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Transcript of Tuberculosis
tuberculin purified protein derivative (PPD)
lack of specificity
Skin testing with tuberculin-PPD -used in 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
bacilli cannot be decolorized by acid alcohol - acid-fast bacilli
Acid fastness - high content of mycolic acids and other cell-wall lipids.
very low permeability of the cell wall - low effectiveness of most antibiotics.
lipoarabinomannan -facilitates the survival within macrophages.
From Infection to Disease
Primary TB is not generally associated with high transmissibility.
bacilli may persist and reactivate after years -
which is more infectious
up to 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
airways and expelled by ciliated mucosal cells,
reach the alveoli.
alveolar macrophages phagocytize the bacilli.
3.Opsonization of bacilli (C3b).
bacilli survive in the phagosomes.
Replication begins inside the macrophage
Macrophage eventually ruptures and releases its bacillary contents.
Other uninfected phagocytic cells ingest these bacilli
thus becoming infected themselves and expanding the infection
Acid Fast Bacilli Microscopy
low sensitivity (40–60%)
two or three sputum specimens collected early in the morning, should be submitted
Transmitted from a person by droplets: 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
duration of contact and the shared environment - important determinants
TB patients whose sputum contains AFB
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
is one of the most important factors in the transmission of tubercle bacilli
M. tuberculosis grows within naïve - unactivated macrophages
Additional naïve macrophages are recruited to the
The mycobacteria induces secretion of
matrix metalloproteinase 9 (MMP9)
by nearby epithelial cells
MMP9 stimulates recruitment of naïve macrophages, thus inducing more bacterial growth.
M. tuberculosis stimulates secretion of
tumor necrosis factor (TNF-alfa)
After repeated bouts of this process,
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 asymptomatic.
The Host Response and Granuloma Formation
2–4 weeks after infection, two host responses develop:
1. T cell–mediated macrophage-activating response -
activation of macrophages
that are capable of killing and digesting tubercle bacilli.
2. tissue-damaging response - result of a
delayed-type hypersensitivity (DTH)
reaction to various bacillary antigens;
destroys unactivated macrophages that contain multiplying bacilli
of the involved tissues
accumulation of large numbers of T lymphocytes and activated macrophages -
the tissue-damaging response can limit mycobacterial growth within macrophages.
this response destroys macrophages and also produces early solid necrosis in the center of the tubercle.
M. tuberculosis survives but its 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.
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 macrophages and monocytes
TH2 cells produce IL-4, IL-5, IL-10, and IL-13 -
promote humoral immunity.
defects of CD4+ T cells in HIV-infected individuals - 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 necrotic material resembles soft cheese (
Even when healing takes place, bacilli may remain dormant within macrophages for many years.
These "healed" lesions may calcify
6. Sometimes the macrophage response is weak, and
mycobacterial growth can be inhibited only by
Delayed Type Hypersensitivity
, which 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 fever
In areas of high TB transmission, this form is often seen in children.
middle and lower lung zones -
most commonly involved in primary TB.
The Ghon focus
- The lesion after initial infection
l and accompanied by hilar or paratracheal lymphadenopathy, which may not be visible on standard 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 young children and in persons with impaired CM immunity - primary pulmonary TB may progress rapidly to clinical illness.
The initial lesion increases in size
Primary pulmonary TB - after the initial infection with tubercle bacilli.
Pleural effusion -
results from the 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 distal 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
one-third 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%
cough - up to 90% of cases,
initially nonproductive cough in the morning and subsequent production of purulent sputum, sometimes bloody
in 20–30% of cases
Pleuritic chest pain sometimes .
Occasionally, rhonchi may be heard.
In some cases, pallor and finger clubbing develop.
mild anemia, leukocytosis, and thrombocytosis
slightly elevated erythrocyte sedimentation rate and/or C-reactive protein level.
reactivation or secondary TB
lymph node TB
- 35% of patients
painless swelling of the lymph nodes - most commonly
posterior cervical and supraclavicular
pulmonary disease is present in <50% of cases
systemic symptoms are 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 epididymis, producing a slightly tender mass, orchitis and prostatitis may also develop
Diagnosis requires biopsy or culture
Genitourinary TB responds well to chemotherapy
- in 20%
of patients. effusion 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 - reveals granulomas and a positive culture in up to 80% of cases.
This form of pleural TB responds rapidly to chemotherapy
straw colored fluid
is an exudate:
>50% of that in serum (usually 4–6 g/dL),
normal to low glucose
pH of 7.3
white blood cells (usually 500–6000/L)
is the typical finding later.
Tuberculous empyema -
rupture of a 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 visceral pleura (decortication) is occasionally necessary to improve lung function
bones and joints
10% of extrapulmonary cases.
spread from adjacent paravertebral lymph nodes.
Weight-bearing joints (the spine in 40% of cases, the hips in 13%, and the knees in 10%
Spinal TB -
- 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 due to a large abscess is a medical emergency and requires rapid drainage
Skeletal TB responds to chemotherapy, but severe cases may require surgery.
Meningitis and Tuberculoma
- 5% of extrapulmonary cases
most often in young children, Adults with HIV
headache 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 - ocular nerves
coma, with hydrocephalus and intracranial hypertension.
CSF: high leukocyte count (up to 1000/L), predominance of
, a protein content of 1–8 g/L (100–800 mg/dL); , low glucose concentration.
Culture of CSF - remains the gold standard.
Imaging studies (CT and MRI) - hydrocephalus and abnormal enhancement of basal cisterns or ependyma
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.
Gastrointestinal TB -
3.5% of extrapulmonary cases
swallowing of sputum with direct seeding, hematogenous spread, or (largely in developing areas) ingestion of milk from cows affected by bovine TB.
terminal ileum and the cecum
- most commonly involved.
Abdominal pain (at times similar to that associated with appendicitis) and swelling, obstruction, hematochezia, and a palpable mass in the abdomen are common findings at presentation.
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 should
paracentesis reveals high protein content and lymphocytosis
peritoneal biopsy is often needed to establish the diagnosis.
- 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 hematogenous spread of tubercle bacilli.
yellowish granulomas 1–2 mm in diameter that resemble millet seeds
Fever, night sweats, anorexia, weakness, and weight loss
hepatomegaly, splenomegaly, and lymphadenopathy
- grow slowly, 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 (e.g., Pott's disease)
diagnosis of intracranial TB.
IFN-gamma Release Assays (IGRA)
- measure T cell release of IFN-gamma in response to stimulation with TB-antigens
IGRAs are specific
positive Tuberkulin Skin Testing should be followed by an IGRA
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.
To prevent isoniazid-related neuropathy, pyridoxine 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
will have negative sputum cultures at the end of the 2nd month of treatment.
should be culture-negative
If sputum cultures remain positive at 3 months - treatment failure and drug resistance should be suspected
a chest radiograph obtained at the end of treatment may be useful for comparative purposes
Patients should be monitored for drug toxicity
The most common adverse reaction is hepatitis
Patients should be educated about the signs and symptoms of drug-induced hepatitis (e.g., dark urine, loss of appetite)
all adult patients should undergo assessment of liver function
For patients with symptomatic hepatitis and those with marked (five- to sixfold) elevations in serum levels of AST, treatment should be stopped and drugs reintroduced one at a time after liver function has returned to normal.
Hyperuricemia and arthralgia
caused by pyrazinamide can usually be 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 permanent dis
continuation of this drug.
- pyridoxine should be added
Orange body Fluids
BCG was derived from an attenuated M. bovis and was first administered to humans in 1921. A
BCG vaccine is safe and rarely causes serious complications.
The local tissue response begins 2–3 weeks after vaccination,
scar formation and healing within 3 months.
Side effects—most commonly,
ulceration at the vaccination site and regional lymphadenitis
—occur in 1–10% of vaccinated persons.
Some vaccine strains have caused osteomyelitis in 1 case per million doses administered.
BCG vaccine is recommended for
routine use at birth in countries with high TB prevalence
However, because of the low risk of transmission of TB in the United States, the unreliable protection afforded by BCG the vaccine has never been recommended in the United States.
HIV-infected adults and children should not receive BCG vaccine.
1. The Merck Manual of Diagnosis and Therapy - 19th Edition
2. Harrison's Principles of Internal Medicine - 18th edition