Mycobacterium Tuberculosis Flashcards
What causes tuberculosis?
Mycobacterium tuberculosis is the major cause of tuberculosis, but this disease can be caused by a group of closely related species of Mycobacterium tuberculosis complex MTC
What’s the definition of tuberculosis?
Chronic disease characterized by delayed hypersensitivity and granuloma
Which bacteria are included in the MTC?
M. tuberculosis
M. Bovis
M. Canetti
M. Microtti
To what is linked the muramic acid of the PGL wall?
Arabinogalactan layer composed of arabinose and galactose
What do we find above this layer?
Large amount of mycolic acid overlain by free lipids and glycolipids
Where polypeptides are located? What derives from them?
Polypeptides are above the lipid layer
PPD, purified protein derivative, derives from them
What is the function of the PPD?
They activate the cell mediated immunity
What makes them virulent?
They are capable of intracellular growth in unactivated alveolar macrophages
What causes the disease primarily?
Disease is primarily caused by the host response to infection
The disease is immunopathological, resulting from the production of granulomas, not caused by exotoxin or LPS..
Who are the reservoir?
Humans
How it is transmitted?
Person to person spread by aerosols from diseased individuals via coughing, sneezing or vocalizing
What are the basic conditions for transmission?
Extent of the disease Extent of the exposure Absence of UV light and improper ventilation Malnutrition Age Frequency of the coughs
When individuals are highly infectious?
When they expectorate the bacteria
What’s the period of exposure in order to be infected?
To be infected, there has to be a long period of exposure to infected individuals
What destroys the bacteria first?
UV light
In which age groups that is a quicker progression of the disease?
In individuals less than 1 year old and in elderly people
How the cough progresses?
It is mild repetitive at the beginning, not as severe as that caused by a viral or different bacterial ideology. In late stages, there is hemoptysis
What’s the problem of MTC?
The resistance to regular disinfectants and detergents
How the primary infection is acquired?
By droplet nuclei because of the small size of the bacteria
Where do they go? Why?
They go to alveoli since there is O2, they also need 5 to 10% of CO2
By which cell they are phagocytosed?
By macrophages
Where do they go then? How they are transported?
They go via these macrophages into regional lymph nodes, hilar lymph nodes
What is the outcome of the primary infection?
Individuals remain chronic carriers of the bacteria, in a dormant state in the granulomas
How the disease is confined?
The disease is confined by these granulomas covered with calcified tissue, that can be detected with a chest x-ray
Are individuals infectious at this stage?
Do they have symptoms? How do we know that they are infected?
They are not infectious, they can live long lives as long as the activated macrophages are controlling, so the macrophage-mediated immunity is stronger
They have no symptoms and the only way to tell they’re infected is the PPD test
When do we talk of a postprimary tuberculosis?
When DTH, delayed type hypersensitivity, prevails
To what is related the disease?
It is related to a chronic granulomatous state that is a DTH disease
What happens in the stage instead of the confinement?
Tissue distruction instead of confinement of the infection
Which other cells participate in the distraction?
Tc lymphocytes and NK cells
How the distruction happens?
There is liquefaction of the casestion part and bursting of the granuloma
What does the bacteria after tissue destruction?
Bacteria multiply rapidly in the caseation part
They will go out, leaving a cavity —> cavitation stage
What happens during the cavitation stage?
It is a source of more extensive coughs with expectoration of more sputum and bacilli
What are the symptoms of this stage?
High fever
Anorexia and weight loss (—>wasting disease)
Which individuals are the most infectious?
Those with open cavities
Where bacteria can go during coughing?
Bronchi, trachea and then the larynx
What is the most infectious stage of tuberculosis?
Laryngeal tuberculosis and it is one of the end stages
What shows a chest x-ray for a postprimary infection?
- Cavitation of the lungs
- An architectural change of the lungs represented by shrinkage and decrease in volume of the lungs because of fibrosis
What is the survival range if individuals are left untreated?
2.5 to 3 years
What happens if they are treated?
They can have long lives, with on and off state, intervals in which they are good, and intervals in which there is reactivation
Why they can’t be cured of the bacilli?
Since they are chronically infected, they can only be cured of the manifestations and the allergic hypersensitivity reaction
What happens if during the primary infection the individual isn’t able to confine the primary complex?
- Bacteria can go to the surface of the lungs without entering them
- In the case of HIV infection before tuberculosis, there is a quick progression of tuberculosis since macrophages are not properly functional and lymphocytes are destroyed
What do we call liquid droplets where bacteria are found?
Droplet nuclei
Why these nonspore forming bacteria are considered as resistant bacteria?
Since they can stay for 9 months to 1 year in an environment without sunlight and ventilation
What is the infectious dose?
5 to 200 bacteria are enough to cause an infection so it is a very small infectious dose
Where bacteria live and replicate? How?
In unactivated macrophages by inhibiting the phagosome-lysosome fusion
In which part of the lungs bacteria are found?
In alveoli
Where bacteria will spread?
In the hilar lymph nodes
From what is composed the primary complex?
From the Ghon focus and the hilar lymph nodes
What are the symptoms? Are they severe?
They are mild symptoms
Low fever, respiratory manifestations, mild cough that can be accompanied with streaking of blood
How the disease is confined in the primary complex?
By the production of the granuloma
Which T lymphocytes will be recruited? When? What is the function?
After 10 days of the infection, activated T cells especially Th type: Th1 that produce lymphokines to recruit macrophages and even Th2
They will produce lymphokines and interleukins to activate macrophages
What is the structure of the granuloma?
- Its central part is formed by unactivated macrophages (multinucleated giant cells that are dead), and necrotic tissue containing bacteria (pus) that has a cheese like consistency, so it is called caseation
- Its outer part is formed of activated macrophages (epithelioid cells) and T cells
Why there will be acidification of the medium?
Because many bacteria are destroyed
What will cover granulomas?
Fibrous tissue and calcification
Why at this stage bacteria are not affected by antibiotics?
Since they are dormant in the center of the granulomas, so there is confinement and recovery of the symptoms not of the bacteria because of chronic infection
By which way we can know that there is an infection?
With the PPD test and chest x-ray where granulomas look like scares in different areas of the lungs
What is the final outcome of the primary infection?
After calcification, bacteria are dormant and the disease is under control
What do we call the lesions forming after the initial infection? What happens to those lesions?
Ghon focus
Mostly, they heal spontaneously and become small calcified nodules
From what is composed of the Ghon complex?
Ghon focus + Regional lymphadenopathy
In which age groups primary pulmonary TB may progress rapidly to clinical illness?
In young children with immature cellular mediated immunity (CMI) and in persons with impaired immunity e.g. those with malnutrition or HIV infection
What happens if bacilli penetrate into the pleural space?
We have pleural effusion
What happens in the primary infection in infants less than 1 year of age?
There is the progression of the disease, there is a tendency to develop a meningitis and a miliary tuberculosis
What do we have during miliary tuberculosis?
There are many white nodules which are the miliary foci of tuberculosis
Why the PPD test in individuals under 1 year with miliary tuberculosis is negative?
Because before invasion of the lungs, PPD test is negative and in those children there is no invasion yet
What causes postprimary tuberculosis after the primary infection?
Depression in cellular immunity
What balance should be present to confine the primary infection?
Between the activity of activated macrophages and TH1 which confine the focus and TH2 which have a destructive effect
How the caseation part gets liquefied?
Because there is destruction of bacteria, and, at the same time, tissues surrounding the bacteria
What happens after this liquefaction?
We are left with an open cavity which is the source of hemoptysis because of open capillaries, blood comes out with every expectoration
What is expectorated?
Sputum and bacilli
Where bacteria can go when coughing?
To bronchi, trachea and larynx
What is the most infectious stage and one of the end stages of tuberculosis?
Laryngeal tuberculosis
Why cavities are a good area of bacterial multiplication?
Since it is an oxygenated area
What causes liquefaction?
Interleukins produced by T cells and proteases of macrophages
What are the symptoms of the postprimary tuberculosis in the middle range?
Fever, night sweats, weight loss, anorexia, general malaise and weakness (wasting disease)
When there is pleuritic chest pain?
In patients with sub-pleural disease
What should we rule out in the case of hemoptysis?
Cancer
What happens in the case of miliary tuberculosis?
Fever is a perplexing fever, it goes up and down like saddle fever
To what leads laryngeal infection? How it is caused?
At least you hoarseness of the voice
It is caused by the fact that with each cough there are bacilli that are going to the larynx
What is the basic rule with tuberculosis?
No matter where bacilli go first, there will be involvement of the regional lymph nodes via unactivated macrophages
Which lymph nodes are involved in the case of pulmonary tuberculosis? Tonsils? GI tract? Skin?
Hilar lymph nodes
Cervical lymph nodes
Mesenteric lymph nodes
Regional lymph nodes
From what is composed the primary complex?
Primary infection + Regional lymph nodes
By what is usually controlled the primary complex?
The formation of a granuloma that gets calcified
Which organs can be affected by extra pulmonary tuberculosis?
Lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum, pericardium, miliary
What is the most common form of tuberculosis infection outside the lungs?
Tuberculous lymphadenitis or tuberculous adenitis (scrofula)
What happens if bacteria go to the surface of the lungs without entering them primarily?
The result is meningitis, miliary tuberculosis, pleurisy.. after a period of time, there will be a pulmonary invasion and bacteria will go to the lungs
What is the presentation when lymph nodes are involved?
Painless swelling, inflammation, of the lymph nodes
How starts the scrofula, and how it progresses? What could be produced?
It starts as painless hard swelling that becomes harder, nontender with time
Many times there is production of sinuses and development of fistula in which we have draining of liquid
What is the major cause of scrofula and G.I. tract tuberculosis?
Ingestion of Koch’s bacilli
What happens when bacilli pass through the tonsils to go to the intestine?
The primary tuberculosis will involve the tonsils and the regional lymph nodes
How much do we need bacteria to cause infection in tonsils? In the stomach?
A small number of bacteria is needed in the tonsils
But a high number is needed in the stomach because it is highly resistant to these bacteria
What are the rates of founding the bacteria in a biopsy?
50% AFB positive
80% positive culture
When could we have an infection of the pleura?
During a primary infection
During a postprimary infection
What happens during a primary infection?
Bacteria go in the pleural space space before invading the lungs
What is the composition of the effusion in this case?
It has a high protein content, a low glucose content and a high amount of lymphocytes
What are the manifestations of pleurisy?
What could be done to relieve the patient?
Chest pain
Aspirate a small amount of the effusion
What is the result of the PPD test? Why?
Do we find AFB?
Negative since there is still no involvement of the lungs
AFB are rarely seen
When there can be invasion of bacteria in the lungs?
After several years of receiving the proper treatment causing a pulmonary tuberculosis
What happens during a post primary infection?
In this case the infected liquid spilling from the cavities go to the pleural space
Is it an effusion in this case?
No it is an empyema which is an abscess in the pleural space
Which one is more severe a primary or a postprimary infection?
Postprimary infection, with high fever
What is the results of the PPD test? Are AFB seen?
PPD test will be positive
AFB are found in large amounts and more cultures are positive
What are the symptoms when the effusion is large?
Fever, pleuritic chest pain and dyspnea
What is the appearance of the fluid?
It is straw colored or hemorrhagic depending on wether there is a primary or postprimary infection
What can cause the bacteria during an infection of the pleural fluid? How?
Pneumonia or bronchitis
Either via lymphatic channels or direct spreads via lungs or through blood to any organ
How the genitourinary tuberculosis is caused?
From hematogenous or lymphogenous spread (from infected mesenteric lymph nodes) from G.I. tract tuberculosis
What can be involved in the case of urinary tract infections?
The bladder and ureters
What are the symptoms of urinary tract infections?
Hematuria, pyuria and abdominal pain
What is the rate of finding the bacteria in the urine?
90% positive culture
Which parts are involved in females when we have genital tract infection?
There can be salpingitis where 20% of them progress to infertility by fibrosis
It can also affect the endometrium
What are the symptoms?
It can lead to pelvic pain and menstrual abnormalities
Which parts in males are involved in the genital tract infection?
There can be inflammation of the epididymis, or inflammation of the testes (orchitis) or prostatitis
Which part of the skeleton are involved?
What’s the outcome of the infection in these sites?
Bones (vertebrae in the lower back especially), and joints (hips and knees i.e. weight bearing joints)
There are chronic abscesses in these sites
What is Pott’s disease?
Spinal tuberculosis involving vertebral bodies
There can be too much spread in lymphatics (paravertebral lymph nodes), causing an unstable spine appearance
How bone and joint disease is caused?
Pathogenesis is related to reactivation of hematogenous foci or to spread from adjacent paravertebral lymph nodes
What do we find in bone biopsy?
We have AFB positive and culture positive
From what results tuberculous meningitis?
From the hematogenous spread
What are the two cases of tuberculous meningitis?
During a primary infection before any lung involvement
After pulmonary tuberculosis after a bacteremia
What is the presentation during a primary infection?
Headache and slight mental changes after weeks of low-grade fever, malaise, anorexia
What are the signs if it is not diagnosed directly?
Severe headache, confusion and neck rigidity
Why meningitis is very dangerous in children?
Because it always precedes lung involvement
Which granulomas are used to confine the disease?
Tuberculomas and they will stay in the CSF and in neural tissues
What happens in the case of reactivation of granulomas in some children?
Seizures will occur but not meningitis
This case is much more difficult to be treated
How meningitis after pulmonary tuberculosis is diagnosed?
What is the composition of the CSF?
What is the rate of finding a bacteria?
By lumbar puncture
Examination of the CSF reveals a high leukocyte count, high protein content and low glucose concentration
AFB positive in 1/3 of the cases, culture positive and 80% of the cases
What is the cause of GI tract tuberculosis?
It results from ingestion of milk from cows affected by bovine tuberculosis
Any portion of the G.I. tract may be affected
It can follow a pulmonary tuberculosis either by hematogenous or by lymphogenous spread
What is the presentation of the G.I. tract tuberculosis?
Non-specific abdominal pain, fever and ascites (accumulation of fluid in the peritoneal cavity causing abdominal swelling)
How it’s diagnosed?
Paracentesis reveals an exudate fluid with high protein content and leukocytosis
Direct smear shows AFB negative and culture negative
For real diagnosis, we need to do a peritoneal biopsy that shows granulomas and the AFB
How pericardium tuberculosis is caused?
Due to hematogenous spread or lymphogenous spread (from lungs lymph nodes after pulmonary tuberculosis)
What are the presentations of pericardial tuberculosis?
Dyspnea, fever and retrosternal pain
How it is diagnosed?
By pericardiocentesis
The effusion is exudative in nature, with proteins and a high count of leukocytes
Direct smear shows AFB negative
Culture of pericardial fluid reveals the bacilli in up to 2/3 of the cases, while pericardial biopsy has a higher yield.
When miliary tuberculosis can happen?
During the primary infection
During the postprimary infection
How it occurs during the primary infection?
In children where we have spread of the bacteria in different organs
It can be followed by a lung infection in which we have involvement of all lungs part not just the lower parts
What is in this case the result of the PPD test?
PPD negative because before invasion of the lungs unless we wait for a longer period of time
What is the cause of the postprimary infection?
Hematogenous spread
And children it is often the consequence of primary infection
In adult it may be due to either recent infection or reactivation of old disseminated foci
What is the appearance of lesions during miliary tuberculosis?
Yellowish granulomas that resemble millet seeds
What is the presentation?
Non-specific depending on the predominant side of involvement
Fever, night sweats and weight loss
What reveals a chest radiography?
Miliary reticulonodular pattern although not a present early in the course and among HIV infected patients
What is the diagnosis?
AFB positive in 20% of the cases, PPD negative in 50% of the cases
Bronchioloalveolar lavage is more likely to provide bacteriology confirmation
If not recognized it is lethal
What is the cause of the ocular tuberculosis?
It is not caused by bacteria since the culture is negative, but by a hypersensitivity reaction
Where do we have granulomas?
In the ocular space
What are other names of the PPD test?
Skin test reactivity
Mantoux test
Tuberculin test
What is the PPD test?
It is a very specific reaction to the proteins of Mycobacterium tuberculosis. There can be some cross-reactivity with atypical mycobacteria.
What is the type of the reaction?
What is the result of this reaction?
It is a delayed type hypersensitivity reaction due to sensitized T cells that act on effector monocytes.
It results in an erythema and induration in case of positive reaction (hardening of the area where there is injection of the PPD). It is felt by palpation.
How this test is done?
By injection of PPD, then drawing a circle of 10 to 15 mm of diameter
What are the conditions for a positive test?
- There has to be an infection with lung involvement (e.g. in the case of miliary tuberculosis or meningitis, the individual can be PPD negative because the T cells have not been properly sensitized, so there is no induration when they reencounter the Ag)
- It should be done in the forearm
- Intradermal (false results if subcutaneous)
- Amount: A standardized amount of PPD antigen will give the results. it is called the intermediate those of PPD (5 IU).
- Time: palpation is performed after 48 to 72 hours
What should we put in the syringe before injecting the PPD?
When we put the amount in syringe, we need to put additional chemicals to prevent sticking of the proteins to the walls, which would decrease their amount
What is the result of repeated PPD test if the person is not infected?
Repeated PPD tests will not convert the person into a PPD positive
What is anergy?
When does it occur?
Negative immune reaction in an infected person
It occurs in elderly who were infected, and who didn’t do PPD for a long time, PPD is negative
What do we do in this case?
In this case we do a repeated PPD test to boost the original reaction
The first PPD dose is to activate the T cells, The second one done after 7 to 10 days will be positive
What do we consider an induration of any diameter in the case of HIV infected individuals?
It is considered positive because the diameter depends on the amount of T lymphocytes
When do we consider an induration of 5 or more mm positive?
- In a recent contact of a person with tuberculosis
- In persons with fibrotic changes on chest radiography consistent with prior tuberculosis
- In patients with organ transplants
- In persons who are immunosuppressed for other reasons (e.g. taking the equivalent of >15 mg/day of prednisone for one month or longer, taking TNF alpha antagonists)
When do we consider an induration of 10 mm or more positive?
- In recent immigrants from high prevalence countries e.g. Africa
- In injection and drug users
- In residents and employees of high risk congregate settings
- In mycobacteriology laboratory personnel
- In persons with clinical conditions that place them at a high risk
- In children under 4 years of age
- In infants, children, and adolescents exposed to adults in high-risk categories
When do we consider an induration of 15 or more mm positive??
In any person, including persons with no known risk factors for tuberculosis.
Why it is important to do the culture?
For antibiogram, to know to which drugs the bacteria are sensitive
Why sputum is not always the proper specimen in the diagnosis of pulmonary tuberculosis?
Because it might not contain bacteria
What do we do in this case?
We can do a bronchioloalveolar lavage or 3 consecutive gastric lavage
Why do we give a synergy of drugs?
Since resistance develops quickly even if bacteria are sensitive to those antibiotics
What is the treatment in case there is no multidrug resistance?
-First 2 months: Pyrazinamide, INH, rifampicin, a 4th drug (streptomycin, ethambutol, quinolones, some microlides, cycloserine, ethionamide, PAS)
After 2 months, we stop pyrazinamide and the 4th drug and we continue with INH and refampicin for 9 to 12 months
What is the treatment in case of multidrug resistance?
We add PAS, or quinolones.
When do we give prophylaxis?
Which prophylaxis is given?
If a person has been in contact with a diseased individual
INH for 12 months
Where are kept individuals suffering from pulmonary tuberculosis?
In the sanatorium
What happens after 2 to 3 weeks?
Symptoms ameliorate, fever and anorexia decrease, individuals start to gain weight, coughs decrease
What happens after 2 months?
When the sputum specimen becomes AFB negative we can send individuals back home
For what we do x-rays? When?
After 4 months x-ray ameliorates. We do x-rays both for chest and bones in case of skeletal tuberculosis. In other cases x-ray is of no use.
What is the vaccine?
It is the BCG vaccine which is a live attenuated mycobacterium bovis, so it multiplies in the system, giving continuous Ag stimulation to the person.
What is the result of the PPD test in vaccinated individuals?
It will be positive for 5 to 7 years
What if after 7 years the individual is still PPD positive?
If after 7 years the individual is still PPD positive, it means that during this interval, he was infected with a virulent type
What are the most common sites of infection of lymph nodes?
The posterior cervical and supraclavicular site
