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Transcript of Tuberculosis
tuberculin purified protein derivative (PPD)
against this antigen
Screening for latent M. tuberculosis
low sensitivity and specificity,
unable to discriminate between latent infection and active disease
False-positive reactions may be caused by infections with other mycobacteria and by BCG vaccination.
Often neutral on Gram's staining
- cannot be decolorized by acid alcohol
- high content of
and other cell-wall lipids.
low permeability of the cell wall - low effectiveness of most antibiotics.
-facilitates the survival within macrophages.
From Infection to Disease
Primary TB - not associated with high transmissibility.
Secondary TB -
is more infectious - Bacilli may persist and reactivate after years
10% of infected persons
will develop active TB in their lifetime.
The risk is much higher in
The risk that latent M. tuberculosis infection will proceed to active disease is
directly related to the patient's degree of immunosuppression.
the incidence of TB is highest during late adolescence and early adulthood;
the reasons are unclear
Infection and Macrophage Invasion
majority of inhaled bacilli are
trapped in the upper
and expelled by ciliated mucosal cells,
reach the alveoli.
3.Opsonization of bacilli (C3b).
in the phagosomes.
ruptures and releases
its bacillary contents.
uninfected phagocytic cells ingest
these bacilli - becoming infected themselves and expanding the infection
Acid Fast Bacilli Microscopy
low sensitivity (40–60%)
two or three
should be submitted
coughing, sneezing, or speaking.
There may be as many as
3000 infectious nuclei per cough
The tiny droplets dry rapidly;
the smallest (<5–10micrometers) may remain in the air for several hours
and may reach the terminal air passages when inhaled
duration of contact
and the shared environment - important determinants
TB patients whose
sputum contains Acid-Fast Bacilli
are the most likely to transmit the infection.
The most infectious patients have
cavitary pulmonary disease
Patients with sputum -negative/culture-positive TB are less infectious,
Crowding in poorly ventilated rooms
- one of the most important factors in the transmission of tubercle bacilli
1. M. tuberculosis grows within
naïve - unactivated macrophages
The mycobacteria induces secretion of
matrix metalloproteinase 9 (MMP9)
by epithelial cells
of more naïve macrophages
= more bacterial growth.
Additional naïve macrophages are recruited to the
2. M. tuberculosis stimulates secretion of
tumor necrosis factor (TNF-alfa)
recruits more inflammatory cells
3. After repeated bouts of this process,
dendritic cells (APC)
migrate to the lymph nodes
and present mycobacterial antigens to
At this point, the development of Cell Mediated Immunity and humoral immunity begins.
These initial stages of infection are usually
The Host Response and Granuloma Formation
2–4 weeks after infection, two host responses develop:
T cell–mediated macrophage-activating response
activation of macrophages
that are capable of killing and digesting tubercle bacilli
- result of a
delayed-type hypersensitivity (DTH) -
reaction to bacillary antigens;
destroys unactivated macrophages
that contain multiplying bacilli
the tissue-damaging response can
limit mycobacterial growth
this response destroys macrophages and also produces early
solid necrosis in the center
of the tubercle.
of the involved tissues
growth is inhibited
within this necrotic environment by low oxygen tension and low pH.
some lesions may
heal by fibrosis
, with subsequent calcification,
inflammation and necrosis occur in other lesions.
Large numbers of T lymphocytes and activated macrophages
1. Macrophages phagocytose bacilli and present it to T lymphocytes
2. Activation and proliferation of
CD4+ T lymphocytes
3. Activated CD4+ T lymphocytes differentiate into
TH1 cells produce
IFN - gamma
- activation of
TH2 cells produce
IL-4, IL-5, IL-10, and IL-13
promote humoral immunity -
activation of B cells
defects of CD4+ T cells in
= Inability to stop mycobacterial proliferation.
4. T lymphocytes activate macrophages by i
nterferon gamma (INF-gamma)
5. activated macrophages
aggregate around the lesion
and neutralize tubercle bacilli without causing further tissue damage
In the central part of the lesion, the
Even when healing takes place,
bacilli may remain dormant within macrophages
for many years.
These "healed" lesions may
6. Sometimes the macrophage response is weak, and
mycobacterial growth can be inhibited only by
Delayed Type Hypersensitivity -
leads to lung tissue destruction
The lesion enlarges and the surrounding tissue is progressively damaged
Bronchial walls and blood vessels are destroyed, and
cavities are formed
The caseous material, containing large numbers of bacilli, is drained through bronchi.
Within the cavity, tubercle bacilli multiply, spill into the airways, and are discharged into the environment through coughing and talking
are transported by macrophages to regional lymph nodes
from there they
reseed the lungs
and may also disseminate beyond the pulmonary vasculature throughout the body
The resulting extrapulmonary lesions may undergo the same evolution as those in the lungs, although most
tend to hea
In persons with poor immunity, hematogenous dissemination may result in
fatal miliary TB or tuberculous meningitis
may be asymptomatic or present with
In areas of high TB transmission - often seen
middle and lower lung zones -
most commonly involved
The Ghon focus
- The lesion after initial infection
l and accompanied by hilar or paratracheal
- may not be visible on chest radiography.
In the majority of cases, the
lesion heals spontaneously
and is seen as a
small calcified nodule
The Ghon focus, with overlying pleural reaction, thickening, and regional lymphadenopathy
In persons with impaired Cell Mediated immunity -
primary pulmonary TB may progress to clinical illness
Primary pulmonary TB - initial infection with tubercle bacilli.
Pleural effusion -
penetration of bacilli into the pleural space
In severe cases, the primary site rapidly enlarges, its central portion undergoes
necrosis, and cavitation develops
(progressive primary TB).
TB in young children is accompanied by
hilar or paratracheal lymphadenopathy
Enlarged lymph nodes may compress bronchi, causing obstruction with collapse
Lymph nodes may also rupture into the airway
1. Reactivation of latent infection
2. Recent infection (primary infection or reinfection)
- higher O2 favors mycobacterial growth.
- necrotic contents are discharged into the airways
1/3 of patients develop
severe pulmonary TB
within a few months
others may undergo
chronic, progressive course
some pulmonary lesions become fibrotic and calcify,
Individuals with chronic disease continue to discharge bacilli into the environment.
symptoms and signs are often nonspecific and insidious -
low grade fever and night sweats, weight loss,
anorexia, general malaise, and weakness in 80%
- up to 90% of cases
nonproductive cough in the morning and subsequent production of purulent sputum, sometimes bloody
in 20–30% of cases
Pleuritic chest pain
Occasionally, rhonchi may be heard.
In some cases,
pallor and finger clubbing
mild anemia, leukocytosis, and thrombocytosis
elevated erythrocyte sedimentation rate and/or C-reactive protein
Reactivation or secondary TB
lymph node TB
- 35% of patients
painless swelling of the lymph nodes -
Posterior cervical and supraclavicular -
pulmonary disease is present in <50% of cases
systemic symptoms - uncommon
The diagnosis - by
fine-needle aspiration biopsy
or surgical excision biopsy
- 10–15% of all extrapulmonary cases
Can involve any portion of the genitourinary tract.
Urinary frequency, dysuria, nocturia, hematuria, and flank pain
Urinalysis is abnormal in 90% of cases -
pyuria and hematuria
Genital TB is diagnosed more commonly in females - it affects the
fallopian tubes and the endometrium
In males - affects the
, producing a slightly tender mass,
orchitis and prostatitis
may also develop
biopsy or culture
Genitourinary TB responds well to chemotherapy
2. pleural Effusion
- in 20% of patients.
may resolve spontaneously or may cause symptoms:
fever, pleuritic chest pain, and dyspnea
dullness to percussion
and absence of breath sounds.
A chest radiograph reveals the effusion
Needle biopsy of the pleura
- granulomas and a positive culture in up to 80% of cases.
responds rapidly to therapy
Straw colored fluid
protein concentration >50% of that in serum (usually 4–6 g/dL),
normal to low glucose
pH of 7.3
white blood cells
is the typical finding later.
Tuberculous empyema -
rupture of a pulmonary cavity,
spillage of organisms
into the pleural space.
A chest radiograph shows
hydropneumothorax with an air-fluid level
The pleural fluid is
purulent and thick
large numbers of lymphocytes
Acid-fast smears and cultures are positive.
may result in severe
pleural fibrosis -
Removal of the thickened pleura (decortication) is occasionally necessary to improve lung function
Bones and joints
10% of extrapulmonary cases.
paravertebral lymph nodes
Weight-bearing joints -
Spine in 40%, hips in 13%, and knees in 10%)
Spinal TB - Pott's disease - involves vertebral bodies.
CT or MR
I reveals the characteristic lesion
of the abscess or bone
A catastrophic complication of Pott's disease is
due to spinal cord compression.
Paraparesis is a
Skeletal TB responds to chemotherapy, but severe cases require surgery.
Meningitis and Tuberculoma
- 5% of extrapulmonary cases
most often in
young children, Adults with HIV
and slight mental changes
low-grade fever, malaise, anorexia, and irritability.
may evolve acutely with
severe headache, confusion, lethargy, altered sensorium, and neck rigidity
paresis of cranial nerves -
coma, with hydrocephalus and intracranial hypertension.
high leukocyte count (up to 1000/L) - predominance of
a protein content of 1–8 g/L (100–800 mg/dL); , (Normal - 15 to 45 mg/dl)
low glucose concentration
Culture of CSF - gold standard
Imaging studies (
CT and MRI
) - hydrocephalus
one or more space-occupying lesions, causes seizures and focal signs.
CT or MRI reveals contrast-enhanced ring lesions,
is necessary to establish the diagnosis.
3.5% of extrapulmonary cases
swallowing of sputum
with direct seeding, hematogenous spread, or
ingestion of milk from cows
affected by bovine TB.
terminal ileum and the cecum
- most commonly involved.
(resembling appendicitis) and swelling, obstruction, hematochezia, and a palpable mass in the abdomen - common findings
Fever, weight loss, anorexia, and night sweats
are also common.
- direct spread of tubercle bacilli from ruptured lymph nodes, or hematogenous seeding.
Nonspecific abdominal pain, fever, and ascites
- high protein content and lymphocytosis
is often needed
- direct extension, hematogenous spread
dyspnea, fever, dull retrosternal pain
, and a
pericardial friction rub
signs of cardiac tamponade
under echocardiographic guidance.
The effusion is exudate -
high count of lymphocytes
Without treatment, pericardial TB is usually fatal.
with thickening of the pericardium
Miliary or Disseminated TB
- due to
of tubercle bacilli.
1–2 mm in diameter that resemble millet seeds
Fever, night sweats, anorexia, weakness, and weight loss
Hepatomegaly, splenomegaly, and lymphadenopathy
4–8 weeks may be required
Nucleic Acid Amplification -
Diagnosis of TB in several hours
"classic" picture of
upper-lobe disease with infiltrates and cavities on X-ray
virtually any radiographic pattern can be seen
- diagnosing extrapulmonary TB ( Pott's disease)
diagnosis of intracranial TB.
IFN-gamma Release Assays (IGRA)
T cell release of IFN-gamma
in response to stimulation with TB-antigens
positive Tuberkulin Skin Testing should be followed by an IGRA
IGRAs are specific
the majority of the bacilli are killed, symptoms resolve, patient becomes noninfectious.
The continuation phase:
to eliminate persisting mycobacteria and prevent relapse
2-month initial phase of
isoniazid, rifampin, pyrazinamide, and ethambutol
followed by a
4-month continuation phase
of isoniazid and rifampin
For patients with
sputum culture–negative pulmonary TB,
the duration of treatment may be reduced to a total of 4 months.
should be added to the regimen given to persons at high risk of vitamin B6 deficiency
Monthly sputum examination
until cultures become negative.
>80% of patients - negative sputum cultures
at the end of the 2nd month of treatment
should be culture-negative
If sputum cultures remain positive at 3 months -
and drug resistance should be suspected
a chest radiograph at the end of treatment - useful for comparing
Patients should be monitored for drug toxicities:
The most common adverse reaction is hepatitis
all adult patients should undergo assessment of liver function
Patients should be educated about symptoms of drug-induced hepatitis ( dark urine, loss of appetite)
Symptomatic hepatitis and those with
marked (five- to sixfold) elevations
in serum levels of AST-
treatment should be stopped
drugs reintroduced one at a time
after liver function has returned to normal.
Hyperuricemia and arthralgia
caused by pyrazinamide - managed by the administration of acetylsalicylic acid;
pyrazinamide treatment should be stopped if the patient develops gouty arthritis.
secondary to rifampin therapy
with ethambutol is an indication for
of this drug
- pyridoxine (B6) should be added to drug regimen
Orange body Fluids
BCG was derived from an
attenuated M. bovis
and was first administered to humans in 1921.
BCG vaccine - safe and rarely causes serious complications.
The local tissue response begins
2–3 weeks after
scar formation and healing within 3 months
Side effects—most commonly,
ulceration at the vaccination site and regional lymphadenitis
— 1–10% of vaccinated persons.
Some vaccine strains have caused osteomyelitis in
1 case per million doses
BCG vaccine is recommended for
routine use at birth in countries with high TB prevalence
1. The Merck Manual of Diagnosis and Therapy - 19th Edition
2. Harrison's Principles of Internal Medicine - 19th edition
Estimated tuberculosis incidence rates in 2013 (per 100,000 population)
ACTIVATION OF T cells
MAJOR SIDE -EFFECTS:
Erythema - not
used only for the treatment of patients with TB resistant to first-line
the fluoroquinolones -
levofloxacin and moxifloxacin
2) the injectable
kanamycin, amikacin, and streptomycin
Streptomycin - formerly a first-line agent,
now rarely used - resistance are high and it is
more toxic than the other drugs
(3) the injectable polypeptide
ethionamide and prothionamide
cycloserine and terizidone
para-aminosalicylic acid (PAS)
Six classes of second-line drugs
HIV-infected adults and children should
receive BCG vaccine.
Because of the low risk of transmission of TB in the United States and the unreliable protection afforded by BCG - the vaccine
has never been recommended in the United States.