TUBERCULOSIS

Tuberculosis is a serious infectious disease that effects one in three people around the world. It's
most commonly caused by a strain of bacteria called Mycobacterium tuberculosis. And even
though tuberculosis can infect many parts of the body, most frequently it affects the lungs. Once a
person becomes infected with Mycobacterium tuberculosis, the bacteria can stay dormant in the
lungs for years before it reactivates and starts causing disease. As it did in the case of a 68-year-old
grandmother, living in the township of Khayelitsha, outside of Capetown, South Africa. You were
doing an elective rotation at a rural hospital near Khayelitsha when this grandmother brought her
six-month-old grandson in after the child had suffered a seizure. The grandmother, Numbulelo,
had been looking after this child since his mother died only a few months after he was born. At the
hospital, you noticed that Numbulelo looked very sick herself. She tells one of the nurses that
she's been suffering from prolonged coughing spells and that she's been coughing up blood. She
also says that she's been sweating at night, feeling tired during the day and has had almost no
appetite for food. To you, she looks very thin ,and when you take her temperature, she has a low-
grade fever. So you tell the physician who's examining the baby that you suspect this grandmother
has active pulmonary tuberculosis. Knowing this makes the physician suspect that this baby
contracted TB meningitis from his grandmother. Who is now experiencing a reactivation of the TB
infection in her lungs. When Numbulelo was a young woman, she lived in a shack with six other
family members, one of whom later died of tuberculosis. Now during that time, she inhaled an
infectious droplet coughed out by the sick relative. And because her immune system was strong,
the macrophages in Numbulelo's lungs immediately began containing the infection. There are
resident alveolar macrophages in the lungs and their job is to remove foreign particles that reach
the alveoli. The first macrophage on the scene engulfed the Mycobacterium into a phagosome,
which functions as a temporary holding cell within a macrophage. In most cases, what happens
next is that the phagosome fuses with lysosomes that contains acids, powerful chemicals, and
enzymes to kill invading microbes. In the case of Mycobacterium tuberculosis, the bacteria have
developed a survival mechanism. Whereby they can modify that phagosome so that it can't fuse
with the lysosomes. And in this way, the bacteria can survive and even grow and replicate inside
the alveolar macrophages. After this replication has gone on for a while, the macrophage may die,
and that would release bacteria that can go on to infect other macrophages. And also release the
contents of the lysosomes, which causes damage to the surrounding tissue and recruits even more
inflammatory cells to the area. Infected macrophages also have innate immune sensors that not
only allow them to recognize invading bacterial, but also trigger the release of cytokines and
chemokines. And these summon even more immune system defenders, like neutrophils, dendritic
cells and lymphocytes, to the site of infection. In this way, infection with mycobacteria elicits an
orchestrated immune response that surrounds the damaged tissue and tries to wall off the
infection. The end results of this is called a tuberculous granuloma, a local collection of bacteria
walled off by immune cells. Granulomas are pretty dynamic, with immune cells entering and
exiting. And some of the macrophages or dendritic cells will even travel to nearby lymph nodes in
order to make the adaptive immune system aware of the presence of the infection. If the immune
system is able to control the infection, the resulting granulomas can persist. And often they can
even be too small to be detected on a chest X-ray. Because the infection is contained, it doesn't
cause any symptoms or any organ damage in the host. This is called the latent or primary
tuberculosis infection. Sometimes it is called LTBI for short and this is why Numbulelo was
symptom free as a young woman. She was never tested for tuberculosis back then, but if she had
been, a tuberculine skin test would of come back positive. Indicating that her adapted system
responded to the presence of mycobacteria.

5:01

Many years later, when Numbulelo got older and her immune system lost some of its strength, the
bacteria trapped inside the granuloma inside her lungs began to grow again. Causing an
inflammatory response, and damage to the surrounding tissue. This is when her symptoms of
fever, weight loss, and night sweats first began to appear. As cells on the inside of the granuloma
begin to die, this focus of infection forms a caseating granuloma. And that can erode into the
airways causing in this case, Numbulelo's coughing, hemoptysis, and releasing many bacteria into
the surrounding air. This is how her grandson became infected with the Mycobacterium
tuberculosis as well. At the hospital in Khayelitsha, Numbulelo's sputum samples were found to
contain acid fast bacilli. And her chest X-ray showed a cavity legion consistent with active
pulmonary tuberculosis disease. Numbulelo was treated with four anti-tuberculosis medications
including isoniazid, Rifampin, pyrazinamide, and ethambutol. And luckily, she began to recover.
Shortly after Numbulelo brought her grandson into the hospital, he suffered a second seizure. He
also had a fever and was lethargic upon admission. In a more developed part of the world, the
doctors would likely have ordered an MRI. And it may have shown inflammation of the meninges
at the base of the brain, which is a common finding in tuberculous meningitis. Sometimes also
accompanied by hydrocephalus or swelling of the ventricles because of a blockage of the flow of
cerebrospinal fluid due to the infection.

6:46

At the hospital near Khayelitsha there was no MRI machine, but the baby did receive a chest X-ray.
Which was very different from his grandmother's X-ray because it showed a miliary pattern.
Suggesting that many small granulomas were forming all over the lungs. When Numbulelo was
young, her immune system was able to contain the tuberculosis for many years inside a few larger
granulomas in her lungs. But babies or other immune-compromised hosts have less effected
immune responses, and so the infection often spreads to other parts of the body. The miliary
pattern on this child's chest X-ray also suggests that the mycobacteria had spread, not only inside
the lungs but also to other organs, including the brain. Which is a common sight of TB infection in
babies. It might surprise you to know that this baby's tuberculin skin test came back negative. But
cultures from his cerebrospinal fluid that you obtain by doing a lumbar puncture, eventually grew
Mycobacterium tuberculosis as well. And this confirmed that he had tuberculous meningitis.
Despite being treated with the same four medications that his grandmother had received. And
despite the best efforts of the doctors at the hospital in the Khayelitsha, this baby died from his
Mycobacterium infection.
8:09

When a physician suspects an a infection with Mycobacterium tuberculosis, it helps to understand

how the interaction between the host immune system and the microbe can result in the different
clinical presentations of tuberculosis infection. We know, for example, that granulomas are one of
the hallmarks of an infection with Mycobacterium tuberculosis. And granulomas are the result of
the immune system's efforts to protect the hosts by engulfing the microbe and deploying other
immune cells to try and contain the disease. We also know that mycobacteria have evolved in
ways that allow them to colonize, persist, and replicate inside the host. Despite the immune
system's efforts to eliminate them. And the capacity of the immune system to remember and
recognize this microbe upon re-exposure gives us a powerful diagnostic tool The Tuberculin Skin
Test.

9:10

By understanding that the immune system of a baby is unlikely to be able to contain an infection
with Mycobacterium tuberculosis in the same way. Physicians can interpret the physical
presentation of the disease in hosts with compromised or naive immune function. And choose a
therapeutic approach that's most likely to be successful. Finally, understanding how mycobacteria
are spread, how they enter and exit the host, can help with efforts to prevent the local spread of
disease. And know the epidemiology of this infection, that one-third of the world's population is
infected with Mycobacterium, even though they may be symptom free. This can help with larger
scale prevention efforts. As targeted screening protocols can be put into place for individuals at
increased risk of being infected with Mycobacterium tuberculosis.

1. Seizure: an abnormal electrical activity in the brain that may often go unnoticed, but in
severe form may cause involuntary muscle contractions or convulsions, and loss of
consciousness

2. Pulmonary tuberculosis (TB): contagious bacterial infection in the lung caused

by Mycobacterium tuberculosis that may spread to other organs and pass from infected person
to others by air droplets released during coughing or sneezing

3. Tuberculous meningitis: is an infection of tissues covering the brain and spinal cord
(meninges) caused by Mycobacterium tuberculosis

4. Macrophage: a type of white blood cell that engulfs foreign materials and is involved in the
body’s immune response to infectious microbes

5. Alveoli: are tiny air sacs in the lungs where gaseous exchange of oxygen and carbon
dioxide takes place
6. Phagosome: is a cellular compartment in which infectious microorganisms can be killed and
digested

7. Lysosome: a membrane bound specialized vesicle containing a variety of enzymes that

help in digestion inside a cell

8. Inflammation: process by which white blood cells and their secretions protect the body from
foreign organisms like bacteria and viruses. Inflammation is characterized by swelling, redness,
pain and heat in the affected area.

9. Cytokines: small proteins secreted by cells that help in cell communication and signaling.
They stimulate movements of cells to sites of infection, inflammation or injury.

10. Chemokines: secreted proteins, part of the family of cytokines that can induce chemotaxis
in nearby cells

11. Neutrophil: a granulocyte (a type of white blood cell) containing enzyme-filled granules in
their cytoplasm. Neutrophils fight infections by ingesting microorganisms and by releasing
enzymes that kill infectious microorganisms.

12. Dendritic Cell: a special type of cell of the immune system that acts as a professional
“antigen presenting cell” and is capable of activating naïve T cells and stimulating growth and
differentiation of B cells

13. Lymphocytes: small white blood cells that are a major part of the immune system.
Lymphocytes consist of B cells which produces antibodies that attack bacteria, viruses and
toxins; and T cells that destroys the body’s own cells which have been infected by bacteria and
viruses, or have become cancerous

14. Lymph node: small bean shaped glands that are part of the lymph system and are present
throughout the body. Lymph nodes filter lymph fluid and trap and destroy bacteria and viruses.

15. Tuberculous granuloma: is a chronic inflammatory lesion, a hallmark of tuberculosis (TB)

infection. It typically consists of tubercular bacteria surrounded and contained by immune cells
like macrophages, epitheliod cells, multinuclear giant cells, lymphocytes and fibroblasts.
The Mycobacterium tuberculosis can lie dormant inside the granuloma for decades and get
reactivated under favorable conditions.

16. Caseating granuloma: is a lesion formed by accumulation of cheese-like (caseous)

material consisting of dead cells (necrosis) in the center of the tuberculous granuloma. This
accumulation often leads to the collapse of the granuloma and the spread of infection to
surrounding areas.

17. Latent TB: when a person is infected with Mycobacterium tuberculosis bacteria but does
not have any signs or symptoms of the disease. This person cannot spread the infection to
other people.

18. Tuberculin skin test: a skin test done to diagnose latent TB. The test is interpreted by
measuring the reaction (induration or raised swelling) of the skin in response to the tuberculin
protein injected in the skin. People with latent TB may test positive to a tuberculin skin test;
however this test should be interpreted with caution.

19. Hemoptyis: coughing up blood from the respiratory tract

20. Sputum: thick fluid made in the lungs, usually consisting of mucus materials that are
brought up by coughing. People infected with TB may have blood in their sputum.

21. Acid Fast Bacilli (AFB) Test: This test can be done to microscopically
identify Mycobacterium tuberculosis in people with active TB. Mycobacteria are called acid fast
because they retain the color of their stain after an acid wash. AFB test can be done as smear
test (rapid test) or culture test (confirmatory test).

22. Cavitary lesion: a radiological finding on a plain chest X-ray or CT scan where a gas filled
space is seen in the lung within a zone of pulmonary consolidation, or in the center of a nodule
produced by dead cells. Cavitary lesions may be found in both infectious and non-infectious
conditions of the lung.

23. Meninges: set of three connective tissue layers covering the brain and spinal cord. An
inflammation of the meninges is called meningitis

24. Cerebrospinal fluid (CSF): a clear watery fluid that surrounds the surfaces of brain and
spinal cord. It is formed within the ventricles of the brain and helps maintain pressure within the
cranium at a constant level. It is constantly produced and absorbed in the circulatory system.

25. Hydrocephalus: is the buildup of too much CSF in the brain. When production exceeds
absorption, or circulatory pathways are obstructed, the fluid accumulates leading to rise in CSF
pressure.

26. Lumbar puncture: also called a spinal tap, is a procedure to collect and examine the CSF
to detect disease
27. Miliary TB: a life-threatening type of tuberculosis where a large number of bacteria travel
through the blood and spread throughout the body. In a chest X-ray, it is seen as millet-like
seeding of TB bacilli.

28. Immunocompromised: a person with a weakened immune system

29. Epidemiology: the study of distribution and determinants of disease and health-related
events in a given population, and the application of this study to control health problems

30. Screening: a test done to look for a disease when a person has no symptoms

ESPAÑOL

La tuberculosis es una enfermedad infecciosa grave que afecta a una de cada tres personas en
todo el mundo. Es causada más comúnmente por una cepa de bacteria llamada Mycobacterium
tuberculosis. Y aunque la tuberculosis puede infectar muchas partes del cuerpo, con mayor
frecuencia afecta los pulmones. Una vez que una persona se infecta con Mycobacterium
tuberculosis, la bacteria puede permanecer latente en los pulmones durante años antes de que se
reactive y comience a causar la enfermedad. Como sucedió en el caso de una abuela de 68 años,
que vive en el municipio de Khayelitsha, en las afueras de Ciudad del Cabo, Sudáfrica. Estabas
haciendo una rotación electiva en un hospital rural cerca de Khayelitsha cuando esta abuela trajo a
su nieto de seis meses después de que el niño sufriera una convulsión. La abuela, Numbulelo,
había estado cuidando a este niño desde que su madre murió solo unos meses después de su
nacimiento. En el hospital, notaste que Numbulelo parecía muy enferma. Ella le dice a una de las
enfermeras que ha estado sufriendo ataques de tos prolongados y que ha estado tosiendo sangre.
También dice que ha estado sudando por la noche, se siente cansada durante el día y casi no tiene
apetito por la comida. Para ti, ella se ve muy delgada, y cuando le tomas la temperatura, tiene
fiebre baja. Entonces le dice al médico que está examinando al bebé que sospecha que esta
abuela tiene tuberculosis pulmonar activa. Saber esto hace que el médico sospeche que este bebé
contrajo meningitis por tuberculosis de su abuela. Quien ahora está experimentando una
reactivación de la infección de TB en sus pulmones. Cuando Numbulelo era una mujer joven, vivía
en una choza con otros seis miembros de la familia, uno de los cuales murió más tarde de
tuberculosis. Ahora, durante ese tiempo, inhaló una gotita infecciosa tosida por el pariente
enfermo. Y debido a que su sistema inmunológico era fuerte, los macrófagos en los pulmones de
Numbulelo inmediatamente comenzaron a contener la infección. Hay macrófagos alveolares
residentes en los pulmones y su trabajo es eliminar las partículas extrañas que alcanzan los
alvéolos. El primer macrófago en la escena envolvió a Mycobacterium en un fagosoma, que
funciona como una célula de retención temporal dentro de un macrófago. En la mayoría de los
casos, lo que sucede a continuación es que el fagosoma se fusiona con lisosomas que contienen
ácidos, químicos potentes y enzimas para matar a los microbios invasores. En el caso de
Mycobacterium tuberculosis, la bacteria ha desarrollado un mecanismo de supervivencia. Por lo
que pueden modificar ese fagosoma para que no pueda fusionarse con los lisosomas. Y de esta
manera, las bacterias pueden sobrevivir e incluso crecer y replicarse dentro de los macrófagos
alveolares. Después de que esta replicación haya continuado por un tiempo, los macrófagos
pueden morir, y eso liberaría bacterias que pueden infectar a otros macrófagos. Y también libera
el contenido de los lisosomas, lo que causa daño al tejido circundante y recluta aún más células
inflamatorias en el área. Los macrófagos infectados también tienen sensores inmunes innatos que
no solo les permiten reconocer las bacterias invasoras, sino que también desencadenan la
liberación de citocinas y quimiocinas. Y estos convocan aún más defensores del sistema
inmunitario, como neutrófilos, células dendríticas y linfocitos, al sitio de la infección. De esta
manera, la infección con micobacterias provoca una respuesta inmune orquestada que rodea el
tejido dañado y trata de eliminar la infección. El resultado final de esto se llama granuloma
tuberculoso, una colección local de bacterias amuralladas por las células inmunes. Los granulomas
son bastante dinámicos, con células inmunes entrando y saliendo. Y algunos de los macrófagos o
células dendríticas incluso viajarán a los ganglios linfáticos cercanos para que el sistema
inmunitario adaptativo sea consciente de la presencia de la infección. Si el sistema inmunitario
puede controlar la infección, los granulomas resultantes pueden persistir. Y a menudo incluso
pueden ser demasiado pequeños para ser detectados en una radiografía de tórax. Debido a que la
infección está contenida, no causa ningún síntoma ni daño a ningún órgano en el huésped. Esto se
llama infección de tuberculosis latente o primaria. A veces se le llama LTBI para abreviar y es por
eso que Numbulelo era libre de síntomas cuando era joven. Nunca se le hizo una prueba de
tuberculosis en ese entonces, pero si lo hubiera sido, una prueba cutánea de tuberculina hubiera
dado positivo. Indicando que su sistema adaptado respondió a la presencia de micobacterias.

5:01

Muchos años después, cuando Numbulelo envejeció y su sistema inmunológico perdió algo de su
fuerza, las bacterias atrapadas dentro del granuloma dentro de sus pulmones comenzaron a crecer
nuevamente. Causando una respuesta inflamatoria y daño al tejido circundante. Esto es cuando
sus síntomas de fiebre, pérdida de peso y sudores nocturnos comenzaron a aparecer. A medida
que las células en el interior del granuloma comienzan a morir, este foco de infección forma un
granuloma caseante. Y eso puede erosionarse en las vías respiratorias causando en este caso tos
de Numbulelo, hemoptisis y liberación de muchas bacterias en el aire circundante. Así es como su
nieto se infectó con la Mycobacterium tuberculosis también. En el hospital de Khayelitsha, se
descubrió que las muestras de esputo de Numbulelo contenían bacilos ácidos rápidos. Y su
radiografía de tórax mostró una legión de la cavidad compatible con la enfermedad activa de
tuberculosis pulmonar. Numbulelo fue tratado con cuatro medicamentos antituberculosos,
incluidos isoniazida, rifampicina, pirazinamida y etambutol. Y por suerte, ella comenzó a
recuperarse. Poco después de que Numbulelo llevó a su nieto al hospital, sufrió una segunda
convulsión. También tenía fiebre y estaba letárgico al ingresar. En una parte más desarrollada del
mundo, los médicos probablemente habrían ordenado una resonancia magnética. Y puede haber
mostrado inflamación de las meninges en la base del cerebro, que es un hallazgo común en la
meningitis tuberculosa. A veces también se acompaña de hidrocefalia o hinchazón de los
ventrículos debido a un bloqueo del flujo del líquido cefalorraquídeo debido a la infección.

6:46

En el hospital cerca de Khayelitsha no había una máquina de resonancia magnética, pero el bebé
recibió una radiografía de tórax. Lo cual era muy diferente de la radiografía de su abuela porque
mostraba un patrón miliar. Lo que sugiere que muchos pequeños granulomas se estaban
formando en todos los pulmones. Cuando Numbulelo era joven, su sistema inmunitario pudo
contener la tuberculosis durante muchos años dentro de unos granulomas más grandes en sus
pulmones. Pero los bebés u otros huéspedes inmunocomprometidos tienen respuestas inmunes
menos afectadas, por lo que la infección a menudo se propaga a otras partes del cuerpo. El patrón
miliar en la radiografía de tórax de este niño también sugiere que las micobacterias se habían
diseminado, no solo dentro de los pulmones sino también a otros órganos, incluido el cerebro.
Cuál es una visión común de la infección de TB en bebés. Puede sorprenderle saber que la prueba
cutánea de tuberculina de este bebé resultó negativa. Pero los cultivos de su líquido
cefalorraquídeo que se obtienen al realizar una punción lumbar, eventualmente también
desarrollaron Mycobacterium tuberculosis. Y esto confirmó que tenía meningitis tuberculosa. A
pesar de haber sido tratado con los mismos cuatro medicamentos que su abuela había recibido. Y
a pesar de los mejores esfuerzos de los médicos en el hospital de Khayelitsha, este bebé murió a
causa de su infección por Mycobacterium.

8:09

Cuando un médico sospecha una infección con Mycobacterium tuberculosis, ayuda a comprender
cómo la interacción entre el sistema inmunitario del huésped y el microbio puede dar lugar a las
diferentes presentaciones clínicas de la infección de tuberculosis. Sabemos, por ejemplo, que los
granulomas son una de las características de una infección con Mycobacterium tuberculosis. Y los
granulomas son el resultado de los esfuerzos del sistema inmune para proteger a los anfitriones al
envolver al microbio y desplegar otras células inmunes para tratar de contener la enfermedad.
También sabemos que las micobacterias han evolucionado de manera que les permite colonizar,
persistir y replicarse dentro del huésped. A pesar de los esfuerzos del sistema inmune para
eliminarlos. Y la capacidad del sistema inmune para recordar y reconocer este microbio después
de la reexposición nos brinda una poderosa herramienta de diagnóstico, The Tuberculin Skin Test.

9:10

Al comprender que el sistema inmunitario de un bebé es poco probable que pueda contener una
infección con Mycobacterium tuberculosis de la misma manera. Los médicos pueden interpretar la
presentación física de la enfermedad en huéspedes con función inmune comprometida o ingenua.
Y elija un enfoque terapéutico que sea más probable que tenga éxito. Finalmente, comprender
cómo se propagan las micobacterias, cómo entran y salen del huésped, puede ayudar con los
esfuerzos para prevenir la propagación local de la enfermedad. Y conozca la epidemiología de esta
infección, que un tercio de la población mundial está infectada con Mycobacterium, a pesar de
que pueden estar libres de síntomas. Esto puede ayudar con los esfuerzos de prevención a mayor
escala. Como protocolos de detección dirigidos pueden implementarse para individuos con mayor
riesgo de infectarse con Mycobacterium tuberculosis.