

Introduction

March 24 World TB Day 世界结核病日

Stop TB,

Fight Poverty. World TB Day

2002

World TB Day, March 24, 2004

World TB Day 24 March 2001

"DOTS - TB cure for All " "DOTS : un traitement antituberculeux pour tous"

一

Etiology

The agent of tuberculosis , Mycobacterium tuberculosis is member of the order Actinomycetales and family Mycobacteriaceae, weakly grampositive , and it is an obligate aerobes, Mycobacteria grow slowly, however growth can be detected in 1-3 weeks in selective liquid medium using radiolabeled nutrients(BACTEC)

Mycobacterium tuberculosis / 结核杆菌

 Acid-Fast bacillus, AFB (Robert Koch, 1882) 抗酸染色为红色 --- 抗酸杆菌

 M. tuberculosis ( 人型结核杆菌 ) & M. bovis （牛型结核杆菌） are two main species causing tuberculosis in human.

二： Epidemiology （一） Source of infection The major source of infection is the open pulmonary tuberculosis patients.

（二） 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

Transmission

an open active TB patient

（三） Susceptible population Poverty, over-crowding, poor nutrition and socioeconomic fall behind （ developments slowly ） plays the major role in the incidence.

三： Pathogeny The risk for developing tuberculosis disease in children who had contacted with bacillus tuberculosis at first time concerned with the Immune status of the host , the virulence and the quantity of the bacillus tuberculosis, especially the status of the cell-mediated immunity (CMI). After infected bacillus tuberculosis , the body produces the allergy and immunity at the same time .

[Theallergicreactionandim m unityof TB] pathogen(Tuberclebacillus) throughinfectiveroute(respiratory tract, alim entary placenta)

canal, skinand

child Thethymus

-dependent LCbesensitizedandproliferate

Delayedallergicreaction (Type4of allergic

reation

)

Activatingfactors

Inhibitingfactors of

of macrophage

Macrophagemovement

Activatingmacrophage Engulf andkill tuberclebacillus produce

Eptheloid

cellsandtubercle

Infectionis focused

TBissurrounded bysensitizedTLC

Pathogenesis Acid-Fast bacillus 进入体内（胞内寄生） 致敏 T 淋巴细胞（细胞免疫， 4~8 周 ） 释放 cytokines/lymphokines 激活 macrophages 吞噬和杀灭结核杆菌

四： Diagnosis Try to early diagnosis ． Include ： finding focus on infection; making a decision of it’s character and scope; whether discharge of bacteria or not; and make sure if it is reactiveness.

• Sex: female ＞ male • Age: ＜ 5 yrs

( 一 ) History: Toxic symptom: Prolong low grade fever, cough, night sweats, weakness, loss of weight, loss of appetite and so on. The history of exposure to the infectious tuberculosis, especially the children of contact with the infectious tuberculosis in their home.

The history of BCG vaccination The history with the acute infection diseases, especially , measles 、 whooping cough, The manifestation of hypersensitiveness of TB: such as erythema nodosum, herpes conjunctivitis.

（二） Tuberculin skin tests （ TST ） (1) Test methods: Assessment (Evaluation): The diameter of induration <5 mm (-) ≥5mm (++) ≥20mm (+++) Beside induration, there are still blister and necrosis (++++)

(2 ) Clinical significance positive result ① Bacilli Calmette-Guerin Vaccination (BCG) vaccination ② Older children with non-clinical manifestation, tuberculin test is (+)~ (++)(general reaction) means that the TB germs are probably inactive and TB disease not present.

③ Children < 3 yr of age, especially those who have not vaccinated BCG, positive result mostly represent that there is a new tuberculosis focus in the body, with small ages the active TB is more likely to be than old ages.

④ Strong positive usually means that there is an active TB disease. ⑤ Negative turn into positive result or the induration of the diameter enlarge more then 10 mm from small 10 mm and the amplification more than 6 mm, representation newly infected .

The major distinguishing between nature infection and BCG vaccination BCG vaccination

Nature

Millimeter of induration

Less then 5~9mm

10~15mm

Colour of induration

pink

crimson

texture of induration

Relatively soft; edge untidiness

Relatively hard Edge tidiness (regularity)

Last time of Positive reaction

Shortly 2~3days

Relatively long More then 7~10 days

Change of Positive reaction

Usually transient over months to years the reactivity usually wane in 3~5years

perstetur for several years even lifetime

negative result 1.It can mean that the person has not been infected with TB germs.

2.It can mean that the person was tested 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.

• 3.It can mean that the person's body defenses are weakened and unable to react to the skin test, even though he/she is infected. （ including malnutrition, immunosuppression by disease or drug ,viral infections :measles mumps varicella, influenza; corticosteroid therapy ） When this happens, another type of test is given. • 4. Poor technique or lose efficacy of the reagent

（三） Laboratory examine (1) Mycobacterium Detection and Isolation (2) Immunology and molecular biology diagnosis ① enzyme linked immunosorbent assay (ELISA) ② Enzyme linked immuno-electrophoresis(ELIEP )

③ DNA probes ④ Polymerase Chain Reaction (PCR)

(3) Erythrocyte sedimentation rate (ESR):

( 四 ) Image analysis (1) X-ray Examine: (2) Computerized tomography (CT): (3) Magnetic resonance imaging (MRI)

( 五 ) Other auxiliary examination

(1) Flexible fiberoptic bronchoscopy (2) Peripheral lymph node puncture fluid and smear examination: It can find tubercler and caseification

五 . Treatment General treatment Antituberculosis drugs Goals for treatment of tuberculosis (1) To kill the Mycobacterium tuberculosis in focus (2) To prevent the hematogenous spread

Therapeutic principle early, regular, enough, combine and proper dose (1) Early treatment (2) Appropriate suitable dosage (3) Disciplinary medication (4) Omnidistance (5) Segmentation

① drugs: INH, RFP, EMB, SM, PZA ② principles: early, regular, enough, combine and proper dose.

The most commonly used drugs are classified into two types (1) Bactericidal drugs: INH and RFP are highly bactericidal for M.tuberculosis STM are bactericidal for extra-cellular tubercle bacilli PZA are bactericidal for intra-cellular tubercle bacilli (2 ) Bacteriostatic drugs: EMB;ETH

Other drugs

The major distinguishing between nature infection and BCG vaccination drug

Dosage(kg/day) route of Major side effects {Maximum dose} administratio n

INH

10mg {≤300mg/day}

Po/im/iv.drop Hepatotoxicity; Peripheral neuritis Hypersensitivity reaction

RFP

10mg {≤450mg/day}

po

Hepatotoxicity; Gastrointestinal reactions

SM

20-30mg {≤0.75/day}

im

Ototoxicity nepatotoxicity Hypersensitivity reaction

PZA

20-30mg {≤0.75/day}

po

Hepatotoxicity; hyperuricemia Acute gouty arthritis

EMB

15-25mg

po

Optic neuritis

ETH

10-15mg

po

gastrointestinal reactions; Hepatotoxicity; Peripheral neuritis

Therapeutic regimen 1. Standard therapy regimen: commonly used asymptomatic primary pulmonary tuberclosis. INH RFP and/or EMB (should be given daily ) 9-12 months

2. Segmented therapy regimen: Used for reactive tuberculosis, acute miliary tuberculosis of the lungs, tuberculosis meningitis.

(1) Intensification therapy phase (three-or four-drug regimen): three/four drugs combination in order to kill the sensitive organism and multiply actively organism and hypometabolic (slow-metabolic) organism as soon as possible, preventing or decreasing emergence of drug resistant bacteria. (INH+RFP+SM+PZA) 3-4mo for long-term course 2 mo for short-term course

(2) Consolidation therapy stage: In order to eliminate the Mycobacterium of persistence.. Two antituberculosis drugs are given during this stage. 12 to 18 months for long course, 4 month for short course.

(3) Short course: The tendency of current therapeutic regimen is to increase the strength and shorten the course.

六． Prevention: 1. Control the sources of infection: 2. Bacilli Calmette-Guerin Vaccination (BCG):

Counterindication 1. The patients of DiGeorge anormaly （ congenital thymic aplasia ） and severe combined immunodeficiency 2. Convalescent period of acute infectious disease 3. There is eczema or dermatosis at injection site 4. A positive of tuberculin skin test

Chemoprophylaxis (1) Purpose ① Prevention the active pulmonarytuberculosis in children ② Prevention extrapulmonary tuberculosis ③ Prevention reactivation tuberculosis in adolescence children

(2) Indication ① Household close contacts with an adult of active pulmonary tuberculosis ② ≤3yr children and have not vaccinated BCG, however, positive skin test ③ Negative turn into positive result skin test recently

④ A positive skin test and having the symptom of tuberculosis disease ⑤ A positive skin test and infected measles or whooping cough ⑥ A positive skin test and should accept the therapy of corticosteroids or immunosuppression drugs for a long time

(3) Method The currently recommended regimen is 6-9mo of daily INH 10mg/kg/day (≤300mg/d) therapy. or 3mo of daily INH 10mg/kg/day(≤300mg/d) and RFP 10mg/kg/day (≤300mg/d).

Primary Pulmonary Tuberculosis

Definition • Primary pulmonary tuberculosis is the major type of pulmonary tuberculosis developed in children during initial infection. （原发型肺结核是指结核菌初次侵入肺部后发 生的原发感染，是小儿肺结核的主要类型，占 儿童各型肺结核总数的 85.3% 。）

Pathology • Basic pathological changes

Exudation / 渗出 Proliferation (tuberculous tubercle, tuberculous granuloma) 增殖（结核结节、结核性肉芽肿） Necrosis (caseation)/ 坏死（干酪性坏死）

• Outcome of pathological changes Fully Recover (Calcification/Absorption/Fibrosis) Progression Worsen

Pathology

特征性病理改变 ： 上皮样细胞 结节 tuberculous tubercle 、 Langerhans 细胞浸润

Manifestation The manifestation of TB in children are variable.  Onset of TB, chronic & hiding/ 起病常隐匿  Asymptom cases 80%  Upper respiratory tract infection ： dry cough and mild dyspnea are the most common symptoms.  Toxic symptoms of tuberculous infection  Malnutrition

Manifestation

The manifestation of TB in children are variable.  Hypersensitivity erythema nodosum/ 皮肤结节性红斑 phlyctenular conjunctivitis / 疱疹性眼结膜炎 arthritis / 关节炎

 On occasion, the onset of TB, abrupt  Lung symptoms asthmatic breathing, cough, etc.

Signs  Superficial lymph node swell  Lung signs 多无明显体征 叩诊可为浊音 听诊呼吸音减低 听诊少许湿罗音

Diagnosis  History  Manifestations  Physical examination  Immunology examination tuberculin skin test / ELISA / etc.  Chest X-ray examination  Fibrobronchoscope examination

Diagnosis 

Chest X-ray

 Primary Complex ( 原发综合征 ) primary focus at the site of implantation/ 原发病灶 tuberculous lymphangitis/ 淋巴管炎 regional tuberculous lymphadenopathy/ 淋巴结炎

呈典型 “哑铃状双极 影”

Diagnosis 

Chest X-ray

 Tuberculosis of Tracheobronchial Lymphonodu 支气管淋巴结结核

表现为：肺门影增浓

Tuberculosis of Tracheobronchial Lymphonodu

Turnover of primary pulmonary tuberculosis 1. Absorption and improvement : The primary pulmonary tuberculosis heals completely by fibrosis and/or calcification. (but healing is usually less complete ,Viable mycobacterium can persist for decades within these foci) It is the most common.

2. Progression: 3. Deterioration:

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 occur less often (older children may be have the symptoms).

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.

If the parenchymal focus comparatively large, dullness to percussion, decreased breath sounds. A little of dry / moist rales. Infants may be accompanied by splenohepatomegalia. (Hepatosplenomegaly)

Diagnosis and differential diagnosis 1. Diagnosis : Early diagnosis is very import Diagnosis depend on : ( The most specific confirmation of pulmonary tuberculosis is isolation of M.tuberculosis .But negative cultures never exclude the diagnosis of tuberculosis in a child, for most children, the presence of a positive tuberculin skin test, an abnormal chest radiograph consistent with tuberculosis, and history of exposure to an adult with infectious tuberculosis is adequate proof that the disease is present.)

2. Differential diagnosis ：

Treatment: 1. General treatments and therapeutic principles are the same as those in general introduction 2. Antituberculosis drugs (1) Asymptomatic primary pulmonary (2) Active primary pulmonary

DOTS is recommended INH+RFP+PZA/SM for 2-3mo followed by INH and RFP/EMB to complete a total treatment duration of 6mo

DOTS Directly Observed Treatment, Short-course

直接督导下的短程化疗

DOTS for primary pulmonary tuberculosis

2HRZ/4HR

or 9HR

最坏的治疗是单一用药 标准化疗方案： 2HRZ/4HR 推荐日剂量顿服 提倡直接督导下服药 （ DOTS ）

How to decide the reactiveness of tuberculosis in children? ① A strong positive of tuberculin skin test ② A positive of skin test in the children < 3 yr of age , especially <1 yr of age and have not been vaccinated the BCG.

③ symptoms of tuberculosis ④ Isolation of M.tuberculosis from discharge ⑤ radiographic changes means the reactiveness of primary pulmonary tuberculosis ⑥ ESR raises and there is not another reason to explain ⑦ Flexible fiberoptic bronchoscopy finds the change of bronchial tuberculosis

The tuberculous meningitis The tuberculous meningitis is the most serious type of tuberculosis in children. It often occurs within a year after the first infection of the tubercle bacillus, especially within the 3-6 months. Tuberculous meningitis is most common in children < 3 year of age, about 60%.

pathogenesis The tuberculous meningitis is often a part of the miliary tuberculosis of the whole body, which disseminates through the blood.

Pathology

Clinical manifestation 1.The earlier stage ( prodromal stage): （ lasts 1—2 weeks ） The cardinal symptom is the changes for the child‘s character child may have fever, poor appetite, night sweat, emaciated, emesis, constipation the infants may frown , gaze , drowsiness or delay of developmental. Focal neurologic signs are absent.

2. The intermediate stage ( the meningeal irritation stage) : The increased intracranial pressure causes the violent headache, projectile vomiting, lethargy, dysphorias or seizures.

The patient has obvious meningeal irritation sign, neck rigidity, positive Kernig sign or Brudzinski sign The infant may split of cranial sutures or eminence of anterior fontanel There are the dysfunction of encephalic nerves ， most common is facial nerve, oculomotor nerve, abducent nerve

Some children may have signs of encephalitis

3. The advanced stage ( the coma stage): It is marked by coma.

Diagnosis 1. The disease history 2. The clinical feature:

3. CSF measure: It is the most important laboratory test for the diagnosis of tuberculous meningitis is examination of the lumbar CSF.

Normal regulations check: The cerebrospinal fluid pressure increase and the external appearance is transparent or like frosted glass. When the subarachnoid space is obstructed, the CSF appearance is yellow.

Placing 12-24 hours, there will be the cobweb thin film in the cerebrospinal fluid The CSF leukocyte count usually ranges from 50×106/ L — 500×106/ L, lymphocytes predominate in the majority of cases.

The glucose is typically <2.2mmol/L(40mg/dl) but rarely < 1.1mmol/L(20mg/dl). Chlorides and glucose are lower than the normal level, which is the typical change of the tuberculous meningitis.

The protein level is elevated (1.0-3.0 g/ L) and may be markedly high 40-50 g/ L secondary to hydrocephalus and spinal block.

4. Other measures: ⑴ The tubercle bacillus antigen examination ⑵ Anti- tuberculosis antibody measure ⑶ Live of the adenosine deaminase(ADA) measure

⑷ Tuberculin skin- test ⑸ Mycobacterial culture of the CSF ⑹ Polymerase chain reaction( PCR)

5. X –ray CT and MRI:

Differential diagnosis 1. The purulent meningitis: 2. The viral meningitis 3. The cryptococcal meningitis 4. The brain tumor

Complications and sequelaes

Treatment 1. The general treatment: 2. The anti-tuberculosis treatment: Use several drugs together which can pass through blood-brain barrier easily (INH+ RFP+ PZA +SM) 3-4 mo followed by INH and RFP/EMB to complete the total treatment duration of 12mo

3. Decrease the intracranial hypertension: ⑴ Dehydrater: 20% mannitol ⑵ Diuretic: Diamox ⑶ lateral ventricle stabbing ⑷ Lumbar puncture and note the medicine into neurilemma ⑸ Shunting:

5. Symptomatic treatment ⑴ Treating the convulsion: ⑵ Treating the water-electrolyte disorder: ① Dilution hyponatremia: ② The syndrome of loses salt ③ Hypopotassaemia

6. Follow-up visit: The follow-up visit should last at least 3-5 years

Prognosis