CDL302 Flashcards

Question

how can genetic be useful in the study of lung diseases?

Answer 1

``` diagnosis estimation of risk understanding pathological mechanisms ene therapy guidance for new therapies ```

Answer 2

- lymphocytes (T, B and NKC) - phagocytic cells(monocytes and macrophages) - granulocytic cells (neutrophils, eosinophils and basophils) - dendritic cells

Answer 3

there are anatomical and physiological barriers that the pathogens encounter in the lungs, there are cells that line the airways and produce surfactants, there is ciliary clearance, a low stomach pH and lysosomes in the tears and saliva

Answer 4

they have a barrier function and are also able to detect and respond to pathogens

Answer 5

cellular: NKC, dendritic cells, macrophages, eosinophils, neutrophils, mast cells etc humoral: part of the acute phase response (LPs binding proteins)

Answer 6

cellular: T cells and B cells humoral: antibodies

Answer 7

yes, they communicate a lot | the adaptive immune systems progressed from the innate system

Answer 8

NKT cells and dendritic cells sit on the cusp of the 2 systems

Answer 9

it is important in not getting us sick initially involves a rapid host defence against invading pathogens it is evolutionarily conserved involved in the recognition of invading pathogens and activation of anti-microbial response is emerging as a critical regulator of human inflammatory disease implicated in the development of some diseases e.g. asthma

Answer 10

this means that it will always respond to a pathogen in the same way i.e. if you inhale a bacteria today and again the same bacteria in 6 years, it will respond in the same way and take the same amount of time. this is because the quicker second response is by the adaptive immune system

Answer 11

our genetic attributes are much slower than the pathogens ones and this means that we would struggle to keep up. so, in innate immunity, they recognise very conserved structures within bacteria and also across different sets of pathogens. they have also evolved to recognise some of the biological consequences of infection

Answer 12

they rely on a limited number of genetically predetermined receptors called pattern recognition receptors these are highly conserved structures that are expressed by a large group of pathogens they are common biological consequences of infection

Answer 13

2 of the 3 strategies utilise pattern recognition receptors 1. microbal non-self = pathogen associated molecular patterns (PAMPS) e.g. TLRs, RLRs, NLRs and collecting family 2. consequences of damage/injury = damage associated molecular patterns (DAMPS) e.g TLRs, RLRs, NLRs and RAGE family 3. missing self = MHC class 1 specific inhibitory receptors - these cells are on the cell surface and inordinacy health, they would be presenting host cells to the immune system and NK cells recognise these as host cells and cause an inhibitory signal so that they don't attack themselves

Answer 14

it recognises the PAMPs that are found on pathogens but not usually on host cells PRRs either act to directly bind PAMPs or interacting with other receptors that are bound to PAMPs bacteria, fungi and viruses are all recognised by their PAMPs

Answer 15

they are not easily mutated and they are very crucial to the cells function and so this would be something easy to recognise a pathogen by

Answer 16

they are endogenous molecules that are created to alert the host to tissue injury and to initiate repair can be intracellularly or extracellularly intracellular: molecules released by cell necrosis/activation following injury in the extracellular metric, molecule fragments are released/up-regulated in response to tissue injury these prime the immune system to be ready to attack

Answer 17

proteins = heatshock proteins (TLR2 and 4), high mobility box1 protein (TLR2 and 4) self nucleic acids: mRNA (TLR3), ssRNA (TLR7 and 8), DNA (TLR9), IgG-chromatin complexes (TLR9)

Answer 18

proteins: fibrinogen (TLR4), fibronectin (TLR4), tenascin-c (TLR4) proteoglycans and glycosaminoglycans: billycan (TLR2&4), version (TLR2), hyaluronic acid fragments (TLR2&4)

Answer 19

harmful stimuli e.g. pathogens, injury, heat, auto-antigens, tumours and necrotic cells can all trigger damage leading to release DAMPs. this will activate TLRs and lead to the release of pro-inflammatory mediators which then can feedback and cause an increase tissue damage. if this loop is allowed to propagate and lead to the release of more and more DAMPs, it can have a detrimental effect and cause pathogenesis

Answer 20

associated with many inflammatory and autoimmune diseases swell as atherosclerosis and cancer - although endogenous signals can be good (to prime the host if your under attack immunologically), if they are allowed to propagate and not checked it can do more harm

Answer 21

can be broadly divided into those who recognise bacteria which are on the cells surface and those who recognise viruses which are contained within endosomes

Answer 22

TLRs in endosomes generally can't recognise host molecules where as those on the cell surface recognise any kind of DNA or RNA

Answer 23

TLR10 - cell surface, ligand undetermined in humans | TLR11-13 = expressed in mice

Answer 24

TLR4 can recognise bacterias e.g. lipopolysaccharide and mannan , also Repiratory Sinsitual Virus and a lot of host proteins including Tenascin-C -- this will trigger an inflammatory response to all of these different ligands

Answer 25

they are very different to normal receptors as they have the ability to recognise a wide range of ligands they sometimes use co-receptors to do this e.g. TLR2 can work with TLR1 and 6 which is a way to expand the repertoire of proteins that they can see/recognise

Answer 26

the TIR domains of TLRs interact with TIR domains of the adaptor proteins TLR4-TRIF signalling = initiated within endosomes (in bacteria): phosphorylation cascades activate NF-kB and MAPKs allowing entry to the nucleus to drive expression of cytokine genes - predominantly in response to bacteria (in viruses): phosphorylation of IRFs lead to localisation of the nucleus to drive expression of type 1 interferon (IFN) genes to help control viral infections -in response to TRIF, IRF activation happens -cross talk an occur i.e. TRIF activating NF-KB

Answer 27

all TIRs except TLR3.

Answer 28

there are 4 main TIR adaptors: MYD88, TRIF, TIRAP/MAL & TRAM

Answer 29

it needs a bridge i.e TRF1 as it can't directly bind to Myd88

Answer 30

NLRs detect bacteria from the cytosol | TLRs detect bacteria from the endosomes and cell surface

Answer 31

22 in humans | 34 in mice

Answer 32

they are involved in sensing intracellular bacterial pathogens and DAMPs, and in the regulation of inflammatory and cells death responses

Answer 33

by the presence of conserved nucleotide-binding and oligodimerisation domain (NOD) motif that activates the signing complex

Answer 34

``` there are 5 NRLA - acidic domain NRLB - BIR domain NLRC - CARD domain (NOD1, NOD2) NRLP - Pyrin domain (NRLP3) NRLPX - no known homology ```

Answer 35

there are 2 functional NRLs - NRL C(NOD1 and NOD2) - inflammatory and antimicrobial signalling - NRLP3, NRLP6 and NAIPs - inflammasomes

Answer 36

NOD1 and 2 sense bacterial molecules produced during the synthesis, degradation and remodelling of peptidoglycan (PGN) - which is a major component of bacterial cell walls NOD1 recognises mess-diaminopimelic acid(mess-DAP) containing PGN fragments (MAINLY GRAM NEGATIVE) NOD2 senses muramyl dipeptide (MDP) found in the PGN of nearly all GRAM POSITIVE and GRAM-NEGATIVE organisms

Answer 37

NOD family results in the signalling of NFK-6, MAPKs and the release of pro-inflammatory cytokines

Answer 38

they are different as they also can recognise the microbial products in the cytoplasm and also cellular/metabolic stress which can trigger activation of the inflamasomes which are involved in cleaving/activating cytokines e.g. IL-1B and IL-18. this is an additional control mechanism

Answer 39

RLRs = rig like receptors there are 3 members that detect viral RNA in the cytoplasm RIG-1, MDA-5 and LGP2

Answer 40

RIG-1 = retanoic acid inducible gene 1 short dsRNA (up to 1kb) s' triphosphate (5'ppp) cas (ss or ds RNA) influenza A and RSV

Answer 41

melanoma differentiated gene 5 long ds RNA (over 2kb) with no end specificity replication intermediates rhinovirus

Answer 42

laboratory of genetics and physiology 2 | very high affinity for any dsRNA

Answer 43

ligand binding induces conformational changes and oligomerisation of RLRs to activate the signalling partner IPS-1 on mitochondrial membranes IPS-1 activates signalling cascades leading to activation of IRFs and NF-kB an the expression of interferon and cytokine genes LGP2 functions as a positive regulator in RIG-1 mediated and MDA5 mediated virus recognition

Answer 44

cytokines, chemokine and others (e.g. acute phase response, adhesion molecules) these have 2 roles: immediate defence and direct adaptive immunity

Answer 45

5 main cytokines 1 of the main functions is to recruit the inflammatory cells to the site of infection. could be through effects on the vascular endothelium to make it more leaky so that the cells can get out could upregulate adhesion molecules on these cells allowing them to bind to the endothelium and pass through into the area where the pathogen is

Answer 46

they are induced on circulating immune cells and endothelial cells they work to co-ordinate movement of cells into infected tissues where phagocytosis and killing takes place

Answer 47

the acute phase

Answer 48

cytokines can activate hepatocytes in the liver to generate acute phase proteins

Answer 49

they are endogenous pathogens and so act on the hypothalamus to raise the body temperature (fever)

Answer 50

TNF-alpha stimulates migration to lymph nodes and maturation

Answer 51

because bacteria and viruses find it more difficult to replicate at a high temperature whereas our adaptive immune system works much better at these high temperatures

Answer 52

sepsis is a condition that occurs when the acute phase response goes wrong affects ~200000 people in the UK every year and ~40,000 people die many of these are avoidable but this condition can be very hard to diagnose its usually detected in the latter stages, making it difficult to stop

Answer 53

starts with an infection from insect bites/cuts etc immune response responds to this in a normal way for some reason, wither the body can't control the spread of infection around the body or because the immune system is in overdrive leads to sepsis. this can cause damage to organs

Answer 54

release interferons will then act on interferon receptors (IFNalpha and IFNbeta) activating the STAT pathway has 3 main effects on our cells

Answer 55

1 = induce resistant to viral replication. activates genes that cause the destruction of mRNA inhibits the translocation of viral proteins and some host proteins interferons tend to communicate to neighbouring cells that viral attack is underway thereby priming them for an attack 2 = increases MHC class 1 expression and antigen presenting of viral proteins facilitates recognition and susceptibility to cytotoxic t cells 3 = activates NK cells to kill virus infected cells as well as activating dendritic cells and macrophages + include chemokine to recruit lymphocytes

Answer 56

1 way to target to detrimental effects on over active immune system is to inhibit the response using antagonists

Answer 57

antagonists: block binding of ligands/protein ligands complexes to receptors/ interfere with intracellular adaptor molecules of common signalling pathways antagonists developed to date = small molecules, proteins, oligonucleotides, antibodies and peptides agonists: adjuvant effect (used with a primary treatment) promoting protective responses e.g. interferes with anti viral, vaccines

Answer 58

Antagonists - side effects = potentially repress protective mechanisms Agonists - side effects = potentially enhance inflammation

Answer 59

cartilaginous rings

Answer 60

joined to the middle ear cavity and this is why when you get a cold, your ear is sometimes blocked

Answer 61

respiratory and non-respiratory

Answer 62

ventilation and gas exchange CO2, O2, pH, humidifying

Answer 63

- making, activating and inactivating of vasoactive substances, hormones and neuropeptides - lung defence: compliment activation of host defence proteins, recruitment of leukocytes, cytokines and growth factors - speech, vomiting, defacation and child birth

Answer 64

they are highly vascularised

Answer 65

we inhale ~10,000 litres of air every day and lots of pathogens could potentially come in and infect our lungs but our host defence system can prevent pathogens from coming in and establishing an infection

Answer 66

cells that line the cavities and surfaces of structures thouhout the body

Answer 67

epithelial cells

Answer 68

basement membrane

Answer 69

to line the airways and moisten them. also to protect them by acting as a barrier to prevent potential pathogens or foreigners from infecting the lungs

Answer 70

by work of the mucociliary escalator

Answer 71

1. anti-proteases: SLP-1, lysozyme and phospholipase A - these are to protect the lungs from proteases that could be left behind after an inflammatory response etc 2. anti-fungals 3. anti-microbial peptides 4. surfactant A and D - opsonise pathogens for enhanced phagocytosis - interact with the surface of pathogens and then link the phagocytosis mechanism within the lungs and they mark these pathogens for uptake by professional phagocytosis

Answer 72

bacterial flora - provide a low level induction system that keep the defence system primed

Answer 73

different parts of the tract have different airway epithelium i.e. bronchioles = ticker than in the alveoli as you go down the tract, cells get more cuboidal/columnar and alveoli gets more squamous

Answer 74

they are similar human airways are more cartilaginous and have a greater number of mucosal glands the epithelial cell population is about the same

Answer 75

the bronchioalveolar duct

Answer 76

basal cells which are progenitor cells for repopulation of airways following injury in the trachea and bronchi

Answer 77

there is cilia with pericellar lining fluid above it which is thin watery fluid that the airways secrete on top of this is a mucin layer

Answer 78

there are 2 types of secretory cells. - goblet cells which produce mucus - serous cells which produce a different series of proteins

Answer 79

type 1 and type 2 cells in the alveoli are very thin cells that have a huge surface area with a nucleus that sticks out. they allow reasonably for gas exchange between the capillaries and internal surface of the alveolar structure -surfactant = a lipid based material that serves to lower the surface tension of the respiratory tract

Answer 80

airway mucus is a viscoelastic gel containing water,carbohydrates, proteins and lipids. it is the secretory product of the mucous cells (goblet cels and submucosal glands)

Answer 81

it describes the mucus on top of cilia which brushes it

Answer 82

created by huge proteins- MucSAC/SB

Answer 83

mucus is transported from the lower respiratory tract into the pharynx by air flow and mucociliaryy clearance

Answer 84

mucus protects the epithelium from foreign material and from fluid loss

Answer 85

- encapsulate foreign particles then the cilia beat in organised waves the cilia beat in directional (synchronised) waves to move the mucus up the airways this happens all the time in the body to prevent being clogged up

Answer 86

happens constantly - its innate

Answer 87

an expulsive reflex that protects the lungs and respiratory passages from foreign bodies

Answer 88

irritants - smokes, fumes, dusts etc diseased conditions e.g. COPD, tumours etc infections (influenza)

Answer 89

an involuntary expulsion of air containing irritants from the nose

Answer 90

irritation of nasal mucosa | excess fluid in airways

Answer 91

they target airway epithelial cells | a conséquence of this is damage

Answer 92

a complete repair

Answer 93

there is a cycle of differentiation, damage, spreading an d migration, proliferation then differentiation again

Answer 94

they have a degree functional plasticity which is what allows it to change its phenotype

Answer 95

basal cells | there is no evidence that in different regions, basal cells have been able to form different cells

Answer 96

pulmonary disease

Answer 97

abnormal epithelia responses to insult/injury

Answer 98

when there is mucus and inflammatory cells blocking the airways, mucus plugs can completely obstruct the airways. this can be coughed up by a patent during an asthmatic attack

Answer 99

respiratory diseases kill more people than all cancers combined

Answer 100

Failure of adaptive immunity leads to recurrent respiratory infections, specific to the cell affected

Answer 101

internal: - phagocytic cells - antimicrobials - inflammatory cells - natural killer cells external: - skin - mucous membrane - secretions

Answer 102

``` humoral response (antibodies) cell mediated response (cytotoxic lymphocytes) ```

Answer 103

an antigen is a molecule capable of inducing an immune response a pathogen is a molecule (bacteria or fungi) that are covered in a myriad of unique receptors)

Answer 104

specific - ability to mount a specific immune response to a huge range of antigens including pathogens self-recognising - recognition of self antigens and eliminate of attractive clones memory - development of immunological memory and so is able to remember long lived B and T cells

Answer 105

* T cells and B cells express different unique antigen receptors * The variable region determines the receptor specificity

Answer 106

~10^18 | DNA can't encode all those receptors

Answer 107

• Early in lymph development, diversity comes from DNA recombination • Generation of pathogen specific variable regions in lymphocyte receptors is the basis of diversity and specificity • Much diversity is generated early in development via DNA rearrangements (VDJ recombination) o VDJ lays the blueprint of DNA • Exposure to relevant antigen, triggers replication and somatic hyper-mutation generating further diversity

Answer 108

Selection for higher affinity

Answer 109

• Multiple variable and diverse joining regions • More looping mechanisms which are excised o Very random excision of regions then they are put back together • Random recombination events occur between about 50 Variable (V) 27 Diversity (D) and 6 Joining (J) segments in both heavy and light chains • Recombination (splicing) is not precise (nucleotides inserted or deleted) greatly increasing diversity • Further mutations occur on pathogen exposure (somatic hypermutation) • with selection of higher affinity clones (affinity maturation)

Answer 110

50(V), 27(D), 6(J)

Answer 111

¥ A state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response ¥ Tolerance can be to self, but also to the fetus in pregnancy, or it can develop to pathogens (chronic infections) or cancers

Answer 112

¥ Failure to establish tolerance leads to autoimmune disease, where our immune system attacks our own body. An example is rheumatoid arthritis

Answer 113

central and peripheral - Central tolerance – way to distinguish cells that are self to those that are non self -- most in early life - Peripheral tolerance – way to prevent over-reactivity of the immune system to environmental entities --- continues throughout life

Answer 114

Central tolerance In the thymus, lymphocytes that react with self-antigens are deleted or develop into suppressor ‘Tregs’ Peripheral tolerance In lymph nodes, autoreactive clones escaping central tolerance are deleted or suppressed by Tregs

Answer 115

• T cells that react to an autoantigen (antigen from normal tissues which are targeted by humoral or cell mediated immune system) become t-reg cells o They migrate to migratory tissue and are established there and then mediate peripheral tolerance

Answer 116

¥ Allows rapid immunological response on subsequent exposure

Answer 117

¥ Following activation, a small proportion of high affinity B and T cells differentiate into long-lived memory cells, residing in lymph nodes or tissues ¥ Memory B cells are distinguished from naive B cells by an increased lifespan, faster and stronger response to stimulation and expression of high affinity immunoglobulin (IgG)

Answer 118

* APCs that have interacted with Th are licensed to activate cytotoxic T cells (CD8 +ve) kill virus-infected or tumour cells * Cytotoxic T cells form pores in their target cells which ‘explode’

Answer 119

* Following APC-Th cell interaction, governed by MHC and co-stimulatory receptor interactions, cytokines are produced * Cytokines activate different T cell transcription factors leading to differentiation into different Th cell subsets

Answer 120

* B cells can interact with antigen directly * In some cases, they can produce antibody without ‘help’ (T-independent) * Mostly B cells need input from Th cells (Th2 and Tfh cells)

Answer 121

plasma cells

Answer 122

¥ In isotype switching (class switch recombination or CSR) the ‘variable’ antibody region is unchanged but becomes attached to a different constant region, altering its properties.

Answer 123

initially express IgM and IgD | after maturation - IgM = switched to IgG, IgA or IgE

Answer 124

¥ IgM Produced early in immune response ¥ IgA Mucosal immunity (gut and lung) ¥ IgG >80% circulating antibodies are IgG ¥ IgD Found on the surface of all B cells ¥ IgE Binds mast cells, mediates allergic reactions

Answer 125

• Variable region binds target antigen and constant region interacts with effectors

Answer 126

• IgM are good at neutralising and agglutinating, IgG are good at opsonising and fixing complement

Answer 127

¥ Vaccination – augment the adaptive response ¥ Immune suppression – reduce the adaptive response ¥ Monoclonal antibodies (’biologic therapy’) ¥ Varied applications including ¥ Inflammatory disease (suppress immune system) ¥ Infection (additive to immune system) ¥ Malignant disease (augment immune system)

Answer 128

¥ Vaccines are derived from pathogens or toxins (e.g. dead or attenuated bacteria, capsular polysaccharide, viral proteins) ¥ Vaccines can prevent infection or reduce morbidity in individuals, and also generate ‘herd immunity’ - need to vaccinate 75-95% (disease-specific)

Answer 129

¥ Can be administered by injection, nasally, orally etc.

Answer 130

¥ Annual outbreaks of influenza A lead to massive strains on health services and many deaths ¥ Major antigens are neuraminidase (N) and hemagluttinin (H) ¥ Mutations (antigenic drift – all flu viruses) mean protection is reduced, and genetic re-assortment with viruses affecting other species (antigenic shift – Influenza A only) may lead to pandemics ¥ Influenza A is classified by its expression of N and H e.g. H1N1, H3N1 etc. As influenza A affects other species, antigenic shift can occur ¥ Influenza B causes less severe disease and is less variable (antigenic drift only)

Answer 131

* WHO selects ‘likely’ flu strains for next year in February (2 flu A and 1 flu B). Don’t always guess correctly. * Manufacture low pathogenicity virus to express the relevant H and N * Mass produce virus in eggs and kill virus to generate vaccine * Targets – elderly, chest diseases, diabetes. Immune responses may be insufficient Patients who can’t make antibodies derive limited benefit

Answer 132

¥ Corticosteroids – modulate transcription and suppress both innate and adaptive responses. Multiple side effects ¥ Antimetabolites – suppress DNA synthesis – mainly T cells ¥ Methotrexate inhibits dihydrofolate reductase and prevents synthesis of folic acid ¥ Purine analogues e.g. azathiaprine ¥ Mycophenolate – inhibits guanosine synthesis ¥ Calcineurin inhibitors (cyclosporin, tacrolimus) – prevent G0-G1 cell cycle progression – T cells ¥ Monoclonal antibodies - wide range of targets and applications e.g. rituximab (antiCD20) targets B cells

Answer 133

¥ Clonal antibodies engineered to specific targets for scientific and medical applications ¥ Fuse myeloma cells with spleen cells from immunised mice (Kohler and Milstein) ¥ Can now be made by recombinant technology using viruses or yeast and made chimeric and even ‘humanised’ to reduce allergic reactions

Answer 134

¥ Presentation of tumour antigen with MRC and co-stimulation should lead to an activated T cell response ¥ T cells express inhibitory checkpoints receptors e.g PD-1 (Programmed Death 1). Tumours may express ligands eg PD-L1 to engage these checkpoints, inhibiting the immune response

Answer 135

¥ Monoclonal antibodies have been engineered to prevent this, enhancing recognition and immune responses to tumour cells

Answer 136

A chronic inflammatory disorder of the airways causing recurrent episodes of wheezing, breathlessness, chest tightness, and cough. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.”

Answer 137

both innate and immune cells

Answer 138

o airway inflammation o bronchial hyper-responsiveness o recurrent reversible airway obstruction

Answer 139

♣ 5.4m in the UK receiving treatment. 1.1m children (1:11), and 4.3m adults (1:12) ♣ 1,246 asthma deaths in 2012 (358 males, 888 females) - 21 aged 0-14 years - 204 aged 15-64 years - 1,021 aged >65 years ♣ 1 person dies from asthma every 7 hours ♣ 60% of asthmatics report significant persistent symptoms or symptom burden ♣ 31% said asthma symptoms prevent them doing things in spare time ♣ 65% of asthmatics report severe attacks (exacerbations) - excessive mucus clogs up airways in asthma patent

Answer 140

- difficult to treat severe asthma attack with drugs because the airways would be clogged up and so taking drugs wouldn’t work as they can’t get access - use systemic drugs to open up the airways instead

Answer 141

♣ £1.1bn per annum costs to the NHS - 6.3m primary care consultations (74% costs) - 93,000 hospital in-patient episodes - 1800 intensive-care unit episodes - 36,800 disability living allowance claims (13%) ♣ 1m lost working days per annum

Answer 142

♣ Epidemiological data over the last 50 years shows a steep increase in allergic conditions e.g. asthma and immune disorders i.e. Multiple Sclerosis ♣ During this time, there has been a decline in infectious diseases i.e. measles mumps etc.

Answer 143

Could be due to successful drugs/therapies for these infectious diseases

Answer 144

* Biodiversity hypothesis shows that proposes that reduced contact of people with natural environmental features and biodiversity, including environmental microbiota, leads to inadequate stimulation of immunoregulatory circuits. * Hygiene theory describes the protective influence of microbial exposures in early life on the development of allergy and asthma,

Answer 145

• Exposure to microbial components early in life skews immune response Th2 Th1 o At birth children have a th2 immunology o Exposure to microbial infections drive it to a more th1 phenotype which protects it • Decrease in prototypical Th1-stimulating infections e.g. measles, mumps, tuberculosis

Answer 146

• Declining biodiversity, urbanisation and associated changes to diet and lifestyle ♣ Decrease in infection in early childhood ♣ Elder siblings would be passing on all germs and infections to child earlier than when they would get it so youngest in family would be less likely to get asthma etc ♣ The number of children per family has reduced so this is less of the case ♣ Better hygiene standards and mean that its less common to transfer germs ♣ Children that grew up on farms are more exposed to more microbes and unpasteurised milk etc.

Answer 147

``` ♣ Development of asthma and triggering exasabtions o Allergens o Genetics o Food additives o Smoking o Repiratory infecions o obesity o Medication o Occupational exposures o Pollution ♣ Involved in triggering exasterbations o Temperature change o Exercise o Gastric reflux o Stress and emotions o Cold air o Strong odours ```

Answer 148

``` ♣ Heterogeneous & genetically complex (polygenic) ♣ >100 genes identified ♣ Close relative with atopic disease ♣ 1 parent = 25% risk ♣ 2 parents = 50% risk ```

Answer 149

♣ twin studies used to compare between people with either 100% identical genetic makeup (monozygotic) or 50% of the same genetic makeup (dizygotic) ♣ Twin studies - genetic factors account for: ♣ ~70% variation in disease susceptibility ♣ ~24% variation in overall asthma symptom severity ♣ High heritability does not preclude important contribution of environmental factors

Answer 150

♣ Epigenetics - the transcriptional dynamic alterations leading to changes in gene expression

Answer 151

Chemokines expressed in epithelial cell layer | Spink5 and flag involved in tight junction formation

Answer 152

Physiological (e.g. obesity and diet) -overweight’ higher asthma risk’ nitrites = involved in preserving meat e.g. bacon and they have been linked to asthma Vitamin D – show to reduce colds etc. the cold virus = key trigger of many asthma exacerbations

Answer 153

• Respiratory Virus Infections (Respiratory Syncytial Virus –RSV) - 33.8m RSV infections worldwide per annum in children <5 years - Small proportion develop severe disease - Severe disease = fourfold incidence of asthma - Major trigger of exacerbations - High number of children can develop bronchitis

Answer 154

♣ Tobacco smoke - Pregnancy - Parental smoking in childhood - Genetics (ORMDL3; PCDH1) ♣ All these mean there is an increased risk of asthma in childhood and adulthood ♣ Can cause epigenetic changes ♣ These genes are more closely related to children whose parents smoke

Answer 155

• Asthma has evolved from a term describing a single disease to one encompassing multiple subgroups or ‘phenotypes’ • Asthma used to be associated with only th2 • There are other phenotypes that are eosinophilic • Non-eosinophilic – associated with neutrophils o It tends to be corticosteroid refractive – don’t respond to inhalers

Answer 156

♣ Th2 (eosinophilic) - Early- and later-onset disease over a range of severities - Associated with allergy (atopy – the tendency to develop IgE mediated reactions to common aeroallergens) - Non-allergic variants (late onset, exercise-induced) ♣ Non-Th2 (non-eosinophilic) - Obesity, smoking, neutrophilic - Associated with more severe disease

Answer 157

♣ Eosinophilic asthma o Environmental allergens o Dendritic cells which are APC o Takeup allergen, process it and present tem in lymph nodes oto t cells. This drives a th2 phenotype of the th2cells o Allergic info = driven by the t clls o Cytokines: il4,5 and 13 =key processes o Il4 – eosinophilic o Il4- and 13 – effects on epithelial layer and smooth muscle cells o Mast cells =key as they nind the ag specific IgE leading to degranulation o Tryase – proinflammatory o X – pro fibrotic o Release bronchoconstriction o Causes SM to contract leading to bronchio-hyperactivity

Answer 158

``` • Non-eosinophilic asthma o More theoretical so less I known o Key triggers – pathgens o Toll like receptors o Smoke etc. o Act on epithelial cells and macrophages releasing il8 o Neutrophils cause airway o T cells have a key role o Th1 and th17 cells – drive epithelial cell to produce il8 o Release if Gamma – act on mast cells etc o Known defects – o Interferons ```

Answer 159

Decrease in diameter of the airways

Answer 160

Bronchial hyper-responsiveness (BHR) • Hallmark of asthma – degree of BHR correlates with asthma severity • Caused by airway inflammation • A dynamic and reversible process • Inappropriate and excessive contraction ‘bronchoconstriction’ of smooth muscle ♣ In response to allergen, rapid decrease in lung function within 15 minutes of lung insult ♣ Reversed to normal baseline soon (ACUTE) ♣ In 50% patients, time after that allergic insult, they get a late asthmatic insult 6-24 hours after initial insult ♣ It’s much more severe and prolonged than the initial insult

Answer 161

♣ AAR = triggered by binding of allergen to membrane bound IgE on mast cells o Release of mediators (histamines, cysteinyl leukotrienes, PGs) o bronchoconstriction ♣ LAR = due to influx of inflammatory cells (especially eosinophils) o Influx of inflammatory cells, mainly eosinophils o Airway oedema o Bronchoconstriction ♣ If people have a modest asthma attack and don’t use their inhalers, could get the prolonged attack later which would be much more damaging to the airways

Answer 162

• Airway Remodeling - The development of specific structural changes in the airway wall in asthma accompanying long-standing and severe airway inflammation

Answer 163

o Hypertrophy and hyperplasia (proliferation) of airway smooth muscle cells in response to growth factors (PDGF, endothelin-1) released from inflammatory or epithelial cells = further narrowing of airway lumen o Release of inflammatory mediators = maintained inflammation o Irreversible ‘fixed’ airflow obstruction

Answer 164

♣ Blood vessels o Increased mucosal blood flow o Angiogenesis in response to growth factors (VEGF) o Microvascular leakage from post-capillary venules = oedema & plasma exudation into lumen

Answer 165

• Mucus hypersecretion o Hyperplasia of submucosal glands & increased epithelial goblet cells o Mucus plugs that occlude asthmatic airways – especially fatal asthma o IL-13 & neutrophil elastase are potent inducers

Answer 166

o Aberrant repair to persistent epithelial injury o Basement membrane thickened due to sub-epithelial fibrosis o Type III and IV collagen depositions below basement membrane ♣ Triggered by myofibroblasts ♣ Mucus gland = much larger ♣ Thickened SM ♣ Lymphocytes in the airway o Release of pro-fibrotic mediators (TGFβ) from epithelial cells - associated with eosinophil infiltration o Persistence of fibrosis = asthma would be irreversible due to the airway narrowing

Answer 167

o Bronchial thermoplasty = potential treatment for asthmatic patients – burning SM off the airways which could benefit patients - Epithelial layer shedding - Goblet cell hyperplasia - Collagen deposition beneath basement membrane

Answer 168

♣ Usually controlled using inhaled corticosteroids (ICS) and bronchodilators - long-acting β2-agonists (LABA) ♣ Use both in combination

Answer 169

♣ Could be due to poor adherence of treatment ♣ Compliance increases when a patient has exacerbations ♣ the younger you are, the less likely you are to comply -could lead to the asthma being more severe ♣ poor communication with healthcare professional – ♣ i.e. not using inhalers right etc.

Answer 170

♣ Severe asthma accounts for 5-10% patients, but consumes >50% medical expenditure ♣ Different phenotypes of asthma with different patterns of inflammation may benefit from specific therapeutic targeting ♣ different phenotypes require different medications

Answer 171

A chronic and progressive disease that is characterized by the development of airflow limitation that is not fully reversible and by an accelerated decline in lung function. This usually results from an abnormal inflammatory response of the lungs to noxious particles or gases.

Answer 172

• COPD – encompasses several conditions o Chronic bronchitis - affects bronchi o Emphysema – affects alveloli

Answer 173

the elderly | but can also happen in young people

Answer 174

• Major global healthcare issue • Predicted to become 3rd leading cause of death worldwide and ranked 5th for disease burden. • 1.2m in the UK living with COPD, 2% population (4.5% people >40) = 2nd most common lung disease in the UK • 2nd highest contributor to respiratory mortality (lung cancer 31%; COPD 26.1%; pneumonia 25.3%) • 29,776 COPD deaths in 2012 (15,245 males, 14,531 females) o 2,719 aged 15-64 years o 27,056 aged >65 years

Answer 175

* In developing countries, use biomass fuel which contributes to COPD deaths more so in these countries than smoking which is more prevalent in developed countries * Risk factors vary according to geographical area

Answer 176

• Links to affluence o Highest = north east and north west o Lowest = east and south east

Answer 177

* Over 80% of COPD patients are smokers | * Only 20% of smokers become diagnosed with COPD

Answer 178

• Emphysema – caused by destruction of air spaces in the lungs Initially smoking causes inflammation in walls between the airspaces then becomes one large space o Start to lose its elasticity so inflates but can’t deflate properly o As disease progresses, less and less elasticity o Affects the amount of area for gas exchange to happen -Bronchitis - chronic inflammation of the bronchi and fibrosis

Answer 179

♣ Variable development of chronic airflow obstruction among smokers suggests other factors influence the onset and progression of COPD ♣ Heritability accounts for at least 30% of the variation in COPD risk - Smoking 1st degree relatives = 3-fold risk - Non-smoking 1st degree relatives = no risk ♣ Many candidate genes tested for association with COPD – but not replicated ♣ Genome-wide association studies (GWAS) have identified multiple genomic regions that are associated with COPD - >20 genomic loci associated with lung function (FEV1 levels) - Several of these also associated with COPD susceptibility e.g. CHRNA3 and CHRNA5 (nicotinic acetylcholine receptor) gene cluster on chromosome 15 • Genetics require some sort of environmental influence to progress • GWAS- check fev1 levels and addiction (from nicotine receptor)

Answer 180

♣ α1-antitrypsin is encoded by the SERPINA1 gene ♣ α1-antitrypsin deficiency is an autosomal recessive inherited disorder affecting 1 in 2000–5000 persons in Europe - Protease inhibitor - Produced in liver - Released into blood stream and goes to lungs where it protects it from neutrophil elastase o This can impact the lung if it’s not neutralised - In a-1 deficiency – abnormal form of the protein is made but can’t leave the liver - Lungs = exposed to the N. elastase - In the liver, it builds up and so makes scar tissue in the liver so increasing the risk of liver damage - Cigarettes increase N elastase levels and changes the protein: anti-protease balance

Answer 181

* In COPD – alveoli attachments degrade (become detached) * Wall thickens * Mucus builds up in lumen * Diameter of lumen is educed so airflow is impacted * Irreversible due to structural changes

Answer 182

♣ Chronic inflammation affecting peripheral airways and lung parenchyma ♣ Inflammation increases with disease progression * Degree of inflammation – increased in smokers * Increased in mild COPD * Inflammation progresses even when smoking is stopped * (once a certain stage has been reached, stopping smoking will not affect how the disease still progresses)

Answer 183

- Increased in patients with COPD from exogenous sources and endogenous mechanisms - Have many downstream effects o Inflammation o Making auto antibodies o Decreasing anti proteases ♣ Increases emphysema o Increase in tgfb Patients can be more susceptible to lung cancer as they are not repairing their DNA

Answer 184

- FEV1: shows our lung capacity increases as we age till 25-30 then progressively declines till 85 where you get 50% FEV1 – senile emphysema - In COPD, oxidative stress drives these processes: telomere shortening etc o Drives a more rapid decline in the ling ageing

Answer 185

- In healthy people, macrophages in airways will patrol the airways to look for pathogens and phagocytose these to maintain the health - Efferocytosis - In COPD lung, there’s defect in alveolar macrophages and so have a decreased ability to phagocytose bacteria and so cannot - Becomes necrotic and breaks open

Answer 186

Frequent exacerbations: ♣ worse prognosis ♣ more hospital admissions ♣ faster disease progression ♣ worse health status - Pathogens leaving airway susceptible to bacterial infection - In COPD If you can’t clear this, leads to more issues in the airways - Have high level of air pollution which can contribute to exacerbation – not as common o Increase in inflammatory cells with its cytokines and also an increase in the sympotomoology (cough etc.) o Hospitalised and so decreases quality of life - In severe cases, causes death - Risk = stronger If you are ‘frequent exacerbation’ o Periods of exacerbations drive a faster disease progression

Answer 187

- Goblet cell causes increase in mucus - Neutrophils in sputem (what they cough up) - Contrast with asthma which mainly had eosinophils - Rather than th cells, have cytoxic X - In normal epithelia, severe asthma, ep cells slough from airway o In COPD, get squamous epithelium which is a pre-change that could become lung cancer o Could reverse back (not always fated to become cancerous) - Small increase in airway SM - No real BM thickening as in asthma

Answer 188

Asthma-COPD overlap syndrome (ACOS)

Answer 189

• Increased eosinophil count in COPD patients as well as the usual neutrophil count for COPD o high-dose ICS, IL-5, IL-13, IL-33 blocking antibodies o high does corticosteroid would work on this ohenotype as its asthma like • neutrophilic infammationin asthma patients (would usually be seen in COPD patients) o CXCR2 antagonists, phosphodiesterase 4 inhibitors, p38 MAPK inhibitors, IL-1 and IL-17 blocking antibodies, macrolides • Asthmatic pateints with irreversible airflow obstruction o inhaled combination therapy of corticosteroid, long-acting b2-agonist, long-acting muscarinic antagonist

Answer 190

• Management of stable disease: o Reducing exposure to irritants & pulmonary rehabilitation o Relief of symptoms – bronchodilators (long-acting β2-agonists (LABA) and/or long-acting muscarinic receptor antagonists (LAMA)) o Reducing risk (mainly of exacerbations) • Management of exacerbations: o Oral antibiotics and possibly oral corticosteroids (use of inhaled corticosteroids restricted) o bronchodilators (long-acting β2-agonists (LABA) and/or long-acting muscarinic receptor antagonists (LAMA)) • Virus is a predominant trigger but there isn’t a way of curing this

Answer 191

the nasal cavities, pharynx and the the airways

Answer 192

upper and lower RTIs

Answer 193

``` upper RTI: affects the nasal cavities (nose and sinus) and the pahrynx (throat) nasalpharyngitis sinusitis larangitis pharyngitis influenza ```

Answer 194

``` lower RTIs: affect the airways (trachea, bronchioles, bronchi and alveoli) bronchitis bronchioitis influenza pneumonia tuberculosis ```

Answer 195

it is the 3rd leading cause of death in the world | important cause of death in both children and adults

Answer 196

children - get it 4-5 times anually adults 1-2 times anually by 75years old, will have had ~200 colds in your lie tme

Answer 197

adenovirus - low levels throughout the year influenza A - variable incidence amount and time. very high peaks in the winter, short peaks throughout the year but affects a lot of people influenza B - very low levels generally, peaks occasionally parainfluenza - very low levels generally, peaks occasionally respiratory syncytial virus - peaks every year generally at winter and affects a large amount of people rhinovirus - spikes all throughout the ear and is detected much easier now

Answer 198

PCR - in the 1990s, greatly improved the detection of respiratory viruses (highly sensitive). but, it cant detect what you don't already know as a known primer is needed for it to work High throughput screening - allows us to screen for a high number of viruses but the sensitivity isn't good enough for clinical samples and also it is very costly and less sensitive than PCR they have now come up with VirCopSeq-VERT which is a combination of HRT and PCR. it allows high throughput screening of viruses but with a higher sensitivity. this allows for much more effective screening

Answer 199

respiratory syncytial virus (RSV)

Answer 200

60% infants have been infected with it in their first 'RSV season' (i.e. winter) by 2-3 years old, almost all children will have had it it induces protective immunity which tends to wane overtime RSV sis also a major cause of respiratory infection in older patients with cardiovascular comorbidity, COPD or immunocompromised patients

Answer 201

most kids who get RSV in their first year of life get bronchitis due to the immaturity of their immune system as they get to 2-3 years old, their immune system matures by getting more th1 which is protective and losing their th2 bias if they do get bronchiolitis due to RSV, they are more likely to get post bronchiolotic wheeze which is pre asthma

Answer 202

it is an enveloped negative ssRNA of the paramyoxoviridae family

Answer 203

by many proteins as it is a ssRNA which contains a high number of nuclei the G proteins are highly glycosylated and are know to attach the virus to the host cell fusion proteins work to allow the virus to fuse with the host to allow its entrance in the cell which then allows the virus to self replicate

Answer 204

- uses annexin 11 o airway epithelial cells | - uses L.selectin and CX3CR1 on immune cells

Answer 205

RSV can be detected by multiple PRRs - TLR2/6 -- not known how - TLR4 - fusion f protein - TLR3 - dsRNA replicates - TLR7 - ssRNA - RIG-1 - ssRNA viral genomes bearing 5' triphosphates; dsRNA replicates - Nod2 - NLR3P/ASC - small hydrophobic (SH) RSV viroporin

Answer 206

RSV infects the epithelial cells lining the repiratory tract ad will activate PRRs this will cause inflammation and therefore the relsease of interferons, anti-viral cytokies etc which will lead back to the epithelia that was infected as well as neighbouring clels and so will initiate cell apoptosis other mediators eg TNFa (proinflammatory) and chemokines eg CVCL8 and CXC17 will recruit neutrophils and NK cells causing death to cells that cause this. can also phagocytose and remove the debris

Answer 207

RSV infecting dendritic cells will migrate to regional lymph nodes and present the antigen to cd4 helper t cells causing activation of b cells, activation of ABs and also cytotoxic t cells. this leads to a cycle of inflammatory cell recruitment and inflammation. this also could lead to bronchiolitis etc or otherwise just a cold which passes in ~7 days

Answer 208

1. NS@ can bind to RIG1 to prevent it from interacting with MAVS which prevents/severely reduces this signalling pathway and so limits possible inflammation 2. NS1 can bind to IRF3/7 (tf which generates type 1 interferons and so reduces the ability of this cell to respond 3. fusion f protein and nuclear protein can induce type 1 interferon production - not sure yet how - and then NS1 and NS2 bind to STAT2 which degrades STAT2 and reduces its ability to release interferon stimulated genes 4. F protein can bin to TLR4 and down modulate (prevent) signalling -- and so reducing the host response

Answer 209

1. secreted G protein (attachment protein) can be secreted from the cell and reduce TNF and interferon production by binding CXC3RI both on dendritic cells and CD4 cells 2. can act as AB decay (mop up any ABs you have that are generated against RSV - by inhibiting IFN-Y production) 7. can inhibit synapse formation between dendritic cells and t cells (by N protein) 4. inhibit dendritic cell maturation by NS1/NS2

Answer 210

cytopathic effect of virus and local inflammatory response - airway epithelial cells highly permissive to RSV - RSV replication --> epithelial damage --> necrosis - submucosal oedema - mucus secretion - bronchoconstriction all this causes severe obstruction of airway lumen

Answer 211

they will have cells stuck together (fused) which form a syncytium which is when the neighbouring cells stretch and fuse together. this is a very destructive virus

Answer 212

formalin was a drug trialed but caused o protection, created a higher viral load, made a16-fold increase in hospitalisations and caused 2 infact fatalities

Answer 213

in the normal cell, RSV bids to TLR4 on the cell surface wand is then internalised which then triggers the activation of RIG1, MDA5 and TLRs which are all in the endosome. this causes a large tf activation and antibody affinty maturation. when formalin is added, the RSV is inactivated due to the formalin and so although it bind to the TLR4 on the surface, it cant be internalised because as it cant replicate and so there is limited activation of the RIG1 etc and no real affinity maturation. however, this means that the system is primed so when an active RSV does come along, the response that it will create will be extremely massive

Answer 214

monthly injections of anti-RSV f protein monoclonal Ab (palivizumab)

Answer 215

severe RSV infection in infancy has firmly been established to be a risk factor for subsequent asthma in later childhood and leads to a 4 fold higher incidence of asthma the underlying biological mechanisms are not yet fully understood. thought to be due to: - chronic epithelial and airway reactivity changes to developing infant lung - lung injury altering lung function - immunomodulatory changes (th1-th2 changes) - genetic factors that impact on pattern of immune response to infectious agents

Answer 216

th2 polarisation to the lung immune response happens which enhances the th2 sensitisation to aeroallergens and induces development f a chronic asthma phenotype

Answer 217

it determines ~20% variation

Answer 218

TLR4 mutations Asp299Gly and Thr399lle over-represented in infants <12months of age hospitalised for RSV bronchiolitis compared to infants who have mild RSV fail to translocate TLR4 to the cell surface and so there is a reduced NFkB signalling because they don't, don't detect the virus until its already inside the cell and replicating

Answer 219

RSV is more of an inducer than a trigger of getting the condition - mostly children/infants affected in short epidemic seasons HRV is more of a trigger than an inducer - anyone of any age can be infected in any season

Answer 220

most common cause of upper RTIs causes relatively benign upper respiratory tract illnesses but also exacerbations of chronic pulmonary diseases, asthma development, severe bronchiolitis in infants and children and finally it can cause a fatal pneumonia in the elderly and immunocompromised patients

Answer 221

2/3rds of the colds we suffer

Answer 222

URI: the common cold, acute otitis media (fluid build up in the ears) and rhinosinusits LRI: bronchiolitis, community-acquired pneumonia (very common) and croup(less common)

Answer 223

cause a self-limiting syndrome with a predominantly upper respiratory tract manifestation in healthy adults

Answer 224

it is a ssRNA virus - in the largest subgroup of picornaviradae family with over 150 serotypes having been identified they are small non enveloped positive ssRNAs

Answer 225

it was originally based on the receptor: 1. intracellular adhesion molecule 1 - ~96 major viruses (major) 2. low density lipoprotein receptors - ~12 minor viruses(minor) 3. cadherin related family member 3 - ~50 'c' viruses (relatively new) another way to classify = genetically: 1. HRV-A - 77 serotypes(ICAM-1+LDLr) 2. HRV-B = 30 serotypes (ICAM-1) 3. HRV-C - ~50 serotypes

Answer 226

respiratory ciruses enter and replicate within the airway epithelial cells. HRV infect nasal epithelial cells and sometimes has been detected in lower airways HRV is rarely associated with cytopathology of AECs -AECs - sloughed by airway lining remain structurally intact - disruption to barrier function by dissociation of zena occludens 1 from tight junction complex in contrast to other viruses, the airway remains structurally intact - disruption in barrier function can occur (e.g. tight junctions are effected) which an lead to bacterial infection

Answer 227

HRV binds to receptor (LDLr) gaining entry to the cell and activating PRRs both within the endosome and in the cytoplasm. this leads to release of cytokines, chemokines and b cells (eosinophils) and t cells (PMNs). HRV can also activate TLRs (not sure how this is)

Answer 228

acute exacerbations: - further increase in airway inflammation - major cause of morbidituy and mortality and accelerates disease progeression - significant healthcare costs - asthma:50%, copd - 70%) - frequency = major determiant of health status and quality of life HRV = frequent cause of exacerbations in patients with underlying airway disease - 50-65% same number of infections but associated with higher inflammatory response and therefore with respiratory tract infections RSV causes exacerbations in the older populations wth cardiovascular morbidity, COPD or immuno compromised patients therapeutic options - targeting exacerbations; currently inadequate

Answer 229

HRV infection binding to epithelial cells on the surface (receptors) and also interacting with alveolar macrophages and causing the release of chemokines and cytokines and thus leading to chemotoxins and immune cells. also leads to release of other cells impacting on airway smooth muscle and fibroblasts which is detrimental in asthma and COPD patients due to these changes to the airway

Answer 230

there is some evidence suggesting that structural changes to the lungs (epithelial damage by HRV) couldredisposethe to be more susceptible to viral infections

Answer 231

an experiment using 3 groups of people (asthma patients, COPD patients and healthy controls) were all exposed to HRV found that the viral loads were higher i asthma and COPD patients than in healthy controls one of the factors could be interferons - these could block viral entry and so control viral transcription ad translation cleavage of RNA and induction of apoptosis could occur - could lead to failure to induce a robust IFN response= uncontrolled viral replication and increased inflammatory responses in a 2nd study, they found that asthma patients had a defective type 1 response to the rhinovirus. another group studying the same thing found the same results however another group studying this found no difference the first group studying this found no difference in well controlled asthma (with no interferon deficiency) and so it was in severe therapy resistant atopic asthma

Answer 232

``` - frequent exacerbations = more susceptible to viral infection and/or more severe clinical disease after infection in asthma: could be partly due to deficient IFN production as they aren't producing enough interferons and so get much more replication and acute exacerbations other factors-- less antiviral th1 cytokines(higher viral load) higher SOCS1 (suppressor of cytokine signalling 1) May link th2 inflammation with IFM deficiency more ICAM1 expression which is the receptor that binds majority of the HRV serotypes in COPD: deficient IFN production could be with more ICAM-1 expression ```

Answer 233

1 - dissociation happens because of increased ROS generation which means that bacteria can gain access to epithelial cell wall to colonise it 2 - increased expression of ICAM1: the virus can increase expression of this molecule (an its internalisation). this can also aid the internalisation of s.aureus 3 - increased expression of platelet activating factor receptor (PAFR) which is a way pneumonia gets access to cells - can cause susceptibility to bacterial infection 4 - macrophages: HRCV can infect macrophages (dont replicate in them but can cause changes i.e. less inflammatory cytokine release in response in response to bacteria and so therefore to response and kill bacteria

Answer 234

- immunomodulatory strategies: inhaled interferons can enhance the innate anti-viral immune response. this is most effective when the interferons are given at the same time as the virus but the incubation period for HRV is 1-2 days before you know you are infected so it is too late - targeting inflammatory modulators and binding to them and their receptors antiviral techniques: blocking viral replication and function blocking viral binding and entry vaccination is difficult to develop one that will target all the different serotypes ofHRV

Answer 235

lungs: need to get very small molecules into the body 15-18 times a minute, theres gas in the alveoli and so the lungs and contents sample alot of air. needs to have a thin interface to be able to do this properly. have a 75m2 area which is vulnerable to infection

Answer 236

phayrngitis - viral usuallly(70-80% of the time) and so doesnt require treatment sometimes,can be bacterial which are treated - infected by: --group a steptococcus (b haemolytic) which is identified by how it grows on culture with blood on it -- mycoplasma pneumonis - not easily spotted/doesn't grow well in culture -- fusobacterium necropphorum - invades into the veins and neck and so could affect the jugular vein, drains int the heart into the p.artery then drains into the lungs

Answer 237

it is grown in culture with blood and reacts with the haemoglobin then turns transparent

Answer 238

• grey membrane formed due to bacteria releasing toxins to kill the epithelial cells. A gram-positive infection – Corynebacterium diptheriae o use antitoxins (AB produced to soak up all the toxins used with antibiotics)

Answer 239

• sinuses have narrow openings and Is lined with mucosa, this could block the entrance which fills sinuses with puss. So, causes pain around face. o Sinus should have air but in this condition, its filled with fluid o Usually a virus but could be bacterial o Viruses get better themselves

Answer 240

• Acute epiglottitis – normally seen in children and is caused by haemophilus influenza o Rare now due to new vaccine (HiB) o Mostly capsulated but some = not encapsulated which can’t be treated

Answer 241

• Bordatella pertussis – whooping cough. Has many virulence factors so get irritation of respiratory tract which causes the whooping cough o Have vaccine against it now

Answer 242

• Bronchitis – inflammation in large airway. Triggered by virus o Most pathogens = viral o Get some bacterial – rarely a cause in healthy bacteria

Answer 243

o Build-up of white material in basis of lungs. o The air sacs are filled up with secretions, dead cells and dead bacteria o Listen as lung expands, hear crackles etc. o 1 In 100 mortality o stay in hospital ~ 1 week – costs a lot of money

Answer 244

- alveoli = weak spot – hard to get pre-existing defences as then you wouldn’t be able to do gas exchange properly - alveolar macrophages do tissue repair and phagocytosis - when pathogen arrives, senses it using TLRs, phagocytose it - can do it more effectively for some bacteria - if you have a pathogen that’s able to subvert phagocytosis or too many pathogens, causes suddenly lost of activity here - pro-inflammatory response calls in neutrophils. But if they keep coming in, the normal activity of the alveoli won’t be able to work properly as they would kill the bacteria but then also self-destruct. - Will become breathless as you can’t do gas exchange with all this stuff in the way o Oxygen levels decrease - Inflammation causes pain - Inflammatory response causes fever

Answer 245

- There’s a resolution phase which clears the airways and allows you to recover o Wait 6 weeks for repeat x ray which allows all that stuff disappears

Answer 246

- Symptom of pneumonia - If lining of lung is inflamed, as lung expands, has to move up to chest wall, makes it sticky as the lung lining which feels rough – very painful o Plurosy

Answer 247

• Streptococcus pneumoniae – 40% of pneumonia o Draftsman colony (gram positive cocci) o See lots of dark purple cocci o Split into alpha and beta o Sugar coating the bacteria – very variable ♣ Abs we produce recognise serotypes and so protects us next time but there are so many variations that this won’t be effective for all the other 99 types ♣ Need multivalent vaccines with conjugates ♣ Have 13 valent conjugate vaccines • If treated with this, these types reduce but the other (85 types) would increase

Answer 248

• Legionella pneumoniae – due to warm air (in hotter climates and bad air con etc.): warm air then bacteria = attracted to it

Answer 249

Atypical pathogens – don’t behave the same as when you try to diagnose them in the lab The best way to find what pathogen is in the respiratory system = to grow phlegm in culture Sometimes able to see antigen in the urine –legionaella and streptoccochus

Answer 250

``` Ball of pus with air spaces in the lungs which communicates with lining of lungs and = outside the lungs. Get infection in lung which causes … Lung abscess (unusual) Due to lung compromise or bacteria ```

Answer 251

If immune system isn’t working very well, get a broader range of bacterial viruses and fungi causing infections

Answer 252

- those who have a compromise that makes them more prone to this i.e. getting pulmonary tuberculosis

Answer 253

- Tb has a very thick waxy cell wall

Answer 254

- Used to be an environmental organism then evolved to be a human disease o The fact that it used to be in the environment, means that its used to surviving in very harsh environments/conditions - Key components: mycolic acids and waxes - It’s very good at surviving inside the cells that try to kill it

Answer 255

- Tfb =alcohol fast bacilli (AFC) - Takes long time to make the thick waxy coat and so takes long time to develop/replicate - Bacteria grows at a 25 times faster rate than Tb - Won’t be able to see samples of it early on as it takes 3-4weeks to grow to an amount to be able to see - Grows slowly inside humans

Answer 256

- Resource poor countries have a higher burden of Tb - Tb = spread in environments where people live closely together where there is not much circulation - Incidence is high in non-UK born compared to UK born o Within UK born, if you have family from countries with high Tb prevalence, there is a higher incidence of Tb in your family o More common in bigger cities - Tb used to be called consumption o Because it’s a slow insidious process (losing weight etc.)

Answer 257

- Only can catch it if someone is coughing up tb germs not the environment - Not common as its heavy droplets that would drop to the ground and the light gets rid of it - Must be very close to catch it - If you are smear positive you’re would be diagnosed as having Tb o Can detect how likely you are to spread Tb into the community

Answer 258

- Tb into lungs and macrophages try to kill it - Not possible to kill all - Get a response that because macrophage and to kill the tb, t calls more cells to wall of the tb to stop it from spreading o Called a granuloma - Can withstand phagolysosome

Answer 259

- macrophage starts to take part of the protein from the tb and present it from t cells (it’s a APC), must take it to lymph nodes to find t cells to kill it - Cd4 t cells make pro-inflammatory cytokines which activates more macrophages to make them better at killing the tb - Cells surrounding the tb = are fibroblasts which seal in the tb cells with the tissue and etc. becomes puss. Forms tubercles - If this works kills microbacteria/stop it from working - Sometimes can kill this so the microbacterium can exist in a low activity state for many years

Answer 260

- Tb may land and there is a response which could involve clinical disease in a small number of people - At the local lymph nodes, activate t cells to activate more macrophages - Granuloma expansion becomes an abscess

Answer 261

- 5-10% people get an abscess growing in their lungs - soon this abscess will grow and move into the bronchioles - this has all the microbacterium in it which when coughing would come out into the environment

Answer 262

- to diagnose Tb you need to do special stains that don’t wash out with alcohol o its AFB (alcohol acid farse) - increased diagnostic sensity for AP - increase chance of finding Tb with the more samples of sputem you get to analyse

Answer 263

- Lowenstein jenson = used to be used as a culture to grow Tb o Takes 2-8 weeks in total - Found that liquid cultures are much better and are now used all over the UK o Takes 4-8 weeks in total

Answer 264

- Can do PCR o Alternative to smear o Will tell you more before your culture is ready o Better sensitivity o Could spot any resistance strains using the rapid PCR

Answer 265

- Tb has the ability to go beyond the lungs - If it goes into the blood stream with macrophages with the Tb, could cause a granuloma and cause a disease or stay latent till it ends up anywhere in the body 30 years later i.e. in the brain, kidney etc. - 90% of people who have Tb, actually don’t get Tb till very late - 10% f these never get it - Tb could be sitting there and wait till it wants to reactivate

Answer 266

- If some part of the immune system starts to fail, t cell function doesn’t work and so the Tb bacterium reactivates o Treated with immunosuppressant therapy ♣ HIV = increased risk as this is where the t cells don’t function Cd4 cells could be depleted or TNF alpha in response to granulomas breaking down

Answer 267

• Nocardia – found in the environment o E.g. decaying planst soil water etc • Those who are affected = those whose immune system is compromised o I.e. diabetes, cancer HIV aids o Chronic infections i.e. connective tissue disorders o Alcoholism o Transplants/corticosteroids • (compared to Tb where anyone can be affected) • infection = through breathing in dust that contains the bacteria • when a hospitalised patient is infected from contaminated medical equipment • can be seen as lacy white coverings on lungs on an x-ray

Answer 268

* Melioidosis – found in tropical climates * Slow onset, systemic symptoms but also local systemic symptoms * Similar people as in nocardia which are at risk

Answer 269

* Non-Tb mycobacteria ‘NTM’ * Microbacterium that generally lives in the environment * In healthy lung, can’t cause disease as its not able to live in the harsh conditions and escape the phagocytes * Those with their immune paresis or bronchiectasis issues would be more susceptible * Behaves like Tb if it has these advantages of underlying issues in the airways etc

Answer 270

* A mould that lives in dirt * In southern US and dryer pats of southern America * Considered in patients with pneumonia with mediastinal or hilar lymphadenopathy .., * In bats – so those in caves

Answer 271

o Restriction of lung volumes (measured by FVC) o Reduction in lung gas transfer efficiency (DLCO / TLCO) o Hypoxia (low blood oxygen levels), particularly on exertion / exercise o Reduction in exercise capacity

Answer 272

• Flattening of diaphragm • (IPF = idiopathic pulmonary fibrosis) o x ray shows all the fibrosis o x ray = not great at picking up restrictive lung disease (till it’s at advanced level)

Answer 273

o Look at FVC and FEV1 o FVC = total amount of air in 1 breath? o FEV1= how much air someone can breathe out in 1 second o ILD = restrictive lung disease: reduction in FEV1 and FVC o In obstructive: FVC = normal/increased o Use ratio between FEV1: FVC o Less that 70% = obstructive

Answer 274

* ILD = disease of gas exchange * Difficulty getting oxygen to diffuse across barrier of alveoli int blood stream * ILD- barrier is thickened (fibrosed) so oxygen has much difficulty diffusing across into the blood stream * Why patients get breathless * CO2 = usually fine to get across as it can be easy to go across the barrier

Answer 275

* Uses CO to estimate how well the lung is functioning * Measures amount of CO left I lungs when patient breathes out * Less CO left in lungs after patient breathes out, the better the lungs are functioning * In ILD, O2 struggles to diffuse into bloodstream get more CO left in lungs * Will have reduction n transfer factor in ILD patients

Answer 276

* Incremental shuttle walk test * Walking bleep test around 2 cones * Or 6 minute walk test * Walking continuously around 2 cones for 6 minutes * Studies show that both test correlate with lung function

Answer 277

• Heterogenous mix of lung disease o Inflammation o Scarring ``` • IPF (unknown cause) • Cause unclear, hence ‘idiopathic’ • Fibrosis of lung parenchyma • Affects males more than females • More elderly patients • Smoking = risk factor • Characteristic radiology / histology o Usual interstitial pneumonia (UIP) ```

Answer 278

• Fibrosis on periphery and basis of lungs • Honeycombing (destruction of the lungs) • Traction bronchiactosis? o Airways being widened as scarring/fibrosis = pulling and making them wider • In a subpleaura • As to be in UIP pattern or it can’t be IPF

Answer 279

IPF Diagnosis – Investigations ¥ HRCT – UIP pattern fibrosis ¥ Rule out other causes of UIP ¬ Signs and symptoms of autoimmune conditions (e.g. RA) ¬ History of environmental / occupational exposures (including asbestos) ¬ Bloods ¥ Fibroblasts repair damaged tissue ¥ Lungs get damaged ¥ Fibroblasts migrate to the lungs (to try and fix the damage), becoming myofibroblasts ¥ Myofibroblasts deposit collagen in the extracellular matrix ¥ Myofibroblasts proliferate & form fibroblastic foci ¥ The thickened tissue leads to lower gas exchange efficiency in the lungs

Answer 280

* Sequencing people’s genome * Treating people with the same disease in different ways based on phenotype, differences in immunity, different co-morbidities etc.

Answer 281

• Mutations in genes involved in the maintenance of telomere length • Variations in genes that are responsible for cell adhesion and integrity • A single-nucleotide polymorphism in the promoter region of MUC5B substantially increases the risk of IPF o Most important= MUC5B = significantly increases risk of getting IPF Lung microbiome in IPF ¥ Increased risk of disease progression in patients with IPF • Increased overall bacterial burden • Abundance of streptococcal and staphylococcal organisms ¥ Risk of IPF is increased by genetic variation in TOLLIP • Gene encoding a protein that inhibits responses to microbes

Answer 282

Think that bacteria in lungs = important in IPF | Thinking of giving patients antibiotics to stop microbes in the lungs, may slow down progression of IPF

Answer 283

¥ Collections of fibroblasts (fibroblastic foci) ¥ Thickening of alveolar interstitium ¥ Destruction (honeycombing) of alveoli ¥ Affects periphery and base of lungs (UIP pattern fibrosis) ¥ Spatial heterogeneity (normal lung tissue next to abnormal tissue)

Answer 284

¥ Immune mediated hypersensitivity reaction in a genetically predisposed individual ¬ Recurrent exposure to environmental agents (HP inducers) ¥ Pathogenesis very different to IPF ¬ Inflammation & air trapping ¬ May progress to fibrosis and look like UIP pattern on HRCT (chronic HP)

Answer 285

* Pigeon droppings/feathers causes the inflammatory reaction * Lymphocyte produces abs to the ag * Abs attack themselves to ag * Need Prior sensitisation is required (i.e. previous exposure to antigen) * IgG antibodies produced by lymphocyte retain immune ‘memory’ of antigen * On secondary exposure, antigen-antibody complexes are formed and deposit in lungs and not adequately cleared * Repeated exposure leads to repeated symptoms and physiological decline

Answer 286

¥ HP associated with increase of ¬ CD4+ T cells ¬ CD4+ /CD8+ ratio ¬ Th2 activity ¬ CD4+ Th17 cells involved in the development of lung fibrosis ¥ Tolerance may be mediated by regulatory T cells ¥ Many exposed individuals develop a mild lymphocytic alveolitis but remain asymptomatic ¥ It is likely that a mixture of antigens, rather than a single antigen, contributes to the sensitization and evolution of HP

Answer 287

• Metalworking fluids (MWFs) o Industrial factories that cut/grind metal o Increased over last few years o Coolant put into fluid after metal = cut o Can cause HP

Answer 288

¥ Traditional classification ¬ Acute (symptoms 4-6 hours post exposure) ¬ Subacute (symptoms weeks – 4 months) ¬ Chronic (symptoms 4 months – years) ¥ Suggested novel classification (Vasakova et al, 2017) ¬ Acute (symptoms <6 months) ¬ Chronic (symptoms >6 months)

Answer 289

``` • Mostly reversible with complete resolution possible o Different from IPF – which is progressive over time but in HP can recover • HRCT features: o Upper / middle lobe o ground-glass opacities o Poorly defined o centrilobular nodules o Mosaic attenuation o Air trapping o Consolidation (rare) ```

Answer 290

¥ Potentially reversible ¥ Risk of progression ``` ¥ HRCT features: o Upper / middle lobe fibrosis o Honeycombing o Mosaic attenuation o Air trapping o Centrilobular nodules o Sparing of the bases ¥ Can get similar abnormalities in IPF and HP ¥ But in IPF, affects the basis ¥ In HP, spares the basis ```

Answer 291

¥ Classic triad: ¬ Chronic cellular bronchiolitis ¬ Cellular (i.e., lymphocytes and plasma cells) chronic interstitial pneumonia ¬ Non-necrotizing granulomas and/or giant cells

Answer 292

o Systemic sclerosis (SSc) o Rheumatoid arthritis (RA) o Idiopathic inflammatory myositis (IIM)

Answer 293

o Sjogren’s syndrome (SS) o Systemic lupus erythematous (SLE) o Mixed connective tissue disease

Answer 294

• ILD leading cause of mortality in CTD • Up to 15% of the patients initially diagnosed with idiopathic NSIP are later found to have CTD • ILD can also occur in the presence of autoimmune features that do not meet classification criteria for a specific CTD o Interstitial pneumonia with autoimmune features (IPAF)

Answer 295

¥ Granulomatous disease characterized by the presence of non-caseating granulomas involving multiple organ systems ¬ Lungs affected in over 90% of cases ¬ Significant variations according to age, race, gender and geography

Answer 296

``` o nutrition (some patients lose weight) o prevention vaccinations o adherence to medication o psychological assistance (patients and their families) o palliation of symptoms o long term oxygen therapy o management of infections o lung transplantation o non-invasive ventilation (masks etc.) o physiotherapy (5-6 times weekly, training) ```

Answer 297

o Has a median survival of 2-5 years from diagnosis o Previously hypothesised that IPF was a disease of inflammation, leading to scarring o Thus, immunosuppression was the mainstay of treatment Up until 5 years ago, the main treatment was adrenous treatment till 2012 when there was a landmark journal which changed the way we treat it

Answer 298

PANTHER study (previously used) • Includes randomised trial • ½ patients with combination therapy which included steroids + immunosuppressant’s (azathioprine) + NAC (antioxidant) • up until 2012m this was the standard treatment • it was stopped as they found that patients who had this treatment (8) died within this study. Compared to 1 who died from the placebo group • deaths from any cause or hospitalisation was significantly lower in the placebo group compared to the treatment

Answer 299

``` treatment working on the fibrotic pathways, rather than immune suppression were underway o Pirfenidone ♣ approved by NICE in the UK in 2014 o Nintedanib ♣ Approved by NICE in the UK in 2016 ```

Answer 300

• It has an effect on proliferation of fibroblasts • Has an effect on tgfb and ECM protein synthesis (also migration, CTGF, proliferation, myofibroblast trans-differentiation and apoptosis) • Three tablets 3 tomes a day • Main side effects: (not everyone) o Photosensitivity (skin rash) – need to wear spf50 whenever leaving the house o Gastrointestinal upset (nausea, weight loss, reduced appetite) o Liver function test abnormalities (hepatitis)

Answer 301

the capacity study and ascend study

Answer 302

1 – Pirfenidone – CAPACTITY study • Reduced the decline in FVC over 72 weeks • Fewer patients had FVC decline of >10% compared to placebo • Study had 3 groups: 2 with differing doses of Pirfenidone and a placebo group • The group with the higher dose had a less of a decline in FVC, both were better than the placebo 2 – Pirfenidone – ASCEND study • Reduced the decline in FVC over 52 weeks • Fewer patients had FVC decline of >10% or death • Decline in FVC is a surrogate marker for mortality o If you want the study to show improvement of mortality, the study would need to be followed up for more than a year o Use decline in FVC as a marker for mortality

Answer 303

• Different mechanism of action to pirfenidone • Had already been licenced for the treatment of cancer • One tablet twice a day • Main side effect: diarrhoea (can be quite severe) o Could reduce the dose and stop the diarrhoea and prescribe something to stop this • Can cause LFT abnormities (hepatitis) • Small increased risk of bleeding

Answer 304

no - a recent study showed ocombo of Pirfenidone and Nintendanib = safe

Answer 305

• It is an inhibitor of multiple tyrosine kinase receptors o Platelet derived growth factor o Fibroblast growth factor o Vascular endothelial growth factor

Answer 306

1 – Nintedanib - IMPULSES study • Reduced decline in FVC over 52 weeks • Fewer patients had FVC decline of >10%

Answer 307

Pirfenidone vs Nintedanib - No head:to:head comparison studies - A network meta-analysis concluded that pirfenidone and nintedanib provide similar benefits - Pooled analysis demonstrated that both treatments significantly reduced (by ~50%) all-cause mortality vs placebo

Answer 308

• Lots of studies going on in the field regarding drugs to treat IPF including ones that target fibroblasts and type2 cells etc.

Answer 309

• Main treatment is identification and exposure avoidance o find out what patient is sensitive to and then getting rid of this? o i.e. if it is due to their pillow, get rid of it, if its due to a pet, get rid of it, if its due to their job, may need to leave etc. • cause unidentified in up to 60% of cases • prognosis better in those who avoid further exposure • progression to fibrosis may still occur in those who have removed antigen exposure • treatment strategies focussed on inhibition of adaptive immune system

Answer 310

• corticosteroids commonly used as first line treatment • only 1 randomised, placebo controlled study in 1992 o 20 patients received prednisolone for 8 weeks, 16 received placebo o after 1 month, significant difference in DLCO between the treatment groups. O statistical significant difference in FVC ♣ DLCO – diffusing capacity of the lungs for carbon monoxide ♣ Determines how much oxygen travels form the alveoli to the lungs in the blood stream o after a follow-up of 5 year no statistical significant differences were found between the treatment groups in FVC, FEV1 or DLCO

Answer 311

* Derived from naturally occurring steroids produced by the adrenal glands * Decrease function of lymphocytes and cytokine activity * However, several undesirable consequences from long-term use… ``` Side effects: • Obesity • Indigestion • Increase risk of infectionspsychosis • Osteoporosis (increased risk) • Diabetes (increased risk) ```

Answer 312

``` A personalised approach is required to ensure efficacy, compliance and tolerability • Use of lowest efficacious dose • Use of ‘steroid sparing agents’ • Access to specialist nurse liaison • Monitoring for complications o Bone scanning (DEXA) o Glucose monitoring ```

Answer 313

``` • Methotrexate (MTX) • Azathioprine (AZA) • Mycophenylate mofetil (MMF) • Cyclophosphamide (CYC) • Rituximab (RTX) Other agents may allow a reduction in steroid dose to mitigate long-term effects in some forms of ILD ```

Answer 314

• Inhibits folate metabolism • Reduces T-cell ability to make proteins • Paradoxically can cause pneumonitis o pneumonitis – inflammation of the lungs o hard to know if deteriorating state of person due to ILD or methotrexate (the disease of medicine)

Answer 315

``` ¥ Prodrug – converted to 6-mercaptopurine ¥ Inhibits purine synthesis ¥ Reduces T-cell turnover ¥ Can cause hepatitis ¥ Bone marrow suppression may occur ```

Answer 316

* Inhibits purine synthesis * Reduces T-cell turnover * Immunosuppressive * Susceptible to viral infection

Answer 317

* Depletion of CD20-positive B lymphocytes, thereby inhibiting their differentiation into antibody-producing cells * Inhibition of T cell co-stimulation

Answer 318

¥ Retrospective study ¥ 51 were treated with MMF and 19 with AZA ¥ DLCO increased by 3.9% in MMF group and by 5.1% in AZA group ¥ no statistically significant difference ¥ MMF = better tolerated (less drop-out)

Answer 319

* Retrospective study in Japan * 23 patients with chronic HP * Statistically significant improvement in decline in vital capacity (VC) over 6 months

Answer 320

• A study in 2013 showed that there was an: o improvement in FVC which was statistically significant o improvement of TF – statistically significant o MMF was associated with significant improvements in estimated percentage of predicted FVC% and in estimated DLCO%

Answer 321

A study in 2013 showed that there was a statistically significant improvement in FVC and DLCO in 33 CTD-ILD patients

Answer 322

majority of drugs act on lymphocytes – affecting DNA synthesis

Answer 323

CYC in SSc-ILD (SLS-I) • Mean absolute difference in adjusted 12-month FVC % predicted between the cyclophosphamide (n=79) and placebo (n=79) groups was 2.53%, favouring cyclophosphamide. This was statistically significant • So, provides evidence that CYC has improvement compared to placebo but only 5% CYC/MMF in SSc-ILD (SLS-II) ¥ Showed no significant difference in FVC % change between treatments (p=0·24) ¥ More patients on CYC than on MMF prematurely withdrew from study drug (32 vs 20) ¥ both equally effective but more side effects with CYC ¥ Sixteen deaths occurred (11 CYC; 5 MMF) with most due to progressive ILD

Answer 324

¥ Not all patients with pulmonary sarcoidosis require treatment ¥ Treatment is favoured in following patients ¬ Symptomatic (breathlessness, cough fatigue) ¬ Active inflammation & progressive organ damage ¬ Worsening pulmonary function - An important part of management involves identifying the patients that require treatment and those who can be observed without treatment

Answer 325

¥ Corticosteroids are the first-line therapy ¬ Initial doses of prednisone 20-40 mg daily ¬ No studies to define the optimal dose or duration ¬ Dose is typically tapered every 3–4 weeks to ≤10 mg ¬ Typically, patients are treated for at least 6 months ¬ Chances of relapse after therapy stopped 14-74% ¥ high chance of patients relapsing after they stop steroids ¥ Those patients who can be controlled with <10 mg/day of prednisone are usually not considered candidates for treatment with steroid-sparing cytotoxic medications. ¥ In those patients who relapsed while off steroids, reintroduction of steroids usually stabilized their disease

Answer 326

¥ MTX used as second-line treatment in following patients ¬ Steroid-refractory ¬ Develop steroid-associated adverse effects ¬ As a steroid-sparing agent • Typically begun orally at a dose of 5 mg weekly and gradually increased by 2.5 mg every 2 weeks up to 10–15 mg per week - if steroids don’t work or if they’re having bad side effects, MTX could be given at the same time as steroids - Benefits of MTX therapy require at least 6 months to manifests themselves. Hence tapering of steroids should be delayed for at least several months after starting MTX

Answer 327

Study testing MTX vs AZA a second line therapy for sarcoidosis: • Both have significant steroid-sparing potency • Similar positive effect on lung function • Higher infection rate in the azathioprine group

Answer 328

* Mean change in FVC in the 6 months prior to leflunomide was 0.1L and +0.09L in the following six months (p=0.01) * The median corticosteroid dose at initiation was 10 mg at baseline and 0 mg at 6-month follow-up (p<0.001)

Answer 329

¥ Infliximab therapy resulted in a statistically significant improvement in % predicted FVC at Week 24 ¥ To be used as a third-line agent in severe refractory sarcoidosis cases not responding to conventional immunosuppressive treatment ¥ Adalimumab is an effective alternative for patients intolerant to infliximab

Answer 330

¥ Exercise training significantly increased 6MWD and health related quality of life ¥ Larger improvements in IPF compared to CTD-ILD ¥ Benefits declined at 6 months in IPF but not CTD-ILD ¥ patients go 1-2 times a week to an exercise class

Answer 331

HP may recur in the allograft and negatively impact clinical outcomes. Thus, vigilance for ongoing antigen exposure and disease recurrence after LT for HP is important. The overall survival following LT in this group is good and appears to be improved compared with IPF, the most common ILD indication for LT.

Answer 332

Treatment targeted at mitigating symptoms May involve: ¬ Opioids for breathlessness and pain ¬ Anxiolytics for anxiety (e.g. benzodiazepines) ¬ Supplementary oxygen ¬ Commonly, patients will experience symptoms from ILD, which do not resolve with treatment of disease

Answer 333

• Palliative or ‘long term’ oxygen therapy (LTOT) o >15hrs per day • Hypoxia at rest o pO2 <7.3kPa or <8kPa if evidence of PH • Often delivered by static air concentrator

Answer 334

* Enables greater exertion to be undertaken in patients with hypoxia on exercise * Historically compressed oxygen in tanks, but portable concentrators increasingly common * Ambulatory oxygen studies show improvements in different exercise parameters

Answer 335

``` Innate Immune defenses Mucosal defenses Mucociliary, anti-bacterial proteins Innate cellular defenses Macrophages and neutrophils ``` ``` Adaptive immune defenses B-cell mediated Antibodies T-cell mediated Cytotoxic and helper cells ```

Answer 336

acquired = more common but less dangerous

Answer 337

What is the cause and nature of the defect? Can the underlying cause be corrected or improved by a specific treatment? If not, what are the likely consequences of the defect (what type of infections will the patient get? How severe?) Can we prevent infections by prophylaxis (low dose preventative anti-infective agents) If an infection is present, identify the causative organism and treat or make a ‘best-guess’ or treat multiple potential pathogens

Answer 338

smoking -get rd of it and give nictonie replacement Cancers and SCID, GCD - do stem cell transplantation or gene therapy for severe immune deficiency CF - correction of CFTR HIV - HAART AB deficiency - immunoglobulin replacement

Answer 339

G551D mutations affects 4% of the CF population and causes lack of functioning CFTR (doesnt open) so treat with potentiators (eg ivacaftor) to open it F508del mutation causes misfolding of CFTR so doesnt go to cell membrane and s not stable. need to correc folding so use Correcters e.g. tezacaftor and lumacaftor. need to use with potentiator ivacaftor to see any effect

Answer 340

found that there was a sustained well functioning of the channel so was successful (much higher than in placebo)

Answer 341

CD$ receptors and co-receptors (CXCL4 or CCR5)- t helper cells, macrophages and dendritic cells

Answer 342

use cd4 receptors to infect cells and use T helper cells machinery to make viral proteins and proteases to cleave the,

Answer 343

Glycoproteins on the HIV molecule (gP160 made of gP120 and gP 41) allow it to dock and fuse onto the CD4 and CCR5 receptors The viral capsid the enters the cell and enzymes and nucleic acid are released Using reverse transcriptase single stranded RNA is converted into double stranded DNA Viral DNA then is integrated into the cells own DNA by integrase enzyme When the infected cell divides the viral DNA is read and long chains of viral proteins are made Assembly the viral protein chains are cleaved and reassembled Budding here immature virus pushes out of the cell taking with it some cell membrane Immature virus breaks free to undergo more maturation Maturation protein chains in the new viral particle are cut by the protease enzyme into individual proteins that combine to form a working virus

Answer 344

ARVs work by interfering with the way that HIV virus replicates. They do this by interfering with the docking of HIV and interfering with the action of major HIV enzymes Reverse transcriptase Integrase Protease

Answer 345

``` -NNRTI Non Nucleoside reverse transcriptase inhibitor EFAVIRENZ NEVIRAPINE RILPIVIRINE -NRTI Nucleos(t)ide reverse transcriptase inhibitor 3TC LAMIVUDINE FTC EMTRICITABINE AZT ZIDOVUDINE TDF TENOFOVIR ABC ABACAVIR -Integrase Inhibitor DOLUTEGRAVIR RALTEGRAVIR ELVITEGRAVIR -Protease Inhibitor DARUNAVIR ATAZANAVIR LOPINAVIR -- use combo of all 3 ```

Answer 346

Indications to commence therapy in HIV-positive patients include a CD4 count<350, any AIDS defining illness (eg pneumocystis pneumonia PCP, Kaposis sarcoma), neurological involvement, or to reduce the risk of transmission

Answer 347

many tablets for life Very complex for patients (and doctors) Missed doses encourage treatment failure and resistance Many side effects and interactions Combination tablets have been made by (unprecedented) co-operation between pharma companies 3 diff drugs several times a day = complicated for a chronic illness missed doses causes resistance some pharmaceutical companies – mixed the drugs together which can be taken once a day

Answer 348

Good compliance is associated with better suppression of viral replication/load, improved clinical response and reduced risk of viral resistance and transmission

Answer 349

Anti-CD20 monoclonal antibody therapy (for haematalogical cancer, autoimmune disease) CVID Increased risk of: Encapsulated bacteria (H. influenzae and S. pneumoniae) Oto-sino-pulmonary infection, bronchiectasis

Answer 350

In primary antibody deficiency (CVID or common variable immune deficiency) immunoglobulin replacement has dramatically increased survival (from 12 to over 50 years). Reduces infections including pneumonia Prepared from pooled plasma from healthy donors (50), extensive screening for blood-bourne disease. A small risk remains Can be administered by intravenous (usually every 3 weeks) or subcutaneous (usually weekly) lifelong

Answer 351

The nature and severity of underlying condition and risk of infection Previous infection history The evidence that prophylaxis has benefit in this situation Available agents, route and frequency, side effects Treatment burden Antimicrobial stewardship

Answer 352

``` Antibiotic prophylaxis in myelotoxic chemotherapy when neutropenia can be predicted both in time and severity Antibiotic and antifungal prophylaxis in chronically neutropenic patients eg bone marrow transplant, or those with inherited defects Pneumocystis pneumonia (PCP) prophylaxis in HIV and immunosuppression (Thelper cells compromised) ```

Answer 353

Life-threatening opportunistic lung infection of immunocompromised individuals Caused by Pneumocystis Jirovecii, a fungus with some protozoal features.

Answer 354

Occurs in patients with reduced Th cell number or function. Consider for prophylaxis if: HIV, CD4 <200 or previous PCP Chronic high dose steroids +/- immunosuppressives (that affect the t cell) Solid organ or allogeneic bone marrow transplantation

Answer 355

septrin - 960mg oral three times a week or 480mg daily, Both components inhibit folate biosynthesis Rash (can be life-threatening), bone marrow suppression, gastointestinal problems, caution is had Previous severe reaction, neutropenia, 1st trimester pregnancy, methotrexate, renal and liver failure. Extremely effective ``` Nebulised pentamidine 300mg nebulised monthly Uncertain Anti-parasitic Cough Bronchospasm Need to protect staff Previous reaction, severe asthma Effective but some failures ```

Answer 356

May be non-specific – fever, lethargy or with respiratory symptoms (cough, breathlessness) Chest Xray or CT (computed tomography) changes may give clues Investigate with sputum samples if possible If no diagnosis or no response to initial treatments you may need to take samples from the lung (e.g. bronchoscopy)

Answer 357

Sputum induction - -patient inhales something thats an irritant to help them and fibreoptic bronchoscopy - fibreoptic telescope – inside the lung - so can obtain samples from the lungs to try and grow the pathogen or you could detect the footprint using PCR

Answer 358

High dose co-trimoxazole (120 mg/kg daily, in 2–4 divided doses for 14–21 days) oral or intravenous Adjunctive corticosteroid therapy for moderate-to-severe PCP enhances survival in HIV. ?reduces inflammation to dying organisms Toxicity– fluid load, rash, renal/liver toxicity, low blood potassium, neutropenia, low blood glucose Alternatives include intravenous pentamidine (not nebulised), and intravenous clindamycin-primaquine. Very toxic as well.

Answer 359

Aspergillus fumigatus – environmental fungus Affects neutropenic or immunosuppressed patients Can be progressive and fatal Pulmonary nodules or infiltrates on CT – a ground glass ‘halo’ is classic Treat if classic, or undertake bronchoscopy +/- biopsy – culture, fungal cell wall components (B-glucan, galactomannan), histology

Answer 360

Reduce immunosuppression? Voriconazole (a triazole) is first-line treatment Oral or intravenous, Loading dose required (large volume of distribution), metabolised in liver Side effects – visual disturbance, cardiac rhythm disturbance (QT prolongation), hepatotoxic, rash, convulsions Response rates of 50-90% Fungal resistance emerging Newer agents eg posaconazole and isavuconazole

Answer 361

Echinocandins (caspofungin, micafungin,anidulofungin intravenous only Well tolerated, GI disturbance, heptotoxicity, allergic reactions Amphotericin B – iv only but liposomal formulation to reduce toxicity; intravenous (can be nebulised for prophylaxis) Nephrotoxic, hypokalemia, chills and allergic reactions Both less effective monotherapy than voriconazole, echinocandins have been used with voriconazole

Answer 362

• asthma, COPD, lung cancer, alpha-1 antitrypsin deficiency, cystic fibrosis, many more

Answer 363

* UK 10,461 people affected | * Median age death 31 years old

Answer 364

* Defect in long arm of chromosome 7 coding for the cystic fibrosis transmembrane regulator (CFTR) protein * >1600 mutations of CFTR gene identified * F508del most common mutation causing CF (49% homozygous) * 90% within panel of 70 mutations

Answer 365

• Static incidence with an increasing prevalence o Could be because people are living longer now with the personalised medicine o Predicted that children in 50s will live up till they’re in their 50s

Answer 366

Failure of mucocilary clearance and impaired immune function contribute to continues insult to bronchial wall, through the recruitment inflammatory cells and uncontrolled neutrophilic inflammation More infections, more damage to lungs which just becomes a vicious cycle

Answer 367

– it’s an obstructive lung condition | due to it having lots of inflammation, smooth muscle becomes thicker and respiratory lumen gets narrower

Answer 368

Young children – heel prick foot test – used to pick up a range of conditions including cf • genetic profile – look for number of genes you can identify but some mutations you can’t • clinical symptoms (most identified like this) – frequent infections, malabsorption, failure to thrive • stool block (small bowel obstruction), thick secretion in bowels • people with recurrent pancreatitis also could be thought to have this • late diagnoses via (chesty child and have asthma, not get better then is screened for CF) • mild CF picked up later in life • males with CF, majority of them are infertile as they have an absence of their vas deferens • abnormal salt/chloride exchange – raised skin salt or impaired nasal potential difference (sweat test). o Measure content of sweat o People with CF have abnormal sweat content • 50% diagnosed by 6 months, 90% diagnosed by 8 years of age

Answer 369

* bronchiectasis (a whole host of conditions) – many things can cause this including CF, airways become dilated and distorted for some reason * 90% of people who survive the neonatal period of CF get bronchiectasis * infertility: 98% male and 20% in females (obstruction to sperm getting through which makes them seem infertile) * pancreatic insufficiency malabsorption 85% (airways and tracts in body have thick secretion; in pancreas, ducts and tubes get blocked over time and pancreas is meant to make pancreatic enzymes and also insulin so this doesn’t work well) * CF related diabetes 50% by age 30 (due to the lack of insulin production caused by the pancreas) * CF liver Disease 25% chronic liver disease, 10% cirrhosis (liver filled with ducts and tracts that get blocked – many get liver transplant before lung transplant) * Sinonasal polyps 10-25% * Distal intestinal obstruction syndrome (DIOS) 20% (people with pancreatic insufficiency are more prone to this) – secretions in bowel = thick due to stool in bowel (affects small bowels so need lots of laxatives etc.) * Arthropathy 10% adults (problem with their joints) * Meconium ileus 10-20% infants * Low bone mineral density (osteopenia/osteoporosis) 10-25% * Peneumothorax 4-20% (lack of lung markings so can more easily get collapse of lug/puncture) * Allergic lung disease (ABPA) 7% * Skin – salty sweat/salt loss

Answer 370

``` • Rescue antibiotics o 2-week course o home vs hospital o access – peripheral/central o issues frequent antibiotics - allergies - renal impairment - resistance - access problems as patients live longer, worries that they will see more of these problems ```

Answer 371

Use maintenance preventions (trying to work at this takes most time) • CF prevention management o Segregation o Surveillance –frequent review minimum every 3 months o Eradicate infections early o Suppression of chronic infections – antibiotics o Anti-inflammatory – azithromyocin, steroids o Airway clearance physiotherapy, bronchodilation and exercise o Nutrition – pancreatic enzymes, diet high calorie and fat, supplements including vitamins, percutaneous feeding o Diabetes – insulin o Psychosocial support o Vaccinations – influenza, pneumococcal o (lung transplant)

Answer 372

• Personalised medicine o individual tailored or targeted medicine o move away from a ‘one size fits all’ approach o stratified based on predicted response or risk of disease o genetic information is a major factor Without personalised medicine, some people benefit from the drugs and some don’t (some people can even get adverse effects) With personalised medicine: each patient received the right medicine and so they each benefit from this individualised treatment (using biomarkers and diagnostics to discover the right medicines)

Answer 373

* increase adherence to treatment * improve quality of life * increase life expectancy/prolong life * help avoid adverse drug reactions/intolerances * shift the emphasis in medicine from recue to prevention * help control the overall cost of health care * direct the selection of optimal therapy and reduce trial-and-error prescribing * reveal additional or alternative uses for medicines and drug candidates

Answer 374

* monogenic disorder (i.e. is the result of mutations(s) in a specific gene) [know that it is chromosome 7 where it happens] * less known influence on environmental factors on disease expression * well-characterised pathophysiology with clear therapeutic targets

Answer 375

monogenetic vs complex disorders - complex disorders e.g. asthma have many environmental factors that can influence their disease - monogenetic disorders is mostly a genetic condition with the mutation occurring in 1 gene and has an either dominant or recessive inheritance pattern

Answer 376

* genotype directed therapies * treatment adherence support – tailored behaviour change interventions * targeted treatments based on infectious organisms and resistance patterns

Answer 377

• small-molecule agents facilitate defective CFTR processing or function o Ivacaftor G551D (6%) and other specific mutations - improved lung function (FEV1), BMI, QoL o Orkambi homozygous F508del – only licensed compassionate use UK (beefits don’t outweigh costs so can’t give this to everyone) - Mixed outcomes • Gene therapy – further research as significant problems with delivery

Answer 378

* Don’t make any CFTR protein * Produce it, but can’t move up to membrane to work * Produce it, its trafficked but doesn’t open * It is produced and moves up but it is abnormal so disruption ion flow * Produce CFTR but in smaller quantities

Answer 379

Delta F508 – Class 2 | Gff1D – Class 3 (ivacaftor is useful here) – 5%

Answer 380

Ivacaftor and lumacaftor (Orkambi) (have 2 diff dysfunctions) - combo • Ivacaftor and lumacaftor combined • Lumacaftor is a CFTR corrected – corrects cellular misprocessing of CFTR (e.g. folding) to facilitate transport from the endoplasmic reticulum • Improves stabilisation and processing (folding-trafficking) of CFTR to increase its presence on the cell surface • Class 2 mutation – F508 del/F508edel • Age 6 and above

Answer 381

* Adherence to treatment * High treatment burden * High cost of certain treatments * Genotype determining pharmacogenomics treatments – not available to all * Allergies/intolerances to treatment * Different infectious organisms and their resistance to drugs * Equity/restrictions to prescribe treatments i.e. NHS England restrictions on Orkambi meaning currently only available via compassionate use program * Prevention vs recue treatment – disadvantages of recue – cost, time, decline in quality of life and life expectancy, side effects of recurrent intravenous antibiotic therapy

Answer 382

* Adherence to medication among people with long term conditions is estimated at 30-50% * CF adherence to nebulisers 36% * Adherence often invisible –need objective data * Adherence complex

Answer 383

asthma and COPD

Answer 384

eosinophilic or non-eosinpphilic asthma eosinophilic has 2 subtypes atopic = a tendency (not diagnosis) – to form iGe antibodies to common allergens (cats/pollens etc). not all with atopic get the illeess associated eg astma hayfever etc. its very common and typical for childhood asthma. lab workers could also become allergic – become allergic non-atopic – very common. have allergy bt dont know whta theyre allergic to

Answer 385

eosinophols are rectuied to the airway in this type of asthma they cause airways to be destroyed> very allergic tye of asthma – to dust, pollen etc have igE cells on surface of mast cells which releases cytokines and allergic t cells release other things

Answer 386

non inflammatory control dont know how many sub types of thsu tehre are some people with is have smoking related disease, people that are pverweight can have their fat cells causing them to be astmatic

Answer 387

``` Reduce airways inflammation, mucus production and bronchial hyperreactivity Ameliorate symptoms (bronchodilatation) ```

Answer 388

Persistent symptoms, hyperinflation, emphysema Frequent exacerbators (≥2 exacerbations per year) – go to hospital for intravenous antibodies etc. Division based on eosinophilic or non- eosinophilic inflammation? domt know much about sub types of COPD think COPD probably has something to do with levels of eosinophils but dont know

Answer 389

ACOS (Asthma and COPD Overlap Syndrome) | if you have asthma at young age then start smoking, at 50 years old could have both.

Answer 390

Targeting - get drug to where the disease it – if you dont want to go to the wole body, just to an organ – inhalation =better Minimising adverse effects - adverse effects minimisation – giving frugs just to surface of lungs so no adverse effects of the drug everywhere else

Answer 391

Particle size is one factor that governs deposition. 1-10 µm size generally held to be in the respirable range. – bigger than this, deposits in oralpharynx. smaller, will never interact with the airway wall Depends on device delivering, nature of drug (e.g. hydrophobicity) and flow rates, any underlying disease and regional differences in lung ventilation (if not well ventiated art of lung if you have a disease, dont have an effect

Answer 392

Inappropriate and excessive contraction of smooth muscle | Hypertrophy and proliferation of smooth muscle cells, further narrowing the airway lumen

Answer 393

Short acting bronchodilators open up constricted smooth muscle in both asthma and COPD ‘blue’ inhalers: salbutamol and terbutaline Nebulisers for high dose therapy – inhaled through mask Beta 2 agonists to reduce cardiac side effects (persuade smooth muscle to relax)

Answer 394

Adenaline - rescue from anyphylaxis Isoprenaline - does bad things to the heart - acute rescue use Salbutamol - works very quickly longer lasting Salmeterol - have some versions that are longer acting – hang around in membrane

Answer 395

bind to gcpr, activate adenylate cyclase, to cAMP, pka topka*

Answer 396

Raising cAMP may activate Na/K exchange pump driving cellular influx of potassium Tachycardia (cardiac side effects) Hyperglycaemia: loss of insulin sensitivity, increased liver glucose release

Answer 397

Long-acting beta agonists. Valuable bronchodilators with possible anti- inflammatory actions Never used without steroids in asthma Often used without steroids in COPD

Answer 398

saba = short acing beta agonist – effects wear off saba without steroid treats sypmtoms but not underlying inflammation very powerful to reduce bronchocostriction and improve quality of life

Answer 399

The parasympathetic nervous system regulates airways tone Blocking the action of acetylcholine on the muscarinic receptors, leads to bronchodilatation and reduce mucus secretion Long acting anti-muscarinics (LAMAs) such as tiotropium, glycopyrronium, aclidinium are effective bronchodilators

Answer 400

if you block action of parasymp nervous system less Ach so no bronchoconstriction -airways the relax

Answer 401

LABA/LAMA with SABA as needed | SABAs as a top-up

Answer 402

Steroids treat inflammation.They are therefore the mainstay of asthma therapy and prevent asthma deaths Treat the processes that drive remodelling, airway smooth muscle proliferation, epithelial injury Inhibit inflammation driven by NFkB and related pathways, promote epithelial integrity

Answer 403

because there are side effects Systemic: diabetes, cataracts, osteoporosis, hypertension, skin thinning, easy bruising, growth retardation, osteonecrosis of the femoral head Topical: hoarse voice, oral candida, skin thinning, easy bruising, cataracts (in high dose) Adrenal suppression

Answer 404

topical have less side effects because its localised to the place you wan tit to go

Answer 405

Minimise systemic absorption Reduce side effects to mostly local adverse events (but still include oral thrush, dysphonia, easy bruising, cataract) Range of inhaled steroids of varying potency: beclometasone, budesonide, fluticasone diproprionate, fluticasone furoate

Answer 406

MDI – CFC free. drug suspended in propellant, breath at same time. activates drug, puff and shoots jet and breath into lungs. drug goes to where it needs to go in the lungs not easy to take – difficult flow rate dependent must be timed directly to inhaling and puffing DPI – dry powder devices – drug suspended in carrier devices e.g. lactose. suck in powder which is aerosolised

Answer 407

used to get round problem of getting puffer into spacer, instead of bit that would have deposited into mouth, gets deposited in the spacer so decrease risk of oralpharyngeal X

Answer 408

Often a combination therapy | ICS/LABA combinations are common and effective: seretide, fostair, symbicort, relvar

Answer 409

More controversial Reduces frequency of exacerbations (‘triple’ therapy of ICS/LABA/LAMA) May increase risk of pneumonia May be of particular benefit in people with asthma and COPD, or with eosinophilic COPD

Answer 410

Oxygen 40-60% (CO2 retention not usually a problem) Salbutamol neb 5 mg (+ipratropium neb 0.5mg if life threatening) - repeated/ i.v. infusion (much higher doses than what is in inhalers) Prednisolone 30-60 mg (±hydrocortisone 200mg iv) Magnesium or aminophylline i.v. (bolus/load) ABGs CXR if suspect pneumothorax, consolidation, or fails to respond to treatment (or is very severe)

Answer 411

Chromoglycate – usually in children Nebulised antibiotics – in people with infections? Nebulised steroids

Answer 412

Leukotriene receptor antagonists | Theophyllines – tell muscle to relax

Answer 413

atopy = tendency to form IgE to allergens? atopic = tendency rather than an illness can be atopic but not have illness 1 in 5 = atopic. half of these have an illness

Answer 414

wheel and flare response: wheel = swelling around siite slare = redness- bloody skin prick test: prick is so light that it doesn't draw blood

Answer 415

cyclosporin to stop rejection (suppresses t cell) in kidney transplants cyclosporin = used early on in clinical trials found that it can cause fewer exacerbations, less need for steroids and inhibits T cell proliferation via cyclophilin and calcineurin

Answer 416

Fcer1 binds IgE which coats mast cells and basophils that are in circulation allergen comes along and cross links 2 receptors of Fcer1 and puts them together which causes a signal mast cells then recruit mediators e.g. histamine which is what causes the redness in flare this is very quickly followed by a range of cytokines, proteases and other mast cell mediators

Answer 417

``` removes ige from circulation binds to fc region that normally sits in receptor, so ige cant occupy receptors anymore stops ige initiating inflammation exceptionally effective given as subcutaneous injection given depending on some factors ```

Answer 418

Specific targeting of allergy without side effects of steroids very rare to have side effects Reduces exacerbations by about 3/4, though has less effect on background lung function Doesn’t replace inhaled therapies - starts as an add on therapy Can replace oral steroids – long term can replace this

Answer 419

Hospital (mostly) administration given by injections (1-4 injections very 2-4 weeks) Subcutaneous injection(s) Side effects: ? increased risk of vascular episodes, low risk of anaphylaxis – very low risk Uncertain use in pregnancy Cost - £10,000-30,000 per year for each patient

Answer 420

If you have eosinophilic asthma, mepolizumab… reduces the frequency of attacks decreases the amount of steroids you need orally 4 weekly dosing s/c, relatively few side effects (headache, ? anaphylaxis) No significant immunosuppression side effects Issues over cost; NICE appraisals and implementation convenient nurse goes once a month and do injections in people homes works very well Reslizumab: intravenous anti-IL-5. does same thing but its intravenous single injection without having to find a vein but this reslizumab- more painful and needs someone with high level of skill to do it - -this is less convenient

Answer 421

mepolizumab - not sure yet if it can be used as not 100% sure that eosinophils are the cause of COPD although it has been seen in COPD exacerbations early trials have found that they have a limited benefit when used in COPD patients

Answer 422

reslizumab, mepolizumab and benralizumab are all used and work as anti-il5 agents Neutralising IL-5: reslizumab, mepolizumab Blocking IL-5 receptor and causing immune system- mediated eosinophil death: benralizumab works in2 ways: - doesnt allow il5 to be recognised by e - coats e in itself so immune system kills it *(as it recognises it as foreign)

Answer 423

works in 2 ways 1. doesn't allow il5 to be recognised by eosinophils by binding to its receptor so cant react. immune system sees the cells covered in the drug which it knows to be foreign so it gets rid of it 2. coats the eosinophil in benralizumab so the immune system kills it because it is recognised as being foreign

Answer 424

used to treat only eczema works by targeting the il4 receptor clinical rials have shown that it can reduce frequent exacerbations by 60%, improve lung function and also decrease the need for oral steroids another study found that compared to a control group, those treated with Dup had a 3.5% hospitalisation (compared to 6.5%) of the 210 participants who had been using oral steroids, 50% had been completely taken off them and 80% significantly reduced their steroid use by 1/2

Answer 425

works by binding to TSLP which is a member of the cytokine family and is a central regulator of the type 2 immunity. once bound, stops them from interacting with the TSP receptor. study showed that those who received this drug had lower rates of clinically significant asthma exacerbations compared to the placebo. regardless of the asthma group, it worked i.e. on eosinophilic and neutrophilic related asthmas

Answer 426

targets nfkb etc to reduce infammation fewer acute attacks and better control of asthma not sure how it works completely infection and inflammation both improved used more and more – so more people in public = exposed to this drug az = used a lot in other infections and so the use of this too much risks it being not effective later in these infections (resistance)

Answer 427

400 participants, placebo-controlled AZM 500 mg 3x wk Minimal S/Es, mainly diarrhoea, hearing impairment withdrawals placebo group only Inc ex smokers, ICS/LABA but few LAMA 60% reduction in exacerbations regardless of asthma phenotype Some increase macrolide resistant organisms such as PsA

Answer 428

causes diarrhoea other then that, very few side effects used to only be used to neutrophilic asthma etc Macrolides used to be used but had very little evidence

Answer 429

both eosinophilic and non-eosinophilic asthmas

Answer 430

Biologic: £5k - £30k/ year AZM: £100-200/ year (-) is a lack of license

Answer 431

Are antibiotics necessary? What is the site of infection? What is the organism sensitivity? What is the appropriate or available route of administration? What antibiotics are safe for the patient?

Answer 432

most of the agents used are semi-synthetic derivatives of antibiotics and so are called anti-microbials

Answer 433

Laryngitis – viral Tonsillitis – viral >> bacterial Strep throat (streptococcal infections) Glandular fever – viral (Epstein Barr)

Answer 434

hey use the centor criteria Tonsillar exudate Tender anterior cervical adenopathy (neck glands) Fever over 38°C (100.5°F) by history Absence of cough. If 3 or 4 of Centor criteria are met, the positive predictive value is 40% to 60%. The absence of 3 or 4 of the Centor criteria has a fairly high negative predictive value of 80%.

Answer 435

Bacteria Streptococcus pneumoniae and Haemophilus influenzae >> Moraxella catarrhalis. Staphylococcus aureus (influenza season). Pseudomonas aeruginosa Viral rhinoviruses, influenza, parainfluenza, coronavirus, adenovirus and respiratory syncytial virus. Common pollutants nitrogen dioxide, particulates, sulfur dioxide and ozone more often caused by viruses/pollutants than bacteria

Answer 436

it is hard to tell if the cause is bacterial and so if it isn't, giving antibiotics would be useless but if it is, would have missed this also, takes several days to be able to find out if COPD has been caused by the bacteria after several days of them being diagnosed

Answer 437

prevents transcription of genetic material | a small molecule that works by blocking nucleic acud synthesis r binding to a target site

Answer 438

Antibiotics as defined by Semar Waksman are; “ agents produced by micro-organisms that kill or inhibit the growth of other micro-organisms in high -dilution” Produced by micro-organism so gastric juice (acid), is not antibiotics. Penicillin discovered by Alexander Fleming in 1929 was the the first antibiotic.

Answer 439

Antibiotics Antibacterial agents Antivirals

Answer 440

influenza A and B and RSV

Answer 441

neurominodase – as virus comes out of cell, must disconnect from moitee using neuromindoase enzyme. virus cant bud if there is a neuromindase inhibitor and so can’t infect other cells Oseltamivir ‘tamiflu’ or Zanamivir ‘Relenza’

Answer 442

shorten the symptoms of influenza-like illness by about half a day in adults (but not in asthmatic children), compared to a placebo. no reliable evidence for reducing the risk being admitted to hospital or developing pneumonia, bronchitis, sinusitis or otitis media

Answer 443

by then, the virus would have already spread as this inhibitor is meant to stop the virus leaving and transfecting other cells. so, it would be ineffective

Answer 444

``` Ribavirin is a nucleoside inhibitor. an analogue of guanosine stops viral RNA synthesis good in vitro activity against RSV --antiviral ribavirin prevents nucleic acid synthesis G analogues like RSV, once the enzyme (causing rep), when it puts it in the chain, stops next nucleotide from jining onto it (its an analogue that doesnt have the right side chains so doesnt allow next acid to bind) – so tops rep of RSV ```

Answer 445

- shown to have devastating effects in young children Possible shorter duration, less need for ventilator or oxygen Early use of inhaled ribavirin has been shown to reduce morbidity and mortality in adult bone marrow cell transplant recipients

Answer 446

defined as points of biochemical reaction crucial to the survival of the bacterium penicillin-binding proteins in cell wall cell membrane DNA Ribosomes Topoisomerase IV or DNA gyrase the crucial binding site will vary with the antibiotic class

Answer 447

BINDING TO CELL WALL AND INHIBITION OF CELL WALL SYNTHESIS – Penicillin binding proteins PBP disrupts the ability to maintain and carry on building cell wall so the cell dies BETA LACTAMS (PENICILLINS AND CEPHALOSPORINS) GLYOPEPTIDES

Answer 448

INTERFERENCE WITH NUCLEIC ACID SYNTHESIS OR FUNCTION e.g. METRONIDAZOLE, RIFAMPICIN

Answer 449

INHIBITION OF DNA GYRASE | e.g. FLUOROQUINOLONES

Answer 450

INHIBITION OF RIBOSOMAL ACTIVITY AND PROTEIN SYNTHESIS AMINOGLYCOSIDES, TETRACYCLINES, MACROLIDES, CHLORAMPHENICOL

Answer 451

INHIBITION OF FOLATE SYNTHESIS AND CARBON UNIT METABOLISM | SULPHONAMIDES AND TRIMETHOPRIM

Answer 452

``` Streptococcus pneumoniae (40%) Mycoplasma pneumoniae (~10% peaks in epidemic seasons) Chlamydophila pneumoniae (~10%) Legionella pneumophila and other spp.(<5%) Haemophilus influenzae (<5%) Klebsiella pneumoniae (rare; homeless and in hospital) Staphylococcus aureus (low % in community but increased after influenza and in hospital especially) Viruses (≥10%) ```

Answer 453

atypical pathogens – have certain characteristics that make tem harder to detect and so need diff treatment

Answer 454

``` Gram positive cocci Alpha haemolytic, optochin sensitive >>90 serotypes any age but increases at extremes of age can be severely ill with respiratory failure or sepsis ‘invasive pneumococcal disease’ ```

Answer 455

best drugs in clinical traisl – beta lactams – amoxixillin most time amoxicillin works macrolides – inhibit ribosome fluroquinolones – inhbit DNA gyrase

Answer 456

macrolides and fluoroquinolones are not used in UK as penicillin and b lactams work in other countries, b-lactam has too much resistance and so these ones are more commonly used macrolides more commonly used in those allergic to blactams

Answer 457

``` H. influenzae Gram negative cocobacilli Ealry 20th C thought to be cause of Influenza Encapsulated – e.g. HiB Unencapsulated ‘non typable’ NTHi Staph. aureus May complicate recent influenza, ventilator-associated pneumonia too Klebsiella pneumoniae Gram negative bacilli, Enterobacteriaceae Normal flora of mouth and intestines homeless, alcoholic, Hospital –associated ```

Answer 458

``` H. influenzae -β-lactam antibiotics: Amoxicillin +clavulanic acid ‘co-amoxiclav’ Tetracyclines: Doxycycline But NOT Macrolides ``` ``` S. aureus - β-lactam antibiotics: Flucloxacillin Cefuroxime MRSA? Vancomycin Linezolid ``` Klebsiella pneumoniae β-lactam antibiotics: Co-amoxiclav Cephalosporins

Answer 459

``` Legionella pneumophila Mycoplasma pneumoniae Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetti ``` dont respond to B lactams but do respond better to macrolides and fluoroquinolones

Answer 460

The most common and serious MDR pathogens have been encompassed within the acronym “ESKAPE,” standing for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.

Answer 461

``` Micro-organisms Early onset ≤5d of hospital organisms similar to CAP and also anaerobes Late onset >5d; Staph. aureus including methicillin resistant (MRSA) Pseudomonas aeruginosa Acinetobacter baumanii Klebsiella pneumoniae ```

Answer 462

TB is curable Treat with at least 4 drugs for at least 6 months Standard treatment in UK: ``` rifampicin isoniazid both for 6 months (or 12 months if in CNS) + pyrazinamide ethambutol or the first 2 months ```

Answer 463

extra considerations if tb - -- if in CNS, drugs given for longer to make sure you've gotten rid of all of it

Answer 464

rifampicin – tagets rpob pyrazinamide- has to be converted to where the bacterias are. inhibits fatty acids syntahse (cell wall fromation), disrupts chnges in intracellular ph makign it less lilely to survive isoniazid – KatG – place develops in microbacteria. if it doesnt fit twith the compound, bcteria will survive. if changed int pe stop unfolding of DNA heix and prevemtign transcription adnd translation

Answer 465

- Change antibiotic target - Destroy antibiotic - Prevent antibiotic access - Remove antibiotic from bacteria

Answer 466

The antibiotic is destroyed or inactivated Beta lactam ring of Penicillins and cephalosproins hydrolysed by bacterial enzyme ‘ Beta lactamase’ now unable to bind PBP Staphylococci produce penicillinase so penicillin but not flucloxacillin inactivated Gram negative bacteria phosphorylate and acetylate aminoglycosides (gentamicin)

Answer 467

modify the bacterial membrane porin channel size, numbers and selectivity Pseudomonas aeruginosa against imipenem, Gram negative bacteria against aminoglycosides

Answer 468

Proteins in bacterial membranes can act as an export or efflux pumps Level of antibiotic is reduced S. aureus or S. pneumoniae resistance to fluoroquinolones Enterobacteriacae resistance to tetracylines

Answer 469

- intrinsic - Naturally resistant Example of intrinsic resistance: Aerobic bacteria are unable to reduce metronidazole to its active form Anaerobic bacteria lack oxidative metabolism required to uptake aminoglycosides or some bacteria- dont have target sites to begin with – these are intrinisc classes of resistance - acquired: spontaneous gene mutation or Horizontal gene transfer (conjunction, transduction and transformation)

Answer 470

conjugation - Sharing of extra-chromosomal DNA plasmids “Bacteria sex’ Transduction - Insertion of DNA by bacteriophages Tranformation - picking up naked DNA ``` spontaneous gene mutation - New nucleotide base pair change in amino acid sequence change to enzyme or cell structure reduced affinity or activity of antibiotic ```

Answer 471

Primary Resistance Innate property eg Pseudomonas and penicillin Acquired Resistance Due to mutation or gene transfer Chromosomal eg M.tuberculosis Plasmid mediated eg MRSA

Answer 472

protein binding, pharmacokinetics, distribution into the site of infection, the adequacy of the patient’s host defenses exposure of an organism to an antibiotic needed for its eradication musn't be toxic so ned to find tis minimum inhibitory concentration

Answer 473

(1) release from the dosage form; (2) absorption from the site of administration into the bloodstream; (3) distribution to various parts of the body, including the site of action and (4) rate of elimination from the body via metabolism (LIVER) or excretion (KIDNEY) of unchanged drug.

Answer 474

``` intolerance, allergy and anaphylaxis side effects age renal function liver function pregnancy and breast feeding drug interactions risk of Clostridium difficile (5 ‘C’s) ``` if kidneys arent working, get toxic levels of drug liver not workng, may metabolise the drug too fast/slow etc very rarely give 1 drug to soemone interactions betwenen drug and others given – key antibiotic associated diarrhoes – utgrowth of bacterial inefction (Clostridium difficile) – can allow this which is usually resistant to cause toxic affects in the GI tract

Answer 475

Ciprofloxacin Clindamycin Cephalosporins Co-amoxiclav (augmentin) Carbapenems, e.g. meropenem (for most difficult to treat patients)

Answer 476

``` Nuclear missile Will work (for now) Expensive Adverse effects Harder to give Promotes resistance ``` ``` Sniper Might miss Narrower AE profile More tolerable Saves other choices cheaper ```

Answer 477

Offer a 5‑day course of a single antibiotic amoxicillin, to patients with low‑severity community‑acquired pneumonia. Consider dual antibiotic therapy with amoxicillin and a macrolide for patients with moderate‑severity community‑acquired pneumonia. Consider dual antibiotic therapy with a beta‑lactamase stable beta‑lactam[1] and a macrolide for patients with high‑severity community‑acquired pneumonia.

CDL302 Flashcards

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