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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 gram-
positive , 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 .
[Theallergicreactionandimmunityof TB]
pathogen(Tuberclebacillus)
throughinfectiveroute(respiratory
tract, alimentary canal, skinand
placenta)

child

Thethymus -dependent LCbesensitizedandproliferate

Delayedallergicreaction Inhibitingfactors of
Activatingfactors
(Type4of allergic reation )
of macrophage Macrophagemovement

Activatingmacrophage TBissurrounded
bysensitizedTLC
Engulf andkill tuberclebacillus
produce
Eptheloid cellsandtubercle

Infectionis focused
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; Relatively hard


edge untidiness Edge tidiness (regularity)

Last time of Shortly Relatively long


Positive reaction 2~3days More then 7~10 days

Change of Usually transient over months to years perstetur for several years even
Positive reaction the reactivity usually wane lifetime
in 3~5years
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 Po/im/iv.drop Hepatotoxicity; Peripheral
{≤300mg/day} neuritis
Hypersensitivity reaction
RFP 10mg po Hepatotoxicity;
{≤450mg/day} Gastrointestinal reactions
SM 20-30mg im Ototoxicity nepatotoxicity
{≤0.75/day} Hypersensitivity reaction
PZA 20-30mg po Hepatotoxicity; hyperuricemia
{≤0.75/day} 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