Download M. tuberculosis

TUBERCULOSİS
Prof.Dr.Yıldız Camcıoğlu
Tuberculosis(TB)
• Mycobacterium tuberculosis
• Mycobacterium bovis
• Mycobacterium tuberculosis infects millions of
children every year and yet exact rate of morbidity
and mortality is not known in developing countries
due to difficulties in diagnose of diseases in childhood.
Poverty, overcrowding, inadequate tuberculous control
programmes, MDR tuberculosis and HIV infection
have all contributed to spread of Tuberculosis
worldwide
Childhood TB
• It has been estimated that 3.1 million children
under 15 years of age are infected with TB
worldwide.
• According to the World Health Organization
(WHO), children with TB represent 10 % to
20 % of all TB cases.
M.tuberculosis and M.bovis
0,3-0,6 micron x 2-4 micron
aerobic
Celll wall;A)Plasma membrane;
Peptidoglicans
Arabinogalactan
Micolik aside
B)Complex polymers
Antigens; 38 kd, 88kd, Antigen 5, Antigen A6,
Lipoarabinomannan(LAM), Cord Factor
Transmission
95% TB is an airborne disease, transmitted by particles,
or droplet nuclei that are expelled when persons who
have pulmonary or laryngeal TB sneeze, cough, speak
or sing
1.4% By drinking infected milk
1.4% Inoculation of bacilli by skin and mucosal
contusions
• Congenital TB
Features of The TB in Childhood
• Pulmonary TB in children has a low bacillary load and
cavities are also rarely present.
• Children also lack the forceful cough mechanism seen in
adults
• Adolescents and older children are important exceptions
since their disease closely resembles that of adults
• The disease more often progresses from an initial or primary
infection.
• 50 % of pediatric patients may remain asymptomatic with
subtle abnormalities on the chest radiograph
• Children younger than five years old may develop
disseminated TB in the form of miliary disease or
Stage I
• Droplet nuclei containing between one to 10 bacilli and
a diameter close to 10 μm are expelled with the cough,
suspended in the air and transported by air currents.
• Some of these droplet nuclei, usually larger than 10 μm,
are inhaled and anchored in the upper respiratory tract
• The mucus and the ciliary system of the respiratory tract
avoid further progression of mycobacteria.
Dannenberg, Jr AM Immunol Today 1991
Stage II:Symbiotic stage
• Subsequently, alveolar macrophages
phagocytose the inhaled bacilli
• These first macrophages are unable to kill
mycobacteria
• The bacilli continue their replication inside
these cells
• Logarithmic multiplication of the
mycobacteria takes place within the
macrophage at the primary infection site.
Stage III: CMI and DTH
• Two or three weeks after the initial M. tuberculosis
infection, a cell-mediated immune response is fully
established
• While CD4+ T helper cells activate the macrophages
to kill the intracellular bacteria and finally cause epithelioid
granuloma formation,
• CD8+ suppressor T cells lyse the infected macrophages,
resulting in the formation of caseous granulomas with
central necrosis
• The only evidence of a real and effective infection is a
positive TST
Primary pulmonary Tuberculosis
•Symptoms vary according to the degree of airway
irritation and obstruction
•Frequently a persistent cough that may mimic
pertussis and Mild fever
•70 % of the primary foci are subpleural
•25% of cases have multiple parenchymal foci
• A common radiographic sequence is adenopathy
followed by localized hyperinflation and then
atelectasis of contiguous parenchyma
•Adenopathies are more striking than parenchymal
focus
• Adenopathies heal with calsification
Pulmonary Infection
•Affected regional lymph nodes attach to the bronchus
• In some children, particularly infants, the lymph nodes continue
to enlarge, resulting in lymphobronchial involvement, in which the
affected bronchus may become partially or totally obstructed
•The area of caseation may discharge into a bronchus, resulting in
the formation of a cavity with possible endotracheal spread
•Similarly, regional lymph node involvement may accompany
marked clinical symptoms
•The most frequently affected lobes are the right upper, the right
middle, and the left upper lobe
Differential Diagnosis
• Bacterial pneumonia
S.Pneumoniae
TWAR
B.pertussis
• Viral pneumonia
Influenza A, B
Adenovirüs 3, 4,7
RSV
• Fungal pneumonia
H.capsulatum
C.immitis
B.dermatitis
•Astma
•Aspiration;
•Chemicals; Drugs
Stage IV:Liquefaction
Rapid replication of Bacilli
• Reactivation, liquefaction, cavitation
• Bacilli begins to replicate Extra cellularly
• Airborde spread is possible; Transmission
Progressive primary pulmonary
tuberculosis
Progression of the pulmonary parenchymal component
leads to enlargement of the caseous area and may lead to
pneumonia, atelectasis, and air trapping.
This is more likely to occur in young children than in
adolescents
The child usually appears ill with symptoms of fever,
cough, malaise and weight loss
This form presents classic signs of pneumonia, including
tachypnea, dullness to percussion, nasal flaring, grunting,
egophony, decreased breath sounds, and crackles
Pleural Involvement
•Pleural involvement may result from direct spread of caseous material
from a subpleural parenchymal or lymph node focus, or from
hematogenous spread
• The presence of caseous material in the pleural space may trigger a
hypersensitivity reaction, with the accumulation of serous straw-colored
fluid containing few tubercle bacilli
• This exudate has a high protein count and lymphocyte predominance;
the number of polymorphonuclear cells depends on the acuteness of
onset
• Although direct microscopy often is negative, culture yields may be as
high as 70 percent
Pleural
involvement
85 % acute onset of fever,
52 % chest pain on deep inspiration
28 % shortness of breath
Pleural effusion due to TB usually occurs in older children
The pain accompanies the onset of the pleural effusion,
but after that the pleural involvement is painless.
Fever usually persists for 14-21 days.
The signs of pleural effusion include tachypnea, respiratory
distress, decreased breath sounds, dullness to percussion,
and occasionally, features of mediastinalshift.
TB
Pericarditis
• Directly dissemination or by lymphatic drainage
from subcarinal lymph nodes
• Fever, cough, weight loss, malaise, chest pain
• Physical exam ; Dyspnea and ortopnea
Edema at ankle
Pericardial rubbing
• Pericardial fluid;
Serofibrinous or mild hemoragic
30-70 % bacilli yielded
• Constrictive pericarditis
Miliary Tuberculosis
100 % Fever
63 % Cough
25 % Dyspnea
24 % Malaise
23% Vomiting
16 % weight loss
13 % Abdominal pain
11 % Convulsions
11 % Diarrhea
8 % Wheezing
5 % Headache
Lymph Node Involvement
• 17 % of those all TB cases
• 9 billion new cases
• Drinking of infected cow milk ; M.bovis or
M.avium, M.intracellulare, M.scrofulaceum
• M.tuberculosis
• 30-70 % primary focus is at lung
• Patients with scrofula may complain of enlarged nodes
• Fever, weight loss, fatigue,and malaise are usually
absent or minimal
• Lymph node involvement typically occurs between six
to nine months following the initial infection.
TB Meningitis
• Pathology: meningoencephalitis
• Caseous focusus(Rich focus) at Cerebral cortex or
basal meninges
• Dissemination of subarachnoid area
• Thick exudate enriched of lympocytes and plasma
cells covers interpedincular and pontin cisterna
• Disseminates lateral sulcus and cisterna ambiens,
cisterna magna and chiasmatik cisterna
TB Meningitis
• Cerebral vessel, nerves , choroid plexus in ventriculles
are alll covered by thick exudate
Cerebral vessel damage and brain infarcts
Vasculitis, aneurisma, trombosis and
Focal hemoragic infarcts
• Thick exudate result in(early stage);
Impairment of CSF flow
in late stage; Adhesions and hydrocephaly
• Hyponatremia
• Inapproprite ADH release(%70)
TB Meningitis
I. Onset: insidious onset of the disease, 1-2 weeks, low-grade
persistent fever, malaise, anorexia, weight loss,fatigue,
hepatomegaly, splenomegaly and generalized
lymphadenopathy
II.Meninges irritation: vomiting,headache, nuchal rigidity,
seizures,hypertonia, minor neurological changes; mild
consciousness ,anisochory,double vision, loss of abdominal
reflexes, convulsion
III.The final stage:Alteration in consciousness and sensorium,
III, VI ,VII nerve involvement comprises major neurological
defects, including coma, seizures,and abnormal movements
(e.g. choreoathetosis, paresis, paralysis of one or more
extremities) , decerebrated or decorticated posturing,
opisthotonus
• Gastrointestinal TB
• At every site of GIS
• Rare at oral cavity
lympadenopathies
accompanies painless
ulsers at the mucosa of
month, gums, tonsils
• Eosophagal TB
Trachea-eosophagal
fistula at infants
intestinal TB
• Drinking unpasteurised milk or
milk infected with M.bovis
• mesenteric lymph nodes and
peritoneum infection occurs by
lymphatic drainage
• 60 % ulsers occurs
• Jejunum, ileum and appendices
• Sığ ülserler pain, tenesmus,
diarrhea or constipationveya
kabızlık, abdominal distension,
weight loss , low set fever
Diag; Biopsy
Gastrointestinal TB
Mesenteric TB
• Hematogenous dissemination
• Lymphoma ?
• Pain at exercise
• Intestinal obstruction, peritonitis
Peritonitis
• Disseminate from adjacent tissues
• Palpable lymph nodes, omentum and periton klamps each
other and resembles irregular abdominal masses
• Mild fever, abdominal distension, loss of appetite,, weight loss
and serous effussion(asite) may occur
Osteoarticular TB
• Appear in 1 % to 6 % of untreated primary infections
• Clinical and radiographic presentations vary widely and depend upon
the stage of the disease at the time of diagnosis
• Skeletal TB may remain unrecognized for months to years because of
its lack of specific signs and symptoms and indolent nature
• Bone or joint TB may present acutely or subacutely
• Sites commonly involved are the large weight-bearing bones or joints
including the vertebrae (50 %), hips (15 %), and knees (15 %)
• Less common skeletal sites are the femur, tibia, and fibula.
• Destruction of the bones with deformity is a late sign of TB
• Manifestations may include angulation of the spine or “gibbus
deformity” and/or the severe kyphosis with destruction of the
vertebral bodies or “Pott’s disease”
• Cervical spine involvement may result in atlantoaxial subluxation,
which may lead to paraplegia or quadriplegia
• TB of the skeletal system may also lead to involvement of the
inguinal, epitrochlear, or axillary lymph nodes
Osteoarticular TB
TB Dactilitis
(spina ventoza).
Distal endarteritis
No pain
Cystic enlargement
Rarely occurs abscess
Cutaneous Tuberculosis
Hypersensitvity or haematogenous dissemination
Cutaneous papules
3-8 weeks later regional lymphadenopathies
No systemic symptoms
Papulonecrotic tuberculide
Miliary lesions on skin
On face, trunk,
Upper extremities
Verrucosa cutis
Wart like lesion
On extremities
Dif.diag; Letterer-siwe diseases and urticary
Congenital TB
A very rare event in the whole spectrum of TB
presentations.
This infection is caused by lymphohematogenous
spread during pregnancy from an infected placenta
or aspiration of contaminated amniotic fluid.
Symptoms typically develop during the second or
third week of life
Poor feeding, poor weight gain, cough, lethargy, and
irritability
Other symptoms include fever, ear discharge, and
skin lesions, failure to thrive, icterus,
hepatosplenomegaly,tachypnea, and
lymphadenopathy.
Congenital TB diagnosis
Congenital TB diagnosis is based on clinical features and
the infant should have at least one of the following
proven TB Lesions
• Skin lesions during the first week of life, including
papular lesions or petechiae, necrotic or purpuric
lesions
• Choroidal tubercles in the retina
• Documentation of TB infection of the placenta or the
maternal genital tract
• Presence of a primary hepatic complex (liver and
regional lymph-node involvement)
• Exclusion of the possibility of postnatal transmission
Suspicion Of TB
• Symptoms: persistent cough, fever, night
sweats, weight loss
• Risk factors for exposure to TB: close contact
of case, residence/travel in high prevalence
country, congregate living with other high risk
individuals
• Risk factors for development of active disease
if infected: recent infection, HIV/AIDS, other
underlying medical condition
Blood Cells
Mild anemia
Monocytosis
High ESR
Radiological Studies
(80-85% of TB Cases)
• Chest x-ray
– Standard PA and lateral films; apical lordotic views may be
helpful
– Infiltrates, nodular densities, cavities, +/- hilar adenopathy
– Abnormalities may be subtle in immunocompromised patients
– Previous x-rays for comparison may be useful
• CT scans
– Often obtained
– Nice to have but rarely critical to diagnosis
– Expensive
Diagnosis of Pulmonary TB
• TST
– Positive supports but does not make diagnosis
– Negative does not exclude TB as possible
diagnosis
• Quantiferon
– Screening test only, not diagnostic
> 5mm
• Contact with infectious cases
• Abnormal Chest X ray
• HIV infection and other immunocompromise
>10 mm
• Age ≤ 4years of age
• Certain medical risk factors: Hodgkin, diabetes Mellitus , renal diseases,
malnutrion
• Member of local high –risk group
• Birth or previous residence in high prevalence
• Occupation in health care field, exposure to patients with TB
• Close contact with a high –risk adult
• Residence in long term care or correction facilities
>15mm
No risk factor
TST
Biochemical results
CSF, synovial Fluid;
High Protein level
Lymphocytes 500/ mm3
Pleural ve peritoneal fluid ;
Exudate
Dansity >1016
Protein level >3 gr/dl
Lymphocytes 500/mm3
Glycose
Lactic dehidrogenase
Adenosine deaminase
LOW
HİGH
HİGH
SCAN and US
*CT SCAN;
TB meningitis; Tuberculoma and
hydrosefaly
•Ultrasonography;
Peritonitis, mesenteric adenitis
Laboratory Tests for M.tb
• Culture and Identification of Isolate
–
–
–
–
“Gold standard” for TB diagnosis
Usually complete in 2-4 weeks
Not signed out as negative until 8 weeks
Traditional identification based on growth characteristics,
biochemical tests
– ID by “probe” now standard
• Requires isolate (2-4 weeks)
• Tests DNA – can ID M.tb complex, M.avium, +/others
• More rapid than chemicals, just as accurate
• Cannot distinguish among M.tb complex species
(M.tb vs. M.bovis)
Laboratory Tests for M.tb
• Antimicrobial susceptibility testing
–
–
–
–
–
Requires isolate
2-4 weeks after isolate available
IREZ +/- S testing standard
Second line drug testing only on request
3-10% of VA TB isolates resistant to > 1 first line
TB drug
• Continue IREZ until susceptibility results available
Biopsy
Skin
Lymph nodes
Bone
Pleura
Granuloma formation
Treatment of TB Disease
• The first rules of TB treatment are:
– Enough drugs (4 to start)
– The right drugs (antimicrobial sensitivities)
– Enough milligrams of each drug (patient
weight)
– Enough doses (count doses)
– Enough attention to detail (monitoring of
laboratory studies and clinical course)
Antituberculosis Drugs Currently in Use
• First-line Drugs
–
–
–
–
–
–
Isoniazid
Rifampin
Rifapentine
Rifabutin
Ethambutol
Pyrazinamide
• Second-line Drugs
–
–
–
–
–
–
–
–
–
–
Cycloserine
Ethionamide
Levofloxacin
Moxifloxacin
Gatifloxacin
P-Aminosalicylic acid
Streptomycin
Amikacin/kanamycin
Capreomycin
Linezolid
Drug
Isoniazid
Weekly
2 times a week
mg/kg
(max)
Daily dose
mg/kg (max)
5–10
(300 mg)
Side effect
20–40
(900 mg)
hepatitis , neuritis
hypersensitivity
Rifampin
10–20
(600 mg)
10–20
(600 mg)
Orange coulor of urine, vomiting,
hepatitis, influenza like syndrome,
trhombocytopenia,
Pyrazinamide
2540
(2000 mg)
50–70
(4000 mg)
Hepatotoxick hiperürisemi,artralgia,
GİS symptoms
Optic neuritis, GİS symptoms
after 7 years of age
Ethambutol
15-25
(2500mg)
Streptomycin
20- 40
(1000 mg)
Ethionamide
10–20
(1000mg)
50
(2500mg)
Ototoxidity , nefrotoxic
-
GİS symptoms, hepatotoxic,,
hypothroidy
Preventive therapy
Preventive therapy may be given to persons who have a negative skin
test reaction
– High-risk contacts
– Children younger than 6 months of age who have been exposed to TB
Persons receiving preventive therapy are those who have a positive skin
test, and those who are:
• more likely to be exposed to or infected with M. tuberculosis
• more likely to develop TB disease once infected
All persons receiving preventive therapy should receive a medical
evaluation to:
– Exclude the possibility of TB disease
– Determine whether they have ever been treated for TB infection or disease
– Identify any medical problems that may complicate therapy or require more careful
monitoring
Features of Childhood TB
•
•
•
•
•
•
•
•
Farmacokinetic effects of drugs vary
Few bacilli found in caseous lesion
Development of secondary resistance ratio is low
Extrapulmonary diseases are frequent
Drug tolerance is better than adults
Low side effects against drugs
Drugs are for adults
For that reason children have problems to swallow
the tablets, taste are not good
Treatment
Asymptomatic infection
NO Disease
Pulmonary TB
or
TTS(+) INH 6-9 m
INH+RIF
9-12 m
INH+RIF+SM
or INH+RIF+PZA
or INH+RIF+ETB
(DOT)
INH+RIF
2 months daily +
7 months 2 days weekly
Hilar adenopathy
Same as Pulmonary
Extratorasic TB
Same as Pulmonary
(Except Miliary, meningitis, osteoarticular )
Miliary, meningitis,
osteoarticular
INH+RIF+PZA+SM 2 months daily +
+ INH+RIF
10 months daily
+or INH+RIF 10 months 2 days weekly
Risk of Drug Resistance
• Treated patients with Active TB
• Contact with patients who have drug resistant
TB
• Contact with immigrants
• Living in the population with INH resistance
higher than 4%
• The patients with bacilli(+) sputum after 2
months of antituberculous treatment and
contact with those patients
STEROİD
•
•
•
•
•
•
Meningitis
Pleural involvement
Pericarditis
Peritonitis
Severe Miliary TB
Atelectasis or obstruction
2 mg/kg/day for 15 days. than in decreased doses,
Stop 4-6 weeks after
Diagnosis/Follow-up of Pulmonary vs.
Extra-Pulmonary TB
• Extra-pulmonary
• Pulmonary
– Sputum for AFB smear and
culture
– Chest x-ray helpful
– Follow-up sputum smears
and cultures useful to
monitor treatment
– More variability in presentation;
may be more difficult to diagnose
– AFB smear and culture done on
tissue or fluid
– Follow-up smears/cultures may
not be possible
– Must evaluate for pulmonary
disease
– Chest x-ray may be normal; xrays/scans may be helpful