Lecture 11

Question 1

Haemoptysis and abnormal chest X-ray

Answer 1

2.5 cm diameter cavity in chest, i.e. Hole in lung. sometimes horizontal line (liquid/puss)
(lungs split into lobes/anatomical areas, depending on the bronchi that supply them (3 lobes on right, 2 and 1/2 on left))
Lots of possibilities
Lung cancer: high probability. Main worry. Need to investigate quickly. Coughing blood, heavy smoker, 65 (peak cancer time)
TB: low probability. most people coughing up blood wont have TB as is uncommon in nz.
Pneumonia: bacterial infection of lungs. however not expressing classical features (cough, fever)- is an acute syndrome, relatively short lived. diagnosed in 5-6 days (not weeks)
Chronic Obstructive Pulmonary/Airways Disease/Emphysemia: Smoking related airways disease
- variant called Chronic bronchitis.( Cough productive of sputum every day, for 3 months periods, in 2 consecutive years
-smokers cough for a long time, and poor lung function due to smoking related airways disease
-but wouldnt have lump on x-ray) )
-Bronchiectisus

Question 2

Diagnosis of Chronic Bronchitis

Answer 2

Cough productive of sputum every day, for 3 months periods, in 2 consecutive years

• smokers cough for a long time, and poor lung function due to smoking related airways disease
• but wouldnt have lump on x-ray)

Question 3

Lungs

Answer 3

capacity to clean itself right down to small bronchi

Question 4

Bronchiectisus

Answer 4

small airways (not alveoli where O2 is transferred. no 02 transferred)
small airways damaged and broken and cant clean themselves. and fill up with gunk
-structural damage to the lung's Conducting airways
-Symptoms like above case + haemoptysis -lungs are unable to clear out infections, so people get recurrent infections. perpetuates problems and damage

Question 5

TB Chest x-rays

Answer 5

1. Normal lung can see ribs clearly anteriorly and posteriorly, with black inbetween through it
   - slimy cotton wool lung= puss/inflammatory goo filling the airways
   - nodular fluffiness
2. Heart border on left lung. lung fairly indistinctable. Normal lung tissue been eroded by (cancer/in this case TB) -lung obliterated/entirely diseased

Question 6

Projected global deaths 2002-2030

Answer 6

1. Cancer
2. Ischaemic heart disease
3. stroke
   -chronic illnesses associated with modern living- obesity, smoking, pollution
4. HIV/AIDS (increasing for next 20-30 before we curb it)
5. other infectious disease (communicable. decreasing rapidly)
   6.
6. TB/Malaria (decreasing)- cases transferring categories. classified as AIDS case, not TB, even though containing both. Therefore TB still huge cause of death, but under represented.
   -alot of the increased death rates due to HIV are more due to TB than HIV itself. HIV- makes the person more susceptible to HIV and more likely to die from HIV

Question 7

TB Pandemic

Answer 7

Prominent disease around the world
1/3 of the world is infected (TB bacteria in body)
1.5 million have disease/illness at any time (less than rate of infected)
96% of TB is in the developing world (non-uniform)Africe
10 million have HIV/TB co-infection
-illustrates large number of people infected who dont have disease/illness therefore dont know they’re infected

Question 8

Incidence of TB in 2014 by country (WHO)

Answer 8

Incidence= number of “new” cases
NZ had 7 new cases/100,000 in 2014
Canada 0-24
Tonga had 14 (double in pacific, but no real change with popn size)
Samoa had 17
Australia had 6
India had 167
China had 68
-most of TB cases in auckland, are people who were born in bangladesh, india, pakastan, china and immigrate to NZ (for work/study)
NZ’s 7 cases: mostly people who were born overseas, acquired TB overseas, came to NZ and got Sick

Question 9

Mycobacterium Tuberculosis complex

Answer 9

1. M. Tuberculosis (most common form by miles)
2. M. Bovis (cow TB, causes same illnesses in human)
3. M. Africanum (common in Africa)
4. M. Ulcerans (common in Africa)
   - multiple forms of TB exisiting. not just one species of one genus
   - Discovered by Robert Koch
   - used M. bovis in experiments that lead to the development of Koch’s postulates (made cows sick)

Question 10

Koch 1890 postulates

Answer 10

“germs causing disease”
-thoughts magots spontaneously appeared
how did infections spread?
Flawed:
1. pathogen isolated from sick organisms but not healthy organisms -false as may endogenous infections
2. isolated from sick organisms in pure culture
3. should cause disease when health organism is inoculated - false: Zika more often cuases no illness than illness (didnt account for other states of disease (spectrum: no symptoms-symtoms-about to die)
4. must be re-isolated from the experimentally infected organism

Question 11

Classification of Mycobacteria

Answer 11

2x categories of mycobacteria
1. TB
2. Non-tuberculosis mycobacteria (NTM)
a) rapid growing (lab culture growth take 1-2 days)
b) non-rapid growing (lab culture growth takes weeks)
-makes diagnosing TB hard would take sputum from someone with pnuemonia and would take weeks to grow, and only then you would know have TB
c) other (non-culturable mycobacterium. cannot culture or can only culture under very special conditions)
Leprosy: thickened plaqued ears and ruined fingers. Mycobacterium Lepry. Non-culturable. can culture in Us armadillo foot pad and trangenic mice. Not in agar plates of chicken broth. Elusive germ. PCR /genetic sequencing helped to learn more. Like colds part of body (nose, ears) bumpy plaques. biopsy can see the bacteria. Grow around nerve sheets, damages nerves (mans hands nerve sheets so damaged that whacked with hammer/burn on stove, resulting in repeated injury, couldnt feel)
-therefore hands: partially injury + partially changes when loss of bulk of nerve supply
-condition that can cure readily. but often alot of damage is done before entering the clinic

Question 12

Leprosy

Answer 12

No transmission of Leprasy in NZ
-some in Pacific. Samoa more than others. Keribat has a high rate among children. Some cases in Africa, South east asia, india. (similar distribution to TB)
Leprosy: thickened plaqued ears and ruined fingers. Mycobacterium Lepri. Non-culturable. can culture in Us armadillo foot pad and transgenic mice. Not in agar plates of chicken broth. Elusive germ. PCR /genetic sequencing helped to learn more. Like colds part of body (nose, ears) bumpy plaques. biopsy can see the bacteria. Grow around nerve sheets, damages nerves (mans hands nerve sheets so damaged that whacked with hammer/burn on stove, resulting in repeated injury, couldnt feel)
-therefore hands: partially injury + partially changes when loss of bulk of nerve supply
-condition that can cure readily. but often alot of damage is done before entering the clinic

Question 13

Transmission of TB

Answer 13

1. TB transmitted by someone coughing and another person breathing in the bacteria e.g. singing (laryngeal TB very good at transmitting TB into the air)
   - normal bacteria when coughed/sneezed form droplets/dust that dont travel much further than 1 metre
   - but TB has the capacity to Float (chicken pox, measles and Nori virus can). Therefore can cough and leave the room, someone else can still contract the disease regardless of them leaving.
   - spread by both direct and indirect contact (people dont need to come together)
2. Bacterium particle inhaled and thought to have to reach alveola, come in contact with a Pulmonary Alveolar Macrophage
   - if stuck in nose/throat, less likely to develop infection
   - can Drink TB, get TB of the Gut by drinking infected unpasturised cows milk (myobacterium bovis)
   - Cutaneous spread of TB: catch TB through skin (no longer this extreme exposure)-historical

Question 14

TB initial phase of TB infection

Answer 14

TB wants to be phagocytosed by WBC.
LAM (Lipoarabino mannan) on the surface of the cell stimulates/binds to the complement receptor of pulmonary macrophages (causing TB to become injested)
-TB bacteria has LAM in its cell wall
TB posses an array of factors that enable it to survive intracellularily and to induce the macrophage to remain alive
-once eaten, Inside the WBC the TB can resist being killed and live
-Macrophages (like nuetrophils) normally throw H202 or oxygen free radicals at TB to kill it. but since inside is mostly resistant to killing. Due to tough cell wall, free radical scavengers and superoxide dismutase (turns off free radical production), alter formation of toxic vessels on phagosome, so lysosome doesnt mature.
-LAM also stops macrophage from dying, tricks into staying alive, and prevent them from signalling other cells (what a cell typically does if it isnt capable of handling infection and needs to be killed, especially in viral infections). Blocks this help signal, so rest of immune system half ignores it.

Question 15

TB in lymph nodes

Answer 15

survives within macrophage
is able to communicate to other cells to a degree but not perfectly
-other cells recruit other cells. situation is augments (similar to an acute infection) stimulates other cells. TNFa (tumour necrosis factor alpha) recruits other macrophages and immune cells.
In early stages of infection TB is carried to local lymph nodes
-dendritic cells may ingest some damaged TB proteins and take to local lymph nodes. -lung local lymph nodes located in central Hilum (where BV and bronchi come into lung) (hilum normally seen on Right X-ray as not obscured by heart border).Within few hours of infection, TB germs/proteins are presented to lymph nodes indicated problems
T lymphocytes (same as HIV) proliferate and go back to site of infection to try and help out.
Often TB has not been adequately killed by host immune cells. Instead builds a prison for TB
-in some (many) cases the immune system cannot quite kill TB and instead builds a prison of immune cells around it -granuloma
TB Granuloma:
a) Centre of necrotic muck, both living and dead TB, cell fragments and proteins (similar to puss)
b) Spherical jail build around it of Abnormally large strange looking macrophages that havent been allowed to die. sometimes multinucleated as have coallesed. still alive partially due to TB, but also partially due to:
c) CD4 Helper T Lymphocytes palicade around the outside continuously sends messages to macrophages, telling them what to do: to stay strong and stay alive.
-bodies response to Chronic infection/infection your body cannot deal with. TB cardinal learning point about chronic infections. Also parasites and sifolis bacteria and Salmonella bacteria

Question 16

What do multinucleated cells indicate? and what does central necrosis indicate?

Answer 16

Multnucielated cells hints: Granuloma

Central Necrosis: TB (Necrotising Grnauloma

Question 17

What is an illustration of the body’s response to chronic infection?

Answer 17

Granuloma

• also forms in fungus, other mycobacteria, parasites, sipholis
• reflects disruption of autoimmunity: sarcoidosis, krones disease( affects gut)
• could be TB but could also be other infections

Question 18

What is the difference between the indications of a Granuloma or a Necrotising Granuloma?

Answer 18

Granuloma: could be TB but could also be other infections

Necrotising Granuloma = Granuloma with central necrosis: TB

Question 19

Outcomes of Primary infection not leading to initial sickness

Answer 19

Primary infection (most of time granuloma so small that wont be able to see in chest x-ray. sometimes big enough to see)
Primary complex Gohn focus (granuloma in lung + disease in respective local lymph node (if infection is in top part of lung, then top lymph node is effected)
1. Immune containment (most of time granuloma is effective enough to contain)
a) (most of time) no disease. Latent TB infection (live with TB, die of other causes)
b) reactivation disease (TB wake up. or Granuloma containment can fail).
i) Age. occurs as people get older, immune system sleepy.
ii) HIV. can lead to immune disruption. Helper T cells surrounding granuloma depleted, and stuffed with HIV –> HIV wont get messages to stay alive –> granuloma break down –> TB spread around body
ii) cancer
iv) steroid treatment
v) anti TNFa drugs. TNFa so important for lymphocyte to tell macrophages to stay strong and alive. if drug interferes with this, it is possible that patient TB in body, could wake up and make them sick.
-used for Rheumatoid arthritis. Anti-inflammatory type drugs
-have to check people dont have TB before use these treatments

Question 20

Outcomes of Primary infection which lead to initial sickness after infection

Answer 20

2. Illness
   a) pulmonary/thoracic TB. more common as TB typically inhaled into lungs, infections will be in lungs of chest cavity.
   b) Extra pulmonary. Early on in phase TB can spread in blood stream. common to have TB away from lungs.
   i) Lymph adenitis: Mostly TB in lymph glands-cardinal symptom (fever, sweating, weightloss), often neck , under armpit (axillary) sometimes inside of chest which is only visible after xray
   ii) bones
   iii) brain (lumps)
   iv) meningitis
   v) kidney disease
   vi) gut disease
   vii) testicular/ovarian
   - can go anywhere in body, as was in blood stream. Widespread
   c) Miliary TB. Rareish. Deseminated TB. TB sepsus. Overwhlemed by TB. Culture TB from multiple sites. (blood, urine, spinal fluid)
   - different Chest X-ray. Cotton wool fluff everywhere “millet seeds”= see coallescent dots all through lungs, looking like lungs were full of seeds
   - very high risk of death unless treated promptly

Question 21

Outcome of primary infection (in the lung)

Answer 21

1. 1 Primary focus (Ghon’s focus) = Lung and node (remains as granuloma with associated infected lymph node- can be so small that cannt be seen on xray)
2. Pleural (granuloma/infection at surface of lung)
3. Cavitation (infection ovewhelms at site, causing pneumonia/cavity/abcess)
4. Symptoms from upper nodes (lymph glands get so big they push on other strucutures, e.g. a) recurrent Laryngeal nerve, giving person hoarse voice, as one vocal folds not working. b) push on bronchi and give chronic cough)
5. TB bronchopneumonia (most common form of TB disease)
6. Pericardial disease (constrictive)( infected lymph gland or granuloma erodes into pericardial sac)-RARE
7. axillary = disseminated (go everywhere-UNcommon)

Question 22

How and when did he catch TB? (samoan man)

Answer 22

Born in Samoa- more likely to be caught in child Samoa in Nz, and been living in him for years (e.g. since 1960)
Caughed on and caught it by inhaling/Breathing it in

Question 23

Risks for catching TB as the recipient

Answer 23

Amount of contact with someone is what matters
household contact spouse (sleep in same bed, more likely. still not 100%) –> flatmate
children- most infections believed to be caught during childhood. adults tend to be more resistant. (studies of people with active TB) -someone with TB, more likely to find children associated with this man being infected with TB rather than associated Adults
immune suppression (HIV, Alcohol) greater liklihood of catching TB and getting TB disease
institutional care (prisons)
healthcare workers- coughed upon by people with TB throughout career (all consultants have evidence of TB)

Question 24

Risks for catchin TB re transmission/spreading

Answer 24

Pulmonary disease- very worrying.
-If no TB in lungs then unlikely to spread (e.g. TB just in lymph gland Cannot spread to others).
TB visible in sputum: if can see TB in sputum down microscope, indicates have a large amount of TB in lungs, therefore large likelihood of transmitting it (3x fold difference)
Cavitation visible on xray: very likely to cough out large amounts. Likely to have big cough, and to cough out large amounts of Goo, affect other people
-if people have TB and dont cough, then unlikely to transmit. but can be spread just by talking
Coughing
Failure to cover mouth when coughing - more likely to spread. (coughing into sleeve or handkerchief is actually an effective measure against TB transmission)
Delayed diagnosis -arent diagnoses promptly. early stages TB just looks like someone with a cough and a fever. In NZ mostly flu, or a virus, or bronchitis. Average time to diagnose TB is multiple weeks- has had ample time to cough and transmit disease to others over this time frame

Question 25

Does age influence susceptibility to TB?

Answer 25

more likely to catch TB as a child than as an adult children- most infections believed to be caught during childhood. adults tend to be more resistant. (studies of people with active TB) -someone with TB, more likely to find children associated with this man being infected with TB rather than associated Adults immune suppression (HIV, Alcohol) greater liklihood of catching TB and getting TB disease

Question 26

How should we Diagnose TB?

Answer 26

Collect sputum: not superficial. needs to be representative. Most samples are just saliva and not sputum. -Hypertonic saline mist, cough for 5 mins, result at end is a reliable sample of sputum from deep in lungs -3x samples, a day apart -Children dont cough up sputum. Microscopy to try find TB like germs Grow TB from sample. 1. Suspicion (often not suspicious enough) 2. chest x-ray 3. Sputum specimens - AFB(acid fast basili) 4. TB PCR 5. TB culture (days to weeks)

Question 27

AFB

Answer 27

Acid Fast Basili | -TB wall rich in Fats/Lipids. Mycolic acid layers with intercalated lipids

Question 28

Ziehl-Neelsen Stain

Answer 28

1. Smear specimen on a slide 2. apply carbol-fuchsin stain 3. apply heat (fat in TB cell wall melts slightly. so stain/dye will be trapped when resolidifies upon cooling) 4. wash with HCL in ethanol (but cannot wash stain out as it is trapped in fat of the TB mycobacterium) -TB is acid bacteria/retains the stain: see long slender bacteria in sputum -Doesnt mean TB, just means that the mycobacterium is acid fast. But in conjunction with alot of other TB symptoms indicates high likelihood -mycobacteria retain the stain - incorporated in the lipid cell wall Most other bacteria lost the CF stain Final test: undergo a DNA test of that bacteria (which has now been made visible because of the stain) -if PCR test comes back with TB DNA, then is 100%

Question 29

What happens to ensure the presence of TB after a positive AFB Trapped stain in Acid fast Basili/Mycobacterium?

Answer 29

Final test: undergo a DNA test of that bacteria (which has now been made visible because of the stain) -if PCR test comes back with TB DNA, then is 100%

Question 30

Any reason to diagnose latent TB infection?

Answer 30

There are other Immune system illness, that by knowing the patient has TB would be very helpful, and potentially avoid that person from dying 1. HIV infection, look if they have latent TB (co-infection), as their risk of the TB waking up is higher. Need specific treatment - not likely to do this with every NZ as normally Negative. But if patient if from africa/zimbabwe/india, should test as they have higher liklihood 2. Rheumatoid Arthiritis. Before give drugs. As these drugs increase risk of TB waking up (Anti-TNFa anti-inflammatory drugs. Good for rheumatoid arthritis inflammation. Bad for TB granuloma prison's helper tcell messages to macrophages to stay strong and alive) 3. active screening of Healthcare workers. certain group and age, that by giving preventative treatment will decrease their risk of developing TB illness over their lifetime

Question 31

MAN II test

Answer 31

Syringe contains mycobacteria proteins (not always TB) injected Intradermally (not under, but INTO skin) -if person has TB in body, immune system is alert to TB, and has memory to TB, and will create a reaction to TB to the proteins "TB proteins PPO given intradermally. Dendritic cells process antigen and present to T cells. Results in 72 hours. -if an inflammatory lung is present the person is "hypersensitive" to TB antigen" 1. -some people dont react (anergic) = therefore this test ISNT useful for diagnosing disease 2. Person doesnt return after injection. Doesnt get Read. BIGGEST waste of healthresources- nurse and docotr time, resources etc 3. takes 3 days! if lump of certain size develops (not redness) = yes your immune system displays knowledge of proteins put in 4. not specific (doesnt distinguish between types of mycobacterium 5. interpretation difficult

Question 32

Anergic

Answer 32

When someone can contain a disease but DONT REACT to test | -e.g. Man 2 test for TB

Question 33

Interferon Gamma release Assay (Quantiferon Gold)

Answer 33

1. Whole blood (includes white blood cells) into test tube (WBC which remember TB from before) 2. Positive control: Add a mitogen (e.g pokeweed). Mitogens always causes lymphocytes to go hyperactive and make lymphocytes proliferate -they release interferon gamma 3. add TB antigens - sensitised lymphocytes (WBC in sample that remember TB from before) sampled WBC will recognise protein and will proliferate and release interferon gamma - this person has been exposed to TB in the past - (WBC will release these immune cytokines if stimulated by mycobacterium proteins that is remembers)