PBL 4: Tuberculosis by Léa Pisani https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8 en-us 2022-04-28 08:02:11 UTC 2022-05-16 13:38:29 UTC hello@padlet.com leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161774148 Definition of TB: is an infectious disease that is caused by mycobacterium tuberculosis affecting especially the lungs

Strong reaction to the mycobacterium: spread in the body
No reaction: limited to the lungs

Tuberculosis is highly aerobic (needs oxygen to survive), therefore the apices of the lungs (the oxygen concentration is higher there) is mainly affected 

Symptoms of TB: weight loss, fever (cytokines are released), strong cough, haemorrhaging (due to rupture and erosion of blood vessels)]]> 2022-04-28 08:07:05 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161774148 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161774635 Epidemiology of TB
- Endemic: found among people in a certain area 
- Epidemic: wide spread of the disease at a particular time i.e. Hannah's school
- Pandemic: prevalent in the whole world / multiple regions (widespread)

HIV infected people are also more likely to be infected by tuberculosis: diminished CD4 T cells 

In Africa: 30% - 40% of the HIV patients die because of tuberculosis

]]> 2022-04-28 08:07:36 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161774635 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161776017 2022-04-28 08:08:53 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161776017 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161776333 2022-04-28 08:09:14 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161776333 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161777158 2022-04-28 08:09:56 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161777158 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161777467 2022-04-28 08:10:14 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161777467 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161780226 Diagnosis

  • Initial test - Microscopic examination of smear such as sputum/sputum smear positivity
    • Early morning spata in most reliable because pulmonary secretions accumulate over night
    • Acid fast staining of sputum culture
    • Challenge: slow due to slow growth rate of the bacteria (3 to 6 weeks for a colony to form)
  • Delayed type hypersensitivity and Tuberculin skin test: 
    • Involves injection of purified protein derivative (PPD) from bacteria into the skin.
    • It takes advantage of cell mediated immunity against the bacterium involving sensitised T cells since the pathogen is located on macrophages.
    • Positive test: sensitised T cells react with TB proteins in the case of past infection causing a delayed hypersensitivity reaction in 48 hours which results in hardening(induration) and reddening of the area=>Mantoux test
    • Positive test in young people=active infection, in old people=hypersensitivity from previous infection in most cases.
    • A positive test is usually an indication that X-ray or CT examination is needed to detect lung lesions and to isolate the bacterium.
  • TB blood test
    • Measures release of TNF gamma from WBCS after exposure to mycobacterial antigen=>preferred for people who have received BCG vaccinations.
    • Interferon gamma release assays: Can be used under every circumstance under which the tuberculin test would be used.
    • Nucleic acid amplification tests (NAAT)-detects bacteria 1-2 weeks sooner, can be used to test resistance to TB antibiotic, rifampin.
    • Rapid tests have higher sensitivity and less cross reactivity to BCG  vaccine than skin tests.
  • Imaging: CT is more sensitive than x-rays is identifying TB lesions
- skin test: purified protein derivative 
                  positive reaction: thickening of the skin (phagocytes in the T cell) --> Hannah can u add?:)
- initial test: acid fast staining --> Cristina can u add?:)
                     sputum cells 
- blood test: release of interferon gamma, cytokines are released when the T cells encounter the antigen 
- amplification test: test antibiotic resistance 
]]> 2022-04-28 08:12:44 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161780226 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161780401 Treatment

  • Multiple-drug therapy is needed to minimise the emergency of resistant strains (usually isoniazid, rifampin, ethambutol and pyrazinamide =>first line drugs)
    • Usually involves 130 doses-may lead to cure or resistance in case of poor adherence
  • Second-line drugs: Usually involving aminoglycosides, fluoroquinolones, streptomycin and para-aminosalicylic acid (PAS)=>usually have toxic side effects.
  • Prolonged treatment: important because the tubercle bacillus grows very slowly or is only dormant. (the bacillus may be hidden for long periods in macrophages or other locations that are difficult to reach with antibiotics) 
    • Pyrazinamide-effective for dormant bacillus 
  • Multidrug resistant (MDR) strains: Strains that are resistant to isoniazid and rifampin (first line drugs)
    • Resistance can either be primary (infection with drug strain) or secondary (associated with treatment non adherence in people who have received TB therapy)
  • Extensively drug-resistant (XDR): Strains that are resistant to second line drugs such as fluoroquinolone, aminoglycosides amikacin or kanamycin as well as polypeptide capreomycin - these are usually non treatable
    • HIV patients + XDR tuberculosis died within 3 months.
- medication
    - antibiotics: isoniazid, rifampin, pyrazinamide, ethambutol 
    - other medication --> margrate :))
- because slow growth, you need to take medication for a long time 
]]> 2022-04-28 08:12:52 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161780401 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161780536 Prevention
- Vaccines: BCG (bacille Calmette-Guérin) 
                   - negative skin test before vaccine! 
                   - drug susceptibility ]]> 2022-04-28 08:12:59 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161780536 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161781899 1. Drug resistance: mainly to first line drugs 
2. Immunocompromised individuals: HIV patients]]> 2022-04-28 08:14:15 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161781899 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161930654 Characteristics of the mycobacterium 
- very resistant to drying (bcs of waxy coat made out of a mycolic acid) --> facilitate airborne transmission
- mycobacteria: because waxy barrier
- "myco": similar to fungus, clusters over liquid surfaces 
-  slow growth: the mycobacterium goes "undetected", can delay diagnosis & delay tests for drug susceptibility 
      - slow growth is a mechanism for survival ]]> 2022-04-28 10:27:49 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161930654 mmtzclaros1 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161936111 2022-04-28 10:33:27 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161936111 Transmission leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161941934 How it enters the body
- rapid spread required, it has to be crowded, airborne droplet nuclei, sneezing, coughing

Primary tuberculosis: once bacteria is in the lungs 
1. airborne nuclei 
2. reach the alveoli of the lung 
3. 1st response: alveolar macrophages ingest the bacteria 
- lymph node: Ghon complex (calcification)
4. TB still multiple and destroy the macrophage 
5. facultative intracellular pathogen: multiply in and out of the cell
6. infected macrophage are carried by the lymphatic and regional nodes 
7. cellular immunity or immune response is not effective 

Secondary infection: 2 to 3 years after the infection 
What factors can make this possible: 
- malnutrition
- immunosuppressive drugs 
Gets reactivated, reactivation is mostly affect the apex of the lung 
- a place for mycobacteria to multiply and escape 
What is the immune response involved in this secondary infection? 
- alveoli material is deliquified & necrosis
Bacteria into the alveoli: moist environment & high oxygen levels

]]> 2022-04-28 10:39:39 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161941934 mmtzclaros1 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161943106 2022-04-28 10:40:45 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161943106 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161951003 https://www.nature.com/articles/nrmicro749

]]> 2022-04-28 10:48:53 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161951003 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161951416 https://www.nature.com/articles/nri1666]]> 2022-04-28 10:49:22 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161951416 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161952387 2022-04-28 10:50:20 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161952387 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161952674 2022-04-28 10:50:35 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161952674 Acid-Fast Testing cristina3huezo https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161962454 2022-04-28 11:00:59 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161962454 leaestelle2002 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161963248 - Macrophages produce 2 cytokines in the case of M.tuberculosis: IL-1 & TNF-alpha
- CD4 T cells can recognise mycobacterial antigens if processed & presented by macrophages in the context of major histocompatibility complex class II proteins
- Tubercles (granuloma) formation]]> 2022-04-28 11:01:49 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161963248 Pathogenesis and immune response https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161964765 Almost all tuberculous infections result from 
inhaling infectious particles that were 
aerosolized by coughing, sneezing, or 
talking. The initial source of infection is the 
lung in almost all cases. These so-called 
droplet nuclei dry while airborne, can 
remain suspended for hours, and when 
inhaled can reach the terminal air passages 
(Fig. 23-3). A cough or sneeze can produce 
thousands of droplet nuclei, as can talking 
for several minutes. Accordingly, the air in a 
room occupied by a person with 
pulmonary TB may remain infectious even 
after the person has left the room.
Fortunately, prolonged exposure and 
multiple aerosol inocula are generally 
required to establish infection. Brief contact 
carries little risk, and infection rarely occurs 
outdoors because ultraviolet light kills M. 
tuberculosis. Large drops of respiratory 
secretions or contaminated inanimate 
objects infrequently result in transmission. In the past, TB of the intestine or the tonsils was 
common from ingestion of contaminated milk. This form of TB was caused by M. bovis, an 
organism that is genetically similar to M. tuberculosis and causes infection in cattle.
Airborne spread of TB is efficient for several reasons. In source cases, the host inflammatory 
response to TB creates open lung lesions (pulmonary cavities) that contain huge numbers 
of organisms. Coughing spreads the organisms from such lesions into the air. 
Contagiousness roughly correlates with the number of acid-fast bacilli visible by microscopy 
of sputum. Patients who are acid-fast smear-positive are more contagious than those who 
are acid-fast smear negative but culture positive. However, many new infections are acquired 
from smear-negative but culture-positive patients, reflecting the limited sensitivity of acid-fast 
staining. The small size of droplet nuclei is also ideal for bypassing the mucociliary lining of 
large airways to reach the alveoli.
Tubercle bacilli do not produce exotoxins or endotoxin. Instead, the clinical manifestations 
of TB result largely from the host immune response. Damage is caused by chronic 
inflammation and survival of organisms within macrophages.
In primary infection, airborne droplet nuclei reach the alveoli where multiplication begins. 
This primary infection usually involves the middle lung zone, where airflow is greatest. There, 
the bacteria are ingested by alveolar macrophages, which may eliminate small numbers of 
bacilli. However, M. tuberculosis multiplies mostly unimpeded, destroying the macrophage 
(Fig. 23-4). Its capacity to multiply both inside and outside cells makes M. tuberculosis a 
facultative intracellular pathogen. Lymphocytes and monocytes are attracted from the bloodstream, the latter differentiating into 
macrophages, which ingest bacilli released from 
dying cells. Infected macrophages are carried by 
lymphatics to regional lymph nodes. Some 
individuals develop the so-called Ghon complex, 
in which an area of lung inflammation is 
associated with enlarged hilar lymph nodes 
draining the area. In the nonimmune host, 
organisms may spread hematogenously 
throughout the body. During this early 
lymphohematogenous dissemination, the 
organisms preferentially localize in certain 
tissues, including lymph nodes, vertebral 
bodies, and meninges but most importantly the 
apices (upper parts) of the lungs. During the 
days and weeks before an effective cellular 
immune response develops, the organisms grow uninhibited in the initial pulmonary focus 
and the additional sites.
Primary infection can have various outcomes (Fig. 23-5). Cellular immunity and tissue 
hypersensitivity usually appear 3 to 8 weeks after infection and are marked by a positive 
tuberculin skin test (discussed later in the chapter). In most affected individuals, this response 
controls infection (although viable organisms may persist in the tissues), no symptoms 
develop, and the only evidence of infection is a positive tuberculin skin test. However, in 
some cases, the immune response does not control the primary infection, and progressive 
primary TB develops. This manifestation usually affects the very young, the elderly, and 
persons with advanced AIDS. In such individuals, the primary focus directly progresses to 
worsening pneumonia, and the very young may develop tuberculous meningitis. The most 
important consequence of lymphohematogenous dissemination is seeding of the lung 
apices, where either progressive primary or secondary disease can occur.
 
In persons with immunity from previous 
exposure to M. tuberculosis, organisms 
in newly inhaled droplet nuclei are 
destroyed before significant 
multiplication occurs. Nearly all TB in 
previously infected patients is the result of 
endogenous reactivation. However, when 
the airborne inoculum is large, or when 
host defenses are compromised, 
exogenous reinfection can occur.
Age influences the course of infection. 
Infants and children younger than 5 years
of age who become infected are at high 
risk for developing progressive primary 
disease. In contrast, from age 5 to puberty 
is a period of relative resistance to 
progressive disease, although not to 
infection. From puberty until young 
adulthood, formation of apical cavities 
soon after primary infection is common.
Most disease in this age group is caused by relatively recent infection rather than reactivation of childhood infection. Infection in mid-adulthood has a much better immediate and 
probably long-term prognosis, presumably because of a reduced tendency to develop tissue 
necrosis. In the elderly, infection acquired years earlier can progress as age compromises 
immunity, leading to production of apical pulmonary cavities. In elderly persons who lack 
preexisting immunity to TB, new infection can cause progressive primary disease resem-
bling primary infection in children, with involvement of lower or middle lobes and often 
without cavities.
Endogenous Reactivation (Secondary Tuberculosis) 
Endogenous reactivation usually occurs within 2 years after initial infection but can occur at 
any time thereafter (see Fig. 23-5). Clearly, any impairment of the cellular immune system 
can render a person vulnerable to reactivation of latent mycobacteria. Subtle depression 
of the immune system resulting from stress or hormonal factors may go undetected. Other 
factors include malnutrition, therapy with corticosteroids or other immunosuppressive drugs, 
malignancy, and end-stage renal disease. Worldwide, the most important cause of 
reactivation is coinfection with HIV. The higher frequency of certain histocompatibility types 
(i.e., human leukocyte antigen or HLA) in persons who develop active TB suggests a genetic 
predisposition. The disease may reactivate in the elderly because of a poorly understood 
loss of immune competence that can occur with aging. In addition, local physical 
disturbances at the site of a latent focus can alter the balance between host and pathogen. 
For example, lung surgery can disturb quiescent pulmonary foci and cause active TB at that 
site.
The most common site of reactivation is the apex of the lung. Lesions slowly become 
necrotic, undergo caseous necrosis (named for its cheesy appearance), and eventually 
merge into larger lesions. With time, the caseous lesions liquefy and discharge their contents 
into bronchi. This event has several major consequences. It creates a well-aerated cavity in 
which the organisms proliferate. The discharge of caseous material also distributes the 
organisms to other sites in the lung, which can lead to a rapidly progressive tuberculous 
pneumonia. In addition, the bacteria-laden contents of caseous lesions are coughed up and 
become infectious droplet nuclei. Although the reason for the apical pulmonary localization 
is not known with certainty, it is likely that deficient lymphatic flow at the apices, where the 
pumping effect of respiratory motion is minimal, favors retention of organisms. When 
hypersensitivity develops, tissue damage creates apical cavities characteristic of pulmonary 
TB in adults.
Immune Response 
TB requires a cellular immune response for control, with antibodies playing no apparent role. 
In the first few weeks after exposure, the host has almost no immune defense against M. 
tuberculosis, and small inhaled inocula multiply freely in alveolar spaces or within alveolar 
macrophages. Once inside the cell, mycobacteria increase their chance of survival by 
preventing acidification of the phagolysosome. Unrestrained replication proceeds for 
weeks, both in the initial focus and in metastatic foci, until tissue hypersensitivity and cellular 
immunity supervene. This tissue hypersensitivity is florid compared with other intracellular 
infections.
All persons have CD4+ T lymphocytes that can recognize mycobacterial antigens if 
processed and presented by macrophages in the context of major histocompatibility 
complex class II proteins. When lymphocytes encounter antigen in this manner, they are 
activated and proliferate, producing clones of similarly reactive lymphocytes. These in turn 
produce many distinct lymphokines that attract, retain, and activate macrophages at the site 
of antigen exposure. Activated macrophages accumulate lytic enzymes and reactive metabolites that increase their capacity to kill mycobacteria, but if released into surrounding 
tissues, these macrophage products can cause necrosis.
When the population of activated lymphocytes reaches a certain size, cutaneous delayed-
type hypersensitivity to tuberculin becomes manifest. This response generally takes 3 to 8 
weeks. At the same time, enhanced macrophage microbicidal activity, or cellular immunity, 
appears.
The pathologic features of TB are the result of hypersensitivity to mycobacterial antigens.
Sustained immunity to new infection that follows natural infection is likely the result of 
persistent viable tubercle bacilli in the tissues with in vivo boosting. Although activated 
macrophages usually kill intracellular bacteria, intracellular mycobacteria may persist. An 
uneasy equilibrium is reached; some macrophages kill the organisms, others are themselves 
killed and release their bacterial contents, and still others harbor dormant bacteria for long 
periods. Proteolytic processing of killed bacteria leads to continued immunological 
stimulation. Immunocompromised persons may not contain the primary infection, and organisms may 
invade the bloodstream and disseminate to cause a life-threatening infection known as 
miliary tuberculosis. The term miliary is derived from the resemblance of the tubercles to 
millet seeds (bird seed). Characteristic of the disease are tubercles found in many organs, 
including the liver, spleen, kidneys, brain, and meninges. Caseation and cavitation are less 
frequent than in secondary TB.
The involvement of macrophages in the containment of M. tuberculosis comes at a price. 
Two cytokines produced by these cells, IL-1 and TNF-alpha (see Chapter 6), contribute to 
symptoms of the disease. Among their various activities, these cytokines mediate fever, 
weight loss, and night sweats. In response to the carbohydrates, lipids, and proteins of the 
tubercle bacilli, macrophages also produce many other cytokines that modulate the immune 
response. In particular, increased production of IL-10 may suppress the immune response 
and promote disease progression. The net effects of these complex events are the local 
pathological manifestations of TB, including caseous necrosis and fibrosis with 
calcification.]]> 2022-04-28 11:03:27 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161964765 Diagnosis https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161972579 People infected with tuberculosis respond with cell-mediated immunity against the 
bacterium. This form of immune response, rather than humoral immunity, develops because 
the pathogen is located mostly within macrophages. This immunity, involving sensitized T 
cells, is the basis for the tuberculin skin test, a screening test for infection. A positive test 
does not necessarily indicate active disease. In this test, a purified protein derivative of the 
tuberculosis bacterium, derived by precipitation from broth cultures, is injected cutaneously. 
If the injected person has been infected with TB in the past, sensitized T cells react with these 
proteins, and a delayed hypersensitivity reaction occurs in about 48 hours. This reaction 
appears as an induration (hardening) and reddening of the area around the injection site. In 
this test, known as the Mantoux test, dilutions of 0.1 ml of antigen are injected and the 
reacting area of the skin is measured.
A positive tuberculin test in the very young is a probable indication of an active case of TB. 
In older individuals, it might indicate only hypersensitivity resulting from a previous infection 
or vaccination, not a current active case. Nonetheless, it is an indication that further 
examination is needed, such as a chest X-ray or CT examination to detect lung lesions and 
attempts to isolate the bacterium.
The initial step in laboratory diagnosis of active cases is a microscopic examination of 
smears, such as sputum. According to recent medical opinion, the commonly used 125-
year-old microscopic exam routinely misses half of all cases. Confirming a diagnosis of TB 
by isolating the bacterium poses difficulties because the pathogen grows very slowly. A 
colony might take 3 to 6 weeks to form, and completing a reliable identification series may 
add another 3 to 6 weeks.
Blood tests measure release of IFN-γ from white blood cells after exposure to mycobacterial 
antigen in a test tube. They are the preferred tests for a person who has received BCG 
vaccinations.
Nucleic acid amplification tests (NAATs), such as PCR, can detect M. tuberculosis 1 to 2 weeks 
sooner than cultures and at the same time can determine resistance to a major TB antibiotic, 
rifampin. Evidence indicates that, compared to the skin test, these rapid tests have higher 
specificity and less cross-reactivity with BCG vaccination (see the discussion of TB 
vaccines, following). They do not distinguish latent from active infection. These assays seem 
likely to replace the tuberculin skin test for many uses, especially where cross-reactivity with BCG vaccination is a problem. If they could be adopted worldwide at centers for TB 
treatment, they would help avert millions of TB-related deaths.
BCG vaccination is a problem. If they could be adopted worldwide at centers for TB 
treatment, they would help avert millions of TB-related deaths.

]]> 2022-04-28 11:11:44 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161972579 Treatment and prevention https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161975058 Excellent drugs are available for treating TB. These include isoniazid (INH), rifampin, 
pyrazinamide (PZA), and ethambutol. Persons with pulmonary TB usually become 
noncontagious within 2 weeks of therapy if the organisms are sensitive to the drugs 
administered. Unlike most bacterial infections that can be cured with a single drug, active 
TB requires multiple drugs for cure because of the remarkable propensity of the organism 
to develop resistance. In any population of tubercle bacilli, chromosomal mutations 
associated with resistance to any single drug are already present in about one of every 106 to 
107 bacteria, even though the organisms have never been exposed to the drug. Because 
tuberculous cavities can contain in excess of 1011 organisms, many of the bacteria present 
will be resistant to any single drug, even before treatment is begun. In fact, some organisms 
will be resistant to drugs that are yet to be developed.
Fortunately, the chance that one organism will become resistant to two drugs 
simultaneously is small. Therefore, prescribing multiple drugs in combination prevents 
resistance. Unfortunately, adherence with complex and prolonged treatment regimens is 
difficult. If treatment is sporadic, multidrug-resistant strains can emerge, making treatment 
more difficult or impossible. Spread of such strains to other individuals can be catastrophic. 
For this reason, directly observed therapy for TB has become the standard of care, with every 
dose directly administered by a health care provider, usually a public health worker.
Prescribing multiple drugs also allows for a shorter duration of therapy. In cases of drug-
sensitive TB, 18 months of INH plus ethambutol was once required for cure. In the 1970s, it 
was discovered that including rifampin in the regimen allowed therapy to be shortened to 9 
months. Later, it was discovered that adding PZA allowed cure in 6 months. In the United 
States, individuals at risk for exposure to TB (e.g., health care professionals as well as medical 
students and residents) are routinely screened for tuberculin conversion. INH is administered 
to persons who convert to a positive reaction, which indicates recent infection. Such 
treatment of latent infection is called chemoprophylaxis. Unlike treating active TB, 
chemoprophylaxis requires only a single drug (e.g., INH) because there are so few organisms 
that it is highly unlikely that resistant organisms will be present.
Drug-Resistant Tuberculosis 
Drug-resistant TB is a major challenge to TB control worldwide. Resistance can be either 
primary, as is the case when a person becomes infected with a drug-resistant strain, or 
secondary, which arises in a person who has received TB therapy and is often associated 
with treatment nonadherence. Mycobacterial strains that are resistant to INH and rifampin 
are designated multidrug resistant, or MDR TB. Strains resistant to INH, rifampin, and 
second-line agents such as fluoroquinolones and aminoglycosides are designated 
extensively drug resistant, or XDR TB. Approximately 7% of TB cases worldwide are 
multidrug resistant. Drug-resistant TB is associated with decreased cure, increased morbidity 
and mortality, and can be disseminated to susceptible persons.
Prevention
The history of TB suggests that improving the standard of living decreases rates of disease. 
In many resource-limited countries, that is unfortunately not a reality. Currently, an effective 
vaccine made from killed M. tuberculosis does not exist. The immunology of TB tells us why: 
killed vaccines may generate antibodies, but humoral immunity does not protect against TB. Cell-mediated immune responses are best elicited when antigens are presented by live 
organisms.
The bacille Calmette-Guérin (BCG) vaccine is a strain of M. bovis made relatively avirulent 
(attenuated) by multiple passages in culture. It is routinely given to newborns and young 
children in many countries, including those with limited resources. Administering BCG 
vaccine causes tuberculin skin test positivity, a criterion for a successful “take” of the 
immunization. Long-term persistence of tuberculin positivity varies depending on the 
patient’s age at BCG vaccination; the earlier the vaccination, the less durable the skin test 
positivity. Because BCG-induced tuberculin positivity would decrease the value of tuberculin 
skin testing to diagnose new infections, BCG is not used in the United States. The safety and 
immunogenicity of BCG also make it a potential vector to deliver protective antigens from 
other pathogenic organisms. Genes encoding such antigens have been introduced into BCG 
to generate “multivaccines” that might protect against multiple pathogens.

Another argument against the universal administration of BCG vaccine is its very uneven 
effectiveness. Experience has shown that it is fairly effective when given to young children, 
but for adolescents and adults it sometimes has an effectiveness approaching zero. Worse, 
it has been found that HIV-infected children, who need it most, frequently will develop a fatal 
infection from the BCG vaccine. Recent work indicates that exposure to members of the M. 
avium-intracellulare complex that is often encountered in the environment may interfere with 
the effectiveness of the BCG vaccine—which might explain why the vaccine is more effective 
early in life, before much exposure to such environmental mycobacteria. A number of new 
vaccines are in the experimental pipeline, but they will require large numbers of human 
samples and several years of follow-up to evaluate.]]> 2022-04-28 11:13:51 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161975058 https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161977183 2022-04-28 11:15:59 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2161977183 Summary Image from PBL bnmargrate https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2162753191 2022-04-28 14:37:10 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2162753191 HIGHLY recommended https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2162891953 https://www.nature.com/articles/nrdp201676.pdf]]> 2022-04-28 15:53:30 UTC https://padlet.com/leaestelle2002/7ykulo5rcql1j6c8/wish/2162891953