Resp Flashcards

Question

Compare and contrast obstructive and restrictive disease

Answer 1

Pathophys OBSTRUCTIVE: Airflow problem Roughly: Harder for air to get out of the lungs, which can be for a few reasons 1. Asthma - bronchoconstriction 2. COPD: a. Emphysema - decreased elastic recoil, air trapping, airway collapse b. Chronic bronchitis - increased secretions, airway narrows 3. Bronchiectasis/CF - increased secretions, airway narrows RESTRICTIVE: Lung expansion problem Roughly: Can’t really breathe too deeply. If chronic, mostly due to scarring of lungs from genetic, autoimmune, environmental or idiopathic reasons. Upper lobe fibrosis: SSTARCH (Silicosis, sarcoidosis, TB, aspergillosis, radiation, coal worker’s lung, histiocytosis) Lower lobe fibrosis: RASCO (Rheumatoid arthritis, asbestosis, scleroderma, cryptococcus, other - drugs eg methotrexate) Normally abnormal expiratory breath sounds eg expiratory wheeze Normally abnormal inspiratory breath sounds eg inspiratory crackles  Cough  Very varied, characterise sputum colour  Can be purulent in exacerbations  Dry cough -> Consider pulmonary fibrosis  Chronic purulent cough -> Think bronchiectasis, consider CF  Dyspnoea (Shortness of breath)  Wheezing → more likely asthma  Good social Hx about smoking, occupation and environmental exposures is super valuable. Don’t forget FHx of asthma, lung cancer, etc.

Answer 2

- spiromtery - body plethysmography - iamging - bronchodilator test -

Answer 3

If lobar, - Morphologic changes in the lung tend to follow a classic sequence. - Four stages: - Congestion - Red hepatisation - Grey hepatisation - Resolution - Since the introduction of antibiotics, this sequence is often altered. **Congestion** - Enlarged lobe. - Heavy and congested with blood. - Blood-stained fluid from the cut surface. - Dilated alveolar capillaries. - Air spaces filled with pale fluid. - Scattered red blood cells and neutrophils. - Occasional bacteria. **Red Hepatisation** - Cut surface is dry and red. - Resembles liver macroscopically. - Fluid containing fibrinogen has clotted in alveolar spaces. - Increased numbers of neutrophils. - Bacteria more numerous. **Grey Hepatisation** - After 2-3 days, loss of the red color. - Starts at the hilum and moves out. - Migration of large numbers of neutrophils. - Decrease in capillary congestion. - Virtual cessation of blood flow through the unventilated lobe. **Resolution** - Liquefaction of the previously solid exudate. - Fibrinolytic enzymes. - Apoptosis of neutrophils. - Fluid contents removed: - Expectoration - Lymphatics. - Takes several weeks.

Answer 4

e.g. ARDS - capillary endothelial and alveolar damage - release of cytokines and interleukins, which in turn - activation of neutrophils (release proteases, oxidants), which migrate into interstitium-->oedema, thickened interstitium due to infiltrate - increased vascular permeability - exudation of fluid- alveolar flooding End-result is decreased diffusion Macroscopy: heavy, boggy, oedematous and red lungs Microscopy: hyaline membrane, and widening of interstitial space - CRPD: similar to acute - different mechanisms leading to inflammation ofo alveoli - accumulation of inflammatory cells in the alveolar walls and spaces - release of mediators e..g cytokines and interleukins - alveolar wall damage - fibrosis of the alveolar walls (irreversible and poor prognosis) - Usual interstitial pneumonitis ^[c/c] - Repeated sequential cycles of acute lung injury- alveolitis leads to progressive fibrosis (Wound healing with fibroblastic proliferation) - Early stages: fibroblastic proliferation/fresh fibrosis/fibroblast foci - Late: collagenous, acellular scarred areas/pld Both early and late stages are seen together: - temporal heterogeneity: presence of both fresh and old fibrosis - regional heterogeneity (areas of relative sparing) - ### Non specific interstitial Diagnosis is one of exclusion, as many other diseases mimic this. Characterised by: - Interstitial lymphocytes and plasma cells, interstitial thickening - Diffuse or patchy interstitial fibrosis (temporally homogenous, all old, uniform appearance) - variably cellular (inflammatory) and - Absence of fibroblastic proliferation (all old fibrosis) - **Asbestos** * Pleural plaques: fibrosis in parietal and visceral pleura * Diffuse pulmonary fibrosis (Asbestosis) * Recurrent Pleural effusions Note: usually colourless, but if iron deposits, can see (ferrogenous bodies) - **Carbon and silica** – Initial formation of nodules in the upper lobes of the lung: fibrous scars, "hard" - found in lymph nodes, parenchyma and pleura * Nodules contain dust particle, macrophages and delicate network of collagen * Macrophages secrete mediators: attract lymphocytes, fibroblasts * Cause damage to alveolar cells and interstitium – Disease progression leads to formation of hard collagenous scars – Scars may often be pigmented in coal workers - ## Granulomatous lung diseases Hypersensitivity pneumonitis (extrinsic allergic alveolitis): reaction to inhaled organic antigens or chemicals: e.g farmers lung, Bird-fanciers lung, hot-tub lung ^[type 4?] - Some antigens are actually infectious agents Features: - nodular - multi-nucleated giant cells - macrophages - surrounded by lymphocytes Sarcoidosis: idiopathic multisystem disease - ^not an exhaustive list

Answer 5

**Acute Response** - In sensitized individuals - Exposure of the airways to specific allergens results in crosslinking of IgE present on the surface of mast cells and triggers the release of inflammatory mediators - Increased vascular permeability - Bronchial smooth muscle contraction - Increased mucous secretion. - Allergic airway phenotype results from cytokine production from T cells as well as from inflammatory mediators released from recruited eosinophils and other cells in the lung. - Mucous hypersecretion - Smooth muscle cell hyperreactivity - Airway remodeling with chronic inflammation. **Chronic Response** - Influx of inflammatory cells - Th2 cells, eosinophils - Cytokines produced by both eosinophils and T cells promote the homing of eosinophils to the site of inflammation followed by differentiation, activation and degranulation - Cycle of ongoing tissue injury - Increase in inflammatory infiltrate - Chronic inflammation - perpetuated by both cytokines and the products released by eosinophils - Increasing evidence that other subsets of CD4+ T cells play a role in orchestrating inflammatory changes - Th1, Th17, Treg, CD1d restricted NKT cells, TFH Gross description * Overdistended lungs, small areas of atelectasis, thick mucus plugs in proximal bronchi containing whorls of shed epithelium Microscopic (histologic) description * Curschmann spirals, eosinophils, extracellular Charcot-Leyden crystals (crystalloids composed of galectin-10, an eosinophil lysophopholipase), increased mucosal goblet cells and submucosal glands, thickened basement membrane, bronchial smooth muscle hypertrophy, airway wall edema

Answer 6

There are two factors that contribute to the development of asthma. These include changes to the airway walls and lumen. The airway walls become infiltrated with mononuclear cells, especially CD4+ T cells and eosinophils. Severe asthma is associated with increasing neutrophil infiltration. This is because, as asthma progresses, there are increased numbers of degranulated mast cells, macrophages, plasma cells and neutrophils found in the airway walls. Changes within the airway lumen include increased secretions, containing lymphocytes, activated macrophages, eosinophils and epithelial cells. With inflammation comes remodelling of the airway. This involves cellular and molecular changes to the airway, affecting its structure. Changes include: - epithelial injury - subepithelial thickening and fibrosis - airway smooth muscle cell hyperplasia. This in particular affects recruitment of inflammatory cells. - goblet hypertrophy and hyperplasia - angiogenesis These structural changes contribute to - bronchial hyper-responsiveness which is correlated with inflammation, and is influenced by diameter of lumen, muscle contractility, epithelial injury, neuronal deregulation and microvascular permeability, airway obstruction, and associated symptoms characteristic of asthma including breathlessness, wheezing and coughing - Airway obstruction which is characterised as increased airway smooth muscle mass, increased matrix protein deposition, disruption of surfactant function, and excess mucous with extravasated proteins and inflammatory cells comprising plugs. ## Footnote also TGFb

Answer 7

Spirometry Interpretation** - Use **FEV1/FVC** ratio to detect obstruction. - Use **FEV1 as % predicted** to grade obstruction severity. - Use **FVC to assess restriction: - low FVC or VC in presence of significant obstruction does not necessarily indicate restriction - **confirm and quantify with Total Lung Capacity measurement in respiratory lab - **Bronchodilator reversibility**: Significant reversibility is a ≥12% improvement in FEV1 (FVC) and an increase of at least 200 ml after bronchodilator therapy.

Answer 8

Respiratory - A result of abnormal Pco2 - if elevated = acidosis. If low = alkalosis. Compensated with metabolic alkalosis and acidosis (high and low bicarbonate respectively). Respiratory acidosis as a primary disorder is often caused by hypoventilation. This can be due to multiple causes including chronic obstructive pulmonary disease, opiate abuse/overdose, severe obesity, and brain injury. When respiratory acidosis occurs, the metabolic response should be to increase the amount of bicarbonate via the renal system. This does not always occur, and renal pathology can easily hinder the appropriate physiological response, leading to increased danger for the patient. Any pathology that leads to the increased expiration of carbon dioxide can result in respiratory alkalosis. When excess CO2 is expired, the pH of the human body is increased due to less carbonic acid being created. Physiologically, the appropriate compensation is a decreased amount of bicarbonate being created by the renal system. Some causes of respiratory alkalosis include panic attacks with hyperventilation, pulmonary embolism, pneumonia, and salicylate intoxication

Answer 9

- Cardiac: AMI, overdose on drugs that slow HR, Eisenmernger, pericardial tamponade, valvular disease, HR or dulated CM, acute/ congestive heart failure, aortic aneurysm, acute decompensated heart failure - Anemia, cancer, acidosis, sepsis - Respiratory: PE, (+/- tension) PT, asthma, COPD, hamothorax, Pulmnary infection,

Answer 10

1. Bronchopneumonia o Patchy consolidation of the lung. 2. Lobar pneumonia o Consolidation of a large portion of a lobe or of an entire lobe. Bronchopneumonia * Common at the extremes of life. * Patchy consolidation of the lung. * Extension of a preexisting bronchitis. Lobar Pneumonia * Acute infection of an entire lobe. * Usually due to a virulent organism. * Abrupt onset. * Now infrequent due to antibiotic treatment.

Answer 11

- Static does not change - Dynamic can change - Capacity = two or more volumes

Answer 12

Pathogens: bacterial, fungal, viral; lipid, aspiration Pneumococcal Pneumonia - "Typical" Pneumonia - Abrupt onset - High fever +/- rigors - Productive cough with usu. purulent sputum - Shortness of breath - Pain on breathing (pleuritic) - Lobar consolidation (or anat segments of lobe) on CXR **Haemophilus influenzae** - Gram-negative coccobacillus ^[may look like a bacillus or a short bacillus which is almost coccus] - Unencapsulated - less invasive and less virulent - Capsulated - a, b, c, d, e, f - H. influenzae B (Hib) most virulent **Haemophilus influenzae Non-Invasive Infection** i.e. not on mucosal surfaces - Sinusitis - Otitis media - Conjunctivitis - Pneumonia **Invasive Infection (Hib)** ^[very rare since vaccination introduced] - Epiglottis - Bacteremia - Meningitis - Septic arthritis **Neisseria meningitidis** - Gram-negative diplococcus - Unencapsulated - not often associated with infection - 10-25% of young people carry in pharynx - Capsulated - A, B, C, W, Y - Invasive disease - Vaccination: Previously only C but now also combined tetravalentA, C, W, Y and standalone B **Neisseria meningitidis Invasive Disease** - Risk factors for invasive disease - Age <5 years and 15-25 years ^[living in close quarters] - Asplenia/hyposplenia - Deficiency or **impairment of complement membrane attack complex (C5-C9) - Invasive disease: - Bacteremia (meningococcemia) - Meningitis **Moraxella catarrhalis** - Gram-negative diplococcus - Diseases - Sinusitis - Otitis media - Pneumonia - Infective exacerbations of chronic obstructive pulmonary disease **Atypical Respiratory Tract Infections** **"Atypical" Pneumonia** - "Atypical" bacteria - Not detectable by Gram stain or cultured by standard methods - **Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila, L. longbeachae - "Atypical" symptoms and signs - Constitutional symptoms (headache, fever, malaise, nausea) may predominate over respiratory symptoms (dry cough) - Less likely to have lobar changes on CXR, diffuse or non-specific infiltrates - Most cases are milder, but some, especially Legionella pneumophila, C. psittacii, can be severe and life-threatening **Mycoplasma species** - Smallest and simplest bacteria - Lack of cell wall - Unable to Gram stain - Resistant to cell wall antibiotics e.g. blactam **Mycoplasma pneumoniae** **Respiratory** - Pharyngitis - Otitis media - Pneumonia **Extrapulmonary** - Meningitis/encephalitis - Erythema multiforme, tathet lesions - Autoimmune hemolytic anemia/thrombocytopenia - Pericarditis/myocarditis **Legionellosis** pnumophila and serotypes, longbeachae - Gram-negative bacillus - Difficult to see on Gram stain - Difficult to culture - Specific growth factors - Slow - missed in routine cultures - Antibody response may take several weeks )(false negative) - Urinary antigen (Legionella pneumophila) ^[not all subtypes, not longbeachae] - Nucleic acid amplification ^[not lab validated]

Answer 13

- Complications may be seen in either bronchopneumonia or lobar pneumonia. - Bronchopneumonia: - Healing by fibrosis. - Lobar pneumonia: - Pleuritis - Empyema - Abscess formation - Haematogenous seeding - Death **Organisation / Fibrosis** - Healing by fibrosis rather than resolution is more common in bronchopneumonia. - Leads to organizing pneumonia. - Polyps of fibrous granulation tissue within alveoli. - 'Masson Bodies'. Pleuritis - Inflammation extends to involve the pleura. - Gives rise to typical pleuritic pain. - Initially may just be an effusion. - Followed by fibrinous pleuritis +/- bacteria. - Healing leads to fibrous adhesions between visceral and parietal pleura. Abscess Formation - Localized suppurative process characterized by necrosis of lung tissue. - Associated with Staphylococcus Aureus and Klebsiella pneumoniae. - Ranges from millimeters to centimeters. - Can be single or multiple. - **Macro**: Cavities filled with suppurative debris. **Abscess Formation Histology** - Florid inflammation. - Destruction of alveolar walls. - Liquefactive necrosis. - Chronic abscess surrounded by fibrous tissue. ![Abscess Formation Histology Wall](H+E: Lung wall of abscess x 50) ![[Pasted image 20230904191743.png]] ![[Pasted image 20230904191802.png]] Empyema - Collection of pus in the pleural cavity is called an empyema. - Collection usually loculates, followed by scarring. - Requires drainage. - Heals by fibrosis. ![[Pasted image 20230904191826.png]] ## Haematogenous Spread - Dissemination of bacterial organisms throughout the lungs or other organs. - Bacteraemia/septicaemia. - Seeding to heart valves (bacterial endocarditis), meninges (meningitis), kidneys (pyelonephritis). ![[Pasted image 20230904191834.png]] **Haematogenous Seeding Examples** - Bacterial endocarditis with vegetations on the aortic valve. - Brain with surface purulent exudate. - Kidney with surface petechial haemorrhages. - Meninges (Meningitis). - Kidneys (Acute pyelonephritis). ![[Pasted image 20230904191845.png]] Death - Still one of the commonest causes of death. - Especially in the very young and old. - Often represents the terminal event secondary to some other debilitating process.

Answer 14

Chest radiograph * airspace opacification o filling of the alveoli with infectious material and pus o initially patchy o becomes confluent as infection develops * air bronchograms o air-filled bronchi running through pus-filled alveoli * complications o pleural collection o cavitation CT chest * airspace opacification o looks the same as on a chest x-ray o degree of consolidation assessed more accurately * complications can be seen earlier than a chest x-ray o lung necrosis o cavitation o empyema

Answer 15

Inhaled corticosteroids ### Mechanism of action is complex, and includes although not limited to: - Reduced airway inflammation and bronchial hyper-reactivity. - Reduced clonal proliferation of T-helper cells by reducing IL-2 and reduction in cytokines - Inhibit allergen-induced influx of eosinophils - Up regulation of beta receptors. Adverse effects can be divided into local and systemic effects: - Local effects (can be minimised by rinsing mouth with water and spit immediately after using. The use of a spacer may also limit local side effects) - Local infections eg oral candidiasis - Pneumonia in COPD patients - dysphonia - Systemic effects (less common with inhaled compared with systemic, but still occur in some patients particularly at high dose for long periods) - impaired glucose control - fractures - adrenal suppression - psychosis - glaucoma - bruising

Answer 16

Corticosteroids Mechanism of action: - enter cells where they combine with steroid receptors in cytoplasm - enters nucleus where it controls gene transcription: - synthesis of proteins, including enzymes that regulate vital cell activities over a wide range of metabolic functions including all aspects of inflammation - formation of a protein that inhibits the enzyme phospholipase A2, which is needed to allow the supply of arachidonic acid (which is essential for the formation of inflammatory mediators) ### Adverse effects can be divided into local and systemic effects: - Local effects (can be minimised by rinsing mouth with water and spit immediately after using. The use of a spacer may also limit local side effects) - Local infections eg oral candidiasis - Pneumonia in COPD patients - dysphonia - Systemic effects (less common with inhaled compared with systemic, but still occur in some patients particularly at high dose for long periods) - impaired glucose control - fractures - adrenal suppression - psychosis - glaucoma - bruising

Answer 17

SABA – MoA, side effects, indications Beta agonists relax bronchial smooth muscle by stimulating beta-1 adrenoceptors. Many of the adverse effects are related to activity on beta-1 adrenoceptors in addition to beta-2 adrenoceptors. Examples include: - hypokalaemia (note: salbutamol is used to treat hyperkalaemia) - insomnia - tremor - palpitations - tachycardia - headaches - muscle cramps - lactic acidosis (rarely) **Examples**: salbutamol and terbutaline **Onset of action**: 5-15 minutes **Duration of action**: 3-6 hours **Indications** - first line in managing acute asthema - symptom relief in asthma and COPD - prevention of exercise-induced asthma - previously considered step 1 SABA PRN (as a single agent) only. New guidelines instead recommend LABA (formeterol) with ICS PRN (budesonide) in adult patients **Extra information**: high or increasing use indicates poor asthma control

Answer 18

Adrenaline is a sympathomimetic agent and an endogenous agonist of the beta receptors. As a result, it increases total peripheral resistance by increasing vasoconstriction. Adrenaline relaxes bronchiole smooth muscle. This is used therapeutically to relieve bronchospasm e.g. that occurs during anaphylaxis. Adrenaline also increases the height of the action potential by lowering the threshold. It also triggers the secondary messenger cAMP to enact cellular effects downstream.

Answer 19

Severe shortness of breath, chest tightness or pain, and coughing or wheezing. Low peak expiratory flow (PEF) readings, if you use a peak flow meter.

Answer 20

- Diaphragm via Phrenic nerve (C3, C4, C5) - External intercostals (bucket handle movement) via Intercostal nerves - Accessory muscles: SCM and trapezius via Accessory nerve (CN 11) - recruited e.g. in asthma - Expiration is passive at rest, but internal intercostals and abdominals are recruited for active expiration - not always passive at tidal breathing e.g. some postures

Answer 21

However, intra-abdominal and pleural pressures are increased slightly in obesity, because the downward movement of the diaphragm and the outward movement of the chest wall are restricted when fat accumulates within the thoracic and abdominal cavities [13, 14]. This alters the breathing pattern resulting in a substantial reduction in both the expiratory reserve volume (ERV) and the resting volume of the lung, known as the functional residual capacity (FRC). The reduction in FRC is proportional to the severity of obesity – overweight, mildly obese and severely obese subjects without asthma demonstrate reductions in FRC of up to 10%, 22% and 33%, respectively [15]. Tidal volume is also slightly lower in obese subjects ERV and TLC also down Increase in mean respiratory rate and minute ventilation at rest. Little effect on RV and TLC (small reductions, usually well preserved) RV: TLC normal or slightly elevated.

Answer 22

- Pleura - Lung - Heart – decreases VR due to increased intrathoracic pressure, decreased SV and CO, BP = haemodynamic compromise

Answer 23

The main way people spread Streptococcus pneumoniae to others is through direct contact with respiratory droplets. - Endogenous pathogen of the URT, can cause otitis media, mastoiditis, sinusitis - Can disseminate into the LRT or other parts of the body, causing pneumonia, bacteremia, meningitis **S. pneumoniae Capsule - Virulence Factor** enables evasion - Prevents entrapment in mucus, allowing access to epithelial surfaces - Protects against phagocytosis and complement-mediated lysis: bacteria persist and multiply - Anti-S. pneumoniae capsule antibodies (generated through acquired immune response) are protective, but typically not cross-protective - Vaccine contains purified capsular polysaccharide antigen from many different S. pneumoniae serotypes ^[hence why acquiring one does not necessarily confer immunity against another] People spread H. influenzae, including Hib, to others through respiratory droplets. People who are infected spread the bacteria by coughing or sneezing, which creates small respiratory droplets that contain the bacteria. **Haemophilus influenzae** - Gram-negative coccobacillus ^[may look like a bacillus or a short bacillus which is almost coccus] - Unencapsulated - less invasive and less virulent - Capsulated - a, b, c, d, e, f - H. influenzae B (Hib) most virulent General pathophysiology of H. influenzae, M. catarrhalis, and N. meningitidis infection is similar to S. pneumoniae N. meningitidis: People spread these bacteria by sharing respiratory or throat secretions (saliva or spit) - Gram-negative diplococcus - Unencapsulated - not often associated with infection - 10-25% of young people carry in pharynx - Capsulated - A, B, C, W, Y - Invasive disease

Answer 24

Atopy refers to a predisposition to making IgE antibodies to common environmental proteins such as grass pollens, dust mites, foods, etc. It is: - Familial, with a number of gene clusters associated - Can be modified by environmental factors - Associated with conditions such as eczema, asthma, and food allergies

Answer 25

**Influenza Virus Virions** - *segmented* ssRNA genome - Haemagglutinin = HA = H - adheres to cell receptors and enters cell - RNA synthesis in nucleus - Neuraminidase = NA = N - enables release Note that it is the balance of HA to NA to mediate entry and exit from the cell - in order for infection to be most efficient. Influenza A viruses split into serotypes based on: - Haemagglutinin (H) – H1 to H16 known - Neuraminidase (N) – N1 to N9 known - H1, H2 & H3 + N1 & N2 in viruses adapted to humans Symptoms must include a combination of the following: - central: headache - systemic: fever - muscular: tiredness (due to IFN effect) - joint aches - coughing - GI upset - nasopharyngeal symptoms **Ecology of Influenza Viruses** - Endemic in multiple species - Birds (domestic and wild) - Pigs - People - Can move between these if species barriers can be overcome **Influenza Virus Nomenclature** - Divided into A, B, and C - A is the most prevalent cause of human infection - B also circulates Influenza A viruses split into serotypes based on: - Haemagglutinin (H) – H1 to H16 known - Neuraminidase (N) – N1 to N9 known - H1, H2 & H3 + N1 & N2 in viruses adapted to humans Isolates Named After Place of Isolation, Year & Type: - A/Brisbane/59/2007 (H1N1) - A/Uruguay/716/2007 (H3N2) - B/Florida/4/2006 Note that place of isolation does not mean place of origin. **Immunity to Influenza** Innate immunity, especially interferons, are strong. T cells are required to clear an infection. Antibodies that recognize HA and NA are most important for preventing re-infection with exactly the same strain. - Anti-HA is a classic neutralizing antibody: blocks the binding of HA to its receptor. - Anti-NA is protective but not neutralizing (because it mediates exit but not entry). **Genetic and Antigenic Drift - Evolution in Action** - A low fidelity polymerase + high replication rate result in a relatively rapid mutation rate. - A high percentage of infectable individuals have protective antibodies to HA and NA, creating strong selective pressure to change these proteins, evade antibody recognition, and reinfect. **Genetic and Antigenic *Shift* - Flu as a Genetic Engineer** - If two strains co-infect a single cell, segmented genomes can 're-assort,' creating new strains ^[just a byproduct of assembly, cell cannot distinguish between strain A and B]. - Co-evolution of a strain and its host creates a species barrier, and genetic shift can break or lower species barriers. - note that statistically only a small amount is pathogenic - with multiple rounds of replication becomes more feasible

Answer 26

- Corona – 'Crown' - (+)ssRNA virus - Large RNA genome ~29kB - 14 ORFs (both large and small) - Ribosomal frameshifting - 29 gene products - Host-derived envelope ^[i.e. stolen] - Spherical - 100-160nm - Protruding spike proteins ^[critical, binds to ACE2 receptor, target of vaccination] **SARS-CoV-1 v SARS-CoV-2** - SARS-CoV-1 - 8110 cases, 811 deaths: CFR ~10% - SARS-CoV-2 - 608m (confirmed) cases, 6.5m deaths: CFR ~1% (falling) Note that the CFR for SARS-CoV-2 is much lower than SARS-CoV-1. - SARS-CoV-2 - Higher tropism for the URT - With evolution increases affinity - More **efficient** host-cell invasion - Increased spread - **Higher virus loads prior to symptoms - Pre-symptomatic/asymptomatic spread - it is this factor that contributed to the much greater spread of SARS-CoV-2 - Note also that CoV1 cases are much easier to identify and isolate given that symptomatic individuals had higher load ^[this idea contributed to complacency in COVID-19] - BOTH - Attach via ACE-2 - Respiratory pathogens - Stronger binding to ACE-2 = virus is now adapting to avoid ACE-2, or bind less well, in favour of another receptor The notable feature in this diagram is the viral genome which peaks in the pre-symptomatic phase (within the URT). Consider also that a proportion of the population will be complete asymptomatics. Note also that those with severe illness are theorised to have poorer innate immune systems (IFN). Viral genome curve shifts to the left. **Respiratory Tract and Beyond....** - SARS-CoV-2 does not stay in the respiratory tract - Found viral RNA at autopsy: - Digestive tract tissue – (-ve RNA) - Brain tissue + CSF - Heart tissue– 2/3rds of patients who died of pneumonia! - Multisystem disease (severe illness) ALSO includes: - Renal insufficiency - Reduced liver function - Blood clotting ^[treat to drastically improve outcomes] - Arrhythmias, hypertension, and cardiac dysfunction in long COVID - Direct invasion of cardiomyocytes - Damages/destroys the cells - Dampens ACE-2 function: Usually plays a role in regulating blood pressure. - Cardiac tissue immunopathology - Myocardial injury – 5 of the first 41 patients in Wuhan **COVID-19 Highlights Diverse Outcomes** - SARS-CoV-2 can cause: - Asymptomatic - Never develop COVID-19 symptoms - + RNA test - Mild - Symptoms self-limiting - Severe - Life-threatening - Requires critical care - Long-COVID ^[note also that long COVID fairly common, poorly understood and not well acknowledged] - Symptoms beyond 4 weeks - RNA test

Answer 27

**Rhinovirus – A Picornavirus** - Picornavirus (literally ‘very little RNA virus’). - A large family of very small +ve sense RNA viruses. - Collectively they are a nasty bunch, with rhinoviruses accounting for more specimens tested than influenza. - Other members include Polio, Coxsackievirus (causes myocarditis), and Foot and Mouth Disease Virus (of livestock). - note rhinoviruses are more of an economic problem than a cause of serious disease, but account for more specimens tested than influenza **Rhinovirus (Picornavirus) Genome** - Genome is translated immediately upon entry. - Viral RNA pol is not carried in the virion. - A single open reading frame generates a polyprotein, processed by a viral enzyme. - Note: 5'-UTR has many AUGs therefore ribosome cannot start at the beginning and scan for first AUG - therefore has to jump onto RNA at rifht place-- has IRES which allows ribosome to bind at internal position, which differes mechanistically from host translation - this enables virus to stop host translation but preserve its own - IRES has biorech appliactions **Rhinovirus – A Family Affair** - Most frequently isolated agent from people with the 'common cold.' - Children have more frequent infections than adults. - "The family unit is a major site for the spread of rhinoviruses in contemporary society." - "Infections are generally brought into the home by children." - Secondary attack rates are 30-70%, with spread most common for other children and mothers. - Secondary infections appear at 2-5 day intervals, most within a few days of the index case. - The greater the symptoms of the index, the higher the attack rate. Note that rhinoviruses are not enveloped and thus harder to disinfect.

Answer 28

**Adenoviruses** - Adenoviruses (AdV) were found in the 1950s using cell culture and were associated with human respiratory disease. - Human AdV has 6 species (A-F) and 51 serotypes. - Characteristics include a linear, dsDNA genome ~35 kb, non-enveloped virion, and replication in the nucleus. **Adenoviruses Do Lots of Nasty Things** - Diseases caused by Adenoviruses include upper respiratory infections, gastroenteritis, meningoencephalitis, hepatitis (in kids with transplants), myocarditis, acute hemorrhagic cystitis, and more. - Different serotypes cause different disease **Adenovirus – An Example of Tropism** - Tropism = predilection for certain cell types or tissues. - Adenovirus fiber directs cellular tropism. - Swapping fibers between serotypes redirects tropism. ^[but does not explain the full picture] - Most serotypes seem to get to the GI tract, but why only a few cause disease is not known. - Tropism can be altered in immunocompromised individuals. **Diagnosis – All Viruses** **Samples to Detect Virus:** - Throat swabs. - Nasopharyngeal aspirates (NPA) or washes. **Tests to Detect Virus:** - PCR, often a combined test for multiple pathogens. - Immunochromatographic (ICT) tests (dip sticks). - ELISA. - Immunofluoresecence on cells from samples **Tests for Past Exposure:** Test serum for antibodies (ICT, ELISA). - Remember, it takes time, especially IgG, and is complicated by maternal antibodies in very young individuals.

Answer 29

**RSV – From the Family: Paramyxoviridae** - A big family with two branches: Paramyxovirinae and Pneumovirinae. - RSV belongs to the Pneumovirinae branch, along with Human Metapneumovirus. RSV shares similarities in types of surface proteins with orthomyxoviruses e.g. influenza **Respiratory Syncytial Virus (RSV)** - Enveloped capsid with helical symmetry. - Negative (-ve) sense RNA genome. - note two forms when cultured: spherical or filamentous (which could constitute infectious form) - Makes 10 mRNAs, one for each gene, and replication is entirely in the cytoplasm. - no splicing or polyproteins **How Much of a Problem Is RSV?** - Highly seasonal in temperate climates, with RSV 'season' coinciding with winter – early spring. - On first exposure, 25% to 40% have bronchiolitis or pneumonia, and 0.5% to 2% will require hospitalization. - Hospitalizations with RSV mostly involve infants less than 6 months old. **Who Gets Sick with RSV and When?** - Highly seasonal in temperate climates, with RSV 'season' coinciding with winter – early spring. - On first exposure, 25% to 40% have bronchiolitis or pneumonia, and 0.5% to 2% will require hospitalization Hospitalisations: - Most (~60%) are infants < 6 months old - Nearly all (>90%) are < 1 year old - Anything that compromises breathing, cardiac, or immune function predisposes to the risk of severe RSV (premature babies at risk) - These risk factors exist in adults as well. **RSV Pathogenesis** - Virus-induced - Immunocompromised individuals are at risk. - But direct virus damage is limited. - Disease is largely caused by **immunopathology.** ^[an over-reaction as opposed to histological changes] - The narrowing of bronchioles is due to inflammation and not direct virus damage. - Appropriate immune response is a tricky balance. **Transmission** - Transmitted by droplets, large particles, and fomites. - Incubation time is 4-6 days. - Infectious for 3-8 days after symptoms. - Not especially stable but can survive a few hours on nonporous surfaces. - Medical personnel transmit these viruses readily. - Also childcare. - Toys can be good vectors too. - Nosocomial infection is an enormous problem, especially as many infants at high risk of severe infection are already in the hospital. **Treatment and Prophylaxis** **Treatment** - Supportive care. - Use of antivirals (ribavirin) not well supported by evidence. **Prophylaxis** - No vaccine. - Early trial of formalin-inactivated vaccine a disaster. - Immunized kids had more severe infections. - Potentially the wrong 'type' of immunity generated. - Palivizumab (Synagis) given monthly to babies at high risk. ^[e.g.?] - Studies mixed as to the reduction of disease. - Costs approximately $1000 a shot and is not on the PBS.

Answer 30

**In hospitalised patients, commensal flora changes:** - E. coli and other Gram negatives - Pseudomonas aeruginosa - Staphylococcus aureus - All of the above may colonize the URT and then cause LRTI "Typical" Pneumonia **Pneumonia:** - Abrupt onset - High fever +/- rigors - Productive cough with usu. purulent sputum - Shortness of breath - Pain on breathing (pleuritic) - Lobar consolidation (or anat segments of lobe) on CXR **S. pneumoniae Capsule - Virulence Factor** enables evasion - Prevents entrapment in mucus, allowing access to epithelial surfaces - Protects against phagocytosis and complement-mediated lysis: bacteria persist and multiply - Anti-S. pneumoniae capsule antibodies (generated through acquired immune response) are protective, but typically not cross-protective - Vaccine contains purified capsular polysaccharide antigen from many different S. pneumoniae serotypes ^[hence why acquiring one does not necessarily confer immunity against another] **Haemophilus influenzae** - Gram-negative coccobacillus ^[may look like a bacillus or a short bacillus which is almost coccus] - Unencapsulated - less invasive and less virulent - Capsulated - a, b, c, d, e, f - H. influenzae B (Hib) most virulent **Haemophilus influenzae Non-Invasive Infection** i.e. not on mucosal surfaces - Sinusitis - Otitis media - Conjunctivitis - Pneumonia **Invasive Infection (Hib)** ^[very rare since vaccination introduced] - Epiglottis - Bacteremia - Meningitis - Septic arthritis **Neisseria meningitidis** - Gram-negative diplococcus - Unencapsulated - not often associated with infection - 10-25% of young people carry in pharynx - Capsulated - A, B, C, W, Y - Invasive disease - Vaccination: Previously only C but now also combined tetravalentA, C, W, Y and standalone B **Neisseria meningitidis Invasive Disease** - Risk factors for invasive disease - Age <5 years and 15-25 years ^[living in close quarters] - Asplenia/hyposplenia - Deficiency or **impairment of complement membrane attack complex (C5-C9) - Invasive disease: - Bacteremia (meningococcemia) - Meningitis **Moraxella catarrhalis** - Gram-negative diplococcus - Diseases - Sinusitis - Otitis media - Pneumonia - Infective exacerbations of chronic obstructive pulmonary disease

Answer 31

- "Atypical" bacteria - Not detectable by Gram stain or cultured by standard methods - **Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila, L. longbeachae - "Atypical" symptoms and signs - Constitutional symptoms (headache, fever, malaise, nausea) may predominate over respiratory symptoms (dry cough) - Less likely to have lobar changes on CXR, diffuse or non-specific infiltrates - Most cases are milder, but some, especially Legionella pneumophila, C. psittacii, can be severe and life-threatening

Answer 32

Killed or inactivated vaccines contain an inactive preparation of a pathogen. It is less effective than live vaccines i.e. less immunogenic. However, it is more effective if antigen is a protein, and if adjuvant used. Inactivated vaccines require booster doses to maintain efficacy. It predominantly generates humoral immunity based on production of neutralising antibodies, with rapid production on re-exposure. There is a limited cellular immune response due to absence of replicating organisms, and reduced production of secretory IgA. Examples of inactivated vaccines include polio (Salk), influenza, HepA, rabies, pertussis, cholera. Advantages - safety - easy to produce and store - less affected by pre-existing antibody (maternal antibody can interfere with the response to immunisation) #### Disadvantages - requires boosters - may not preserve the immunoprotective antigen - poor induction of T cell immunity (CD8+) - poor inducers of mucosal immunity - potential for immune response to tissue antigens derived *from cells to which vaccine is produced (allergy)**

Answer 33

**Mycoplasma species**= NO CAPSULE, RESSITANT TO CELL WALL antibiotics e.g. beta lactams Capsules Confer Resistance to Phagocytosis** - Capsules hide the bacterial targets (PAMPs) of the phagocytic receptors (PRRs). - The phagocytic response of the innate immune system is (temporarily) inhibited. - APCs cells unable to present antigen to T-cells (via MHCII molecules). - Bacteria continue to replicate. - BUT… Immune system has evolved to develop a T-cell/thymus independent (TI) response to deal with encapsulated bacteria that avoid stimulating T-cell responses.

Answer 34

PaO2 if PaCO2 is 3 and at 55 kPa, RQ 0.8 Ideal alveolar gas equation Concentration that would exist if V = Q. PAO2 = FiO2 x (PB - SVP H2O) – (PaCO2/RQ) = 0.21*713 – (55/0.8) = 82

Answer 35

The pleura is a serous membrane that envelopes each lung. The membrane is made up of a visceral layer that is adherent to the lung, and a parietal layer that is fixed to the inner thoracic wall, lower cervical vertebra, costovertebral area, mediastinum, and diaphragm. There is a potential space between the parietal and visceral layers known as the pleural cavity. The cavity is filled with serous fluid that allows the parietal and visceral layers to freely glide over each other during breathing; thus, reducing the impedance to the breathing mechanism. At their most basic level, each long is characterized by its apex and base; the apex projects towards the superior thoracic aperture, while the base is placed on the diaphragm. Alternatively, we can describe the lung as having four pleural surfaces (costal, cervical, medial and diaphragmatic) . The two pleura are separate and non-continuous, although they do "break" to form the hila.

Answer 36

Asbestos Asbestos exposure has been associated with a number of pathologic changes in the lungs and pleura, as listed below: 1. Interstitial fibrosis 2. Benign serous pleural effusion 3. Bronchogenic carcinoma 4. Malignant mesothelioma 5. **Fibrous plaques of the parietal pleura Several types of bodies: crocidolite, chrysotile, amosite, anthrophyllite Asbestosis part of umbrella: pneumoconiosis are a lung reaction to inhalation of mineral dust, organic dust, chemical fumes and vapors. Examples include: - carbon and coal workers pneumocnoisos - silica or silicosis - asbestos or asbestosis - insecticides **Factors affecting development of lung disease** – Duration and length of exposure – Amount of retained dust – Size (small1-5 microns- can reach and settle in small alveoli) – Shape, buoyancy of the particles – Particle solubility (insoluble particles can remain in the lungs for years) – Additional irritants (SMOKING!!!!) – Preexisting lung disease **Asbestos** * Pleural plaques: fibrosis in parietal and visceral pleura * Diffuse pulmonary fibrosis (Asbestosis) * Recurrent Pleural effusions * Lung carcinoma * Mesothelioma (lung and abdominal) - incidence high * Other cancers (trachea, larynx, gastrointestinal tract, others?) Identified by asbestos bodies. usually colourless, but if iron deposits, can see (ferrogenous bodies). No need to see in order to diagnose

Answer 37

Pneumonia can be bacterial or viral. If viral, treat with - Rest - Oxygenation - Fluids Bacterial: CAP or HCAP (HAP or VAP) If bacterial and community acquired, treat with IV doxycycline/oral macrolides (clarithromycin) prescribed empirically – if no comorbidities. Depends on pathogen and resistance. Physiotherapy may be required.

Answer 38

Lung relational anatomy: The lungs lie either side of the mediastinum, within the thoracic cavity. Each lung is surrounded by a pleural cavity, which is formed by the visceral and parietal pleura. Each lung occupies the respective hemithorax. the left and right lung differ slightly in their morphology. The left lung is slightly smaller in size due to the presence of the cardiac notch, where the apex of the heart sits, and has only two lobes, and one fissure. The hilum is bordered by *the free edge of the visceral pleura* and contains: - pulmonary artery - left main bronchus - closely followed by bronchial vessels - pulmonary veins - broncho-pulmonary lymph nodes ![[Pasted image 20230821093648.png]] ^[question: compare and contrast the hila, lungs] The right lung by contrast is larger, and contains three lobes and two fissures. The right lung hilum contains: - pulomary arteries - bronchial vessels - pulmonary veins - superior lobar bronchus - ingerior and middle lobar bronchus - all three are contained within the right main bronchus - bronchi-pulmonary lymph nodes Note that the 1st division of the primary bronchus occurs in the hilum. Thus pulmonary arteries and veins also follow this division. Bronchopulmonary segments ![[Pasted image 20230821093718.png]] Both left and right lung have the same number of segments, despite differing numbers of lobes. There are 10 segments for each lung, and they constitute distinct anatomical, functional and surgical units. As they stand alone, if a tumour grows within a single segment, it can be resected and the lung can continue to function. Within the left lung there is an even split of the segments between the superior and inferior lobes. ![[Pasted image 20230821093726.png]] Bronchial tree ![[Pasted image 20230821093740.png]] Note: there are three lobar bronchi as there are three lobes in the right lung. ![[Pasted image 20230821093748.png]] ![[Pasted image 20230821093757.png]] Note that the bronchial tree can be divided into conduction and respiratory portions. - the conduction portion is made up of the bronchi, bronchioles (terminal) - the conduction portion is responsible for filtering (?), warming and humidifying air - bronchi (segmental and subsegmental) have cartilage and smooth muscles, and continue for 10 generations - bronchioles have smooth muscles, and go for 11-16 generations - the respiratory portion is made up of respiratory bronchioles and alveoli, and these go for 17-23 generations Note: terminal bronchioles lined with smooth muscle, but it is more distinct and classed separately from bronchiolesz the left and right lung differ slightly in their morphology. The left lung is slightly smaller in size due to the presence of the cardiac notch, where the apex of the heart sits, and has only two lobes, and one fissure. The hilum is bordered by *the free edge of the visceral pleura* and contains: - pulmonary artery - left main bronchus - closely followed by bronchial vessels - pulmonary veins - broncho-pulmonary lymph nodes ^[question: compare and contrast the hila, lungs] The right lung by contrast is larger, and contains three lobes and two fissures. The right lung hilum contains: - pulmonary arteries - bronchial vessels - pulmonary veins - superior lobar bronchus - inferior and middle lobar bronchus - all three are contained within the right main bronchus - bronchi-pulmonary lymph nodes Note that the 1st division of the primary bronchus occurs in the hilum. Thus pulmonary arteries and veins also follow this division. Bronchopulmonary segments Both left and right lung have the same number of segments, despite differing numbers of lobes. There are 10 segments for each lung, and they constitute distinct anatomical, functional and surgical units. As they stand alone, if a tumour grows within a single segment, it can be resected and the lung can continue to function. Within the left lung there is an even split of the segments between the superior and inferior lobes. Bronchial tree Note: there are three lobar bronchi as there are three lobes in the right lung. Note that the bronchial tree can be divided into conduction and respiratory portions. - the conduction portion is made up of the bronchi, bronchioles (terminal) - the conduction portion is responsible for filtering (?), warming and humidifying air - bronchi (segmental and subsegmental) have cartilage and smooth muscles, and continue for 10 generations - bronchioles have smooth muscles, and go for 11-16 generations - the respiratory portion is made up of respiratory bronchioles and alveoli, and these go for 17-23 generations Note: terminal bronchioles lined with smooth muscle, but it is more distinct and classed separately from bronchioles

Answer 39

- **Perfusion vs Diffusion for Oxygen** - Normally perfusion limited (0.2-0.3s equilibration with capillary blood) - Gas exchange impaired if diffusion membrane affected, to the point where oxygen becomes **diffusion limited** instead of perfusion limited: - initially this will only be seen with decreased capillary transit times (e.g. exercise) - (can happen at rest with severe conditions) - **Clinical Implication**: Impaired diffusion membrane affects gas exchange, especially for oxygen

Answer 40

- **Respiratory Centre** - Located in the medulla - Drives ventilation rate and volume via afferents to respiratory muscles' motor nerves ^[causes contraction] - **Neuronal Groups** - **Dorsal Respiratory Group** - Primarily inspiratory neurons - sending out signals - **Ventral Respiratory Group** - Caudal: Mix of inspiratory and expiratory neurons - Rostral: Airway dilator functions - **Pre-Botzinger Complex**: Likely central pattern generator site ^[pattern of breathing, start and stop] - **Botzinger Complex** - Expiratory neurons - **Pontine Respiratory Group** - Fine control of respiration, influences medullary respiratory center - **Cortex** - **Voluntary breathing interruption**, e.g., singing, talking ^[aka influence pattern of breathing] Respiratory Cycle and Neuronal Firing - No single pacemaker is responsible for generating respiratory activity ^[c.v. cardiac] - Likely a complex interaction of different groups of neurons (6 - half and half): - Early inspiratory, inspiratory augmenting, late inspiratory - Expiratory decrementing, expiratory augmenting, late expiratory - Firing of neurons results in three respiratory phases: - Inspiratory ^[turn on signals, get muscles involved] - Expiratory Phase 1 (passive) ^[i.e. recoil of lungs] - Expiratory Phase 2 (active) ^[turning on signals, get muscles involved] - **Influences on Respiratory Phases** - Various inputs, with CO2 being the most important - CO2 influences central chemoreceptors

Answer 41

- **Surface Tension (ST)** - Force across liquid surface (across imaginary line 1 cm long) - Develops at air-water interfaces - Greater forces between water molecules than water and gas molecules: liquid surface area becomes as small as possible - Result: alveolus has tendency to collapse on itself ^[like a bubble] - **Law of Laplace** - Pressure = 2 x ST/radius - radius inversely proportional to pressure - alveoli would collapse if it weren't for surfactant, reducing surface tension as radius decreases - **Surfactant** - Lipid (90%) fluid from type II alveolar cells - Majority phospholipid: mainly dipalmitoyl phosphatidyl choline (DPPC): hydrophilic end faces alveolar fluid lining alveoli, hydrophobic end faces gas filled alveolus - Acts as detergent, reducing water molecule attraction, thus **reducing surface tension and preventing collapse - Decreases ST as lung volume decreases: as lung vol decreases DPPC squeezed together, decreases water-water interaction and thus decreases surface tension Note: relevant in compliance

Answer 42

- **Flow in Large Airways** - Predominantly turbulent flow - frictional forces influences flow (come from lining of airway wall-- increases with scarring) - note: driving pressures really high, so **overall** frictional forces do not influence flow - **Gas Density** - Different gas densities (e.g., Heliox - gas mixture) to improve flow and oxygen delivery to alveoli - more laminar flow due to He low density-- get into alveoli more easily - **Flow in Small Airways** - Predominantly laminar flow, **resistance** most important factor - Viscosity and length are essentially fixed - radius of airway is the most important factor determining resistance - **Factors Affecting Airway Radius** - Internal: Fluid, smooth muscle hypertrophy/contraction - External: Lung volume, external compression of airway ^[e.g. haemothorax] - **Compliance** - Extent of lung expansion per unit increase in transpulmonary pressure - Factors influencing decreased compliance - Physiological: Age, posture (lying flat is worse), decreased lung volumes - Pathological: Fibrosis, alveolar overdistension (COPD over PEEP), chest wall deformities, obesity - **Time Constants (τ)** - if initial rate of change continued, at what time would process have been completed - alveolar filling and emptying is an exponential process, measured by t - one t = 63% - 3t = 95% - τ = resistance x compliance - normally in 0.2s, alveolar filling emptying 95% complete at 0.6s - **Fast and Slow Alveoli** (imp) - resistance and compliance not uniform across lung, therefore t varies - Fast: Low resistance, compliance, or both (e.g., pulmonary fibrosis): empty and fill quickly - Slow: High resistance, compliance, or both (e.g., COPD): empty and fill slowly

Answer 43

- **Passive Factors** - **Pulmonary Blood Flow**: Adapts to **large** changes in cardiac output with *small* increases in pulmonary arterial pressure; PVR decreases as flow increases - **Distension**: Thin-walled vessels distend easily with increased flow - **Recruitment**: Increased flow opens previously closed pulmonary vessels - **Lung Volume**: - Optimal PVR at FRC - low lung vols = compression of extra-alveolar vessels - high lung vols = compression of alveolar vessels - **Gravity**: Lung and pulmonary vessels act as starling resistor: flow through tube is influenced by driving pressure (coming through) and pressure around tube - divides lung into 3 zones (West’s zones) - 1:alveolar pressure>arterial>venous - - no flow - effectively dead space - not really seen in absence of pathology ^[or can make one] - 2:arterial>alveolar>venous - flow dependent on alveolar volume - 3:arterial>venous>alveolar - flow occurs independently of alveolar volume, an effective shunt - **Active Factors** - **Hypoxic Pulmonary Vasoconstriction**: - most important factor - key difference between systemic and pulmonary vasculature - protective: to optimise VQ matching across lung - away from 'hypoxic' areas e.g. pus filled infected areas - **Primarily mediated by alveolar PO2, arterial plays small role ^[like metabolic regulation of systemic vessels] - Mechanism: ^[debated] - Hypoxia inhibits K+ channels, opens VGCa channels (L-type), leads to Ca influx, smooth muscle contraction - Biphasic response: Rapid decrease then slower increase; PBF halves in first 5 min then plateaus, second slower increase around 40 min - Modulated by various factors: Inhibition (alkalosis, nitric oxide - dilator, prostacyclins, volatile anaesthetics) and enhancement (acidosis, hypercapnoea, hypothermia, endothelin): increases vascular tone - **Neural Control**: - Sympathetic (mixed effects): alpha 1 and vasoconstriction (NA response), beta 2 and vasodilation (Ad response) - para-sympathetic (vasodilation, via M3 receptor) - **Humoral Control**: Vasoconstriction (noradrenaline, adrenaline, thromboxane, serotonin, histamine) and vasodilation (prostacyclins)

Answer 44

Hemoglobin as a Buffer - Hemoglobin (Hb) can bind and release H+, acting as a buffer. - CO2 produced by tissues is quickly converted into HCO3- and H+. - Hb.O2 and Hb.H participate in reactions in tissues and lungs. - H binds Hb and displaces oxygen in tissues; H increases as cells are metabolically active -- conditions optimised for release - the reverse occurs in lungs (in order to deliver oxygen from lungs in tissues) - The Bohr effect describes how pH affects the Hb dissociation curve. - This process is streamlined: Hb affinity for oxygen decreases, so can bind H as pH decreases

Answer 45

Note the reaction is bi-directional/reversible - depends on context - acidity decreases affinity for oxygen (right shift) - alkalinity increases it (left shift) Recall from [[Physiology Lecture 10]] that temperature and CO2 also affect affinity of Hb for oxygen.

Answer 46

Respiratory Disorders - **Obstructive Sleep Apnea**: - e.g. to age, enlarged tonsils, obesity - loss of muscle control of soft palate, tongue, pharyngeal dilator muscles - falls into oropharynx to occlude breathing - chemoreceptors shift at point in order to tolerate high pCO2 resulting in a loss of both voluntary and involuntary control, apnoea n.b. respiratory paradox: chest is sucked in, abdomen out - **Central Sleep Apnea**: completely different, related to diaphragm ^[innervate to treat] - **Sudden Infant Death Syndrome (SIDS)**: Disorder of homeostasis where infants with brainstem abnormalities struggle with metabolic challenges during sleep. - cant adjust to or defend against asphyxia or other challenges Other Conditions - **Ondine's Curse**: cannot breathe involuntarily but **CAN** voluntarily. Must be ventilated - **Cheyne-Stokes Respiration**: cycles of erratic breathing and apnoea. Opioids can create this - **Kussmaul Breathing**: i.e. in DKA, ketones results in acidosis. Patient compensates with hyperventilation. Rapid AND deep breathing. Minute ventilation is very high, and bicarbs low ^[mixed disorder]

Answer 47

Exercise - CO2 does not change significantly, except at peak activity with a bit of hyperventilation, despite augmented metabolic conditions, and changes to respiratory rate - O2 is also maintained - Thought to be a mix: - cortical control - SNS activation - muscle stretch and mechanoreceptors All of these increase minute ventilation Note: what does change is oxygen uptake, and venous oxygen content as a result. Note 2: in heart disease, no VQ match- results in deadspace. Altitude - **Everest**: 8848m - Atmospheric pressure: 33% of sea level (pO2 54 vs. 160 mmHg) - **Alveolar pCO2**: 7 vs. 35 - **Alveolar pO2**: 35 vs. 100 - low even with compensation - **Acclimatization**: - Hb 15 g/dl - EPO increased - Hyperventilation and decreased CO2 - Acute alkalosis (pH 7.7) - 2,3 DPG increased - Peripheral chemoreceptors active - Central chemoreceptors CO2 sensitivity increased - **O2-Hb Dissociation Curve** shifts - But, takes days to weeks Side note on COPD: - severe, always hypoxic - set point changed: supplementing with 100% o2 reduces drive and results in paradoxic hypoxia: so saturate with normal O2 (for patient) - chemoreceptors are desensitised i.e. pick up at higher pCO2 - peripheral receptors are key drivers

Answer 48

Nasal cavity - Houses receptors for olfaction - adjust temperature and humidity of inspired air - trap and remove particulate matte from airway by filtering air through hair in vestibule; trapping foreign material in abundant mucus (i.e. first line of defence, physical barriers, see [[Immunology Lecture 2]]) ^Gray's note the choanae or entry into the pharynx note also the minor and major alar cartilages as part of the nasal lateral wall note too the uncinate processes, which separate components of spaced between conchae and direct air flow Skeletal framework of nasal cavity The skeletal framework of the nasal cavity is comprised of the following bones: - nasal - maxilla - ethmoid (which extends into cranial cavity, crista galli, cribriform plate where olfactory bulb sits. note dura mater attaches here) - vomer - lacrimal - inferior concha - palatine - sphenoid (medial pterygoid) The septum is composed of septal cartilage, vomer, and perpendicular plate of the ethmoid bone. The nasal cavity can be categorised into three regions: - the nasal vestibules - small space, just internal to naris (Anterior opening). It is lined by skin and contains hair follicles ^[Gray's for students] - respiratory regions - largest part. Well vascularises and supplied by nerves. Lined by respiratory epithelium (mainly ciliated and mucous cells) [see [[Histology Lecture 2]]] - olfactory regions - small, at apex. Lined by olfactory epithelium, contains olfactory receptors.

Answer 49

There are four groups of paranasal sinuses: - frontal (bilateral) and mostly superiorly - sphenoidal (midline) - more posteriorly - ethmoidal ('air cells') - superior aspect - maxillary - laterally ![[Pasted image 20230816214744.png]] Not included in this table is the semilunar hiatus Notable features include: - ethmoidal bulla under middle conchiae - uncinate process which controls air flow Note: drainage of sinuses usually follows gravity i.e. draining downwards, with the exception of the sphenoidal sinus, which drains into an adjacent structure (the spheno-ethmoidal recess, above the superior nasal concha) Note 2: naso-lacrimal duct drainage explains why sniffly nose when crying Functions of paranasal sinuses - reduction of skull weight (Debated) - resonance of voice - protection - humidification -- due to mucosal lining

Answer 50

**Complement** - Soluble proteins produced mainly by the liver - "Complements" antibodies, enhancing opsonization and bacterial killing - Sequential cascade activation upon pathogen presence, culminating in pathogen killing - Cascade amplifies response **Complement Proteins** - Names can be confusing - Some named C followed by discovery number (e.g., C4, C5) - Others without C are part of alternative or lectin pathways **Complement Activation** - Most proteins activated by proteolysis - Many proteins are proteases - Activated proteins cleave and activate next proteins in cascade ^[note: does larger fraction typically activate?] **Classical Complement Pathway** - most recent evolutionarily, despite name - C1, C4, C2, C3, C5, C6, and C7 (though not in that order) - "Membrane attack complex" formed from C6, C7, C8, and C9: forms pore in membrane, disrupts ion balance, and results in pathogen cell death - In total, 3 pathways activate C3: 3 pathways of complement activation Notes on the pathways - all pathways culminate in cleavage of C3, resulting in formation of MAC, binding to C3b receptors to engulf and destroy pathogen, and recruitment of inflammatory mediators to site of infection - all pathways occur on the cellular membrane ^[which?] **Functions of Complement** - Membrane attack complex - Active intermediaries (C3a, C4a, C5a) - anaphylatoxins, inflammatory cell recruitment (chemoattract properties) ^[?] - Opsonization - Complement deposition aids phagocytosis - Complement receptors augment B cell activation (especially if no T help) - Complement receptors assist B cells in transporting non-cognate antigens to lymph nodes, where the reactive B or T cell can interact with it

Answer 51

**Regulation of Complement** - Regulatory proteins: C1 inhibitor, Factor H, Factor I, CD59 - c1 inhibitor targets begining of cascade, and keeps C1 contolled - H and I targets middle of cascade, targets products of cascade, binds and prevent activation -- controlling C3 deposits - CD59 at end of cascade, inhibits final assembly **Evaluating Complement in Diagnosis** - Serum testing for complement component levels - C3 and C4 levels tested in practice - intact not activated byproducts - Patterns of C3 and C4 levels indicate pathway activation - C4 down: mild classical pathway activation - C3 and C4 down: classical activation, formation of antibody complex - C3 down: alternate pathway activation ^[wb lectin?] **Measuring Complement in the Diagnostic Lab** - Detecting complement in tissue biopsies - C3 frequently detected; C1q found in diseases strongly activating classical pathway - Laboratory looks at levels of “intact” C3 and C4 – therefore when the numbers are low this means that the complement has been activated

Answer 52

Active immunisation is the administration of a vaccine that elicits a protective immune response. - killed or inactivated preparation of a pathogen - **live-attenuated pathogen** - conjugate vaccine - subunit vaccine - DNA vaccines - peptide vaccines - often requires use of an appropriate adjuvant Live attenuated vaccines are the most effective of all vaccines. These contains organisms cultured to reduced pathogenicity. They retain some of the antigens of the virulent form. Examples include: - Bacille Calmette-Guerin (BCG) ^[TB], Salmonella typhi - Measles, mumps, rubella vaccines - Varicella zoster - Yellow fever Advantages Live, attenuated vaccines confer long lasting immunity: cell mediated, humoral and memory. Disadvantages However, there is a risk of restoration of virulence, or reversion, particularly in immunosuppressed or immunodeficient individuals ^[also consideration in vaccinating immunodeficient communities with BCG - IL-12 issue]. Unclear if there is an optimal number of vaccinations as eradication of natural disease occurs.

Answer 53

Toxoid vaccines Some bacterial pathogens such as diphtheria and tetanus produce exotoxins. Toxoid production involves the purification of the exotoxin, followed by inactivation with formaldehyde. Vaccination with toxoid induces anti-toxoid antibodies capable of binding to, and neutralising the effects of, the exotoxin. Therefore, the epitope structure of the toxoid must be maintained in order to ensure efficacy. Conjugate vaccines Encapsulated organisms are an important cause of morbidity and mortality in those under 2 years of age. This is due to impaired response to polysaccharide antigens in this group. A solution to this is conjugate vaccines. These contain polysaccharide antigens conjugated to a carrier protein to which the immune system has already been exposed such as diphtheria, tetanus toxoids or OMPC. The resultant immune response is T cell dependent and rapid antibody production. It also significantly reduces morbidity associated with Hib and S. pneumoniae. ![[Pasted image 20230920181540.png]] - T independent antigen - cross linking with B cell receptors - leads to differentiation into plasma cells - no affinity maturation or memory B cells i.e. can't mount effective response on re-exposure ![[Pasted image 20230920181558.png]] - Conjugate vaccine = processing of carrier peptide specific T cells along with polysaccharide specific B cells - delayed but specific - class switching, memory, and production of high affinity antibody - faster and better response on re-exposure Subunit vaccines Subunit vaccines rely on recombinant DNA technology. Examples include HepBsAg. The immunogenicity is compounded due to spontaneous aggregation into virus like particles. However, failure has been demonstrated in a small group (MHC linked - HLA A1, B8, DR3) ^[receive immunoglobulin therapy]. Another example is the acellular pertussis vaccine, which is a purified subunit vaccine containing defined protein constituents prepared from B. pertussis. Subunit vaccines: targeting antigen presenting pathways An example is the HPV vaccine. Virus-like particles or VLPs self-assemble when L1 protein of HPV is produced in isolation. Vaccines comprise a mixture of types 16, 18, 6, 11; or types 16 and 18 alone. This vaccine is highly immunogenic, and contain an aluminium salt adjuvant that precipitates VLPs, resulting in a slow release of antigen and monocyte activation ^[macrophages to site of infection that process antigen]. The second HPV vaccine contains monophosphoryl lipid A, which activates the innate immune response via TLR-4. Both vaccines result in the production of virus-neutralising antibodies.

Answer 54

- Age, season, social factors, and mode of transmission influence commensal flora prevalence. - age: Prevalence of S. pneumoniae, H. influenzae, and M. catarrhalis decreases with age; N. meningitidis peaks in teenagers-adolescents - season: prevalence of many pathogens increases in winter - social factors: Prevalence of S. pneumoniae and H. influenzae is highest in low socioeconomic classes; Children with siblings have increased carriage of S. pneumoniae, H. influenzae, and M. catarrhalis - mode of transmission: carriage of pathogens requires close proximity; droplets are created by coughing, sneezing; and transmitted by person-person contact or via fomites

Answer 55

- Physical defenses include nasal hairs, irregular nasal chambers e.g. sinuses and turbinates - channel air, increase surface area to trap, mucus, ciliated epithelium (nasal cavity, sinuses, bronchi and trachea), cough reflex and epiglottic reflex, and mucociliary escalator. - Chemical defenses include mucus secretions (phagocytes and lysozyme ^[antibacterial]), alveolar fluid(surfactant) - Immunological defenses include alveolar macrophages and secreted antibodies (IgA). **Mucociliary Escalator** - Aids in expelling pathogens and maintaining commensal balance. - Prevents overgrowth of upper respiratory tract commensals. - Helps keep middle ear, mastoids, and lungs sterile. - mucus: - A viscoelastic gel containing water, carbohydrates, proteins, and lipids - salty and sticky - Secreted by goblet cells of the respiratory surface epithelium and the submucosal glands - Traps inhaled particles and microorganisms - motile cilia: - Hair-like projections that cycle synchronously, continually - Move trapped particles and microorganisms in mucus toward pharynx where they’re swallowed ![[Pasted image 20230904185353.png]] Note: the mucociliary escalator can be inhibited - Viruses can disrupt the mucociliary escalator through: – Direct or indirect ciliary impairment, e.g. direct damage to the ciliary system or by inducing excess mucus formation – Secretion of enzymes that breakdown mucus - Allows microorganisms to migrate to sterile regions - secondary bacterial infection - Physical injury, smoking, alcohol and **diabetes** ^[hgih blood sugar impacts neutrophil activity] can also disrupt the mucociliary escalator

Answer 56

- Problems with drainage - Blocked sinuses or auditory tube due to viral infection or allergies - Problems with normal physical motion - Poor cough, aspiration, intubation, paralysis - Problems with mucociliary escalator: Poor cough, aspiration, intubation, paralysis - specific immunocompromise or lack of immunity

Answer 57

**Streptococcus species** are commensals and common causes of respiratory tract infections. (lobar pneumo if microaspiration into LRT) **Streptococci: General Characteristics** - Gram-positive cocci in chains - Streptococcus pneumoniae classically in pairs (diplococci) - **Facultative anaerobes **Haemolysis and Lancefield Classifications** - β-hemolytic Streptococci - S. pyogenes (Group A Streptococcus/GAS) - S. agalactiae (Group B Streptococcus/GBS) - S. dysgalactiae (Group C and G Streptococcus) - β-, α- or γ-hemolytic - S. milleri group (Group A, C, F, G or untypable) - α- and/or γ-hemolytic - S. pneumoniae (α-hemolytic; untypeable) - S. viridans group (α- or γ-hemolytic; untypeable) **S. pneumoniae as an Endogenous Pathogen** - A commensal of the URT of healthy people - More common in children (40 %) than adults (10 %) - Children initially colonized ~ 6 months of age - Highest concentration of organisms usually in nasopharynx - Children are **transiently colonized by different serotypes (sometimes simultaneously) - 91 known capsular serotypes - Endogenous pathogen of the URT, can cause otitis media, mastoiditis, sinusitis - Can disseminate into the LRT or other parts of the body, causing pneumonia, bacteremia, meningitis - Note: Risk of developing these infections appears highest immediately after colonization *because patients have not yet produced specific antibodies to the organism

Answer 58

**7. Role of Epithelial Cells** - Upregulation of Pattern Recognition Receptors (PRRs) on basal surface, allowing them to recognize bacteria that have invaded the epithelial barrier: - Basolateral surface/vacuoles: Toll-like receptors (TLRs). - Cytoplasm: nucleotide-binding oligomerization proteins (NODs). - This recognition triggers an influx of inflammatory cells/lymphocytes into mucosa from the bloodstream, assisting in induction of a specific immune response to antigens of infectious agent. **8. Phagocytic Cells** - Macrophages*: Phagocytic cells that live in tissues, abundant in: - Lungs (interstitium and alveoli) - Connective tissue - Submucosal layer of the gastrointestinal tract - Certain blood vessels in the liver (Kuppfler cells) - Spleen - Neutrophils/PMNs: Short-lived phagocytic cells in the blood (not typically found in healthy tissue). - Dendritic cells*: Found in most tissues of the body, abundant in those that are interfaces between the external and internal environments (e.g., skin, lungs, and the lining of the GIT). *Form a critical link between innate and adaptive immunity by activating components of the adaptive immune system through the presentation of antigen, i.e., referred to as antigen-presenting cells (APCs). **13. Role of Phagocytes** - Recognize/bind pathogen: Step 1. - Ingest/internalize pathogen in the phagosome: Step 2. - Fuse phagosome with lysosome, which contains antimicrobial chemicals that destroy pathogens without the aid of the adaptive immune response: Step 3. - Exocytosis of cellular debris: Step 4. **14. Binding of Phagocyte to Pathogen** - Directly: - Phagocyte PRRs (e.g., TLRs) bind to pathogen-associated molecular patterns (PAMPs)*. - e.g., Gram-positive bacteria: peptidoglycan, teichoic/lipoteichoic acids, flagella. - e.g., Gram-negative bacteria: lipopolysaccharide (LPS), flagella. *Relatively invariant molecular surface structures (not found in eukaryotes) that are shared by many related pathogens - can be obscured by bacterial capsules. **15. Binding of Phagocyte to Pathogen** - Indirectly: - Antibody mediated - Antibody-coated pathogen bound to Fc receptors on phagocyte surface - Complement* mediated - Antibody-and-complement-coated pathogen bound to Fc receptors and complement receptors (e.g., CR1) on phagocyte surface. - *Marks foreign particles for destruction **16. Bacterial Mechanisms to Evade Phagocytosis** - prevent encounters with phagocyte: C5a peptidase and cytolytic toxins - avoid recognition and attachment: capsules, M protein, Fc receptors - survive within phagocyte: escape from phagosome, prevent phagosome-lysosome fusion, survive within phagosome

Answer 59

**10. Role of T-Cells** - Major population in spleen and lymph nodes. - Typically only recognize peptide fragments presented by major histocompatibility complex II (MHCII) molecules on the surface of APCs. - When stimulated by APCs, T-cells proliferate into: - CD4 TH1 cells produce macrophage-activating cytokines. - CD4 TH2 cells produce cytokines that stimulate B-cells to produce antibody. - After a T-cell response, T memory cells persist, remembering particular antigens, thereby responding faster and more potently to re-exposure. **11. Role of B-Cells** - Present in bone marrow, other lymphoid tissues (e.g., spleen, lymph nodes, tonsils, and other mucosal surfaces), and circulate in blood and lymphatic system. - Bind intact antigens via membrane-bound antibodies, phagocytose them (i.e., are also APCs), digest them into fragments, and display them at their cell surface via MCHII molecules. - CD4 TH2 cells bind B-cells and produce cytokines that stimulate B-cells to differentiate into: - Plasma cells, which secrete antibodies. - Memory B-cells, which persist, remembering particular antigens, thereby responding faster and more potently to re-exposure.

Answer 60

- prevent encounters with phagocyte: C5a peptidase and cytolytic toxins - avoid recognition and attachment: capsules, M protein, Fc receptors - survive within phagocyte: escape from phagosome, prevent phagosome-lysosome fusion, survive within phagosome **17. Capsules Confer Resistance to Phagocytosis** - Capsules hide the bacterial targets (PAMPs) of the phagocytic receptors (PRRs). - The phagocytic response of the innate immune system is (temporarily) inhibited. - APCs cells unable to present antigen to T-cells (via MHCII molecules). - Bacteria continue to replicate. - BUT… Immune system has evolved to develop a T-cell/thymus independent (TI) response to deal with encapsulated bacteria that avoid stimulating T-cell responses.

Answer 61

**18. T-cell/Thymus Dependent (TD) Response** - Unencapsulated bacteria are susceptible to phagocytosis (provided they don't use other evasion mechanisms). - Proteinaceous bacterial antigens (TD antigens) can be presented to T-cells via MHCII molecules on APCs. - Proteinacious bacterial antigens: - Referred to as TD antigens because they require recognition by T-cells to elicit an immune response. - Induce a long-lasting immune response due to formation of memory B-cells and T-cells. - Production of anti-TD antigen antibodies is delayed, but antibodies are of high affinity and of multiple isotypes (IgA, IgM, IgG1, IgG2a, IgG2b, IgG3) **19. T-cell/Thymus Independent (TI) Response** - Encapsulated bacteria are able to (temporarily) evade phagocytosis. - Proteinaceous bacterial antigens (TD antigens) can't be presented to T-cells via MHCII molecules on APCs. - BUT, bacterial capsules: - Referred to as TI antigen because they don't require recognition by T-cells to elicit an immune response. - TI antigens do not give rise to immunological memory. - TI antigens divided into TI type 1 (TI-1) and TI type 2 (TI-2) antigens based on their interaction with B-cells. - Humans/animals with T-cell deficiencies are able to make antibodies against bacterial antigens through a TI response. **20. TI-1 Antigens: Interactions with B-cells** - e.g. LPS, bacterial DNA in high concentrations: - Directly stimulate (i.e. inducing proliferation and differentiation of) both immature and mature B cells in the absence of T-cell help. - Capable of directly stimulating B cells regardless of their antigen specificity (polyclonal activation*). - Rapid antibody production in infants and adults (primarily IgM because TI-1 antigens do not induce isotype switching). - *Polyclonal B-cell activation results in a non-specific antibody response because specific TI-1 antigen binding to surface Ig not necessary (B-cell-activating moiety of TI-1 antigen sufficient to induce proliferation and antibody secretion) **21. TI-1 Antigens: Interactions with B-cells** - e.g. LPS, bacterial DNA in low concentrations: - Directly stimulate both immature and mature B cells in the absence of T-cell help. - Rapid antibody production in infants and adults. - Only B cells specific for the TI-1 antigen bind enough of it to focus its B-cell activating properties onto the B-cell*. - *Only those B cells whose B-cell receptors also specifically bind the TI-1 molecules become activated. Gives a specific antibody response to epitopes on the TI-1 antigen. **22. TI-2 Antigens: Interactions with B-cells** - e.g. bacterial capsules, viral envelopes: - High molecular mass repetitive polysaccharide structures. - Activate only mature B-cells (immature B-cells are inactivated by repetitive epitopes). - Since most of the B-cells in infants are immature, they do not make antibodies against TI-2 antigens efficiently. - Contain no intrinsic B-cell-stimulating activity. - Simultaneously cross-link B-cell receptors of mature B-cells specific for the TI-2 antigen, resulting in production of antigen-specific antibodies. - Rapid antibody production in individuals over 5 years of age (primarily IgM, but also some IgG- isotype switching induced by co-stimulatory signals from TH cells). **23. Only Certain Types of Mature B cells Can Respond to TI-2 Antigens** - Spleen marginal zone (MZ) B cells: - Unique set of nonrecirculating B cells in the spleen. - Rare at birth and take years to mature in children, also underlying the lack of antibody response in infants to TI-2 antigens. - B-1 cells/CD5 B cells: - Autonomously replicating subpopulation of B cells. - Reside mainly in the pleural and peritoneal cavities, but also found in the blood and spleen.

Answer 62

Under hypoxic conditions, the human body undergoes a number of changes to adapt. Immediately, the decrease in arterial oxygen saturation is detected by chemoreceptors located in the aortic arch and carotid body, which triggers the **hypoxic ventilatory response**. An increase in ventilation of up to 65% is possible (i.e. 1.65x the normal), but is limited by changes to the blood pH balance. With increased ventilation comes increased elimination of CO2 and therefore an increase in blood pH. The respiratory centre of the brainstem therefore limits any further increase in ventilation to avoid respiratory alkalosis. Over time, renal compensation and mediation of chemoreceptor sensitivity can allow up to a 5x increase in ventilation**.** Over the first few days at high altitude, the body also produces **hypoxia-inducible factors**, which are transcription factors that upregulate the production of several genes: - Vascular endothelial growth factor → increased vascularity of peripheral tissue - Erythropoietin → increased production of red blood cells (polycythaemia) - Haematocrit may increase from 40% up to 60% - Haemoglobin may increase up to 25% - Mitochondrial genes → increased ability of tissues to use oxygen - Glycolytic enzymes → anaerobic metabolism → production of 2,3-bisphosphoglycerate - Genes that increase the availability of nitric oxide → vasodilation.

Answer 63

- 2,3-diphosphoglycerate (2,3-DPG) is produced from 1,3-diphosphoglycerate, an intermediate product of glycolysis. - The shape of 2,3-DPG allows it to bind to and stabilise deoxygenated haemoglobin. Therefore, this decreases the affinity of haemoglobin for oxygen, promoting oxygen delivery to peripheral tissue. - This decrease in haemoglobin affinity for oxygen is reflected as a right shift of the oxygen-haemoglobin d

Answer 64

If the body travels to high altitude suddenly without acclimatising, it is prone to developing **acute mountain sickness (AMS)**, or more severely **high altitude cerebral oedema and pulmonary oedema (HACE and HAPE respectively).** AMS ### Acute Mountain Sickness (AMS) Acute mountain sickness is observed in: - 20% of people who rapidly ascend to 2500 metres above sea level. - 40% of people who rapidly ascend to 3000 metres above sea level. It often manifests within the first ten hours of ascent and subsides within two days, and the presentation is highly variable. Common symptoms include: - headache - fatigue - lightheadedness - anorexia - nausea and vomiting - disturbed sleep with frequent awakening - mild shortness of breath on exertion - tachycardia. It is important to note that in AMS, there is a lack of neurological symp HACE ### High Altitude Cerebral Oedema (HACE) High altitude cerebral oedema is defined by the onset of neurological symptoms. These may include: - ataxic gait - severe lassitude - progressive decline of mental function and consciousness: - irritability - confusion - impaired mentation - drowsiness - stupor - coma. HACE can occur between 12 hours and 3 days after the development of acute mountain sickness. HAPE As part of the response to hypoxia, parts of the lung will vasoconstrict to redirect blood flow to better ventilated parts of the lungs, normally facilitating ventilation-perfusion matching. However, prolonged vasoconstriction can lead to breakdown of the blood-gas barrier, leading to pulmonary oedema. HAPE is less common than HACE, and presents with a non-productive cough initially. Other symptoms may include: - dry cough - decreased exercise performance - dyspnoea at rest - orthopnoea - cyanosis - tachypnoea - tachycardia - low grade fever - crackles on auscultation.

Answer 65

Exercise at high altitude Exercise at high altitude is different in many important respects from exercise at sea level. Ventilation Because of the decrease in air density and the lower amount of oxygen, greater ventilation is required to achieve the same oxygen uptake at high altitude. As a result, the ventilatory response to exercise is augmented at altitude compared to sea level. For example, at 6300 m, the ventilation for a given metabolic rate is almost four times as great as at sea level At extreme altitude, the oxygen cost of breathing during exercise may be as high as 40% of the overall metabolic rate and may result in allocation of cardiac output to respiratory muscles that could otherwise be dedicated to muscles of locomotion. Extreme dyspnea with exercise may affect the intensity and duration of exercise; with rest, dyspnea typically resolves rapidly. Cardiovascular Response For any given _submaximal_ work rate, cardiac output and heart rate are higher during exercise at altitude compared to sea level. With acclimatization, cardiac output at submaximal workloads returns to sea-level values while the heart rate remains elevated. However, _maximal_ exercise capacity and peak heart rate and cardiac output at altitude are reduced relative to sea-level values. With acclimatization, maximal exercise capacity is not restored to sea-level values over time and maximum cardiac output, heart rate, and stroke volume all remain decreased.

Answer 66

Hypoxia and exercise Even exercise at sea level (where the partial pressure of inspired O2 remains stable) can induce hypoxic changes in the body. This is primarily due to limitations in the amount of oxygen consumed by the tissues as exercise intensity gets higher. The highest amount of oxygen that can be consumed by tissues is termed maximal oxygen consumption, or VO_2max_ and can be determined by measuring expired O2 and CO2 response during an exercise test which increases in intensity over time. There are various physiological changes that occur when exercising at increasing levels of intensity. These will be explored further in the following pages and later in the laboratory. Note: hypoxia occurs even at stable altitudes because as exercise intensity increases, tissues in the body are not able to uptake and utilise inhaled O2 efficiently.

Answer 67

Phases of pulmonary ventilation during exercise On commencement, and while physical activity continues, there are unique phases of pulmonary ventilation that occur as depicted in the image above. They include: - **Phase I**: Neural stimuli from the brain (i.e., 'central command'), combined with feedback from active limbs, stimulate medulla to initially increase ventilation by about 20L/min. - **Phase II**: There is an exponential increase in minute ventilation in order to meet metabolic demands, primarily driven by central command. Chemoreceptors likely play a role in phase II as well, but not substantially because metabolic demand is being met, therefore there is a limited role of chemoreceptor activation. - **Phase III**: Chemoreceptors play an increasingly important role to assist with 'fine-tuning' the ventilatory response to meet metabolic demands. If exercise intensity is low enough that metabolic demands are met, ventilatory responses plateau and remain stable. If exercise intensity increases, the ventilatory response will also increase.

Answer 68

Compliance - **Definition**: Ratio of volume change to corresponding pressure change (C = ∆V/∆P) - slope of PV relationship - Extent to which lungs expand for each unit increase in transpulmonary pressure (if enough time allowed to reach equilibrium) - Two determinants of compliance in respiratory system: - **Lung Compliance** - Determined by lung's elastic recoil (connective tissue, surface tension) - Normal value: 200ml/cmH2O - Influenced by factors: Surfactant (most important), age (shape and size), posture, size, lung volume, fibrosis (Stiff, more difficult to expand) - **Chest Wall Compliance** - Normal value: 200ml/cmH2O - Impaired by factors affecting chest wall expansion (e.g., scoliosis, obesity ^[more tissue on chest wall,m ore pressure]) - **Total Lung Compliance**: Combination of lung and chest wall compliance (around 100ml/cmH2O)

Answer 69

**COPD Treatment Aims** - Relieve symptoms - Prevent exacerbations - Maximize exercise capacity - Limit further damage - Minimize treatment adverse effects **Smoking Cessation and Vaccines** - Smoking cessation significantly improves COPD outcomes. - Vaccines can also provide benefits to COPD patients. **Pulmonary Rehabilitation** - Pulmonary rehab improves quality of life and exercise tolerance. - It reduces hospital admissions and mortality. * Minimum length of an effective rehabilitation program is 6 weeks * The longer the program continues, the more effective the results * Offer to all patients following hospitalised AECOPD and to those with mMRC ≥ 2 * Effects wear off over time **Non medical management COPD** Management – non medical – Allergen avoidance – Food avoidance/supplementation – Probiotics – Air ionisers – Mist – Salt caves – Acupuncture – Homeopathy **Long-Term Oxygen - Studies on these treatments' effects and potential side effects.? **Long-Term Macrolides** 1000 exacerbation rich participants * 1 year follow up * FEV1 <80% * SE – cardiovascular events, hearing, emergence of resistant bacteria and non tuberculous mycobacteria **Roflumilast and Mucolytics** * Phosphodiesterase-4 inhibitor * Not available in Australia * Cannot be used with theophylline * SE GI upset, weight loss * Improves lung function and decreases the rate of moderate or severe exacerbations in patients with FEV 1 <50%, chronic productive cough and a history of exacerbations. **Ventilatory Support** * Consider NIV when PaCO2 >53 mmHg (7kPa) * Bring CO2 down (high pressures and back up rate) this may well require hospital admission * ?initiate immediately after AECOPD * Early studies suggest may worsen QoL * Always look for (and treat) OSA

Answer 70

**What is sleep** Sleep is a natural, recurring state of relatively suspended sensory and motor activity in animals. It is characterised by: - total or partial unconsciousness - nearly complete inactivity of voluntary muscles It is: - easily reversible and self-regulating - essential for survival - occurs in all living animals Quality as well as quantity of sleep is essential. Sleep disorders affect quality. **Function of sleep** Many proposed theories, with no clear answer. - restoration - memory - immune - energy conservation - circadian homeostasis - prevention Different centres in the brain regulate "wake" and "sleep". - Wake - Reticular formation - Sleep - Thalamic relay ^[i.e. not a uniform event] When awake, brain waves are fast and have low amplitude. As sleep gets deeper, waves get slower and deeper, with higher amplitudes. There are four stages of sleep. 4 is the deepest. Note that REM is an active stage of sleep. Different stages have different functions: - deep sleep has a pruning function - REM aims to refresh networks **Drivers of sleep** - Sleep debt - Circadian “body clock” **Sleep debt** - Paid with slow wave sleep - Mostly first half of the night **Body clock** - Regulates cycle of sleep - Influences REM sleep - REM mostly second half - note also that the duration of REM increases in the second half

Answer 71

**Risk factors for OSA** - Craniofacial - Nose - resistance - Mouth - large tongue, soft palate, retrograde mandible and overbite - Jaw - Tonsils - General - Muscle tone - impacted by alcohol and hypothyroidism, obesity, especially central obesity - Overnight testing - Polysomnography

Answer 72

Cardiovascular Pathophysiology of SDB (Sleep Disordered Breathing) - Intermittent hypoxia - Arousal response - Oscillation of: - systemic and pulmonary arterial blood pressures - Heart rate - Cardiac function Consequences of SDB (Sleep Disordered Breathing) Consequences can be the result of multiple pathways: - Arousal - sleep disruption - Sympathetic NS stimulation - Hypoxaemia - Deox-reox flux - reactive oxygen species - Cardiovascular effects - Neurohormonal effects - Airway, chest pump effects - Inflammatory effects

Answer 73

Causes OSA? When airways collapse Airway obstruction usually occurs in oropharynx i.e. is retropalatal and retroglossal ![[Pasted image 20230922130315.png]] OSA is caused by: - Factors that Increase Compliance of Tube - ![[Pasted image 20230922130407.png]] - a reduction in transmural pressure (Plumen - Ptissue) Factors that Increase Compliance of Tube 1. **Reduction in Longitudinal Tension of the Tube** - Reduction of lung volume (e.g., due to central obesity) 2. **Suppression of Pharyngeal Muscle Activation (Reduces Airway Tone)** - Alcohol, sleep deprivation, anaesthesia - note that some people only have it with alcohol consumption A Reduction in Transmural Pressure (P tm) is Due to A. **Increase in Surrounding Tissue Pressure (P tissue)** or B. **Decrease in Intraluminal Pressure (P lumen)** Increase in Surrounding Tissue Pressure - Rigid box too small: bordered by mandible (anterior and lateral walls) and cervical spine (posterior wall) - neck and jaw posture also influence the size of the box - neck flexion closes airway - neck extension opens it - jaw opens slightly : increases size of box - jaw opens wide: decreases size of box by moving genu of mandible posteriorly Too Many Other Things in the Box - Soft palate (muscle and fat) - Tongue (muscles and fat) - Muscles (posterior constrictors and oropharyngeal muscles) - Tonsils (lymphoid tissue) - Adipose tissue (parapharyngeal fat pads) - - Note: Edema (e.g. due to inflammation and tissue swelling) resulting from OSA can therefore make OSA worse Box Too Small - Rigid box = - Mandible (anterior and lateral walls) - Cervical spine (posterior wall) - Neck and jaw posture also influence the size of the box - Neck flexion – closes airway - Neck extension - opens it - Jaw open slightly – increases the size of the box - Jaw open wide – decreases the size of the box by moving the genu of the mandible posteriorly Position of Tongue and Soft Palate - Affected by gravity and surface tension - Mouth opening - decreases mucosal surface tension, thus freeing mucosal attachment of tongue and soft palate, allowing tongue and soft palate to move posteriorly - Sleeping supine causes gravity to pull the tongue and soft palate posteriorly Obesity and OSA ![[Pasted image 20230922130715.png]] Decrease in Intraluminal Pressure - Nasal obstruction - Airway obstruction due to - Loss of energy due to work done in overcoming flow resistance, and - The Bernoulli effect - Conversion of energy from static to kinetic due to increased velocity of airflow when the lumen size decreases

Answer 74

Illnesses That Can Exacerbate OSA - Anything that causes weight gain (e.g., hypothyroidism, or conditions that reduce mobility and ability to exercise), or requires medications that cause weight gain (e.g., corticosteroids, some anti-epileptics, some anti-psychotics) - Hypothyroidism also causes myxoedema which can exacerbate OSA. It also results in daytime symptoms that can be similar to those resulting from OSA. - Anything that causes nasal obstruction (e.g., hayfever) - Anything that results in craniofacial abnormality Conditions That Can Increase the Adverse Health Risks of OSA - Conditions that result in nocturnal hypoventilation can cause worse overnight O2 desaturation and increase the risk of **pulmonary hypertension** (e.g., COPD, Obesity Hypoventilation Syndrome) - Hypertension, diabetes, elevated cholesterol increase the cardiovascular risks associated with OSA Conditions That May Be Exacerbated by OSA - Afib - Hypertension - Obesity - GORD - CVA - IHD and cardiac failure - Depression (this may, however, also cause daytime sleepiness)

Answer 75

7. Name 3 bacterial microbes which commonly cause URTI and LRTI, and describe their gram stain appearance and organization Step pneumoniae – gram +ve diplococci Step pyogenes – gram +ve cocci in chains Haemophilus influenzae – Gram –ve coccobacilli Neisseria meningiditis – gram –ve diplococci Moraxella catarrhalis – gram –ve diplococci

Answer 76

- **Flow Definition**: Substance passing point per unit time - Flow governed by Ohm's Law - Two main types of flow: - **Laminar Flow**: Straight, unbranched tube; fastest center flow ^[i.e. in middle of tube] - **Turbulent Flow**: Irregular or branched tubes; eddies, higher resistance - n.b. **Transitional Flow**: Mixture of laminar and turbulent - in lung: mix of laminar, turbulent and transitional - **Flow Equation**: Flow = Pressure difference (pressure coming in - going out) / Resistance - **Resistance Formula**: R = 8nl / πr ^4 - n = viscosity ^[usually fixed] - l = length ^[usually fixed] - r = radius - radius most important e.g. half radius = 16 fold change ^[relevance in pathology] - **Laminar Flow** - 'series of concentric cylinders sliding over each other' - Faster in center, slower at edge - 'even front' - **Turbulent Flow** - higher flow rates/flow through branched or irregular tubes - causes concentric circles to breakdown - flow becomes small currents or eddies, higher friction - **Reynolds Number (Re)** - describes tendency towards turbulent flow - Dimensionless number indicating likelihood of turbulent flow - Re = ρDv / η - ρ = Gas density - D = Tube diameter - v = Flow velocity - η = Viscosity of gas - >2000 associated with turbulent flow