1. Pulmonary Pathophysiology II (Please look over these slides – they will be reviewed on 16 Nov) Iain MacLeod, Ph.D imacleod@hsph.harvard.edu Iain MacLeod 9 November 2009

2. Primary determinant of partial pressure of arterial CO 2 (P a CO 2 ) is alveolar CO 2 partial pressure (P A CO 2 ), which in turn is determined by alveolar ventilation. It should be obvious that alveolar ventilation (V A ) is dependent on how much we breathe – how much we breathe per minute (V E ) will rely on the size of the breath (V T ) and the number of breaths/min (f): V E = V T x f Review – Pulmonary I - Hypercarbia

3. Primary determinant of partial pressure of arterial CO 2 (P a CO 2 ) is alveolar CO 2 partial pressure (P A CO 2 ), which in turn is determined by alveolar ventilation. It should be obvious that alveolar ventilation (V A ) is dependent on how much we breathe – how much we breathe per minute (V E ) will rely on the size of the breath (V T ) and the number of breaths/min (f): V E = V T x f But not all of the air we breathe reaches the gas exchange regions of our lungs, so the dead space (V D ) has to be taken into account when determining V A : V A = (V T - V D ) x f It is important to realize that P a CO 2 = P A CO 2 thus something that could affect alveolar ventilation will have a knock-off effect on arterial CO 2 levels by altering P A CO 2, with the primary determinant of hypercarbia being hypoventilation. Review – Pulmonary I - Hypercarbia

4. What can cause hypoventilation? (Discuss) Remember: you can still have a high minute ventilation (= tidal volume x freq.) but still be hypoventilating if the dead space has increased  overall this serves to decrease alveolar ventilation What can cause an increase in dead space? (Discuss) Review – Pulmonary I - Hypercarbia

5. What can cause hypoventilation? (Discuss) Remember: you can still have a high minute ventilation (= tidal volume x freq.) but still be hypoventilating if the dead space has increased  overall this serves to decrease alveolar ventilation What can cause an increase in dead space? (Discuss) Breathing through a tube Pulmonary embolus Disease (such as?) Review – Pulmonary I - Hypercarbia

6. Review – Pulmonary I - Hypoxemia Hypoventilation: can result from a defect anywhere in the stimulation of respiratory muscles, from the controlling centres of the medulla down to the muscles themselves. occlusion of the upper airway / thoracic cages injuries hypoxemia by hypoventilation is accompanied by a rise in arterial P CO2 Diffusion Impairment: either a thickening of the alveolar cell well and / or a decrease in surface area leads to impairment of equilibria between arterial and alveolar P O2 Pa CO2 is either normal or reduced (if ventilation is increased to offset hypoxemia) Shunt: an anatomical abnormality that allowed mixed venous blood to by-pass ventilation and enter arterial blood. can also occur when blood passes through alveoli that are unventilated thus the blood in the capillaries does not become perfused Pa CO2 is normal due to increased ventilation to counteract hypoxemia Ventilation-Perfusion Inequality: most common cause of hypoxemia – found in lung diseases such as COPD – ie. an increase in dead space. Ventilation is the same but perfusion (gas exchange) is impaired. Pa CO2 is increased or normal if increased ventilation is possible

7. Influenza - Basics

8. Influenza is a viral infection that can affect the upper and lower respiratory tracts Until the advent of AIDS, it was the last uncontrolled pandemic killer of humans. In the USA it kills ~36,000 people during non-pandemic years. Rates of illness are highest among children with rates of serious illness and death highest in those over the age of 65. Three type of influenza: A, B and C, with A being the most common. Influenza is further subdivided based on two proteins – hemagluttinin (HA) and neuraminidase (NA), which is where classifications such as H1N1 and H5N1 are derived. HA allows the virus to enter epithelial cells in the respiratory tract, with an immune response to HA preventing infection (such as those stimulated by vaccines) Influenza - Basics

9. Virus is constantly changing, which is why we need a new vaccine each year As with many viral respiratory tract infections, influenza is more contagious than bacterial respiratory tract infections. Transmission is through aerosol or direct contact. The incubation is 1 to 4 days (mean = 2 days). Infected individual is infectious 1 day before onset of symptoms and remain infectious for approx. 5 days after symptoms start – children can be infectious for longer. Severely compromised people (such as individuals with AIDS or on immunosuppressant drugs) can be infectious for weeks. Influenza - Basics

10. Influenza viruses can cause three types on infections: 1. An uncomplicated upper respiratory infection 2. Viral pneumonia 3. Respiratory viral infection followed by bacterial infection Influenza initially establishes upper airway infection – the virus first targets and kills mucous-secreting, ciliated and other epithelial cells. This leaves holes between the underlying basal cells and allows extracellular fluid to escape – the reason behind having a runny nose If the virus spreads to the lower respiratory tract, it can cause severe shedding of bronchial and alveolar cells By removing natural defenses (i.e. ciliated cells and mucous production), influenza leaves the way open for pneumonia as a result of secondary bacterial infection. Influenza - Pathogenesis

11. Early stages are often indistinguishable from other viral infections – fever/chills, malaise, muscle aches, headaches, runny nose, non-productive cough and sore throat. One of the distinguishing features is the rapid onset of profound malaise. In an uncomplicated case, the upper respiratory tract infections peaks by 3 to 5 days and disappears by 7 to days after infection. Viral pneumonia occurs as a complication of influenza infection – usually in the elderly and those with cardio-pulmonary disease. Typically develops rapidly – within 1 day of the onset of symptoms – rapid progression of fever, fast shallow breathing, tachycardia, cyanosis and hypotension. It can cause hypoxemia and death within a few days of the manifestation of symptoms Influenza – Clinical Features

12. An inflammatory illness that is described as affecting the parenchyma (the functional areas of the lung such as alveoli, respiratory bronchioles, the alveolar duct and terminal bronchioles) or just the alveoli. In additional feature is the filling of alveoli with fluid. The inflammatory process stimulates the production of cytokines that promote the influx of fluid A combination of cell death and fluid in the alveoli prevents functional gas exchange Those who survive are usually left with diffuse pulmonary fibrosis, which chronically impairs O 2 diffusion Side step – what is pneumonia?

14. Influenza – H1N1 vs. H5N1

15. The genes carried by a particular flu strain dictate their resultant pathophysiology Increased virulence and dissemination by H5N1, when compared to H1N1, is due to the range of proteases that the virus can use to cleave HA:

16. Influenza – H1N1 vs. H5N1 The genes carried by a particular flu strain dictate their resultant pathophysiology Increased virulence and dissemination by H5N1, when compared to H1N1, is due to the range of proteases that the virus can use to cleave HA: mild and avirulent strains of influenza can only be cleaved by a small number of proteases found in the throat and lungs, while highly virulent strains can be cleaved by multiple proteases, allowing the virus to spread through the body.

17. Influenza – H1N1 vs. H5N1 The genes carried by a particular flu strain dictate their resultant pathophysiology Increased virulence and dissemination by H5N1, when compared to H1N1, is due to the range of proteases that the virus can use to cleave HA: mild and avirulent strains of influenza can only be cleaved by a small number of proteases found in the throat and lungs, while highly virulent strains can be cleaved by multiple proteases, allowing the virus to spread through the body. strains that are easily transmitted between people have hemagglutinin proteins that bind to receptors in the upper part of the respiratory tract, such as in the nose, throat and mouth. In contrast, the highly-lethal H5N1 strain binds to receptors that are mostly found deep in the lungs. This difference in the site of infection may be part of the reason why the H5N1 strain causes severe viral pneumonia in the lungs, but is not easily transmitted by people coughing and sneezing.

18. Influenza – H1N1 vs. H5N1 Treatment ?