RES Exam 3

Barotrauma

Trauma caused by rapid or extreme changes in air pressure, especially affected enclosed cavities within the body such as the middle ear (otic barotrauma), the sinuses (sinus barotrauma), and the lungs (pulmonary barotrauma)

Treatment and prevention of Mycoplasma pneumoniae

Treatment: - Erythromycin or azithromycin- Z pak Prevention: - No vaccine

High V/Q until cause _______

dead space and represent wasted ventilation Note: can identify these via decreasing levels of PACO2 Note: do not hypoxemia (because there is no blood flow)

An increase in alveolar ventilation without an increase in CO2 production leads to _______ PaCO2

decreased

The commonly associated clinical orders of ARDS can be divided into those associated with ____

direct lung injury and those that cause indirect lung injury

M. tuberculosis control

disease can be controlled with a combination of active surveillance, prophylactic and therapeutic intervention, and careful case monitoring

Dermatitis is associated with ______

disseminated histoplasmosis

The absorption of tetracycline is inhibited by _____

divalent cations in anti-acids and dairy products

Adaptive immune responses are initiated in _____

draining lymph nodes Note: these lymph nodes are generally difficult to detect in normal lungs

Antigenic drift

drift results from small mutations in the regions of HA or NA that bind antibodies. (Due to Error-prone RNA polymerase)

Stimulation of the carotid body causes ______

dyspnea

M. tuberculosis culture

egg-based (e.g., Löwenstein-Jensen) and agar-based (e.g., Middlebrook) media -3-4 weeks for growth Specially formulated broth cultures -10-14 days

Other active regulators of pulmonary blood flow

endothelin-1 (vasoconstrictor) and platelet derived growth factor (vasoconstrictor). Nitric oxide and prostaglandin (vasodilators), are released by the pulmonary endothelial cells constitutively and in response to increases in shear forces on the vessel. At baseline, in health, it is thought that the pulmonary circulation is maximally dilated. This would mean that infusion of a vasodilating agent, like nitroglycerin or nitroprusside (nitric oxide donors) or prostacyclin would not drop pulmonary pressures or alter V/Q matching. Only in disease (or at altitude) would these agents significantly change pressure or matching.

Management of ARDS patents with pH <7.15

Increase respiratory rate to 35 (If pH remains < 7.15, VT may be increased in 1 ml/kg steps until pH > 7.15 (Pplat target of 30 cm H20 may be exceeded)) May give NaHCO2-

Management of ARDS patents with pH 7.15 - 7.30

Increase respiratory rate until pH > 7.30 or PaCO2 < 25 (Maximum set respiratory rate = 35)

Caspofungin

Mechanism of action: Caspofungin and other echinocandins inhibit cell wall synthesis. Uses: Serious infections with Candida, empiric treatment of febrile neutropenia. Toxicity: Hepatotoxicity when combined with cyclosporine.

Pyrazinamide

Mechanism of action: Conversion to pyrazinoic acid, which disrupts cell membrane metabolism and transport. Resistance: Mutations in the pyrazinamidase that converts the drug to pyrazinoic acid. Pharmacology: Administered orally, penetrates cells. Toxicity: Common hepatotoxicity (5% of patients).

Zanamivir

Neuraminidase inhibitor Low oral bioavailability, administered with an inhaler. Side effects: : Bronchospasm and rare fatal lung deterioration in patients with airway disease; contraindicated in such patients

Compensated respiratory acidosis

PCO2 is increased pushing into acidosis The kidneys begin to increase HCO3- retention This allows the pH to move back towards the normal range May take 48-72 hrs! Ex: too much morphine, etc.

Oxygen dissolved in blood (in plasma) is solely dependent on ____

PO2 CdO2 = .0031 ml O2/mmHg/100 ml blood x PO2 (mmHg) CdO2 = .003 ml O2/100 ml blood/mmHg x 90 mmHg = 0.27 ml O2/100 ml blood

Respiratory alkalosis

PaCO2 < 36 mmHg as the primary (i.e. initial) disorder Common Causes: -Interstitial lung disease -Neurologic injuries -Aspirin intoxication -Hypoxia Note: these all decrease alveolar ventilation

Winter's formula

PaCO2 = 1.5 [HCO3-] + 8 ± 2 This is derived from normal people and predicts expected PaCO2 for degree of acidosis.

Respiratory acidosis

PaCO2 > 44 mmHg as the primary (i.e. initial) disorder Common Causes: -Intrinsic Lung Disease -Chest wall disease -Neuromuscular disease -Chronic opiate use

95% saturation of hemoglobin generally occurs at what PO2

80 mmHg

97% saturation of hemoglobin generally occurs at what PO2

97 mmHg

What is the normal partial pressure of O2 in the alveoli?

100 mmHg

VO2 max for patients with pulmonary arterial hypertension

> 10.4 ml/kg/min low "risk" of death < 10.4 ml/kg/min high "risk" of death

Why is MMR given around 9 months?

It is a live attenuated virus therefore the maternal antibodies would destroy it. Must be given once maternal antibodies wane

Clinical diphtheria is caused by:

Toxigenic strain of Corynebacterium diptheriae. In low bacterial iron, this produces diphtheria toxin which inhibits protein synthesis

What are some other immunocompromised conditions?

Transplant Vasculitis Lymphoproliferative disorders

_______ is not normal in asthma

Ventilation

_______ is not normal in emphysema

Ventilation

_______ is not normal with full consolidation such as in pneumonia

Ventilation

________ can be impaired with severe environmental pollution

Ventilation (can be caused by bronchoconstriction)

_______ is not normal in CHF with pulmonary edema

Ventilation (because of alveolar flooding)

Can actinomycetes cause aspiration pneumonia?

YES, can arise from (Alcoholism, poor dental hygiene), cervicofacial infections, and abdominal infections.

Is LVEF nearly maximal during sub maximal exercise at ventilatory threshold?

YES, during steady state LVEF continues to increase with continuation of steady state exercise

Cepacia syndrome

a fatal combination of necrotizing pneumonia, worsening respiratory failure, and bacteremia

Gamow bag

a portable hyperbaric chamber Note: could be used to transport a high altitude pulmonary edema patients, etc.

ventilation-perfusion scan

A detection device records radioactivity after an injection of a radioisotope or inhalation of small amount of radioactive gas. Often used for the detection of pulmonary emboli

Pneumonia

A disease of the lungs characterized especially by inflammation and consolidation of lung tissue and by fever, chills, cough and difficulty in breathing that is caused especially by infection. Those cells involved are: -neutrophils -lymphocytes -eosinophils

Ciprofloxacin

A fluoroquinolone (Inhibits DNA gyrase and topoisomerase IV) Most active against aerobic gram-negative bacteria Penetrates cells, so can be used to treat infections with intracellular pathogens

Levofloxacin

A fluoroquinolone (Inhibits DNA gyrase and topoisomerase IV) Spectrum extended to gram positive Useful in empiric treatment of respiratory tract infections

Frequency of apnea activity in adults

A frequency of more than 5 episodes each hour occurs in 25% of adult men and 9% of women These individuals are usually asymptomatic, but as apnea frequency increased, symptoms of daytime hyper somnolence and decreased vigilance also increased

Legionella pneumophilia

A gram negative bacterium Arises from water sources Leads to legioneers disease

Clarithomycin

A macrolide (protein synthesis inhibitor) Longer half life Used (like azithromycin) to treat mycobacterial infections and community acquired pneumonia

Erythromycin

A macrolide (protein synthesis inhibitor) Old Short half life Drug of choice for treating pertussis and diphtheria

Azithromycin

A macrolide (protein synthesis inhibitor) Very long half life Drug of choice for treating Legionnaire's disease

Atypical pneumonia

A penumonia not caused by on oof the more traditional pathogens It can be caused by: - Legionella pneumophila - Mycoplasma pneumoniae - Chlamydophila pneumoniae Generally presents with only moderate amounts of sputum, no consolidation, only small increases in white cell counts, and no alveolar exudate CXR generally show both lungs filled with patchy, diffuse areas of inflammation

Metabolic Equivalent of Task (MET)

A physiologic measure that expresses the energy cost of physical activities and is defined as the ratio of metabolic rate (or rate of energy consumption) during a specific physical activity to a reference metabolic rate (rate of energy consumption during rest). 1 MET= 3.5 ml/kg/min

Tetracyclines

A protein synthesis inhibitor via binding to the bacterial ribosome and blocking binding of aminoacyl tRNA Bacteriostatic Broad spectrum but resistance is more common Used for Rickettsial diseases and empiric therapy of lower respiratory tract infections

Normal CaO2

About 20ml O2/dL blood (1.34 x 15 x .98) + (0.003 x 100) = 20 mL O2/dL blood Note: this represents the amount of oxygen present in 100 ml of blood

Hantavirus pulmonary syndrome

About 30-40 cases in US annually Deer mice are reservoir Transmitted by inhaling dried mouse urine

Ratio between bacteria and human cells

About 3:1, with about 39 trillion bacteria and roughly 30 trillion human cells

M. tuberculosis vaccination

Accination with attenuated M. bovis (bacille Calmette-Guérin [BCG]) is commonly used in countries where tuberculosis is endemic and responsible for significant morbidity and mortality Ranges from ineffective to 80% protection Not used in the US; case tracking via skin test is used Contraindicated for HIV+ individuals

What is the most commonly used preventative therapy for acute mountain sickness

Acetazolamide which is a carbonic anhydrase inhibitor (though its efficacy is unclear) It generates metabolic acidosis by wasting HCO3- in urine - ? if related to improving a blunted HVR - ? if related to improving an increased ECF Spironolactone is also helpful

Arterial blood gases can provide information on:

Acid-base status of the patient PaCO2 of a patient (a measure of the effectiveness of alveolar ventilation) Saturation of oxy-hemoglobin, SaO2 (this is directly measured) The presence of gas-exchange abnormalities (the A-a PO2 gradient) The presence of other gases (carbon monoxide, methemoglobin)

________ and ______ denote that the process has resulted in an abnormal pH. This frequently indicates that the initial acid-base abnormality is uncompensated or inadequately compensated.

Acidemia and Alkalemia

_____ and ______ are pathologic processes in which the values for acid and base are out of the normal range

Acidosis and Alkalosis

What two principle immune cell types produce TNF-α

Activated T cells and Activated macrophages TNF-α can then bind TNF-α receptors and lead to pro-inflammatory events and cell mediated immunity

Macrolides affect:

Aerobic, gram-positive bacteria, mycobacteria, mycoplasma

Streptococcus pneumoniae is spread via:

Aerosol, it colonizes the upper respiratory tract (no disease)

Cryptcoccus pathogenesis

After inhaled, it reaches the alveoli where production fo the polysaccharide capsule is the prime determinant of virulence Intracellular survival in phagocytes is aided by melanin production, which interferes with oxidative killing mechanisms The capsule is antiphagocytic and has a number of other immunomodulating effects such as interference with antigen presentation, leukocyte migration, specific antibody responses, and the development of Th1 immune responses It has a striking affinity for the CNS with proposed mechanisms of crossing the BBB inside macrophages (Trojan horse) and the ability of lactase to convert abundant catecholamines in the CNS to melanin

Ceftriaxone also good for Meningitis Why?

Also inhibits Neisseria, Listeria

Non-tuberculous mycobacteria (NTM) growth properties

Also referred to as mycobacteria other than tuberculosis (MOTT) or atypical mycobacteria Can be slow- or rapid-growing, pigmented or non-pigmented Historically the Runyon classification scheme was used for assignment of NTM into 4 groups; more rapid detection methods are now available Note: Pigmented or a rapidly growing mycobacterium should never be mistaken for M. tuberculosis

Three General Mechanisms of Bacterial Resistance

Altered critical enzyme Protein that degrades drug Efflux pump

Phaeohyphomycoses examples

Alternaria, Curvularia, Bipolaris, Cladosporium...and others

Causes of hypoxemia with normal A-a O2 gradient (usually <12-14)

Altitude Hypoventilation This tells you that it is not due to abnormal gas exchange in the lung

Causes of Hypoxemia (PaO2 <80 mmHg)

Altitude (decrease in Pb) Hypoventilation Diffusion (altitude or extreme exercise) Low V/Q mismatch Shunt (intrapulmonary- areas of atelectasis or pneumonia or intracardiac)

Defenses in airways and their mucosa: Lumenal defenses

Anatomical barriers -nasopharyngeal anatomy and airway bifurcation -prevent entry of particles (>2-3µm) into lower airways Cough -generated by forced expiration -shearing forces in major bronchi and trachea extrude material Mucociliary transport -ciliary beats in mucus of bronchi -material moved from bronchi to trachea Anti-microbial agents in mucus -lysoszyme, lactoferrin, peroxides, defensins -combat bacteria Secretory IgA -Transcytosed across epithelial cells -neutralize toxins, viruses, and bacteria

How can Streptococcus pneumoniae lead to meningitis

(Kids) Organism spreads from Eustachian tube thru mastoid sinuses directly to CSF (Adults) Spread from lungs, to blood, to choroid plexus to CSF

VD/VT

(PaCO2 - PECO2) / PaCO2 For each tidal breath, how much is in dead space It normally should be around 1/3

Coxiella burnetti

(Q fever; obligate intracellular causes atypical pneumonia). Grows in acidified vacuoles. Zoonotic disease. Causes abortions in cattle, goats, sheep. Transmitted thru inhalation of contaminated dust. Onset slow in humans. Consolidation in single lobe common. Treat with Doxycycline

Crackles

(also known as rales): discontinuous and heard more frequently during inspiration. Caused by disruptive air flow through the small airways although the specific cause is not clear. Depending on the scenario these are associated with pulmonary edema, pneumonia, interstitial lung disease.

Hyperresonance to percussion

(anything that increases air in the lung): pneumothorax emphysema large air-filled bullae in the lung

M. tuberculosis pathogenesis

It is an intracellular pathogen that can establish life long infection It enters the respiratory airways and penetrate to the alveoli and are phagocytize by alveolar macrophages Here it can survive and multiply within non-activated alveolar macrophages -It prevents fusion of the phagosome with lysosomes -the phagosome is able to fuse with other intracellular vesicles, permitting access to nutrients and facilitating replication within the vacuole

How is carbon dioxide removed from the body?

It is excreted through the lungs - dissolved CO2 diffuses into the alveolus because it has a lower partial pressure of CO2 - HCO3- enters the RBC bindings the H+ that is bound to Hb now that O2 is binding the Hb instead, H2CO3 uses carbonic anhydrase to generate CO2 which then diffuses into the alveoli - Carbamino-hemoglobin in the presence of O2 has less affinity for CO2 and releases it where it can then diffuse into the alveoli It reaches the lungs via: - dissolved in blood - as HCO3- via the enzyme carbonic anhydrase - bound to hemoglobin (carbamino-hemoglobin)

How is amphotericin B selective to fungal cells?

It is selectively toxic toward fungal cells because the primary sterol in their membranes is ergosterol, whereas in our membranes, it's cholesterol.

In the tissues, how is the curve shifted?

It is shifted to the right due to higher PaCO2 and lower pH from metabolically generated H+ This decreases the hemoglobin's affinity for oxygen and facilitates O2 release to the tissues

Immunology of primary infection of TB

It is the battle between nonspecific defenses and bacilli virulence. Which ever wins determines if you have complete clearance or development of latent TB The mycobacterium droplets need to get to the alveoli and can do so by containing only 1-3 bacilli These are taken up by the alveolar macrophage where it can be killed and result in no infection ( - PPD) or it can begin intracellular replication This can lead to killing of the alveolar macrophage and the release of all the mycobacterium Non-activated monocytes are then recruited to the site there the mycobacterium can continue replication and 1 bacilli can yield 10^4 organisms You can then have the onset of cell mediated immunity and DTH (21 days). At this point, it is considered an infection (+ PPD)

Mechanism for High altitude cerebral edema

It is unclear! Hypoxia may induce an increase in extracellular fluid Cerebral edema which can be due to a low PaO2 which increases cerebral blood flow

How does influenza promote bacterial adhesion and secondary infections (pneumonia)

It kills off mucus secreting and ciliated cells to establish infection

When do apnea events occur most?

It may occur as frequently as 2x per min during all stages of sleep, but it is usually worse during REM- dreaming sleep

What is the role of the oxygen-hemoglobin dissociation curve?

It relates the partial pressure of O2 (PO2) to O2 saturation of hemoglobin (SO2) PaO2 (usually around 98% and 90 mmHg) Medicare begins to pay at a PO2 of 60 mmHg and SO2 of about 90% PVO2 (usually around 75% and 40 mmHg) P50 (partial pressure at which 50% of hemoglobin is saturated)

J receptors (C fiber type)

Juxtapulmonary-capillary receptors adjacent to pulmonary microvessels Stimulated by vascular emboli, interstitial edema, and chemicals Information is sent via vagal afferents Their stimulation results in rapid shallow breathing (tachypnea) Might explain the sensation of dyspnea Note: collagen deposition in the interstitium might stimulate as well

______ occurs when oxygen is not present to accept electrons

Lactic acidosis

Trachea pushed away from affected side

Large pleural effusion, tension pneumothorax

Injury to medullary central controllers

Leads to Biot's or chaotic ataxic respirations Can be caused by intracranial pressure elevations (e.g. meningitis) Poor prognosis

Injury to PRG: Kolliker fuse central controller

Leads to apneustic breaths: tachypnea followed by inspiratory apnea Can be caused by head trauma or neurologic disorders compromising basilar flow

Carbon monoxide shifts the oxygen-hemoglobin dissociation curve to the ____

Left, which decreases the offloading of oxygen from hemoglobin at the tissue level

Amphotericin B

Mechanism of action: Binds to ergosterol via its hydrophobic face, forming pores in the fungal cell membrane through which cell contents can leak. Spectrum: Very broad. Uses: Life-threatening fungal infections. Side effects: Fever and chills, nephrotoxicity.

VO2 max

Maximum volume of oxygen that the body can consume during intense, whole-body exercise, while breathing air at sea level

Interpreting arterial blood gases: Acid base

Primary acid-base abnormality Is there a presence of second acid-base abnormality (signs of compensation) Presence or absence of compensation - adequate or not?

Bradypnea

RR < 10 respirations/ minute

Hemoglobin saturation values throughout

RV (SVO2): about 70% Capillary: ScO2: 98% LA (SaO2): 97%

Changes in Oxygen content (CO2)

RV: CVO2: 14.2 ml O2/dL Capillary: 20 ml O2/ dL LA: CaO2: 19.8 ml O2 / dL

Clinical course of disease caused by HIV

Rapidly leads to a loss of CD4 T cells within the acute phase. In this period there is wide dissemination of the virus and seeding of lymphoid organs It then generally go into clinical latency where the plasma viremia titer is very low CD4 T cell count can continue to decrease and eventually lead to increased plasma viremia titer and death by infection from opportunistic infections

How is pulmonary artery pressure relatively normal during exercise?

Recruitment and distention of pulmonary capillaries

Vancomycin side effects

Red man syndrome: extreme flushing on rapid IV infusion

Arterial baroreceptors

Reduction in arterial blood pressure stimulates ventilation

Plateau pressure

Reflects small airway and alveolar pressure Note: if this is high, it can cause ventilator induced lung injury

Why might swimmers pass out after trying to swim underwater after blowing down their CO2

Remember when you wanted to swim the entire length of the pool underwater in one breath? It was usually preceded by a period of deep breathing to loss the lungs with oxygen. This decreased PaCO2(hyperventilation). As you began swimming, the body consumed oxygen and the PaO2 dropped. Once the PaO2 dropped below 60 mmHg, the carotid body would normally be stimulated giving a sense of dyspnea, forcing you to the surface. If the PaCO2 is still very low, however, (due to your pre-swim hyperventilation), the carotid body is not stimulated by the low oxygen tension. If the PaO2 drops below 50 mmHg, swimmers can become unconscious, without ever becoming dyspneic.

Things many people do in regard to TB, but they shouldn't

Repeat a skin test on a person with known infection -won't cause a problem, but a waste of resources -once positive, considered always positive Check routine yearly CXRs on asymptomatic people with latent TB infections -waste of resources -should check CXR only for symptoms

What is the primary mechanism that humans use to increase oxygen hemoglobin affinity at altitude?

Respiratory alkalosis pH will be increased and PaCO2 will be decreased

Levels indicative of alkalosis/acidosis

Respiratory alkalosis: ≤ 35 mmHg Respiratory acidosis ≥ 45 mmHg Metabolic alkalosis: ≥ 28 meq/L Metabolic acidosis: ≤ 22 meq/L Note: obviously look at pH too

Clinical manifestations of Blastomycosis

Respiratory infection - mild, may resolve spontaneously Chronic granulomatous disease affecting lungs, skin, and mucous membranes Chronic cutaneous blastomycosis: -Ulcerated lesions -Exposed or mucocutaneous tissues Systemic Blastomycosis -Dissemination to subcutaneous tissues is common -May become chronic -Involves any organ - bone lesions and osteomyelitis are often encountered

Relationship between minute ventilation and alveolar ventilation is based on _______

Respiratory pattern Critical thing here that that regulating carbon dioxide is all about the alveolar ventilation Note: though the minute ventilation plays a role, it is also determined by dead space so it is not exclusively alveolar ventilation

Medulla: Pre-Botzinger central controller

Respiratory rhythm generating Regulate rhythm with VRG, dictates gasping and sigh Function: Initiate action potentials during the latent phase at the end of expiration (rhythm generator)

_____ are critical to the induction of high affinity antibodies and immune memory

T cells

Common organisms causing pneumonia immunocompromised individuals on medications

TB Aspergillus Nocardia Candida Pneumocystis

Common organisms causing pneumonia immunocompromised individuals with medical conditions such as diabetes or renal failure

TB Mucor

M. tuberculosis in patients with HIV

TB disease usually appears before the onset of other opportunistic infections Is twice as likely to spread to extra pulmonary sites Can progress rapidly to death In people co-infected with M. tuberculosis and HIV the rate they develop tuberculosis is 10% per year

M. tuberculosis overview

TB is a systemic infection manifested only by evidence of an immune response in most exposed individuals In some infected people, the disease progresses or reactivates after an asymptomatic period (years) Most common reactivation form is a chronic pneumonia with fever, cough, bloody sputum and weight loss Spread outside lungs occurs, particularly devastating when reaches CNS Natural course of chronic wasting to death referred to as "consumption" in the past

Blastomycosis skin test

THERE ISNT ONE

Irritant receptors in the upper airway (rapidly adapting)

Stimulated by deformation, dust, smoke, or toxic gases Afferent signals via CN V or X, ends in coughing or sneezing

Are lung infections a major health problem?

YES they are the leading cause of DALY Bacterial pneumonia is the #1 cause of childhood mortality in the world and #1 cause of childhood hospitalizations in the US

Acute change of PaCO2 of 10 mmHg changes the pH by about ___

0.08

New approach for treatment of ESKAPE pathogens: novel vaccine development

1 - "Reverse Vaccinology" - use of genomic sequencing to discover multiple cell surface epitopes for vaccine design 2 - Convalescent screens - identify neutralizing antibody epitopes that are pathophysiologically relevant 3 - DNA vaccines - optimizing amplification and surface expression of germane epitopes

What do the ESKAPE pathogens have in common

1 - Cause of lower respiratory track infection 2 - Problem in immunocompromised individuals 3 - Tracheal tubes, catheters

What is considered to be the amount of anatomic dead space

1 ml per pound

ARDS ventilator set-up

1. Calculate predicted body weight - Males: 50 + 2.3 [height (inches) - 60] - Females: 45.5 + 2.3 [height (inches) - 60] 2. Select any ventilator mode 3. Set ventilator settings to achieve initial VT = 8 ml/kg PBW 4. Reduce VT by 1 ml/kg at intervals ≤ 2 hours until VT = 6ml/kg PBW. 5. Set initial rate to approximate baseline minute ventilation (not > 35 bpm). 6. Adjust VT and RR to achieve pH and plateau pressure goals.1.

Low V/Q mismatch responds to _______

100% Low flow oxygen (2-3 L/min) You can increase the pO2 in the alveoli getting rid of the pN2. Note that the pCO2 and pH2O dont change Diseases such as asthma,chronic bronchitis, and emphysemaare low V/Q mismatches and respondrapidly to oxygen.

Normal range of hemoglobin in adults

12 to 16 g/100 ml of blood

What is the capsule of cryptococcous neoformans made of?

A complex polysaccharide polymer A major component being glucuronoxylomannan (CXM) The production of this capsule can be repressed under environmental conditions and stimulated in the physiologic conditions found in tissues and in culture on the common clinical laboratory media, such as blood agar, chocolate agar, and Sabouraud's agar.

Histoplasmosis infection cycle

1. Histoplasma capsulate spores are inhaled 2. Spores enter lungs and travel to alveolar spaces where immune cells trap them 3. Immune cells transport cells though the lymph system to mediastinal lymph nodes where they multiply and, if not eliminated, enter your blood stream and spread though your body

M. tuberculosis immune response

1. Infection -primarily infects macrophages -early in infection, bacteria replicate essentially unchecked -later in infection, the T helper response activates macrophages to contain the bacteria 2. Response - INF gamma activates infected macrophages -Infected macrophages secrete cytokines - Increased localized infection - Recruitment of T cells and NK cells 3. Effect - INF gamma leads to increased phagosome-lysosome fusion, acidification and intracellular killing. It also stimulates production of NO and reactive nitrogen intermediates 4. DTH - May occur during the time the bacteria are multiplying I.e. generate sufficient proteins to trigger this response - Adds to tissue destruction

Process of Streptococcus pneumoniae development of pneumonia

1. Pneumonia: after patient aspirates to lower respiratory tract- (bacterial cell surface proteins are used to attach- 2. Settle in Alveoli -Bacteria possesses IgA protease -People that are particularly susceptible: Smokers, alcoholics, post-viral infection 3. In Lung, org. produces little tissue damage. Damage is due to the inflammatory response. (teichoic acid and peptidoglycan activate alternative complement pathway (starts with spontaneous cleavage of C3, C3b binds gram negative membrane or teichoic acid in gram positives, C3b binds factor B to make C3 convertase, properdin converts C3 convertase into C5 convertase)) 4. Edema interferes with gas exchange 5. PMN infiltration 6. Bacteremia common if no opsonizing Antibodies. However, innate immunity can clear infection -C-substance (phosphorylcholine on S. pneumo) binds acute phase reactant -C-reactive protein (CRP) and triggers complement cascade via C1 binding -But.... An S. pneumoniae surface protein, PspC, binds factor H, inhibits complement cascade. 7. Organism may also cause sinusitis, otitis media and meningitis.

Influenza pathogenesis

1. Virus membrane fuses with host, virus enters via endocytosis 2. Virus uncoats, and neg sense RNA enters nucleus 3. RNA converted to positive sense (viral RNA polymerase enters cell with virus) 4/5. Positive sense RNAs are replicated to neg sense for packaging, and are also exported to ER for translation. 6. NA and HA proteins are inserted into host membrane, neg sense transcripts with associated proteins are packaged into virion that buds thru membrane

Major ESKAPE pathogen antibiotic targets

1. ß-Lactam and Cell Wall Inhibitors - Penicillins - target PBPs - Cephalosporins - target PBPs - Carbapenems - target PBPs - Glycopeptides - target cell wall rigidity - Polymyxins - target cell wall permeability 2. Protein Synthesis Inhibitors - Macrolides - target 50S ribosome - Aminoglycosides - target 30S ribosome - Lincomycins - target 50S ribosome - Tetracyclines - target 30S ribosome 3. DNA Replication - Quinolones - target DNA gyrase or topoisomerase IV 4. Folate Inhibitors - Sulfonamides - target paraaminobenzoic acid - Trimethoprim - target dihydrofolate reductase

About how much of a normal tidal volume will be dead space in a healthy 70kg person

1/3 VD/VT = [(PaCO2 - PECO2) / PaCO2)

Small pox (Variola) history

1200 BC: evidence of small pox in Egypt 100-1800: It spread throughout the world 1000: Variolation developed in India/China 1650-1800: Variolation introduced to Europe/US (lady montagu) 1774: First (known) use of cowpox innoculation to protect against smallpox 1796: First use of cowpox innoculation by Edward Jenner to prevent smallpox 1800: International spread of smallpox vaccine (used orphans to ferry the cowpox virus) 1800-1900: smallpox vaccine changed from cowpox to vaccinia virus. However, there was still around 400,000 annual deaths from smallpox 1900-1950: Increased efforts to vaccinate world's population. Used 3 stock strains of Vaccinia virus 1950-1980: WHO begins intensive international effort to eradicate smallpox 1980: Smallpox was declared eradicated

First report of ARDS

1967, when Ashbaugh and colleagues described 12 patients with acute respiratory distress, cyanosis refractory to oxygen therapy, decreased lung compliance, and diffuse infiltrates evident on the chest radiograph In 1988, an expanded definition was proposed that quantified the physiologic respiratory impairment through the use of a four-point lung-injury scoring system

At altitude does the oxygen-hemoglobin curve shift left or right?

2,3 BPG increases with adaption to altitude shifting the curve to the right, However, respiratory alkalosis shifts the curve to the left in vivo Therefore, it is though that the respiratory alkalosis will progressively left shift the curve more

Normal range (at sea level) of HCO3-

22-28 meq/L Most people are between 22-26

Max heart rate

220-age

ARDS mortality

30+ % mortality - reduced from 40-60 % mortality due improved mechanical ventilation (low tidal volumes) and better ICU supportive care Low tidal volumes reduces "volutrauma" and improves outcomes Mean time to death > 20 days

What is a normal PaCO2 in a healthy person at sea level?

36 to 44 mmHg (or torr)

Normal range (at sea level) of PaCO2

36-44 mmHg Most people are between 38-42

Ceftriaxone

3rd generation cephalosporin used to treat community acquired pneumonia Long half life Broad spectrum Can cross BBB

Hantavirus pulmonary syndrome Epidemiology

4 corners region of New Mexico, Arizona, Colorado, Utah

70-75% saturation of hemoglobin generally occurs at what PO2

40 mmHg

PCO2 of blood leave the alveoli in a healthy person is:

40 mmHg

Immigrants and TB

41% of active tuberculosis cases in US in 1998 were in foreign-born individuals (despite constituting only 10% of population) Foreign-born cases exceed 70% of total cases in some states (Californian and Hawaii) Recent immigrants develop active tuberculosis at a rate similar to that in their native country for first 3-4 years in US After 5 years their case rate approaches that in the US All TB infected immigrants from high risk countries who have come to the US within the previous 5 years should be treated regardless of age

Co-infection with HIV and (latent) tuberculosis

5 million worldwide are co-infected with HIV and M.tuberculosis (80% in Africa) Progression to active disease is very high (10%/per year) Dissemination is common Cavitary disease is uncommon due to lack of strong cytotoxic immunity Most tuberculosis in HIV patients in the US is due to re-activation Re-activation can occur early in disease (often when CD4 count is > 600 cells/mm3 Considered infected if PPD > 5 mm Two step PPD skin testing is not helpful High dose PPD (250 TU) is not specific and not recommended in HIV patients Treating anergic HIV (+) people empirically is not effective and not recommended Which HIV patients should be treated? -PPD positive (induration > 5 mm) -Recent known exposure even if remains PPD (-)

There is an increase in minute ventilation (VE) when arterial PO2 drops to about _____

55 mmHg

What is used clinically to gage cardio-respiratory fitness

6-minute walk test 1000 meters for VO2 max of ≈ 30 ("running") Normal: ≈ 600 meter + PAH patients: - too well for clinical trials >450 m - too ill for clinical trials <150 m - mortality improves > 380 m

90% saturation of hemoglobin generally occurs at what PO2

60 mmHg

the relationship between the partial pressure of oxygen (PO2) and the % saturation of oxy-hemoglobin (SO2) is non linear above_____ or below ______

60 mmHg 20 mmHg

pH goals for ARDS patients

7.3- 7.45

Normal pH values for arterial blood gases

7.36 - 7.44 Average is around 7.4

Amoxicillin

A beta lactam (cell wall inhibitor) More activity against gram negative bacteria, longer half-life an better oral absorption than Penicillin G. Used empirically to treat respiratory tract infections or in definitive therapy to trace susceptible S. pyogenes

Ampicillin

A beta lactam (cell wall inhibitor) Similar to amoxicillin, but typically used IV for more serious infections

Cephalosporins

A beta-lactam (cell wall inhibitor) Better activity against gram-negative bacteria More resistant to beta-lactamase These properties increase each generation

Ghon Focus

A calcified granuloma Pretty good indication that someone has been exposed to a granulomatous disease (worldwide- tuberculosis; US- histoplasmosis) Note: this CXR finding doesn't increase the risk of developing active TB

Vancomycin

A cell wall inhibitor via inhibition of transglycosylase and chain elongation by binding to cell wall precursors attached to a lipid carrier Bactericidal Usd for MRSA and penicillin resistanat pneumococcal infections

Myoglobin

A single heme containing subunit Has a P50 of 5 mmHg (binds O2 very tightly at low pressures) Acts as an oxygen depot in cells (delivers the oxygen to the tissues needed) Note: particularly in smooth muscle

Steady state exercise

A state of aerobic exercise in which the intensity remains consistent The oxygen consumption is delayed in reaching the steady rate VO uptake needed to meet the metabolic demands creating an oxygen deficit Once exercise is over, Oxygen consumption slowly decrease but is higher than normal. This is in order to pay the O2 debt (EPOC)

Branching of the airways

A total of 23 generations Starting around the 17th generation is respiration

Itraconzaole

A triazole (Inhibition of sterol demethylase, a fungal cytochrome P450 enzyme involved in ergosterol synthesis) Azole of choice for treating histoplasmosis, blastomycosis. Not a replacement for amphotericin B in rapidly progressing infections Lacks the endocrine side effects of ketoconazole, but has drug interactions due to strong inhibition of CYP3À. (E.g., increased levels of macrolides leading to increased risk of QT prolongation, increased levels of warfarin, leading to increased risk of bleeding.)

Voriconazole

A triazole (Inhibition of sterol demethylase, a fungal cytochrome P450 enzyme involved in ergosterol synthesis) Azole of choice for treating invasive aspergillosis. Side effects include drug interactions due to P450 inhibition, transient visual disturbances, and photosensitivity.

Ketoconazole

A triazole (Inhibition of sterol demethylase, a fungal cytochrome P450 enzyme involved in ergosterol synthesis) Oldest drug in the azole class. Inhibition of human cytochrome P450 affects steroid hormone synthesis, leading to endocrine side effects as well as drug interactions.

Fluconazole

A triazole (Inhibition of sterol demethylase, a fungal cytochrome P450 enzyme involved in ergosterol synthesis) Widest therapeutic index of all the triazoles due to fewer drug interactions. Can be used to treat some pulmonary fungal infections. These include coccidiomycosis, cryptococcosis, candidemia.

Cryptococcus neoformans

A yeast that produces a characteristic capsule consisting of a complex polysaccharide polymer that stains with India Ink Divided into 4 serotypes (A-D) and three varieties (neoformans, grub, gattii). Note that their pathogenic biology is essential the same At 25C or 37C, mucoid yeast colonies are produced in 2-3 days

Aspergillosis in culture

A. fumigates is a rapid grower Septate, hyaline hyphae conidiophores with phialides pointing upwards, bearing chains of conidia

When compared to the normal PaO2 at steady state exercise, PaO2 at VO2 max is _____? A. increased B. decreased C. the same

A. increased As we blow down CO2 in the alveolus, it increases our alveolar PaO2 leading to an increased driving forcing O2 onto venous blood as it goes through circulation/lung

Isoniazid induced hepatitis

AST (SGOT) > 5 times normal (about 250) Increases with age (1-1.8% incidence overall) Resolves with discontinuation (usually) Incidence of fatal hepatitis in over 35 age group with regularly monitored LFT's (1983-1992): 0.002% -much lower than 0.1% fatality rate from 1972 USPHS report Risk increases with longer duration of therapy

How can you generate ATP during oxygen deficit

ATP + H2O→ ADP + Pi CP + ADP → ATP + C (uses creatine kinase) ADP + ADP → ATP + AMP (uses adenylate(myo) kinase) Glucose → 2 ATP + 2 Lactate (via rapid glycolysis)

What is the ideal V/Q

About 0.9 Alveolar ventilation estimated at 4.5 L per min Alveolar perfusion averages 5 L per min

Normal CvO2

About 14.2 mL O2/dL blood (1.34 x 15 x .70) + (0.003 x 40) = 14.2 mL O2/dL blood

Defenses in alveolar spaces

Alveolar epithelial cells -Type I and II pneumocytes -major producers of surfactant proteins Alveolar macrophages -resident mononuclear phagocytes -first line of defense in lower airways Lymphocytes -effector CD4 and CD8 T cells -memory T cells -NK cells IgG and opsonins - IgG most abundant Ig in alveoli; diffuses from blood into alveoli - IgG1, IgG2 and IgG3: neutralization - IgG1 and IgG3: opsonization and complement fixation - complement protein C3b is an opsonin (classical and alternative pathway) - C-reactive protein (CRP, a pentraxin): opsonization; complement fixation (classical pathway) Neutrophils - major defender against bacterial pathogens - move from blood into alveoli during infections

Alveolar macrophages

Alveolar macrophages can interact with particles via PRRs or indirectly though CD91 and surfactants This leads to NFk-b, INRs all leading to pro-inflammatory cytokines such as TNF-α and IL-1 These cytokines can then act on endothelial cells and lead to further NFk-b activation allowing the endothelial cell itself to begin producing chemokine, CSFs, and adhesion molecules all causing neutrophil recruitment

The amount of ______is critical in determining CO2 excretion

Alveolar ventilation, not minute ventilation

Best estimate of low V/Q mismatch is

Alveolar-Arterial oxygen gradient (P(A-a)O2) Note: normal should be <12 mmHg (which represents the anatomic right to left shunt that occurs through arteries and veins that empty directly into the left atrium and dont undergo gas exchange such as the thebesian and bronchial veins) Note: the larger the gradient, the more blood is going past unventilated or poorly ventilated areas and the worse oxygenation will be Note: has limitations and a mixed venous PO2 would be more accurate, but requires pulmonary artery catheter

What is the best estimate of Low V/Q mismatch?

Alveolar-arterial oxygen gradient - P(A-a)O2 Note: should normally be about 10-12 mmHg

What are some of the several factors that likely contribute to the burden of TB in certain populations

Among foreign-born people, TB disease may result from infection acquired in their country of origin Immunocompromized persons are at increased risk of infection, e.g.: -HIV infection -malnutrition, alcoholism, diabetes, old age, homeless, IV drug use Exposure to TB patients -healthcare workers -prisoners, individuals in close quarters

Cryptococcus treatment

Amphotericin B plus flucytosine followed by an extended course of fluconazole is the primary treatment for systemic cryptococcal disease Although 75% of persons with meningitis respond to treatment, a significant percentage suffers relapses after anti fungal therapy is stopped and become chronic requiring repeated courses of therapy Note: one half of those cured have some kind of residual neurologic damage

Streptomycin

An aminoglycoside (protein synthesis inhibitor) An older drug Still used sometimes to treat drug resistant tuberculosis

Amikacin

An aminoglycoside (protein synthesis inhibitor) Broader spectrum More resistant to aminoglycoside-modifying enzyme

Tobramycin

An aminoglycoside (protein synthesis inhibitor) Similar properties to gentamicin Inhaled formulation used to treat early Pseudomonas aeruginosa infections in cystic fibrosis

Gentamicin

An aminoglycoside (protein synthesis inhibitor) The most commonly used aminoglycoside

Allergic bronchopulmonary aspergillosis (ABPA)

An asthma type response that is noted by pulmonary infiltrates, peripheral eosinophilia, and elevated serum IgE Initiated due to a hypersensitivity to aspergillus antigen (can be determined via skin test)

CXR of Respiratory syncytial virus

An x ray of a child with RSV showing the typical bilateral perihilar fullness of bronchiolitis.

Bronchus-associated lymphoid tissue (BALT)

Analogous to gut-associated lymphoid tissue (GALT) - Peyer's patches (within wall of small intestine) Located mostly at bifurcations of the bronchus More prevalent after infections Another site for initiation of adaptive immune responses

Deadspace producing pathology

Anatomic - rapid shallow breathing Alveolar deadspace - pulmonary vascular disease - acute pulmonary embolus - decrease in cardiac output Ventilation in excess of perfusion - positive pressure ventilation - emphysema

Causes of deadspace

Anatomic - rapid shallow breathing Alveolar deadspace - pulmonary vascular disease (obliteration of vessels) - acute pulmonary embolus - decrease in cardiac output Ventilation in excess of perfusion - positive pressure ventilation - emphysema (large dilated airspaces)

Shunt and low V/Q producing diseases

Anatomic 1. Congenital Heart Disease 2. Pulmonary Fistula 3. Vascular lung tumor Capillary shunting 1. Acute atelectasis 2. Alveolar fluid 3. Consolidation Perfusion in excess of Ventilation 1. Hypoventilation 2. Uneven distribution of ventilation 3. Diffusion Defect

VD (dead space) =

Anatomic dead space + alveolar dead space Anatomic: gas that remains in the conducting airways (about 1 mL per pound in normal)

Paracoccidioidomycosis

Another endemic dimorphic mycoses; Paracoccidioides brasiliensis Endemic to Latin American countries Pulmonary infection - asymptomatic, self-limiting Dissemination to mucous membranes and skin Histopathology - yeast with multiple buds - "mariner's wheel"

Penicilliosis Marneffei

Another endemic dimorphic mycoses; Penicillium marneffei HIV-infected individuals in Thailand and Southern China Only species of Penicillium that is dimorphic -Intracellular yeast, with single septum Infection mimics tuberculosis or histoplasmosis Patient presentation: -Fever, cough, pulmonary infiltrates, organomegaly, anemia, leukopenia, thrombocytopenia

Immune mechanisms triggered by vaccines

Antibodies CD4 T cells CD8 T cells

Why do we have to get a flu shot each year?

Antigen drift (minor changes) and Shift (major changes)

Steps to T cell activation

Antigen recognition Activation (via the 2 signals) Clonal expansion (IL-2 dependent) Differentiation Effector Functions

Naming of flu

Antigenic type (ABC) / Geographic origin / strain number/ year of isolation

Initiation of vaccine response

Antigens are recognized by PRRs on APCs such as DCs. These antigens are then processed and presented on MHC II (CD4) or MHC I (CD8) to T0 cells in the lymph nodes. From there they can differentiate into the CD4 which helps to drive antibody formation or CD8 which is cytotoxic

Peripheral chemoreceptors send their activation signals via:

Aortic bodies: X cranial nerve Carotid bodies: Hering's nerve via IX cranial nerve

Injury to the cervical spinal medulla causes what type of abnormal breathing problem?

Apnea

Location of single cavities in TB

Appear apical and posterior segments Rarely in the anterior segments

Low V/Q mismatch

Areas of increased perfusion but decreased ventilation

High V/Q mismatch

Areas of increased ventilation but low perfusion

What's the relationship between lactate, VCO2 and VE?

Around 75-80% VO2 max there is a non-linear increase in the production of CO2 This parallels blood lactate and minute ventilation

________ are required to diagnose respiratory failure

Arterial blood gases

Common organisms causing pneumonia immunocompetent individuals with a structural lung disease (CF/bronchiectasis, COPD, ILD)

Aspergillus S.Aureus Pseudomonas sp Enterobacter sp. MAC

Common organisms causing pneumonia immunocompromised individuals who are neutropenic

Aspergillus S.aureus Candida GNR

How does Streptococcus pneumoniae get into the lower respiratory tract?

Aspiration

For pneumonia occur, some organism had to get to the lower respiratory tract, how does this happen?

Aspiration Inhalation Hematogenous spread Direct extension

Interpreting arterial blood gases

Assessment of pH and PaCO2 -acid base -adequacy of ventilation -adequacy of compensation Assessment of arterial oxygenation

M. tuberculosis Primary infection

Asymptomatic or may manifest only by fever and malaise Radiography may show mid-zone infiltrates in the lungs and lymphadenopathy ~5-10% of patients → active disease within 2 years ~90-95% of persons do not develop disease (heal/contain infection/LTBI)

Where is most perfusion and ventilation in the lungs?

At the bases It was thought this was due to gravity, however, about 75% of pulmonary blood flow is dictated by structural changes in the lung (asymmetric branching of vessels) and not gravity The strongest determination of ventilation is regional blood flow/perfusion They are matched!

ARDS recovery phase

Attempts to remove fluid out of the airspace thought to be dependent on the Na+/K+ ATPase and ENaC There is a laying down of matrix and scarring of that space which can contribute to decreased compliance There is a bunch of Type II cells that are differentiating into Type I cells

Bacille Calmette-Guerin (BCG) vaccine

Attenuated (but live) strain of M.Bovis (1924) Used to prevent tuberculosis in developing (and some developed) countries. Not used in U.S. Results regarding efficacy are equivocal - probably effective at preventing disseminated tuberculosis (esp. meningitis) in children -can cause a false positive PPD

7 y old girl, previously in good health, developed a mild fever, headache, and dry cough. 12 y old brother had similar symptoms 2 wks earlier. Over the next 2 days, her temp increased and cough worsened, becoming productive with small amounts of clear sputum. Respiratory rate was 40/min (ref 15-30), scattered rales (crackles) were heard over right posterior lung. White cell count in normal range. Gram stain of sputum revealed no bacteria. Chest X-ray showed right lower lobe infiltrate. Cold agglutinin test was positive

Atypical pneumonia caused by mycoplasma pneumoniae

Histoplasmosis serologic test

Available and requires careful interpretation EIA: Histoplama polysaccharide antigen in urine is useful in diagnosis of disseminated disease

Legionellosis Treatment and prevention

Azithromycin Levaquin No vaccine

When compared to the normal PaCO2 at steady state exercise, PaCO2 at VO2 max is ________? A. increased B. decreased C. the same

B. decreased

Mycoplasma pneumoniae

Bacteria No Cell Wall; NO Gram Stain Pleomorphic Smallest free-living organism known (0.2 mm) Filterable Sterols in their membranes (unique feature among bacteria) Will grow on artificial media (horse serum) as tiny microscopic colonies NOT an INTRACELLULAR PATHOGEN Spread Person-to-person, aerosolization

Nocardia asteroides treatment and prevention

Bactrim (trimethoprim/sulfomethoxazole) There is no vaccine

Barometric pressure and PiO2 as you increase altitude

Barometric pressure and PiO2 both decrease

Viral like particle vaccines

Basically a protein coat is generated without the genetic material. Recombinant DNA technology can be used. The particle is formed and it looks exactly like the virus that is non-infectious Examples: -HPV -Rotavirus

Doxycycline

Belongs to the tetracyclines (protein synthesis inhibitor) Newer drug with a long half-life

Tetracycline

Belongs to the tetracyclines (protein synthesis inhibitor) One of several old drugs with short half lives

Where do we exercise?

Below the lactate threshold or ventilatory threshold If above, we can't sustain that exercise for long Note: so if you're trying to improve VO2 max, you should vary your intensity to exceed that threshold and then go back below it (alternating this)

Strategies to combat complications of altitude

Best is oxygen Slow acclimation Acetazolamide Nifedipine Avoid alcohol

Penicillin G

Beta lactam The original penicillin with a short half life that can be extended by co-injection with benzathine One drug of choice for S. pyogenes infections

Antibodies prevent/reduce infection by:

Binding to enzymatic active sites or preventing diffusion of toxins Neutralizing viral replication by blocking cell adhesion and entry Promoting opsonization/phagocytosis of bacteria Activating complement

Carbon monoxide

Binds hemoglobin with 210x greater affinity than oxygen This means that breathing 0.07% carbon monoxide for a period of time (overnight in a house with a malfunctioning heater) can lead to 50% oxy-hemoglobin and 50% carboxy-hemoglobin (0.07% CO in the alveoli is about 0.5 torr compared with 100 torr for oxygen at sea level) It reduces oxygen content by competing with oxygen for sites on hemoglobin (it decrease only the SaO2) Note that some smokers can have 8-10% carboxyhemoglobin It is odorless, doesn't cause dyspnea, and doesn't cause cyanosis

Chlamydophila psitacci

Bird pathogen and can cause abortion in cattle. Transmitted by inhaling aerosolized dust contaminated with infected bird droppings or animal placenta. Not person to person Macrolides work for these and most atypical pneumonias (Once Chlamydophila is known, however, switch to doxycycline)

Blastomycosis lab diagnosis

Blastomyces dermatitidis: Thermally dimorphic fungus Specimen: Sputum, BAL, BM or skin lesions In tissue: thick-walled, large yeast (8-15 um) with single budding cells w/ wide junction between the cells Not intracellular! In 25°C culture: -SDA and SDA-CC positive, 2-4 weeks; SABHI positive, 1-2 weeks -Hyaline, septate hyphae with single laterally-borne oval to round conidia (3-4 μm) At 37°C: Large single budding yeast cells -(broad-based bud)

Methods of isolating organisms

Blood cultures Sputum cultures/ gram stain Nasal swabs/aspirates Bronchoalveolar lavage Serologies Note: over 50% of community acquired pneumonia have no definitive diagnosis

Acidemia

Blood pH ≤ 7.35 Problems: -enzyme dysfunction -myocardial/ cerebral dysfunction -electrolyte imbalance (usually pushes K+ out of cells) -increase in PVR -unpredictable response to drugs

Alkalemia

Blood pH ≥ 7.45 Problems: -electrolyte abnormalities -lowered seizure threshold -myocardial instability -change in drug interactions -reduced cerebral blood flow

Patients without spleens:

Blood-borne encapsulated bacteria are a major threat May require vaccination against certain pathogens May require prophylactic antibiotics before invasive surgical procedures or dental work

Where is the majority of oxygen in the blood?

Bound to hemoglobin (98.5%) Note: made up of two α and two ß chains with iron bound in the center of each of the subunits. The iron group in the hemoglobin is Fe++ (ferrous iron). The +2 valence allows it to bind reversibly with oxygen

Types of lower respiratory tract infections

Bronchitis Bronchiolitis Typical pneumonia Atypical pneumonia Influenza Empyema

How is M. tuberculosis spread?

By close person-to-person contact through the inhalation of infectious aerosols It is spread only from those individuals with an active TB infection!

How is ventilation regulated?

By constant changes in the respiratory rhythm -rate (frequency) -depth (amplitude) -ratio of inspiratory/expiratory time (I:E)

How do vaccines protect?

By inducing cells and molecules to rapidly control pathogen or inactivate toxins Antigens are recognized by PRRs on APCs such as DCs. These antigens are then processed and presented on MHC II (CD4) or MHC I (CD8)

A 70-year-old man was admitted to the intensive care unit with acute hypoxemic respiratory failure. 48 hours earlier, he underwent a surgical resection of the lower lobe of the left lung for stage IIIB adenocarcinoma of the lung. During the 6-hour operation, he received a total fluid infusion of 5.5 L (including 3 units of packed red blood cells). The cumulative fluid infusion given during the peri-operative period (during surgery and the first 24 hours post-op) was 8.0 L with a net negative 0.7 L. While the patient was in the recovery room, the endotracheal tube was removed without complications, and he transferred to the ward a few hours later. Approximately 36 hours later, dyspnea and hypoxemia were noted, and after 4 hours of continued hypoxemia, the trachea was intubated to facilitate mechanical ventilation. The development of acute respiratory failure in this patient was due to: A. Pulmonary edema due to fluid overload B. Cardiogenic pulmonary edema due to left-sided heart failure C. Acute lung injury/Acute respiratory distress syndrome D. Pneumonia E. Massive pulmonary embolism

C. Acute lung injury/Acute respiratory distress syndrome

Diphtheria vaccine (1891)

C. diptheriae produced a soluble toxin, the first described exotoxin. Heat-inactivated Diptheria toxin was injected into guinea pigs which protected them from subsequent toxin injections Serum from an animal given heat-inactivated Diptheria toxin protected an unimmunized animal that was given virulent toxin -Referred to as 'anti-toxin' In 1891, Emil von Behring used some animal immune serum to treat a child with diphtheria and they survived

Effector T cells

CD4 T cells - Activation of macrophages, B cells, and other cells - They help B cells in the lymph nodes and they exit the lymph node where they migrate into lung airways and parenchyma - Can become memory CD8 T cells -kill infected "target cells" and lead to macrophage activation - Can become memory

Factors that affect minute ventilation

CNS Lungs Chest wall Respiratory muscles

Minuet to minuet breathing is controlled by _____

CO2 This is sense by chemoreceptors and stimulates respiratory activity

How can the central chemoreceptors sense the levels of H+ if H+ is not BBB permeable?

CO2 can easily permeate the BBB. Once inside the blood brain barrier, CO2 is hydrated to carbonic acid (H2CO3) in the presence of carbonic anhydrase and then dissociates to H+ and HCO3-. It is these hydrogen ions, formed in the CSF from the hydration of CO2, that directly stimulate the central chemoreceptors which then stimulate the medullary inspiratory neurons Note: after time, HCO3- is retained, diffuses to the CSF, and this pushes the CSF pH back to normal

Minute ventilation is matched to ______

CO2 production

How is ventilation controlled?

CO2, pH, and O2 levels can be sensed locally by peripheral sensory or enter the blood and travel to central sensors These send information to central controllers in the brain stem This then produces efferent responses to effectors (muscles) which can then produce changes in CO2, pH, and O2 levels

Cell mediated immunity

Can be caused by phagocytosed microbes in macrophages. This leads to a Helper T lymphocyte response causing activation of macrophages which then kill and phagocytose microbes Can also be caused by intracellular microbes (e.g. viruses) replicating within infected cells. This leads to a cytotoxic T lymphocyte respond causing killing of infected cells and elimination of the reservoirs of infection

Influenza vaccine schedule

Can get around 6 months, and it is yearly

PaCO2 is regulated by:

Carbon dioxide production Minute ventilation Dead space PaCO2= (VCO2 (0.863) ) / (VE -VD) Note: can simply to carbon dioxide production and alveolar ventilation (VE- VD)

3 factors that determine PaCO2

Carbon dioxide production (in general this is thought to be relatively constant at rest (200ml/min). It can be increased by fever, seizures, agitation, and excessive enteral feeding in the ICU, however.) Minute ventilation ((respiratory rate x tidal volume) can be decreased by drugs, neuromuscular disease, or lung disease.) Amount of dead space (can be increased due to a number of things such as positive pressure ventilation, rapid shallow breathing, pulmonary embolism, pulmonary vascular disease and decreases in cardiac output. In the intensive care unit, abnormalities in PaCO2 are frequently due to changes in dead space (i.e. too little Q for the V).)

Acute compensation to increased PaCO2

Carbon dioxide will diffuse into the red cell where, in the presence of carbonic anhydrase, CO2 will be hydrated to carbonic acid; carbonic acid then dissociates into H+ and HCO3- (this is the same reaction that occurs in the tissues when CO2 is transported to the lung using the bicarbonate system). The H+ is buffered by hemoglobin and intracellular proteins and HCO3 exits the red cell down its concentration and electrical gradient: H2CO3+−Hb -->HHb+−HCO3. (Chloride shifts into the cell to maintain electrical neutrality). This acute buffering will raise the HCO3 about 1 meq/L per 10 mmHg change in PaCO2. Thus an increase in PaCO2 from 40 to 50 mmHg will lead to an immediate increase in HCO3- from 24 to 25 meq/L. Not a great buffer, but important.

Fick equation at VO2 max

Cardiac output and CvO2 will differ

What determines VO2 max

Cardiorespiratory efficiency Muscle - type 1 (slow oxidative): high endurance and use O2 efficiently - type IIa (fast oxidative): can have high VO2 maxes but to lesser extent than type 1 - type IIb (fast glycolytic): great sprinters but unable to sustain aerobic activity for periods of time Cellular respiration

How can you control TB?

Case-finding and treatment of active disease Chemoprophylaxis of infected cases BCG vaccination

Chlamydophila pneumoniae

Cause 10-20% of atypical pneumonias. Replication- elementary (infectious) vs reticulate bodies. Human-to-human transmission via lung secretions Macrolides work for these and most atypical pneumonias (Once Chlamydophila is known, however, switch to doxycycline)

Pulmonary histoplasmosis

Caused by histoplasmosis Enters the lung via environmental inhalation CXR show a nodular pattern scattered throughout, but cannot provide the diagnosis CT would also show nodular patterns Generally doesn't affect immunocompentent individuals greatly Endemic to the Midwest area

Damage to Supra-pontine central controllers

Causes Cheyne- stokes respiration: Crescendo-decrescendo pattern followed by apnea: - loss of the feedback integrative ventilatory capacity - respiratory alkalosis (hyperventilation > apnea) Can be caused by high altitude, CHF, stroke, and sleep apnea

Haemophilus ducreyi

Causes chancroid

Haemophilus aegyptius

Causes conjunctivitis and purpuric fever

Influenza C

Causes mild respiratory illnesses and are not thought to cause epidemics

M. Kansasii

Causes ~3% of non-M. tuberculosis mycobacterial disease in the US, most common in Illinois, Oklahoma and Texas -unknown reservoir Resembles tuberculosis and tends to be slowly progressive without treatment -cavitary pulmonary disease, cervical lymphadenitis and skin infections; disseminated infections can also occur -important cause (2nd to MAC) of disease in AIDS patients; clinical features closely resemble TB in AIDS patients -positive PPD tests may result from clinical/subclinical M. kansasii infection Prolonged combined therapy with isoniazid, rifampin and ethambutol is usually effective

What type of immunity involved in influenza

Cell mediated immunity, T cells --> recovery and immunopathogenesis

Beta lactam drugs MOA

Cell wall inhibitors via inhibition of transpeptidase

How is carbon dioxide generated in the body?

Cellular respiration

The responsibility for regulating PaCO2 levels rests primarily with:

Central chemoreceptors localized in the medulla They are more sensitive to change in blood PCO2 than to changes in blood hydrogen ion concentrations. Therefore acute elevations in PaCO2 is much more potent ventilatory stimulus than an acute elevation of [H+]

Parrots and domesticated birds exposure increases risk of inhalation of:

Chalmydia psittaci (psitaccosis)

Strategies to increase hemoglobin-oxygen affinity

Change HB chain: Llama - The llama that changes its HB chain and generates a hemoglobin with a lower P50 (left shift) Goose: -genetically left-shifted hemoglobin -ability to markedly increase VE -countercurrent gas exchange Fetal hemoglobin: fetus: -This type of hemoglobin as a higher affinity for oxygen within hypoxic environments (left shift). This type of hemoglobin contains two chains of α chains and two gamma chains which do not bind 2,3 DPG. This beings to shift to adult hemoglobin around 4-6 months Smaller Bohr Effect -hemoglobin that does not bind carbon dioxide very well and therefore doesn't shift the curve to the right Respiratory alkalosis Decrease 2,3 BPG

How is ventilation modified?

Changes in ventilatory rate (frequency): tachy- or brady-pnea Changes in ventilatory depth (amplitude): hyper or hypo-pnea

Acute respiratory distress syndrome (ARDS)

Characterized by diffuse alveolar infiltrates often in the dependent lung zone (bottom). This means that there is fluid with protein and sometimes bacteria that are filling the airways. This leads to alveolar collapse and areas of consolidation (the difference in these is that in consideration the alveolar airspace is open and you can see the borders of the septa; however, it is difficult in both cases to get oxygen into the airspace) Clinical definition: - acute onset - diffuse bilateral infiltrates on X-ray - refractory hypoxemia - low pulmonary artery wedge pressure (≤ 18 mmHg) - Decreased lung compliance

Sensors throughout the body

Chemoreceptors -Central -Peripheral (Carotid body and Aortic body) Lung receptors -Stretch (mechano-receptors) -Irritant -J -Bronchial C-fibers -Propio-receptors Other receptors: -Upper airway irritants -Joints and muscles -Gamma system -Baroreceptors

The inputs to the central respiratory controller include:

Chemoreceptors which monitor arterial PCO2, PO2, and [H+] (i.e. pH) levels Lung sensors which monitor lung mechanics and can alter the depth of respiration in response to changes in stretch or following exposure to noxious stimuli Central (cortical) input to voluntarily alter the respiratory pattern to allow speech, eating, or recreational inhalation

H7N9

China, 2013, flu strain Contained a triple reassortment 30% death rate Came from poultry

A 62 year-old male with a previous diagnosis of COPD presents to the emergency room with severe dyspnea that have progressively increased during the last 24 hours. Physical examination: diaphoretic, tachycardic, temp 38.2°C, respiratory rate 28Xmin, peripheral cyanosis. ABGs: 7.35/56/54/31/72. After 1 hour controlled O2 support new ABGs are 7.24/62/54/32/72 Question: What happens?

Chronic adaptation to high levels of CO2 involves up-regulation of CA in the CSF causing increases in HCO3- which buffers decrease in pH and decreases H+ stimuli Thus, in COPD, acute rises in CO2 are thus, not accompanied by increases in ventilatory drive as experienced by normal subjects

What is the primary disease caused by cryptococcus?

Chronic meningitis The onset is slow, with low grade fever and headache progressing to altered mental state and seizures In the CSF and tissue, the inflammatory responses if often remarkably muted Most patients have obvious signs of immune compromise, although some show none

Bacillus anthracis treatment

Ciprofloxacin Administer antiserum to PA subunit if septic anthrax

Coccidioidomycosis Lab diagnosis

Coccidioides immitis: Thermally dimorphic fungus In tissue: Huge (20-60 μm) thick-walled, round "spherules" filled with small (2-5 μm) endospores Spherules rupture In 25°C culture: -SDA and SDA-CC positive, 2-4 weeks; SABHI positive, 1-2 weeks -Hyaline septate hyphae forming barrel-shaped arthroconidia At 37°C: Thermal conversion requires animals, but is not done

Coccidioidomycosis skin test

Coccidioidin skin test, not available in the US

Aspergilloma (fungus ball)

Colonization of the organism in the paranasal sinuses and the lower airways Obstructive bronchial aspergillosis Occurs in pre-formed cavitary lesions such as those in cystic fibrosis, chronic bronchitis, and TB Causes no tissue damage is these patients are usually asymptomatic Will see the hyphae growing the the tissue and also the terminally differentiated structures the organism uses to form conidia (conidiaphores)

Coccidioidomycosis serologic tests

Combination of latex agglutination and immunodiffusion tests detects >90% early in symptomatic illness Complement fixation (CF) tests for Dx Serial CF titers are useful for prognosis - Rising titer = poor prognosis

Pulmonary Coccidioidomycosis

Comes from Coccidioidomycosis endemic to the southwest Presents with coccidioimycosis spherules in the lung CXR can't provide the diagnosis, will just see lung infiltrates Enters the lung via environmental inhalation Generally doesn't affect immunocompentent individuals greatly

Pulmonary blastomycosis

Comes from blastomycosis which is a broad-based yeast Endemic to the East

Disseminated Coccidioidomycosis

Comes from coccidioides immitis for example and enters the lung through the blood. Therefore it is more prominent in the bases where blood flow is the greatest. It presents with fine nodules on CXR but culture would be needed for diagnosis Often presents as pneumonia in those who are immunocompromised

Miliary Histoplasmosis

Comes from histoplasmosis that enters the lung through the blood. Therefore it is more prominent in the bases where blood flow is the greatest. It presents with fine nodules on CXR but culture would be needed for diagnosis Often presents as pneumonia in those who are immunocompromised Note: where they live can help distinguish

Direct causes of lung injury (ARDS)

Common causes • Pneumonia • Aspiration of gastric contents Less common causes • Pulmonary contusion • Fat emboli • Near-drowning • Inhalational injury • Reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy

Indirect causes of lung injury (ARDS)

Common causes • Sepsis • Severe trauma with shock and multiple transfusions Less common causes • Cardiopulmonary bypass • Drug overdose • Acute pancreatitis • Transfusions of blood products

Causes of hyperventilation (PaCO2 ≤ 35 mmHg)

Compensation for a metabolic acidosis In response to hypoxemia/hypoxia Stimulation of central nervous system

Injury to the RTN central chemoreceptors causes what type of abnormal breathing problem?

Congenital Central Hypoventilation Syndrome (CCHS)

How can you make polysaccharide vaccine induce a long term memory B cell response with immune memory

Conjugate it with a toxoid (protein)! The B cells and Helper T cells are activated leading to further B cell activation and the formation of memory B cells who mainly secrete IgG Examples: -Typhoid -Pertussis (acellular) -S.pneumo (PS, Conj) -H.Influenzae (b)(PS, Conj) -N.meningoccus (PS, Conj)

Clinical approach to diagnosing pneumonia: Patient location

Consider if they are coming from the community or some health care facility Usually considered to be from a health care facility if they were exposed to one within the last 2-3 months

Hypoxic pulmonary vasoconstriction (HPV)

Consists of contraction os smooth muscle in the small arteries in a region of lung with alveolar hypoxia Mechanism likely involves inactivation of ion channels (likely potassium) in the smooth muscle cells of the small muscular arteries This will reduce the amount of ventilation perfusion inequality in a diseased part of the lung and liming arterial hypoxiema

increased tactile fremitus

Consolidation in the lung (replacement of air with fluid, blood, pus, or other fluid) as occurs in pneumonia Atelectasis not due to an obstructed central bronchus or pleural effusion

Medulla: VRG central controller

Constitutively inactive, activated during situations other than eupnea ("intense" breathing) Function: rostral area stimulates inspiration and caudal area stimulates active expiration (contraction of abdominal and internal intercostal muscles): -N. ambiguus: laryngeal and pharyngeal muscles -N. retro-ambiguus: diaphragm, intercostal, and abdominal muscles

Lymph nodes

Contains afferent and efferent lymphatics flowing in/out The follicles contain the B cell zone. Within these are germinal center which are where B cells undergo class-switching, somatic hypermutation, etc The paracortex contains the T cell zone

Adequate tissue oxygenation is mainly dependent on:

Content (CaO2) -hemoglobin -oxygen saturation Flow -cardiac output

Standard oxygen-hemoglobin dissociation curve

Controlled at: pH: 7.40 PCO2: 40 mmHg Temp: 37 C

Injury to Suprapontine and PRG: LPBr central controllers

Could increase activity leading to increased frequency (tachypnea) and depth (hyperpnea) Central neurologic hyperventilation is caused by tumors, trauma, and tectorial herniation and is a common example of this

Sheep exposure increases risk of inhalation of

Coxiella burnetti (Q fever)

Blastomycosis serologic tests

Cross reactions with histoplasmin and coccidioidin Lack sensitivity and specificity

Definitive Identification of Blastomyces dermatitis

Culture must show temperature regulated-phase conversion Exoantigen test can allow for definitive ID without regulated phase conversion!

Active tuberculosis

Culture positive for M. tuberculosis or clinical disease consistent with tuberculosis in absence of positive culture Children are frequently culture negative

Oxygen acts at _______

Cytochrome C oxidase to accept electrons and makes H2O

52 year old male with HIV and a CD4 count of 25 presents with fever, cough, and dyspnea on exertion for 3 week. He is not on any retroviral or prophylactic therapy The Patient's Medical History Puts Him at a Particularly Increased Risk for Which Of The Following Organisms? -Pseudomonas aeruginosa -Bacillus anthracis -Neisseria meningitidis -Cytomegalovirus

Cytomegalovirus (has inclusion bodies) With the significantly low CD4 T cell count, he is most at risk for CMV infections

Side effects of Fluoroquinolones

Damage to growing cartilage and thus contraindicated in children Rare tendonitis with possible tendon rupture Photosensitivity QT prolongation

Volutrauma

Damage to the lung caused by overdistension by a mechanical ventilator set for an excessively high tidal volume. It results in a syndrome similar to ARDS

Complications of Untreated apnea

Daytime sleepiness with increased risk for automobile and industrial accidents have been demonstrated in this population. The increased risk for systemic hypertension and ease in risk for cerebral vascular accidents, congestive heart failure, and coronary artery disease. This increased risk appears to be related to both systemic hypertension and possibly the hypercoaguable state that accompanies untreated apnea Interestingly, effective therapy, i.e. that which decreases apnea frequency to less than five episodes per hour decreases the risk of cardiovascular morbidity up to ten fold when compared to the untreated apneic population. Alarmingly, it is estimated that approximately 1 in 10 adult with apnea frequency greater than five per hour of sleep has been diagnosed and is undergoing effective therap

Things that lead to low oxygen-hemoglobin saturation (SaO2)

Decrease PaO2 Right shift of the oxygen-hemoglobin curve -fever, acidosis, hypercarbia Abnormal hemoglobin -carboxy-hemoglobin (CO-Hb) -methemoglobin (Fe+3)

Why would you abnormally retain carbon dioxide?

Decrease in minute ventilation -Neuromuscular disease -Severe lung disease -Drugs that suppress respiratory drive -CNS issues (stroke, obesity hypoventilation) Excessive increase in dead space -Emphysema -Drop in cardiac output * Cardiogenic shock * Cardiac arrest * Hypovolumic shock * Pulmonary embolism

Things that shift the oxygen-hemoglobin dissociation curve to the right

Decrease in pH Increase in DPG Increase in Temp Increase in PaCO2 Note: this helps to offload oxygen in the tissues

In a normal person (not in hospital) what is the only way to effectively increase the PAO2

Decrease the arterial CO2, which can be done via hyperventilating and blowing it down

What is the effect of PEEP on oxygenation?

Decrease the shunt fraction Decrease dead space Improve compliance

Management of ARDS patents with pH > 7.45

Decrease ventilatory rate

What can lead to lactic acidosis

Decreased CaO2 -decreased hemoglobin -low SaO2 Decrease in cardiac output -decrease in volume (pre-load) -decrease in contractility -decrease in heart rate Drugs -cyanide -carbon monoxide -HIV drugs

What two things improve mortality in ARDS patients

Decreasing tidal volume Improve ICU supportive care

Kussmaul respirations

Deep regular, sighing hyperventilation Caused by academia (e.g. diabetic ketoacidosis) This minimizes the percent of anatomic deadspace and leads to more effective ventilation.

The diseases processes of mycobacterial diseases are primarily due to what two related host responses?

Delayed type hypersensitivity (DTH) reaction to mycobacterial proteins → results in the destruction of non-activated macrophages Cell mediated immunity (CMI) → activates macrophages enabling them to destroy intracellular mycobacteria

Defenses in airways and their mucosa: blood derived cells of the mucosa

Dendritic cells (DCs) - positioned above and below the basement membrane, dendrites extend between the epithelial cells - sentinels, use PRRs to detect pathogens - after antigen intake and activation, they migrate to pulmonary lymph nodes and activate naive T cells - These are the bride to innate and adaptive defenses Eosinophils, mast cells, and basophils - immediate hypersensitivity reactions - allergic diseases Lymphocytes - in absence of inflammation: few T and B cells - after infection: T and B cells are found in bronchus associated lymphoid tissue: BALT

What bacteria are within the mouth?

Dental plaques: culture positive in 25% of NH patients -Pseudomonas, Staph aureus, E.coli Organisms in dental plaques found in BAL 3 days later. These can be aspirated and lead to pneumonia

Side effects of Tetracyclines

Dental staining in children and photosensitivity

Treatment for High altitude cerebral edema

Descent Dexamethasone Gamow bag

Treatment for high altitude pulmonary edema

Descent Oxygen Nitric oxide Nifedipine Note: these all cause vasodilation in the pulmonary circulation

Purified protein deviated (PPD)

Developed in 1931 It is precipitated protein fraction from a single strain of human tubercle bacillus Precipitated protein from cell wall It is purified and potent Non sensitizing (can be given repetitively and will not itself induce a positive skin test) Dose could be standardized and delivered subcutaneous (Mantoux test) - standard PPD: 5 TU = 0.0001 mg

Effectors that regulate the ventilatory drive

Diaphragm (C3-C5 via phrenic nerve): inspiration Intercostals: -External (T1-T12 via intercostals): inspiration -Internal (T6-L3 via intercostals): expiration Abdominals (T4-L3 via lumbars): expiration Neck (via XI cranial nerve): inspiration (accessory) Oral cavity/upper respiratory tract (via XII cranial nerve): inspiration (accessory)

Causes of hypoxemia with increased A-a O2 gradient (usually >14)

Diffusion (blood moves too quickly) Low V/Q mismatch Shunt This tells you that blood is coming form poorly or unventilated areas

59-year-old white male Presents in Pensacola, FL with a 3 month history of fatigue, weakness, intermittent fever, chills, shortness of breath Development of ulcerative lesions on his right thigh and left forearm Purulent discharge Previous oral antibiotics have failed Past medical history: -Hypertension, arthritis and gout Patient is an avid gardener Travel history over past year: Minnesota, Wisconsin and Ohio Spelunking trip to Indiana Physical exam -Mildly tachypenic -Dyspnea upon exertion Chest x-ray: -single, large patchy density in the upper left lung Vital signs: -Temp = 102.5F -HR = 131 -BP = 115/70 -RR = 20 Skin: -Right thigh showed scattered erythematous 3-4 cm ulcers -Left forearm showed a single 1 cm subcutaneous nodule Initial Lab data: WBC: 17,100 /µL (4,000-11,000) with 83% PMN's Hgb:10 g/dL (13-16.7) ALP: 385 U/L (32-148) Hct: 30% (38-50) AST: 65 U/L (15-37) BUN: 23 mg/dL (6-20) ALT: 160 U/L (30-65) Creat: 0.9 mg/dL (0.4-1.3) GGT: 887 U/L (11-49) Total Bili: 3.8 mg/dL (0.4-1.2) An aspirate of the subcutaneous lesion was submitted fro C&S and fungal culture -Direct gram stain report showed large budding yeast - Acid fast stain report showed large broad-based budding yeast was seen

Disseminated Blastomycosis For our patient: -Hospitalized for 10 days -Treated with Amphotericin B, followed by long term azole therapy Our case highlighted common features of disseminated Blastomycosis -Seemingly previously healthy patient -Chronic cutaneous involvement

Bacillus anthracis toxins

EF toxin (edema factor) an inactive form of adenylyl cyclase that becomes active once it enters the cell and binds host calmodulin. cAMP increases, setting up a cascade leading to water leaving the cell LF toxin (lethal factor) is a protease that cleaves certain MAP kinases, altering cytokine production

31-year-old, African-American US Army Soldier Presents with fever, chills, night sweats, non-productive cough of 4 weeks Past medical history unremarkable Recently detected a painless right breast mass Stationed at Fort Irwin, CA Physical exam: -Unremarkable -Firm, nontender, 3-cm subcutaneous mass over right breast -Multiple small nontender lymph nodes were palpable in the axillae and groin Lab results: -WBC = 11.9/µl, 30% eosinophils -Elevated alkaline phosphatase Blood cultures = negative Cryptococcus antigen = negative Histoplasma urine antigen = negative HIV antibody = negative Tuberculin test = negative CT scan of chest revealed diffuse, 1-2 mm micronodules in all lobes and right chest wall mass. Fine needle aspirate of the mass revealed spherules filled with endospores Culture grew Coccidioides immitis Serology panel for C. immitis was positive CSF = normal Bone scan revealed multiple region of increased osteoblastic activity

Disseminated Coccidioidomycosis For our patient: -In spite of Amphotericin B treatment, neck pain increased and progressive enlargement of the mass was noted -Surgical debridement -Long-term antifungal therapy Clues to the diagnosis of disseminated coccidioidomycosis included an infectious prodrome, peripheral eosinophilia, hilar lymphadenopathy, characteristic pattern of organ involvement (lungs, bones, soft tissues), residence in an endemic area, and African-American ethnicity.

A 42-year-old woman Admitted to hospital for evaluation of progressive dermatosis involving the right nostril, cheek, and lip Antibiotic therapy failure Originally from southern Indiana, but has lived in Miami for the last 18 years -HIV +: CD4 lymphocyte = 21/µl Lesion first appeared on the right nostril 3 months before admission -Patient sought medical treatment -Oral antibiotics were unsuccessful The lesion increased in size over the next 2 months, to include the right nare and malar region -Fever, malaise, weight loss -Necrotic area developed from right nostril to lip Laboratory studies: -Anemia -Lymphopenia -Normal chest x-ray -CT scan of head showed a soft-tissue mass in the right nasal cavity Histopathology of skin biopsy showed chronic inflammation, with intracellular budding yeasts Culture grew Histoplasma capsulatum Histoplasma antigen test was positive (detects polysaccharide in urine)

Disseminated Histoplasmosis Our case study underscores important aspects of Histoplasmosis Dormancy: -H. capsulatum is not endemic to Miami, but is to the Ohio River Valley -Reactivates upon immune suppression Cutaneous presentations are often a consequence of progression from primary to disseminated disease High index of suspicion and confirmation with skin biopsies, cultures and testing for urinary antigen were crucial for timely and appropriate treatment of disseminated histoplasmosis -Our patient was treated with amphotericin B followed by intraconazole with recovery

What two ways are oxygen carried in blood?

Dissolved in blood (plasma) (1.5%) Bound to hemoglobin (98.5%)

Carbon dioxide is carried from tissues to the lungs in what 3 ways?

Dissolved in the blood (dCO2) (5%) It can bind to hemoglobin and generate carboxyhemoglobin (HbCO2) (30%) It can enter the RBC and uses carbonic anhydrase and is transported as HCO3- (65%)

Opportunistic hyalopyphomycoses

Diverse agents Many are ubiquitous - inhaled conidia Many are resistant to antifungal agents In tissue, they appear indistinguishable from Aspergillus! (I.e. branching, septate hyphae) For these, repeated isolation from multiple sites/multiple times is the best criteria to determine the clinical significance and determine the treatment!

Latent TB infection (LTBI)

Do not feel sick and do not have any symptoms Only signs of TB infection is a positive reaction to the tuberculin skin test or TB blood test; normal CXR but may have evidence of calcification of granulomas in the lungs or other organs Cannot be spread to others in its latent form!

CD4 T (helper) cells

Do not prevent infection, but help in the reduction, control, and elimination of intracellular and extracellular pathogens Th1, Th2, Th9, Th17

CD8 (cytotoxic) T cells

Do not prevent infection, but reduce, control, and clear intracellular pathogens by: -Directly killing infected cells -Indirectly killing cells by antimicrobial cytokine release

The arterial blood gases can:

Document the type and severity of acid-base disorders Document the adequacy of compensation for acid-base disorders Document the type and severity of gas-exchange disorders

What questions should you ask yourself in determining if a TB patient with a positive PPD requires treatment?

Does the skin test represent a true tuberculous infection -size of induration -risk of exposure - CXR What is the risk of progressing to active disease - time from initial infection - co-existing medical problems - CXR What can you do about it

Working thorough latent tuberculosis

Don't test low risk individuals.... -unless they are going into a high risk environment (Peace Corp, military, health fields, jail, nursing home) If infected (+ PPD or IFRA) -ask about symptoms -check CXR -check sputum if indicated (based on sx and CXR)

Prevention of Hantavirus pulmonary syndrome

Dont sniff mouse piss

Dullness to percussion

Dullness to percussion (occurs when fluid or solid tissue replaces air-containing lung or occupies the pleural space beneath your percussing fingers). large pleural effusions lobar pneumonia areas of atelectasis

How does exercise influence blood pH?

During exercise, there is increased CO2 and lactate. This lads to an overall decrease in blood pH Note: most of this is corrected by blowing off a lot of CO2

Overall, ESKAPE pathogen antibiotic resistance mechanisms

Efflux Immunity & bypass Target modifications Inactivating Enzymes

Treatment for Streptococcus pneumoniae

Empiric therapy for community acquired pneumonia (CAP) -Macrolides or doxycycline (both inhibit protein synthesis) Once identified as S. pneumoniae -Ceftriaxone - some resistance emerging- altered PBP; backup is Vancomycin (inhibits cell wall synthesis, only used IV) Last resort includes Chloramphenicol (worry about aplastic anemia); or quinolones (preferably not in young kids- inhibits growth plates). (inhibits protein synthesis)

Asplenic patients are at higher risk of infection by:

Encapsulated organisms -Streptococcus pneumoniae -Salmonella typhi -Neisseria meningitidis -E. coli -Hemophilus influenzae -Streptococcus agalactiae -Klebsiella pneumoniae

Histoplasmosis epidemiology

Endemic - MS & OH river valleys. Soil enriched with nitrogen (bird/bat droppings, caves, urban renewal projects) Transmission by inhalation of airborne microconidia No disease in birds; disease in man, and some animals

Blastomycosis Epidemiology

Endemic around the midwest (MO, MS & OH U.S. river valleys ) Ecologic niche is unclear - moist soil w/ high organic content Rarely isolated from soil; microconidia believed to be infective Infection initiated by inhalation of infectious propagules

Coccidioidomycosis epidemiology

Endemic in arid, temperate, desert climate -especially Southwest United States Travel history - Central-Southern CA; south NV, AZ,NM,TX Fungus grows in soil and matures to form arthroconidia Infection is initiated by inhalation of infectious arthroconidia Filipinos, African/Native Americans & Hispanics - greatest risk of dissemination

ESKAPE pathogens

Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Acinetobacter baumannii Pseudomonas aeruginosa Enterobacter spp.

3 general ways of inhalation

Environmental inhalation Animal Exposure Inhalation from other humans

Pneumocystosis

Etiology: Pneumocystis jirovecii Most common opportunistic infection among individuals with AIDS -Incidence has decreased significantly with HAART Reservoir in nature unknown Pneumonia is clearly the most common presentation -Interstitial pneumonitis, mononuclear infiltrate -Onset insidious -Diagnosis based on microscopic examination of BAL

Nocardia asteroides diagnosis

Examination of sputum pus for Gram positive branching organisms. Bronchoscopy gets a better sample Acid Fast positive. Differentiates Nocardia from Actinomyces

Major mechanism of ESKAPE antibiotic resistance: Edit the antibiotic

Examples 1: Post-translational -Phosphorylation -Acetylation -Adenylation 2: Destruction

Major mechanism of ESKAPE antibiotic resistance: Increase antibiotic efflux

Examples for Gram positive: -ATP Binding Cassette Superfamily (ABC) -Major Facilitator Superfamily (MFS) -Multi-drug and Toxic Compound Extrusion Family (MATE) -Small Multidrug Resistance Family (SMR) Examples for Gram negative: -ATP Binding Cassette Superfamily (ABC) -Major Facilitator Superfamily (MFS) -Resistance Nodulation Division Family (RND) These all allow a greater efflux of the antibiotic out of the cell

Major mechanism of ESKAPE antibiotic resistance: Change/modify drug target

Examples include mutations causing rRNA methylation (23S rRNA of the 50S subunit) which alters the ribosome such that it is not affected by the antibiotic Another example is PBP being changed to PBP2a which has a low ß-lactam affinity preventing the actions of those antibiotics targeting PBP

decreased tactile fremitus

Excess air in the lungs (emphysema, pneumothorax) Fluid in the pleural space (pleural effusion) Atelectasis due to an obstructed central bronchus

Compensation for respiratory alkalosis

Excretion of HCO3- (by Kidney) Takes time (48-72 hours minimum) for compensation -Can move pH into normal range given time Winter's Equation can be used to confirm that a respiratory alkalosis is present

What things increase carbon dioxide production (VCO2)

Exercise Seizures Fever Excessive feeding Hyperthyroidism

Exercise effect on venous PCO2 and PaCO2

Exercise Increases venous PCO2 and decreases PaCO2 at a high intensity (the reduction is due to high alveolar ventilation) Note: PaO2 actually increases with near maximal and maximal exercise bouts (due to a decrease in alveolar CO2)

How to RTN sensor cells work?

Express VGLUT2 proteins Increases in H+ and potentially increases in CO2 as well causes activation of: - H+-regulated G-protein coupled receptor 4 (GPR4) - H+-sensitive two pore domain K+ channel (TASK-2) Net effect of activation: cell depolarization leading to neurotransmitter release and activation of the respiratory pattern generator (RPG).

Respiratory compensation is ____

FAST

Presumed mechanisms of acute mountain sickness

Failure to diurese at altitude leading to increased extracellular fluid Blunted hypoxic ventilatory response leading to increased cerebral blood flow

Hypercapneic (ventilatory) respiratory failure

Failure to excrete CO2 Note: can also be combined with hypoxic respiratory failure

High strength PPD increase _______

False positive rate Therefore the standard PPD is 5 TU= 0.0001 mg

What is the VO2 max in the general population

Female (20-29 yr): 35-43 ml/kg/min Male: (20-29 yr): 44-51 ml/kg/min Note: there have been really impressive recorded VO2 max with the best being 97.5 ml/kg/min

Clinical presentation of pneumonia

Fever/cough Leukocytosis Infiltrate on CXR Sputum production Hypoxia Note: due to virus, fungus, parasite, or bacteria

Usual interstitial pneumonia CXR

Fibroblastic foci Honeycombing Heterogeneity

Tuberculin

Filtrate of culture broth which would cause severe reaction in patients with active TB Attempted to cure TB with this, though it failed, the diagnostic utility of the test has been recognized Was used to help control bovine tuberculosis (would kill those infected) Problem was that is was non standardized (1% active, 99% inert)

PRG: Kolliker fuse central controller

Fine tuning rhythm, increase frequency (respiratory rate) and decrease amplitude (tidal volume) Function: Support inspiratory ramp

Suprapontine and PRG: LPBr central controllers

Fine tuning rhythm, increase frequency (respiratory rate) and decrease amplitude (tidal volume) Function: Switches inspiration to expiration. Increases rate (frequency) and decreases depth (volume) of ventilation

1998 Consensus definition of ARDS

First, it recognizes that the severity of clinical lung injury varies: patients with less severe hypoxemia (as defined by a ratio of the partial pres- sure of arterial oxygen to the fraction of inspired ox- ygen of 300 or less) are considered to have acute lung injury, and those with more severe hypoxemia (as defined by a ratio of 200 or less) are considered to have the acute respiratory distress syndrome. It is simple to apply in the clinical setting

M. tuberculosis prophylactic regimens

For use in patients (HIV+ and HIV-) exposed to M. tuberculosis Daily or twice weekly INH for 6 to 9 months or daily rifampin for 4 months Short course regimen: weekly rifapentine (rifampin derivative) and INH for 12 weeks

Influenza A

Found in animals (pigs, birds, humans) Genetically unstable Responsible for epidemics

Neutrophils in the alveolar spaces

Found within the alveolar spaces really when they are recruited (via CXCL8 and NCP1) These are professional phagocytes and when activated ingest a large number of microbes and destroy them via oxygen dependent mechanisms They also produce ROS and other proteases that can lead to tissue damage They also produce NETs though which they release their DNA and trap microbes and prevent them from dissemination

Environmental inhalation

Fungus -Coccidiomycoses -Histoplasmosis -Blastomycosis -Cryptococcus neoformans -Aspergillus pneumocystis Legionella -Water sources Anthrax -Contaminated wool -disgruntled microbiologists

Examples of Opportunistic hyalopyphomycoses

Fusarium (R to ampB), immune reconst. + new triazoles Scedosporium (R to ampB) - surgical resection Acremonium (S unestablished) Paecilomyces - voriconazole

Requirement for calculation of VO2 max

Graded exercise Measure volume of inspired oxygen Measure volume of expired oxygen measure oxygen consumption Standardize to size EKG, oxygen saturation Mask with 2-way valve: Inspire room air, expire through sensors to measure volume and oxygen concentration Treadmill: Increasing speed and/or incline

Legionella pneumophila

Gram negative Rod Very difficult to grow Requires cysteine and hemoglobin BCYE media (buffered charcoal yeast extract) Facultative intracellular pathogen Source: Natural and Treated water, Lakes, ponds, water heaters, Cooling towers L. pneumophila is harbored in amoeba in natural environment. Invades alveolar macrophages

Acinetobacter baumannii

Gram negative coccobacillus, non-motile On skin (not in usual subjects); recovered with body lice In oropharynx and respiratory secretions of infected patients Makes biofilm and colonizes medical devices Virulence due to: OmpA - an outer membrane protein that causes host mitochondrial swelling, fimbriae, phospholipase C and D At risk: -Immunocompromised patients -Prolonged use of medical devices -Operation Iraqi Freedom

Enterobacter spp.

Gram negative facultative, anaerobic rod Motile - peritrichous flagella and fimbriae Can colonize the lower GI tract, skin and urinary tract Virulence due to: Lipid A/endotoxin, siderophores, adhesions At risk: - Immunocompromised patients -Prolonged use of medical devices

Pseudomonas aeruginosa

Gram negative motile rod Aerobic and non-aerobic Common in wet and moist areas, can be commensal in GI tract Makes biofilm and colonizes medical devices Virulence due to: Type III secretion system, lipopolysaccharide, exoproteases, flagella, pili At risk: -Immunocompromised patients -Prolonged use of medical devices

Haemophilus influenzae

Gram negative rods (Lipooligosaccharide) Typeable strains - ribitol capsules Most common pathogenic type is type b (Hib). Also Nontypeable strains Humans are the Only Reservoirs Transmission by aerosolization Chocolate Agar, No Grow on Blood agar Require X (Hemin) and V (NAD) Oxidase positive

Klebsiella pneumoniae

Gram negative, encapsulated, non-motile rod Natural inhabitant of oropharynx, GI tract, skin Makes biofilm and colonizes medical devices 3-8% of nosocomial infections Virulence due to: polysaccharide capsule, LPS, fimbriae, siderophores At risk: -Immunocompromised patients, i.e., alcoholism, diabetes -Prolonged use of medical devices

Vancomycin only affects:

Gram positive bacteria only

Staphylococcus aureus

Gram positive coccus Natural inhabitant of skin microbiota Makes biofilm and colonizes medical devices Cell wall sieves 100,000 Da limit Methicillin-susceptible vs -resistant

Streptococcus pneumoniae

Gram positive diplococci Polysaccharide capsule (soluble, sheds "decoy" capsule) Catalase negative Alpha hemolytic on blood agar (due to H2Ó production on blood plate) Also produces pneumolysin (released upon bacterial lysis and causes tissue damage (apoptosis, C' activation at a distance) It is very autolytic, which is related to bile solubility > 80 Serotypes (Capsular Ag)- Antiphagocytic

Enterococcus faecium

Gram positive facultative anaerobe Inhabits the gut of humans/animals 3rd most prevalent nosocomial pathogen Prominent resistance Not principal cause of lower tract infections

Nocardia asteroides

Gram positive, branched bacteria (looks like fungi) Weakly acid fast Organisms are inhaled from environment. No person-to-person transmission Survive inside phagocytes Granules of dense masses of filaments in tissues. Cavitation can develop Very slow growth, can take 2 weeks to form colonies. Blood cultures are possible but may take 4 weeks

Bacillus anthracis

Gram positive, sporeforming rods In vivo capsule (polypeptide) Secretes tripartite toxin (EF, LF, PA components) Zoonotic disease - spores are in soil, can contaminate animal hides Spores enter body via inhalation (Workers handling animal hides; Wool sorters disease), or in wounds (cutaneous anthrax is the most common form, Black Eschar) Pulmonary anthrax- spores germinate in alveoli, release toxins Toxins affect Alveolar Macrophages - apoptosis (LF); inhibit phagocytosis and cause fluid accumulation (EF) Pneumonia develops Person-to-person transmission via direct contact (wounds), rarely aerosolization (need too many spores)

Ranke complex

Granuloma plus ipsilateral calcified lymph node Pretty good indication that someone has been exposed to a granulomatous disease (worldwide- tuberculosis; US- histoplasmosis) Note: this CXR finding doesn't increase the risk of developing active TB

Cow exposure increases risk of inhalation of:

Group C streptococcus Bacillus anthracis Coxiella burnetti

RTN cells sense _____

H+ and potentially CO2 CO2 moves into the interstitial space and then into the CSF where it generates H+ and HCO3- via carbonic anhydrase This H+ can then diffuse into the interstitial space and be sensed, and potentially the CO2 involved in the interstitial space can be sensed as well

What causes the non-linear increase in VE during non-steady state exercise?

H+ stimulation of the carotid body

3 Important membrane envelope proteins of influenza

HA- hemagglutinin - These proteins bind to silica acid residues on host cells NA- neuroaminidase - NA cleaves sialic acid residues as the virions try to bud through the membrane, this releases virions M2- protein channel protein - allows acidification of vision which is needed for uncoating

Metabolic acidosis

HCO3- < 22 meq/L as the primary (i.e. initial) disorder Common causes: -Lactic acidosis -Ketoacidosis -Toxic ingestions (ethylene glycol in aspirin or methanol) -Loss of HCO3- (severe diarrhea or renal failure)

Metabolic alkalosis

HCO3- > 28-29 meq/L as the primary (i.e. initial) disorder Common Causes: -Vomiting -Chronic nasogastric suctioning can have same effect -Diuretics (with volume depletion) -Contraction alkalosis -Hypokalemia -Excessive Tums (calcium carbonate) ingestion (Milk-Alkali Syndrome) -hyperaldosteronism

Compensated metabolic acidosis

HCO3- is decreased pushing into acidosis The respiratory system beings to increase alveolar ventilation and decreases PCO2 This allows the pH to move back towards the normal range

Normal Cardiac Output

HR x SV Normal is around 5 L/min or 5000 ml/min (70 bpm x 71.5 ml/beat)

Cardiac output

HR x Stroke volume

33 year old male presents to the emergency room complaining of cough, subjective fever and chills. His blood pressure is 88/60, pulse is 124, temperature 39.0 C, and a saturation on room air of 90%. Blood smear shows evidence of Howell-Jolly bodies The Patient's Medical History Puts Him at a Particularly Increased Risk for Which Of The Following Organisms? -Mycobacterium tuberculosis -Nocardia asteroides -Haemophilus influenzae -Pseudomonas aeruginosa

Haemophilus influenzae (a gram negative coccobacillus) Blood smear shows Howell-jolly bodies that are evidence of a non functional spleen increasing the risk for infection by encapsulated organisms

Acute mountain sickness

Headache, anorexia, nausea -6 hour onset -peak sx at day 2 and 3 Uncommon below 2000m, but almost universal if acute exposure to 3800m No protection with fitness Self-limited (by definition)

The oxygen content (CO2) is mostly determined by:

Hemoglobin (gm/dL) Oxygen saturation (%)

Oxygen content is controlled by _____ and _____

Hemoglobin content and SaO2 CaO2 = k x Hb x SaO2 increase oxygen saturation or increase hemoglobin would increase oxygen content

Methemoglobin

Hemoglobin which has had its iron atom oxidized Reduces ability to bind O2

Prevention of Haemophilus influenza

Hib conjugate Vaccine- made from polyribitol phosphate capsule This uses either non toxic diphtheria mutant toxin, tetanus toxoid, or meningococcal outer membrane protein as the protein part of the conjugate

Is the edema in high altitude pulmonary edema high or low in protein?

High The presumed mechanisms is pulmonary capillary stress failure in overloaded vessels (similar to race horses and can occur in elite athletes at maximal exercise)

The higher the levels of CO2, the _____ the ventilation rate

Higher Ventilation is driven mostly by CO2 levels!

Coccidioidomycosis virulence factors and pathogenesis

Highly infectious Not highly virulent, ~99.5% of infected individuals resolve Defects in CMI predispose to systemic disease

The Vietnamese man described previously goes to live with his 55 year old brother who immigrated to the US in 1975 following the fall of Saigon. His brother did not have a skin test at that time. His PPD now is 18 mm. He is asx with a normal chest radiograph and no medical problems Do you treat or not?

His skin test likely represents a true tuberculous infection because he has a high risk of exposure coming from Vietnam and also with 18mm it is likely to still be positive even if he was from a low risk population However, the risk of progressing to active disease is low. After 5 years in the US, the TB rate of immigrants is similar to (infected) U.S. citizens Therefore, the risk of developing Isoniazid induced hepatitis leads to a contraindication in treating him given his low likelihood of reactivating his TB

Pigeons exposure increases risk of inhalation of:

Histoplasma capsulatum Cryptococcus neoformans

Histoplasmosis Lab diagnosis

Histoplasma capsulatum: Thermally dimorphic fungus In tissue: intracellular 2-4 μm oval yeast Specimen: Sputum, BAL, BM or skin lesions 25°C culture: -SDA and SDA-CC positive, 2-4 weeks; SABHI positive, 1-2 weeks -Septate hyaline mycelia, macroconidia with finger-like projections on their cell walls (tuberculate) and oval microconidia 37°C: Mycelial form begins to convert to small oval yeast

Histoplasmosis skin test

Histoplasmin Skin test Positive indicates a current or past infection

Animal exposure inhalation

Histoplasmosis/Cryptococcus -Birds, pigeons (mainly droppings) Anthrax (the sixth plague) -Cattle, sheep Psittacosis -birds Coxiella burnetti (Q fever) -Cattle, sheep, goats Group C Strep -cattle

What is the "k" in the CO2 equation

How much oxygen we can carry per gram of hemoglobin that is completely saturated Should be 1.34

Reservoir of Streptococcus pneumoniae

Humans In the winter, asymptomatic carriers may reach up to 60%

What is the natural reservoir of M. tuberculosis?

Humans are the only natural reservoir

Why has lifespan increased so dramatically?

Hygiene Antibiotics Vaccination

Types of respiratory failure

Hypercapneic (ventilatory) respiratory failure: failure to excrete CO2 Hypoxemic (hypoxic) respiratory failure: inability to oxygenate Combined hypoxemic (hypoxic) and hypercapneic respiratory failure: inability to both oxygenate and excrete CO2

Beta lactam side effects

Hypersensitivity reactions. Cross-allergenicity between penicillins and cephalosporins (and carpapenems) can occur. Aztreonam does not exhibit this cross-sensitivity

What is the compensation for a metabolic acidosis

Hyperventilation to increase alveolar ventilation in excess of CO2 production Causes PaCO2 < 36 mmHg

An increase in minute ventilation without an increase in CO2 production causes ______

Hyperventilation, more specifically if you increase alveolar ventilation it will cause this

Does hemoglobin increase at altitude?

YES! Due to: -Decrease in plasma volume -Increase in red cell mass (erythropoietin secretion stimulated by a decreased CaO2, low SaO2, and anemia)

Coccidioides spp. Lifecycle

Hyphae differentiate into arthroconidia, which break loose and may be suspended in the air Soil disruptions and wind facilitate spread and the probability of inhalation into lungs In the human host environment, in vivo differentiation produces cleavage planes and eventually huge spherules containing endospores Spherules rupture releasing endospores, which can then repeat the in vivo cycle

When V/Q matching is disrupted by disease, principally _______ occurs

Hypoxemia (decreased oxygenation) or hypercarbia (high CO2)

Types of hypoxia

Hypoxemic hypoxia (PaO2) Oxygen affinity hypoxia (SaO2) -Carbon monoxide poisoning -Methemoglobin (Fé+ to Fe 3+) -Massive transfusion (decrease in 2,3 DPG) Anemic hypoxia (CaO2) Circulatory hypoxia (DO2) Note: these lead to a type A lactic acidosis (inadequate O2 delivery to the cytochrome C oxidase) Histologic hypoxia -defects in aerobic metabolism (CN, CO) Note: this is type b lactic acidosis

Normal lifespan

IN high income countries: 85 However, it was generally around 25-35 years (past 3 million yrs) in 1900 it was around 50 yrs

What is the two step approach to treating ESKAPE pathogens

Identify the organism's susceptibility Limit antibiotic overuse

Aspergillosis prevention

If patients are neutropenic, you should filter air to minimize the exposure

Responses to Hypoxia

Increase minute ventilation -acute component: Initial hypocapnic inhibition of carotid body limits full response -chronic component: Leads to more significant increase in alveolar ventilation Increase cardiac output -acute, not chronic response Increase in hemoglobin Increase in 2,3 BPG Increased myoglobin (peripheral) Increased capillary density (peripheral) -reduces diffusion distance to cells

Chronic compensation for increased PaCO2

If the CO2 content in the blood remains elevated chronically (as can happen with advanced lung disease or with chronic use of opiates), the kidney is stimulated to reabsorb HCO3-. This occurs primarily in the proximal tubule and leads to increase bicarbonate reabsorption and an increase excretion of acid. The Na/H anti porter leads to secretion of H+intothe lumen coupled with Na+uptake. The secreted H+combines with the filtered HCO3- to form carbonic acid. The formed CO2 then diffuses into the tubular cell where, under the influence of carbonic anhydrase, dissociates into HCO3- and H+. HCO3- exits through the basolateral membrane into the interstitium; H+ is again secreted into the lumen where it is buffered by titratable acids and ammonia. Thus the kidney regenerates new HCO3- which raises the serum HCO3-. This moves the pH back towards normal and in many cases, can return the pH to the normal range (7.36-7.42) with time.

What are the key Igs in the lung

IgA and IgG

Is there immunity for influenza

Immunity develops but wanes over time There is no lifelong immunity against future infections due to antigenic variations in HA and NA antigenicity

MDR-TB

In 1990, the first outbreaks of multidrug-resistant M. tuberculosis (MDR-TB; resistant to at least isoniazid and rifampin) were observed in patients with AIDS and in homeless persons in New York City and Miami These strains are relatively uncommon in the US, they are dramatically increasing in prevalence in developing countries - represent ~5% of worldwide cases BDR-TB is significantly higher in the Eastern European and Central Asian countries, with an average of 10.0% MDR-TB among new TB cases, and 37.7% among previously treated TB cases (WHO 2008)

Cryptococcous neoformans virulence factors

In addition to the capsule, extracellular virulence-related products include urease and laccase enzymes. A melanin pigment, providing protection to host immune defenses, is the product of laccase activity.

Strategy for treating exposed individuals

In adults, you can treat or wait pending repeat PPD in adults In children, always treat pending repeat PPD

Distribution of carbon dioxide in arterial and venous blood

In arterial side, most is transported by the carbonic acid In the venous side, most is transported by the carbonic acid, though there is some more seen transported dissolved and as carbamino

Alveolar hyperventilation occurs for 3 general reasons:

In compensation for a metabolic acidosis (due to H+ ion stimulating central chemoreceptors) In response to hypoxia (low oxygen stimulates the carotid and aortic bodies) Due to stimulation of the central nervous system (pain, agitation, stroke, head trauma, drugs, or voluntarily)

New approach for treatment of ESKAPE pathogens: Bacteriophage therapy

In eastern Europe...phages have been successfully used to treat patients. However, in the absence of placebo-controlled trials, a lack of statistical analyses, and difficult economic situations in these countries have make it challenging to obtain proof Most studies showed efficacy (87%) and safety (67%) of the tested phages

Chronic mountain sickness (Monge's disease)

In high altitudes, the oxygen-carrying capacity of the blood may increase the viscosity of the blood, which places a greater load on the heart and actually may impair blood flow into the capillaries of some tissues.

Balancing Immunity and Inflammation in the Lung

In normal individual, there is small numbers or low-virulence microbes within the lungs. There are immune defenses that allow for microbe clearance without an inflammatory response In those with large numbers or high-virulence microbes, the immune defenses initiate an inflammatory response and activation of the adaptive immune system which leads to microbe clearance but at the cost of tissue damage

Do we desaturate with exercise

In normal people, NO! However there is an increase in A-a differences after the anaerobic threshold is reached Some athletes can occasionally desaturate, but most commonly those that desaturate with exercise are those with lung disease (obstructive, pulmonary vascular disease, ILD)

Hypoxic respiratory failure

Inability to oxygenate Note: can also be combined with hypercapneic respiratory failure

Shunt and Low V/Q represent areas of ______

Inadequate ventilation Note: intrapulmonary shunt and Low V/Q mismatch are primary cause of the A-a gradient

M. avian complex (MAC)

Includes two species: M. avium (4 sub-species) and M. intracellulare -found worldwide in soil and water -both species produce disease in immunocompetent individuals -disease in HIV-infected patients is primarily caused by M. avium -second only to M. tuberculosis in significance and frequency of the diseases they cause in developed countries (US, Japan, Switzerland) Cause infection when inhaled or swallowed -pulmonary involvement is similar to TB -diarrhea and abdominal pain are associated with gastrointestinal involvement -typical symptoms include fever, fatigue, and weight loss

How then does your body try to compensate for the hypoxemia due to a large shunt such as pneumonia?

Increase cardiac output This increases the saturation of the venous blood (less oxygen is extracted by the tissues from each 100 ml of blood) Note: If you cannot increase your cardiac output (because of hypovolumia or heart disease) you will be in double trouble and hypoxemia will be quite severe.

Things that shift the oxygen-hemoglobin dissociation curve to the left

Increase in pH Decrease in DPG Decrease in Temp Decrease in PaCO2 Note: this helps to increase hemoglobins affinity to oxygen

Converter

Increase of >10 mm in the size of the skin test after exposure

Complications of long term residence of high altitude

Increased incidence of pre-eclampsia Decrease in infant birth weight with an increase in mortality -many give birth at lower elevations Pathologic polycythemia (too much hemoglobin that exceeds 20 g/dL or hematocrit of 60%) -Monge's disease Right ventricular failure

Adaptation of altitude in peripheral tissues

Increased myoglobin -monomer that can bind oxygen, it doesn't bind cooperatively and has a strong affinity for it. It is thought to carry oxygen that diffuses from the capillaries to the mitochondria of the cells) Increased capillary density -reduces diffusion distance to cells, though it can lead to a loss of muscle mass

Tachypnea

Increased respiratory rate (>20)

Hering-Breuer reflex

Increases in inflation (depth) elicits a negative feedback whereas decreases in inflation (depth) elicits a positive feedback Due to the pulmonary stretch receptors!

Exercise _______ the A-V O2 difference

Increases, due to greater oxygen extraction (due to increase in heat, H+, CO2, and 2.3 BPG) This is the difference of the oxygen concentration going into the exercising muscle and the oxygen concentration leaving the exercising muscle

Minute Ventilation _____ as CO2 production increases

Increases, more specifically it is the alveolar ventilation that matches it

Licensed Products for Passive Immunity to Infectious Diseases/Toxins: Animal derived immunoglobulins (mostly equine)

Indicated in Envenomation: black widow, scorpion, rattlesnake/cottonmouth; diphtheria, botulism

Licensed Products for Passive Immunity to Infectious Diseases/Toxins: Monoclonal antibodies

Indicated in RSV and inhalation anthrax

Licensed Products for Passive Immunity to Infectious Diseases/Toxins: Hyperimmunoglobulins (human)

Indicated in anthrax, infant botulism, hepatitis B, CMV, rabies, tetanus, varicella Note: these come from people with a high serum antibody level

Licensed Products for Passive Immunity to Infectious Diseases/Toxins: Standard (human) immunoglobulins (IV,IM, SQ)

Indicated in primary humoral immunodeficiencies; hepatitis A, measles, varicella, rubella

Howell-Jolly bodies

Indicates evidence of a non-functional or absent spleen

hospital acquired pneumonia

Individuals who develop pneumonia after being a patient in a health care facility Staph aureus Gram negative bacteria -Escherichia coli -Klebsiella pneumoniae -Pseudomonas aeruginosa Note: immunocompromised patients are susceptible to all the above plus fungi (e.g. Aspergillus) and Viruses

What is the most common cause of death throughout humanity

Infection, however, the introduction of antibiotics greatly improved mortality outcomes Note: Example would be between 4.000 BCE and 2017 an estimated 11 out of 77 billion people died from tuberculosis

Influenza B

Infects only humans, upper respiratory tract Designation based on HA and NA antigens (e.g. H1N1 or H5N1)

Phases of ARDS

Inflammatory or exudative phase (0-7 days) (injured/swollen/sloughing/ gaps in junctions of vasculature, activated WBCs, cellular debris, inactivated surfactant, RBCs, fibrin deposits, and hyaline membrane are all found here) Proliferative phase (7-21 days) Fibrotic phase (after 7-10 days) Note: these can overlap

A 22 year old med student started having a sore throat, headache, myalgia, fever, dry cough and malaise. Her cough worsened over the next day and she could barely get out of bed. X ray below. CBC was 11K with 55% PMN, 6 % bands. When asked, the patient said she "felt like CRAP!" CXR: nodular consolidation and patchy ground-glass opacities are visible in mild and central zones of left lung

Influenza

Viral causes of lower respiratory tract infection

Influenza Adenovirus SARS-coronavirus MERS-CoV Hantavirus

Those agents that are commonly Inhaled from other humans

Influenza A Tuberculosis Coronavirus (SARS) Pneumonic plague Other viruses - RSV, adenovirus, rhinovirus

Vaccines Contain Weakened or Killed Disease Antigen(s) Plus:

Ingredients -Preservatives (thimerosol) -Stabilizers (Sugar, gelatin) -Adjuvants (Aluminum salts) Byproducts: -Cell culture products (Egg/cell protein and media) -Inactivating ingredients (formaldehyde) -Antibiotics (Neomycin)

Legionnaires disease (more severe form)

Inhale aerosol, contaminated plumbing systems Incubation period 2- 10 days post inhalation Starts as acute pneumonia Headache, malaise, fever, chills Dry cough progresses to productive cough X-ray shows patchy lung infiltrate Diarrhea, vomiting, confusion are notable Chest pain Untreated- 10 to 15 % mortality

Blastomycosis Virulence factors and pathogenesis

Inhaled microconidia evolve to form yeast phase Yeast escape recognition by macrophages, and disseminate via bloodstream Defects in CMI predispose to systemic disease Biggest threat to immunocompromised

Can NO and other vasodilators be used in ARDS?

Inhaled nitric oxide cannot be recommended for the routine treatment of acute lung injury and the acute respiratory distress syndrome, but it may be useful as a rescue therapy in patients with refractory hypoxemia. Treatment with several less selective vasodilators, including sodium nitroprusside, hydralazine, alprostadil (prostaglandin E1), and epoprostenol (prostacyclin), has also not been shown to be beneficial.

Triazoles

Inhibition of sterol demethylase, a fungal cytochrome P450 enzyme involved in ergosterol synthesis.

Fluoroquinolones

Inhibits DNA gyrase and topoisomerase IV Bactericidal Resistance arises in mutations in DNA gyrase or topoisomerase

Legionella pneumophila effect on alveolar macrophage

Inhibits phagolysosome fusion Organism produces proteases, lipases, DNAses that will eventually kill macrophage. Infected macrophage releases cytokines that produce inflammatory response.

Aminoglycosides

Inhibits protein synthesis via binding to the bacterial ribosome and causing abnormal reading of mRNA Bactericidal Used for serious infection with gram-negative bacteria. However, the narrow therapeutic window and common serious side effects require plasma level monitoring

Edward Jenner's Experiment

Innoculated his gardener's son with cowpox Six weeks later, innoculated him with SmallPox via variolation

How to improve oxygen delivery (DO2)

Inotropes/ IVF (increase cardiac output) Transfusions (increase hemoglobin) Supplemental O2 (increases SaO2) Hyperbaric O2 (increases SaO2)

Nocardia asteroides Symptoms

Insidious onset, usually victim is immunocompromised Prominent cough Purulent sputum Fever Anorexia Weight loss common Can also disseminate. For example, and can cause brain abscess

Medulla: DRG central controller

Integrates its function via the nucleus of tractus solitarius Function: Excitatory to inspiratory neurons (inspiratory rhythm generator); constitutively active

34-year-old woman Presents with 2-day history of weakness dizziness, left calf pain, and black tarry stools. Denies chest pain, cough, or shortness of breath Medical history: -Diabetes leading to renal failure and renal transplant -3 weeks before presentation, acute graft rejection developed -Began an immunosuppressive regimen On admission -Tachycardic, hypotensive and febrile -Initial chest x-ray was normal Lab results: -Anemia -WBC = 4800/μl, 80% neutrophils -Blood cultures were positive for E. coli -Antibiotic therapy initiated Day 6: -Vesicular rash developed on buttocks and left calf -Cultures positive for HSV, antiviral therapy initiated Day 8: -Renal function continued to decline -Intermittent hemodialysis started Day 12: -Decreased responsiveness -Intubated for respiratory distress Chest x-ray: -Diffuse bilateral lung nodules Culture of BAL: -Positive for Aspergillus spp. -Immunesuppression decreased -Liposomal Amphotericin B started Condition deteriorates: -Acute MI, comatose -Mulitple acute infarcts in frontal lobe and cerebellum by MRI -Multiple skin nodules form on arms and trunk

Invasive Aspergillosis Our patient: -Expired on hospital day 23 -At autopsy, A. flavus was detected in multiple organs: Heart, lungs, adrenal galnd, thyroid, kidney, and liver Extreme example of disseminated aspergillosis in an immunocompromised host

Aspergillosis treatment

Invasive disease is difficult to treat Amphotericin B, caspofungin (echinocandins), voriconazole Decrease immunosuppression or reconstitute immune defenses Surgical debridement, if possible

Zygomycosis treatment

Invasive disease is very difficult to treat/control Amphotericin B ... plus supplement abx Surgical debridement Immune reconstitution Posiconazole appears to be active against most species

Control of ventilatory rhythm

Involuntary (depends on): -arterial CO2 and O2 -arterial and CSF pH -musculoskeletal movement (anticipation/exercise) -other stimuli (e.g. cough, sneeze, deglutition, vomit, fear, pain, sigh, gasp, yawn, laugh, cry, and other emotions) Voluntary (depends on): -functions that are or could be voluntary (speak, changes in the rate or depth, others described in the list above)

Central controllers of ventilatory rate

Involuntary: -Brain stem: * Pons * Medulla (oblongata) * Midbrain - Limbic system - Thalamus and hypothalamus Voluntary: -Brain cortex

Supra-pontine central controllers

Involves the midbrain (and includes higher brain) Function depending on the signal: - induce tachypnea during exercise, fight or flight - induce inspiratory apnea during deglutition - induce changes associated with vocalization/ speech

Tuberculosis drugs

Isoniazid Rifampin Ethambutol Pyrazinamide

Approved treatment regimens for latent TB infections (I.e. PPD(+) without symptoms or positive cultures)

Isoniazid daily for 6-9 months Rifampin daily for 4 months Isoniazid + Rifapentin weekly for 12 weeks

Increasing VE increases PaO2, but has what effect on SaO2 at sea level?

It has little impact At sea level, we have a PaO2 of about 90 mmHg. If you hyperventilate and increase PaO2 to about 130 mmHg, you won't saturate the hemoglobin that is already pretty saturated

At altitude, VE increases PaO2, but has what effect on SaO2?

It increases as well At altitude, you will have a lower PaO2 (e.g. 40 mmHg). If you hyperventilate and increase PaO2 (e.g. 60 mmHg) this allows for an increase in SaO2!

A 72-year-old man presented with 5 day history of altered mental status. Not eating well for several days. No recent travel, No previous hospitalization, No sick contacts. Smoking history 45 pack years. After admission he developed visual hallucinations, respiratory insufficiency and diarrhea. Temperature 39.5ºC, pulse rate 130 beats per minute (tachycardic), respiratory rate 26 breaths per minute (tachypnea), blood pressure 119/86 and oxygen saturation of 95% on room air. White blood cell count 17,400 /µL with 94% neutrophils (leukocytosis). Empiric therapy of ceftriaxone and vancomycin started. Over the next several days he developed culture negative sepsis and multiple organ failure (respiratory, requiring ventilation; ventricular arrythmias, positive troponin; acute renal failure). Urine immunochromatography assay for Legionella antigen LP1 came back positive. Subsequently a 4 fold rise in legionella antibodies was demonstrated (acute vs convalescent sera). Therapy was switched to azithromycin for 11 days followed by 21 days of Levaquin.

Legionellosis

Partial Pressure of O2 in Arterial Blood (PaO2) is ______ Than Alveolar (PAO2) and Capillary (PcO2) O2

Less

High altitude cerebral edema

Less common than high altitude pulmonary edema Similar symptoms to acute mountain sickness but progressive to include ataxia, hallucinations, and coma

Risk of developing active tuberculosis after infection with mycobacterium tuberculosis

Lifetime risk: 10% Risk in first 18 -24 months after infection: 5-7% -(i.e. most of your lifetime risk occurs within first 2 years after infection)

Whether to treat a person exposed to multi-drug resistant TB is determined by:

Likelihood that the contact is newly infected Likelihood that the contact, if infected, will develop active TB

PCO2 correlates ____ with CO2 content over human range

Linearly

6 methods for generating vaccines

Live (attenuated) virus Inactivated (killed) virus Toxoid Polysaccharide (conjugate with protein) Recombinant protein Viral like particle

Inactivated (killed) viral vaccines

Live strains are obtained from the CDC/CBER A monovalent strain is incubated with 11 day old embryonate chick egg (or human diploid cell) The virus is harvested: titer, infectivity, sterility, specificity assessed Virus is inactivated with formaldehyde All inactivated monovalent strains can be combined into a single vaccine (trivalent or quadrivalent) Examples: -Polio (Salk) -Pertussis (whole cell) -Influenza -Rabies -Hepatitis A -Japanes-Enceph -Cholera

Causes of low V/Q and Shunt

Low V/Q -asthma -chronic bronchitis -emphysema -ILD Shunt -pneumonia -atelectasis -ARDS -CHD -anomalous venous return

Desaturation

Low arterial oxygen saturation (SaO2) Less than 90%

Hypoxemia

Low arterial oxygen tension (PaO2) Less than 80 torr at sea level (some debate)

Respiratory syncytial virus symptoms

Low-grade fever Cough Coryza (inflammation of nasal mucous membranes) Cyanosis Retractions- indicates difficulty breathing Wheezing Crackles (rales) Dehydration can be a serious problem (evaluate skin turgor, capillary refill)

Histoplasmosis clinical manifestations

Low-intensity inoculum: asymptomatic in 90% Heavy inoculum: primary pulmonary infection - subclinical, fever, mild, 95% spontaneous resolve Progressive (chronic) pulmonary histoplasmosis: 1 in 100,000; granulomas; positive skin test & chest X-ray Dissemination: 1 in 2000 adults; higher in children and immunocompromised; hematogenous spread = liver, spleen, lymph nodes, bone marrow -Subacute - fever, weight loss, oropharyngeal ulcers, hepatosplenomegaly; untreated = death in 2 to 24 mos -Acute - severe immune suppression; septic shock-like features; untreated = death in days to weeks

The higher the ventilation the ____ the levels of CO2

Lower (e.g. hyperventilation = PaCO2 < 35 mmHg)

Lymphocytic interstitial pneumonia CXR

Lymphocytes infiltrate the airway causing gas-exchange abnormality Classically dont have a lot of sputum production

Growth properties of the MTB complex

M. tuberculosis and closely related species in the M. tuberculosis complex -are slow-growing bacteria; colonies usually appear following 3-6 weeks of incubation at 37°C -colonies are non-pigmented or a light tan color; dry, rough appearance M. leprae cannot be cultured in cell- free systems

What is the most common mycobacterial disease in AIDS patients in the US?

MAC infection Overwhelming disseminated infections with M. avium are common in patients in the terminal stages of AIDS, when CD4+ T lymphocyte counts are declining -most infections are believed to develop after ingestion of the bacteria -the tissues of some patients are literally filled with the mycobacteria -progressive weight loss, intermittent fever, chills, night sweats and diarrhea -response to treatment is marginal, prognosis is grave

Location of Re-infection tuberculosis

Mainly within the apical and posterior segments of the upper lobes May also see some in the superior segments of the lower lobes

Rifampin

Mechanism of action: Inhibition of RNA polymerase. Active against bacteria as well as mycobacteria. Resistance: Mutations in RNA polymerase. Pharmacology: Administered orally, penetrates cells. Side effects: Rare hepatotoxicity. Drug interactions: Strong induction of many different cytochrome P450 isozymes, decreasing efficacy of oral contraceptives, protease inhibitors, anticonvulsants, methadone.

Ethambutol

Mechanism of action: Inhibition of arabinosyl transferases important for mycobacterial cell wall synthesis. Resistance: Mutations in these enzymes, overexpression of the enzymes. Pharmacology: Administered orally, penetrates cells. Side effects: Retrobulbar neuritis, causing loss of visual acuity and red/green color blindness. Contraindicated in children too young to be assessed for these visual problems.

Isoniazid

Mechanism of action: Inhibition of mycolic acid synthesis, and thus cell wall synthesis. Bactericidal. Resistance: Arises readily in the absence of multi-drug regimen. Exception - prophylactic use. Pharmacology: Administered orally, penetrates cells, hepatic metabolism. Stimulates pyridoxine excretion, so must be given with pyridoxine. Side effects: Peripheral neuropathy if pyridoxine isn't used. Hepatotoxicity. Used by itself as a prophylaxis for those exposed to TB

Influenza

Member of the Orthomyxovirus family Negative sense, ssRNA, enveloped virus Includes strains A, B, and C

Treatment of Blastomycosis

Mild cases = bed rest Amphotericin B for severe, life threatening pulmonary, disseminated or CNS disease Itraconazole for less severe cases -Relapses may occur long-term oral itraconazole may be needed -Success rates range from 70-95% AIDS & immunocompromised: -Long-term itraconazole -survival rates range from 35-50% in this later group

Histoplasmosis Treatment

Mild cases: bed rest Prolonged symptoms: Itraconazole for up to 2 years Severe cases (Severe respiratory distress & dissemination): Amphotericin B, followed by itraconazole for up to 2 years AIDS complicated: lifelong itraconazole

Hematogenous spread pneumonia

Miliary tuberculosis Miliary fungal infections Bubonic/pneumonic plague Tularemia Candida from line infections Staph aureus -Septic emboli in IVDU -Soft tissue infections -Line infections

If dead space goes up, then ______ will go up to compensate

Minute ventilation As long as alveolar ventilation stays the same (for a steady CO2 production) then PaCO2 will remain the same regardless of what happens to the dead space or minute ventilation

Treatment of Respiratory syncytial virus

Monitor hydration (IV fluids) For severely affected, administer aerosolized ribacvarin antiviral agent (a guanosine analog that inhibits replication)

Zygomycosis Lab diagnosis

Monomorphic ,true mould In tissue: -Try to get tissue for direct preps!! -Aseptate hyphae that branch at RIGHT angles, rare septations are possible (may see sporangial fruiting bodies) In culture: -Several etiologies are differentiated by sporangia -Rhizopus spp.- Aseptate hyphae; sporangiophore arises from rhizoids, huge sporangia (100-300 um), filled with sporangiospores.

Lab diagnosis of aspergillosis

Monomorphic true mold Difficult because of the universality of the fungus Repeat isolations are essential for definitive diagnosis Serum: galactomannan Af + --> invasive aspergillosis

TH2 and Th17

More involved in humoral immunity They also contain CD40L which binds to B cell's CD40 They also produce a variety of different cytokines which bind B cell's cytokine receptors This leads to isotype switching, antibody secretion, and thus neutralization and elimination of antigen

Aspergillosis epidemiology

Most common fungus worldwide- Ubituitous Can be a hospital acquired infection (major problem)

Obtaining arterial blood gasses

Most commonly obtained from the Radial artery (must have ulnar artery flow as well to obtain from here) Other sites include -Brachial artery -Femoral artery -Posterior Tibial artery -Dorsalis Pedis artery

Coccidoidomycosis Treatment

Most do not require anti-fungals Azoles - pneumonia & nonmeningeal dissemination Amphotericin B - meningeal infection and previous treatment failures

M. tuberculosis clinical disease

Most infections in immunocompetent patients are restricted to the lungs Initial pulmonary focus is the middle or lower lung fields, where the M. tuberculosis can multiply freely Once cellular immunity is activated mycobacterial replication ceases, in most patients within 3 to 6 weeks after exposure Approximately 5-10% of patients exposed to M. tuberculosis progress to having active disease, and another ~10% experience disease sometime in their lifetime (reactivation disease) Likelihood that infection will progress to active disease is a function of both the infectious dose and the patient's immune competence

Diagnosis of Mycoplasma pneumoniae

Most lab test are nonspecific Cold agglutinins (antibodies, IgM, made in response to some infections, primarily M. pneumoniae, that can agglutinate RBCs in the cold) Serology- Fluorescent antibody tests

Defenses in airways and their mucosa: epithelial cells

Mucosal barrier and mucociliary clearance -epithelial barrier -mucin production Pro-inflammatory (have PPRs) -In response to stimuli (bacteria, viruses) -produce chemotactic factors, cytokines Anti-microbial -produce anti-microbial factors -defensins, lactoferrin

Oseltamivir

Neuraminidase inhibitor Excellent oral bioavailability. Pro-drug (oseltamivir phosphate) cleaved in gut or liver to form active oseltamivir. Bronchoalveolar levels similar to plasma levels. Side effects: Transient neuropsychiatric effects (rare), nausea (common).

IgA and mucosal immunity

Mucosal lymphoid tissue: located in lamina propria, major site for IgA production in mucosa of gastrointestinal and respiratory tracts Cytokines that induce isotype switching to IgA produced in mucosal lymphoid tissue Poly-Ig receptor: expressed on basal surface of mucosal epithelial cells Transcytosis: poly-Ig receptor binds dimeric IgA and transports it to lumenal surface where the IgA is released by proteolytic cleavage

General considerations for drugs used to treat tuberculosis

Multiple drugs, to avoid resistance, for long periods of time Drugs should penetrate cells Drugs need to penetrate the lipid-rich mycobacterial cell wall

Definitive identification of Histoplasma capsulatum

Must demonstrate thermal conversion However, ExoAg or NA probe allow definitive ID without temperature-regulated phase conversion

53 year old male with long-standing rheumatoid arthritis was started on the tumor necrosis factor (TNF) soluble receptor antagonist, Etanercept, 4 months ago to improve control of his disease. He now complains of night-sweats, weight loss, and cough productive of blood-tinged sputum. He is a native of Mobile, but worked in the Peace Corps in Malawi during his 20's. The Patient's Medical History Puts Him at a Particularly Increased Risk for Which Of The Following Organisms? -Streptococcus pneumoniae -Mycobacterium tuberculosis -Haemophilus influenzae -Streptococcus anginosus (milleri)

Mycobacterium tuberculosis TNF-α is important in maintaining granuloma formation

Bacterial causes of lower respiratory tract infections

Mycobacterium tuberculosis (Rod, Acid Fast) Streptococcus pneumoniae (Gram Positive) Bacillus anthracis (Gram Positive) Haemophilus influenzae (Gram Negative) Legionella pneumophila (Gram Negative) Klebsiella pneumoniae (Gram Negative) Mycoplasma pneumoniae (No Gram Stain) Nocardia asteroides (Gram positive, acid fast) Actinomyces israelii (Gram positive, Non acid fast) Coxiella burnetti Chlamydophila pneumoniae Chlamydia psittaci

P(inspired) (PiO2)

N2= 563 mmHg O2= 150 mmHg H2O= 47 mmHg

P(alveolar) (PAO2)

N2= 573 mmHg H2O= 47 mmHg O= 100 mmHg CO2= 40 mmHg

P(atmosphere)

N2= 600 mmHg O2= 160 mmHg

Treatment of influenza

NA inhibitors - Relenza (Zanamivir) and Tamiflu (Oseltamivir) - prevents virus release.. These shorten the duration of symptoms by a little more than a day Amantadine- too much resistance, not used anymore (affects the M2 proton channel) Pt. may require hospitalization (maintain oxygenation and hemodynamics)

Is there a vaccine for Respiratory syncytial virus

NO

Is there evidence that apnea patients loose more upper airway tone during sleep then non-apneic controls?

NO

Do normal people let their PaCO2 rise?

NO If CO2 production increases (exercise) then minute ventilation increases to compensate If dead space increases, minute ventilation usually increases to compensate unless severe or underlying respiratory problem Note: an elevated PaCO2 is (almost always) abnormal

Is prior BCG vaccination a factor in considering need for chemoprophylaxis?

NO People from high risk countries are considered TB infected if PPD > 10 mm regardless of BCG status. People from low risk countries still using BCG are considered TB infected if PPD > 15 mm.

Is V/Q homogenous throughout the lung

NO You would expect that the V/Q of the apical units would be higher than the ideal 0.9 (because there is less blood flow (Q) to the apices) and that the bases would have lower V/Q because of greater perfusion (Q) to the base. This is true. In disease states such as pneumonia and chronic bronchitis (low V/Q) and pulmonary embolus or pulmonary vascular disease (high V/Q) the abnormalities can occur anywhere in the lung

Do Polysaccharide Vaccines Induce a Robust Secondary Immune Response?

NO!

Is dissolved oxygen sufficient for metabolism?

NO! Normal oxygen consumption at rest: 250 ml O2/minute Cardiac Output would need to be 83 Liters/min (at rest) if only dissolved O2 were delivered

Can you look at a CXR and say "this is pneumonia or what type of pneumonia"

NO! It is a clinical diagnosis

Do polysaccharide vaccines induce B memory cells?

NO! Polysaccharide Vaccines Do not Activate Helper T Cells and Thus Do Not Induce B Memory Cells Only antibodies really made are IgM, IgG, IgA acutely

Should you treat a patient for latent TB if they have active TB?

NO!!!!!!!!!!!!!!!!!!

Can central chemoreceptors sense changes in H+ (pH) in the blood?

NO, Blood brain barrier impermeable to H+ and semi-permeable to HCO3- Though they are stimulated by H+ not CO2

Can rifampin be used with birth control?

NO, can lead to pregnancy

Is there an increase of SVR at altitude?

NO, hypoxia tends to cause vasodilation of systemic circulation

Do shunts respond to 100% low flow oxygen?

NO, it responds minimally Because the oxygen can't get in to make a difference Diseases such as pneumonia, atelectasis, and ARDS are shunt diseases and supplemental oxygen is not as effective.

Can surfactant therapy be used for ARDS?

NO, treatment with a synthetic surfactant had no effect on oxygenation, the duration of mechanical ventilation, or survival

Does max exercise lead to max breathing?

NO, when you stop running it will usually be due to leg pain, acidosis or maxed HR

Types of adaptive immunity

Natural - Passive (maternal) - Active (infection) Artificial - Passive (antibody transfer) - Active (immunization)

Meningococcal pneumonia

Neisseria meningitidis

Aminoglycosides Side effects

Nephrotoxicity and ototoxicity (tinnitus, hearing loss, vertigo)

Histologic studies of lung specimens obtained early in the course of the disorder show a marked accumulation of ______

Neutrophils Neutrophils predominate in the pulmonary edema fluid and bronchoalveolar-lavage fluid obtained from affected patients, and many animal models of acute lung injury are neutrophil-dependen

XDR-TB

New strains of resistant M. tuberculosis, called extensively drug-resistant (XDR)-TB, have emerged in every region of the world XDR-TB is defined as MDR-TB resistant to fluoroquinolones and at least one of the second line drugs (e.g. kanamycin, amikacin, capreomycin), are potentially untreatable In 2006, there was a large outbreak of XDR-TB in an HIV-positive population in Tegula Ferry (KwaZulu-Natal, South Africa) -extremely high mortality (of the first 53 patients, 52 died); highlights the vulnerability of TB patients co-infected with HIV As of October 2011, XDR-TB had been reported in 77 countries

Rules for compensation for metabolic acidosis

No overcompensation -overcompensation suggests second disorder Winter's Formula: PaCO2= 1.5 HCO3- + 8 ± 2 -estimates expected PaCO2

How can you determine if Respiratory compensation for a metabolic acidosis is appropriate?

No respiratory overcompensation - pH does not return to normal range (7.36-7.44) - whereas overcompensation suggests second disorder Winter's Formula: PaCO2= 1.5 HCO3- + 8 ± 2 -this is derived from normal people and predicts expected PaCO2 for degree of acidosis.

18 y/o white male who lives in Beverly Hills has 12 mm of induration on his PPD during a screen to obtain a food handler's card. He has no known exposures to TB and has lived his entire life next to the Kardashians. He is asymptomatic with a normal chest radiograph Do you treat or not?

No treatment, it was likely a false positive skin test

Is the oxygen content in the blood directly correlated to the PaO2?

No, but it correlates to the SaO2 Increasing the saturation fo hemoglobin increases oxygen content. If you increase the saturation of oxygen from 50% to 100% you will double oxygen content for the same amount of hemoglobin. In the linear range of the oxy- hemoglobin curve increasing PaO2 will increase SaO2 and thus increase oxygen content. Above 60 mmHg PO2, however, the oxy-hemoglobin curve becomes relatively flat. Therefore increasing PaO2 from 80 mmHg to 160 mmHg has little impact on oxygen content.

A 24-year-old, HIV positive female was brought to the ED with complaints of breathlessness, abdominal pain and vomiting for six days. She had productive cough with purulent sputum mixed with blood for 12 days, but was normal two weeks ago. She was conscious, oriented, febrile and tachypneic. She was not taking any medications. Pulse 126/min, temp 39.1°C (102.4°F), RR 32/min, and BP 110/80 mm Hg. Chest auscultation revealed bilateral crepitations. Leukocyte count 16,000 cells/ul with 2% bands, 74% neutrophils and 24% lymphocytes. CD4+ count 135. Chest X-ray revealed bilateral irregular nodules (cavitating) with haziness. Sputum Gram Stain was negative. Diagnosed with CAP, placed on meropenem. But treatment failed. A pleural tap then revealed numerous neutrophils and Gram positive filamentous bacilli that were weakly acid fast. Treatment switched to Bactrim.

Nocardia asteroides

46 year old female with long-standing rheumatoid arthritis complains of non-productive cough, low-grade fever, and dyspnea for 3-4 weeks. For her RA she takes, aspirin and prednisone (15 mg per day) both of which she has been taking for over 2 years. The Patient's Medical History Puts Her at a Particularly Increased Risk for Which Of The Following Organisms? - Streptococcus pneumoniae - Nocardia asteroides - Haemophilus influenzae - Neisseria meningititis

Nocardia asteroides This is due to her steroid use

ARDS is characterized by:

Non-cardiogenic edema Hypoxemia (refractory to oxygen supplementation)

Genus Mycobacterium

Non-motile, non-spore-forming, aerobic rods -Neutral or weakly Gram-positive, occasionally form branched filaments Acid-fast bacteria (AFB) -once stained, the rods cannot be decolorized with acid solutions Cell wall is rich in lipids (sometimes called "waxy" outercoat) -presence of long-chain fatty acids called mycolic acids -hydrophobic surface; resistant to many disinfectants and common laboratory stains >130 species of mycobacteria -high G+C content (61-70%) Fastidious, most grow slowly -12 to 24 h doubling time; can be up to 8 weeks before growth in detected in lab cultures

PaO2/FiO2

Normal: around 476 mmHg Example of lung injury where PaO2 decreases: 252 mmHg Example of lung injury with intubation where PaO2 is decreased and FiO2 is increased: 88 mmHg

Normal gradients seen in the lung between alveoli and pulmonary vasculature

Normal: ideal unit with a V/Q ratio of 0.9(In this acinus ventilation is sufficient to achieve an alveolar oxygen tension (PAO2) of approximately 100 mmHg which is adequate to attain almost 98% saturation of hemoglobin leaving this acinus) Shunt: V is zero bu the Q is normal. Therefore the blood is not oxygenated and no CO2 is removed leading to arterial hypoxemia. This occurs when disease completely eliminates gas flow to the acinus as can occur in pneumonia or atelectasis Dead space: There is V but the Q is zero. The acinus doesn't take part in CO2 and oxygen exchange. However, this doesn't cause hypoxemia and rarely leads to increased PCO2

Major mechanism of ESKAPE antibiotic resistance: Reduce antibiotic uptake

Normally porins allow the antibiotic to be uptaken into the periplasmic space or cytoplasm where it has its effect By inhibiting the activity of the porins, the bacteria can reduce its uptake of the antibiotic

Surfactants bound to PAMPs vs not

Not bound to PAMPs, the alveolar macrophage is inhibited Bound to PAMPs, they interact with CD91 which is an activation receptor on the alveolar macrophages which induces an inflammatory response

What causes an increase in minute ventilation during exercise?

Not central chemoreceptors wince PaCO2 actually decreases with maximal exercise H+ promotes carotid body activation and contributes significantly to the increased minute ventilation at maximal exercise (makes it more sensitive to oxygen levels). Lactate is though to assist as well (lactate threshold and ventilatory threshold occur at same exercise intensity)

Alveolar gas equation

PAO2 = (Pb - PH2O) x FIO2 - (PaCO2 / R)

Coccidoidomycosis clinical manifestations

Not contagious Route of infection: inhalation Incubation: 10-21 days Respiratory infection - 60% asymptomatic, all convert to skin test + < 1% dissemination - soon after primary infection or years later Often produces: -Meningitis -Lesions in viscera or cutaneous granulomatous lesions which may form draining ulcers Incidence in HIV-infected persons has increased

Example of primary metabolic acidosis

Note: using winter's formula you can determine that is is an appropriate compensation

Diagnosis of M. tuberculosis via Nucleic acid based tests

Nucleic acid amplification techniques (e.g., polymerase chain reaction) -commercial assays currently used are specific for M. tuberculosis but are relatively insensitive Improved real-time PCR assays are now available (2010) -Xpert MTB/RIF assay; near patient PCR on sputum samples, takes ~2h

EPOC (excess post-exercise oxygen consumption) (oxygen debt)

Occurs after exercise Allows for: • Replenish creatine phosphate • Metabolize lactate • Temperature recovery • Heart rate recovery • Re-establish hormonal balance • Ventilation recovery

Adaptive immunity

Occurs within days and includes: - B lymphocytes - T lymphocytes These respond to specific antigens!

Cryptococcal pneumonia

Often asymptomatic or mild Sputum production is minimal, and no findings are sufficiently specific to suggest the etiology

CXR of hematogenous spread via septic emboli from endocarditis

Often see straight lines which represent gas/fluid interface

Legionellosis diagnosis

Older Patients (usually) Atypical pneumonia Diarrhea Serology Urine Antigen PCR

Amantidine and rimantidine

Older drugs formerly used to treat influenza A; not used in recent years due to widespread resistance. Mentioned here because sometimes drugs like this come back as resistance fades due to their lack of use. This happened with doxycycline. In the case of influenza, little resistance to the neuraminidase inhibitors has been observed in the ~15 years they've been on the market. But this flu season (2017-2018), between October and March, 1.7% of isolates have been resistant to oseltamivir (Tamiflu). Those isolates were still sensitive to zanamivir, perhaps because it's used less.

Beta lactam drugs resistance

One of the major one is degradation of bacterial beta-lactamases, also called penicillinases. Some drugs are more resistant to beta-lactamases than other

Berlin definition of ARDS

Onset within 1 week of a known clinical insult or new or worsening respiratory symptoms Chest imaging shows bilateral opacities- not fully explained by effusions, lobar/lung collapse, or nodules Origin of edema not explained by cardiac failure or fluid overload; need objective assessment (echo) to exclude hydrostatic edema if no risk factor present Mild: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg with PEEP or CPAP ≥ 5 cmH2O Moderate: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg with PEEP or CPAP ≥ 5 cmH2O Severe: PaO2/FiO2 ≤ 100 mmHg with PEEP ≥ 5 cmH2O

Changes in causes of death 1850 vs 2000

Originally was mostly due to infections, now not so much Thanks in part to vaccines and clean sources of water Note: infectious disease deaths has decreased dramatically in 20th century America!

Influenza drugs

Oseltamivir Zanamivir

Low V/Q and Shunt can be differentiated by response to _____

Oxygen

Cooperative oxygen binding to hemoglobin

Oxygen binding increases hemoglobin affinity for subsequent O2 molecules This characteristic is responsible for the linear part of the hemoglobin saturation curve (20-60 mmHg) (or the sigmoid shape of the curve)

VO2

Oxygen consumption (mlO2/min) VO2= cardiac output x C(a-v)O2 Basically means how much oxygen is sent to the tissues and how much oxygen returns

Oxygen content (CO2)

Oxygen content of blood (mlO2 / dL blood (100ml) ) CO2 = k x Hb x SO2 + (0.003 x PO2)

DO2

Oxygen delivery (mlO2/min) Flow x Content CO x CaO2

SaO2

Oxygen saturation of hemoglobin (%)

Haldane effect

Oxygenation of blood in the lungs displaces carbon dioxide from hemoglobin which increases the removal of carbon dioxide. Note: shift oxygen-hemoglobin curve to the left

PAO2 - PaO2

PA-a gradient About 10-12 in a normal person Tends to increase with age

Why do we need to regulate O2 and CO2?

PaCO2 is tightly regulated to maintain pH and is the major ventilatory driving force PO2 is regulated to maintain optimal SaO2 and thus CaO2 necessary to satisfy tissue demands Because "high" SaO2 is achieved over a wide range of PaO2 levels (e.g., 60-100 mmHg), PaO2 is not tightly regulated (unless < 60 mmHg)

Hyperventilation

PaCO2 ≤ 35 mmHg at sea level Note: this may also be called hypocapnia or respiratory alkalosis Overall, this means the alveolar ventilation is greater than the CO2 production

Hypoventilation

PaCO2 ≥ 45 mmHg at sea level Note: may also be called hypercapnia or respiratory acidosis

Oxygenation goals for ARDS patients

PaO2 of 55-80 mmHg or SaO2 of 88-95% There are different ways to achieve this: - Lower PEEP/ Higher FiO2 - Higher PEEP/ lower FiO2 (can help prevent oxygen toxicity)

Respiratory syncytial virus

Paramyxovirus (-) ssRNA virus Enveloped Replicates in nasopharynx Spreads from upper to lower Respiratory tract Transmission by aerosolization

West zone 2

Part of the lung in which pulmonary arterial pressure exceeds alveolar pressure, but alveolar pressure exceeds venous pressure (Pa> PA> Pv). The driving pressure in this zone therefore is the difference between arterial and alveolar pressure. Flow is greater than in zone 1, but less than in zone 3. Of note, alveolar pressure is constant throughout the lung (from apex to base). Because of gravity, however, pulmonary artery pressure increases from apex to base. Therefore the closer to the base in the upright person, the greater the driving force (Pa) for blood flow.

PO2

Partial pressure of oxygen (mmHg or torr) At sea level (760 mmHg), about 21% of the atmosphere is oxygen so therefore its partial pressure is 160mmHg

Pasteur rabies vaccine

Pasteur gave series of SQ injections containing minced dessicated rabies-infected rabbit spinal cords to Joseph Meister (who was bitten by a rabid dog) - he injected progressively less-dessicated (I.e. fresher) rabbit spinal cord over time This allows Miester to live This is the rust known use of vaccine for Treatment!

What evidence is there to support uneven HPV as a cause of high altitude pulmonary edema?

Patchy radiographic and autopsy findings Increased incidence in patients with congenital absence of right pulmonary artery

Pathogen recognition receptors (PRRs) recognize ______

Pathogen associated molecular patterns (PAMPs). This triggers a signaling cascade which leads to expression of transcription factors (NFk-b and IRF-3) which leads to gene transcription of various cytokines, etc. Note: some of the most common PRRs are the TLRs Note: dendritic cells and macrophages are well equipped with PRRs

Clinical approach to diagnosing pneumonia

Patient's location -Community or health care associated Patient's immune status -Medications, medical problems Possible routes of entry -Aspiration, inhalation (more common) -Hematogenous, direct extension (less common) Should be started on empiric treatment of likely organisms pending the definitive culture

MOA for corticosteroids

Pharmacological derivatives of members of glucocorticosteroid f amily of steroid hormones Example: Prednisone, a synthetic analog of Cortisol Steroids act through intracellular receptors expressed in almost all cell types. Once bound to a steroid, these receptors release HSP90 and travel to the nucleus. There, the steroid receptor binds to specific gene regulatory sequences and activates transcription

Cause of obstructive sleep apnea

Pharyngeal occlusion during sleep In obese individuals show lipid accumulation in the subcutaneous tissues of the pharynx resulting in upper airway narrowing that is asymptomatic during wakefulness where high levels of electromyographic input activates pharyngeal dilator muscles and maintains patency. During sleep all normals loose skeletal electromyographic tone predisposing the upper airway to collapse if it is anatomically predisposed (increased fat). However, obesity alone is unlikely to fully explain the occurrence of occlusive apnea events Facial anatomy also appears to have role in the development of sleep apnea. Those with under developed jaws usually demonstrate an overbite and are predisposed to apnea particularly when they become obese. Some individuals with severe retroagnathia have apnea from childhood and often require tracheostomy to maintain a patent upper airway. The combination of predisposing pharyngeal anatomy combined with the growing prevalence of obesity appears to explain the increasing occurrence of obstructive sleep apnea.

What are the proteins used in the PPD skin test (tuberculin)

Plasma associated and cell wall associated proteins These help in the transport of proteins and porins 15% of the cell wall weight

Important diseases caused by intracellular organisms that are difficult to target with vaccines

Plasmodium falciparum (malaria) HIV Mycobacterium tuberculosis Burkholderia pseudomallei Orientia tsutsumagumshi

Direct extension leading to pneumonia

Pleural effusion or Pericardial effusion

36 year old female with HIV and a CD4 count of 145 presents with fever, cough, and dyspnea on exertion for 1 week. She is not on any retroviral or prophylactic therapy The Patient's Medical History Puts Him at a Particularly Increased Risk for Which Of The Following Organisms? -Pseudomonas aeruginosa -Pneumocystis jiroveci -Mycobacterium avium intracellulare -Cytomegalovirus

Pneumocystis jiroveci With her level of CD4 T cells, it is likely due to Pneumocystis or toxoplasmosis

Treatment of Haemophilus influenzae

Pneumonia - A Cephalosporin Meningitis - Ampicillin and any close contacts given Rifampin ( inhibits bacterial RNA polymerase and can turn breast milk and urine red)

Polysaccharide vaccines

Polysaccharide coating of bacterium can be isolated and a vaccine can be generated

Location of central controllers

Pontine respiratory group (PRG): - Kölliker fuse (KF) - Lateral parabrachial region (LPBr) Medullary respiratory centers (ventral column): - Bötzinger complex: ventral upper 1/3 - Pre-Bötzinger complex (PBC): ventral upper 1/3 - Rostral ventral respiratory group (R-VRG): ventral middle 1/3 - Caudal ventral respiratory group (C-VRG): ventral lower 1/3 - Dorsal respiratory group (DRG): dorsal middle 1/3

Structure of Mycobacteria

Possess a complex, lipid-rich cell wall (60% of cell wall weight) that is responsible for many of the characteristic properties of the bacteria -e.g., acid-fastness, slow growth, resistance to detergents, resistance to common antibacterial antibiotics, antigenicity, clumping Basic structure of the cell wall is typical of Gram-positive bacteria, but is far more complex -an inner plasma membrane overlaid with a thick peptidoglycan layer and no outer membrane Anchored in the plasma membrane are proteins, phosphatidylinositol mannosides, and lipoarabinomannan (LAM: these are functionally related to LPS)

Interferon gamma release assays

Potential replacement for tuberculin skin test Measures interferon gamma release from sensitized T cells in the patient's blood They draw your blood and separate the Buffy coat. The positive control tube contains lymphocytes but no antigen and the other tube contains TB antigens. You then measure the interferon gamma levels and subtract that from the nil tube

Heart rate reserve

Predicted HR - Measured HR It should be <20 bpm

Location of primary calcified foci in primary TB

Predominantly in the lower lobes where blood flow is greatest

Classification of mycobacteria

Preliminary classification based on growth characteristics (no growth, slow growing, and rapidly growing) and colony morphology

The value of skin testing is related to the ________

Prevalence of disease! It has a high positive predictive if there is a high prevalence of latent TB infection (90%) It has a low positive predictive value if there is a low prevalence of latent TB infection (1%)

What is predictive of future high altitude pulmonary edema?

Previous high altitude pulmonary edema Note: pretreatment with nifedipine can help to protect against it and avoid a job as a sherpa

Respiratory syncytial virus presentation

Primarily bronchiolitis or viral pneumonia Leading cause of LRTI in infants and young kids Peak age 2-8 months By 3 yo everyone has had it

Mycoplasma pneumoniae causes:

Primary Atypical Pneumonia - 2 million cases per year/USA Walking Pneumonia M. pneumoniae is one of the most common causes of community-acquired pneumonia; Especially below 40 yo. In summer can cause up to 50% of CAP Transmitted between people in confined areas - close contact Incubation period 1-3 weeks

pH: 7.46 ; PaCO2: 20 mmHg; PaO2: 115 mmHg; HCO3-: 14 meq/L Cause and is compensation appropriate?

Primary Respiratory Alkalosis with Metabolic Compensation (Primary Respiratory Alkalosis and a Primary Metabolic Acidosis) Expected PaCO2: 27-31 mmHg: This is not respiratory compensation for metabolic acidosis Example of a patient with salicylate toxicity with combined metabolic acidosis and respiratory alkalosis

Too much aspirin leads to what acid-base disorder?

Primary Respiratory alkalosis Note: it can also interfere with with electron transport chain and generate a primary metabolic acidosis

pH: 7.10 ; PaCO2: 30 mmHg; PaO2: 105 mmHg; HCO3-: 9 meq/L Cause and is compensation appropriate?

Primary acidosis with inadequate respiratory compensation (or respiratory acidosis) expected PaCO2 based on Winter's Formula: 20-24 mmHg Actual PaCO2: 30 mmHg Inadequate Respiratory Compensation Patient example could be one with neuromuscular weakness with severe diarrhea

M. tuberculosis pathogenesis steps

Primary infection -The bacteria are inhaled -Bacterial multiplication occurs within the alveoli -They spread though lymphatic drainage to hilar lymph nodes -They can then spread to the bloodstream throughout the body Alveolar macrophage -Ingested bacteria multiply in non-activated macrophages -Th1 cellular immune responses activate macrophages via INF gamma secretion - IF activation is successful, disease is arrested (90-95%). If not, the disease and injury continues -Inflammatory elements of DTH are attracted and cause tissue destruction Active or Reactivation TB - Granuloma formation and DTH mediated cavity formation; bacteria can be coughed up and spread

WHO priority pathogens list for R&D of new antibiotics

Priority 1: CRITICAL -Acinetobacter baumannii, carbapenem-resistant -Pseudomonas aeruginosa, carbapenem-resistant -Enterobacteriaceae, carbapenem-resistant, 3rd generation cephalosporin resistant Priority 2: HIGH -Enterococcus faecium, vancomycin-resistant -Staphylococcus aureus, methicillin-resistant, vancomycin resistant -Helicobacter pylori, clarithromycin-resistant -Campylobacter spp., fluoroquinolone-resistant Salmonellae, fluoroquinolone-resistant -Neisseria gonorrhoeae, 3rd generation cephalosporin-resistant, fluoroquinolone-resistant Priority 3: MEDIUM -Streptococcus pneumoniae, penicillin non-susceptible -Haemophilus influenzae, ampicillin resistant -Shigella spp., fluoroquinolone resistant

Hantavirus pulmonary syndrome symptoms

Prodrome of fever, muscle aches, dry cough; rapidly followed by pulmonary edema, resp. failure, and death within days. 60% mortality in 1993, But more like 30% today

Th1

Produce IFN-y which can bind cytokine receptors on the macrophage They also contain CD40L which binds to macrophage's CD40 This leads to macrophage activation and killing of phagocytose microbes

Acute phase reactant

Produced by liver in response to inflammation Cytokine rebased at the site of infection trigger this response in the liver Factor H possesses both cofactor activity for the Factor I mediated C2b cleavage, and decay accelerating activity against the alternative pathway C3- converatase, C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses, because it binds to GAGs that are generally present on host cells but not, normally, on pathogen surfaces

Phaeohyphomycoses

Produces hyphae that are pigmented with or without yeast present Those infected are often neutropenic and present with brain abscesses and sinusitis --> CNS Again, must be cultured for the appropriate diagnosis and therapy

Antibiogram

Profile of antimicrobial sensitivity Institutions develop an overall profile of antimicrobial susceptibility testing results of a specific microorganism to a battery of antimicrobial drugs

Cytokines in ARDS

Proinflammatory cytokines may be produced locally in the lung by inflammatory cells, lung epithelial cells, or fibroblasts. The regulation of cytokine production by extrapulmonary factors has also been described Glucocorticoids can mediate inhibition of cytokine secretion Several endogenous inhibitors of proinflammatory cytokines have been described, including interleukin-1-receptor antagonist, soluble tumor necrosis factor receptor, autoantibodies against interleukin-8, and antiinflammatory cytokines such as interleukin-10 and 11

Macrolide side effects

Prolongation of the QT interval, increasing risks of ventricular arrhythmias Do not combine with other drugs that prolong QT!

Macrolides

Protein synthesis inhibitor via binding to the bacterial ribosome and inhibiting translocation of peptiyl tRNA Bacteriostatic

What is a leading cause of pneumonia in CF patients

Pseudomonas aeruginosa

47-year-old male Type II diabetes mellitus for 13 years Developed diabetic neuropathy and end-stage renal disease Renal transplantation and immunosuppression One month post-transplant -Fever, chills, pleuritic chest pain -Chest x-ray = cavitary lesion in right upper lobe -Sputum examinations negative for acid-fast bacilli -ATT initiated ATT failed Blood sugar 153 - 226 mg/dl Insulin therapy Fine needle aspirate of lesion -Direct microscopy = no fungal elements -Fungal cultures were negative at 4 weeks No improvement at 20 days -Open-lung biopsy of lesion, no mass noted Periodic acid-Schiff stain revealed acute inflammatory infiltrates and ribbon-like hyphae Culture of the biopsy: -Fast growing, floccose white colony turning grayish -Isolate identified as Rhizopus spp.

Pulmonary Zygomycosis For our patient: -Liposomal Amphotericin B was administered -Striking improvement both clinical and radiological -No relapse at 5 months Classical presentation of a susceptible diabetic host -Localized, primary pulmonary zygomycosis

Are the pulmonary artery or veins superior?

Pulmonary artery

ARDS survivors

Pulmonary function remains impaired up to 12 months In severe ARDS patients, pulmonary function may never return to normal levels Cognitive deficits are noted in the ICU and persist for at least one year

How much does VE increase during exercise?

Resting: 5-6 L/min -Tidal volume ≈ 500 mL - Breathing frequency ≈ 12-18 bpm Exercise: > 100 L/min -Tidal volume ≈ 60% of vital capacity, ≈ 3,000 mL - Breathing frequency ≈ 40-50 bpm - A-a O2 difference < 20 mmHg at max - Consume bicarbonate at the anaerobic threshold - PaCO2 should drop progressively "metabolic acidosis"

Compensation for respiratory acidosis

Retention of HCO3- (by Kidney) Takes time (48-72 hours minimum) for compensation -Can move pH into normal range given time Acidemic pH (< 7.35) indicates that the respiratory acidosis is acute (i.e. no time for compensation)

How do you compensate for metabolic alkalosis?

Retention of PaCO2 (hypoventilation) Very weak compensation -Limited by hypoxia -Range of normal responses is wide Winter's Formula is not useful for metabolic alkalosis

Central chemoreceptors

Retrotrapezoid nucleus-RTN located in the rostral medulla close to its ventrolateral surface Responsible for 80% the normal respiratory drive Sensitive to changes in H+ (pH) in the interstitial space adjacent to the cerebral spinal fluid and argued to be sensitive to CO2 although to a lesser extent No sensitivity to O2

Ventral, dorasal, rostral, caudal in terms of neuroanatomy

Rostral- up ventral - forward dorsal- backwards caudal- down

Zygomycosis Clinical manifestations

Route - inhalation Incubation - ??? Forms of infections: 1. Rhinocerebral zygomycosis - oropharyngeal, periorbital -paranasal sinus --> eye, brain -Risk factor = metabolic acidosis 2. Primary cutaneous zygomycosis (contaminated bandages) 3. Disseminated - fulminant and fatal, very poor prognosis -Cutaneous zygomycosis

Clinical manifestations of aspergillosis

Route of infection is inhalation of conidia Incubation is days to weeks Forms of infection include: -allergic aspergillosis -cavitary colonization- aspergilloma -primary pulmonary aspergillosis -Invasive aspergillosis Note: they grows as a mold in human tissues

What is the most common Health-care facility acquired pneumonia organism?

S. aureus Gram negative rods: - E. coli - K. pneumonie - P. aeruginosa

Common organisms causing pneumonia normal immunocompetent individuals

S. pneumonie H. influenza N. meningitidis

Common organisms causing pneumonia immunocompromised individuals who had a splenectomy

S.pneumonie H.influenza N.meningitidis

Common organisms causing pneumonia immunocompromised individuals with HIV

S.pneumonie (most common) TB Pneumocystis MAC CMV Fungal

MDR-TB treatment

SIRTURO™ (bedaquiline) approved by FDA for the treatment of pulmonary MDR-TB as part of combination therapy in adults (≥18 years) SIRTURO™ interferes with bacterial energy metabolism SIRTURO™ specifically inhibits mycobacterial ATP synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis

Metabolic compensation is ______

SLOW

Arterial blood gases calculates ____ based on hemoglobin desaturation curve or directly measures oxygen-hemoglobin (co-oximetry)

SaO2

_____ not PaO2 mostly determines oxygen content

SaO2

Variolation

Scraped lesions and innucolated others with the collected fluid It reduced mortality to 1-2% Innoculated individuals however could spread smallpox virus

What is the major cause of death in those affected with influenza?

Secondary infections This is due to IF-gamma that is produced causing decreased alveolar macrophage function

2 main functions of the spleen

Secondary lymphoid organ (white pulp) Filter for the blood (red pulp) - removes aged or abnormal red blood cells and microorganisms For the microorganisms: -some are recognized and engulfed directly by phagocytes in the red pulp - some must first be coated (opsonized) by antibodies (mainly IgG) generated in the white pulp (protects against dissemination of these pathogens to other sites such as the lung)

hyaline membrane

Seen within the alveoli of ARDS patients

Peripheral chemoreceptors

Sensitive to sudden arterial blood changes in: - CO2 - H+ (pH) - O2 (only when PaO2 < 60 mmHg or altered CO2 / pH) Possess a high metabolic rate, compensated by high arterial flow, thus their high sensitivity for PaO2 Senses PaO2 not CaO2

Does influenza have a segmented genome?

YES, 8 separate segments with each encoding one or two proteins only

_____ is associated with the highest risk of progression to acute lung injury or the acute respiratory distress syndrome, approximately 40 percent. The presence of multiple predisposing disorders substantially increases the risk, as does the presence of secondary factors including chronic alcohol abuse, chronic lung disease, and a low serum pH.

Sepsis

Histopathology of aspergillosis

Septate hyphae Dichotomous branching at acute angles May see full conical structures (fruiting bodies)

Hantavirus pulmonary syndrome diagnosis

Serologic tests to detect IgM anti-Hanta RT-PCR is still experimental

Reactivation TB CXR

Shows right upper lobe infiltrate Cavity in the upper right lobe as well

Hantavirus pulmonary syndrome CXR

Shows the rapid progression of pulmonary edema

Injury to higher brain centers effect on respiration

Sighing respirations, loss of voluntary control and emotional responses

Mycobacterial diseases

Significant cause of morbidity and mortality -particularly in countries with limited medical resources Most human infections caused by: M. tuberculosis, M. leprae, M. avium complex, M. kansasii, M. fortuitum, M. chelonae, and M. abscessus Diseases caused by mycobacteria typically develop slowly, follow a chronic course and elicit a granulomatous response

Nonconverter

Signifies person who remains skin test negative at least 8 weeks after exposure and are considered non-infected

High altitude pulmonary edema

Signs and symptoms of pulmonary edema but they have a normal left atrial (wedge) pressure Presents with marked pulmonary hypertension (60 to 140 mmHg)

Medical conditions that increase the likelihood that latent tb will become active tb

Silicosis Diabetes (mainly insulin dependent) Chronic renal failure Gastrectomy Malnutrition Jejunoileal bypass Diseases requiring immunosuppressive drugs - TNF-alpha blockers, steroids, cyclophosphamide Malignancies (esp. hematologic)

M. tuberculosis treatment

Slow-growing mycobacteria are resistant to most antibiotics used to treat other bacterial infections Patients must take multiple antibiotics for an extended period (e.g., a minimum of 6 to 9 months), or antibiotic-resistant strains will develop Most treatment regimens begin with 2 months of isoniazid (INH), ethambutol, pyrazinamide, and rifampin, followed by 4 to 6 months of isoniazid and rifampin or alternative combination drugs -First line drugs: isoniazid, ethambutol, rifampin, pyrazinamide -Second line drugs: para-Aminosalicylic acid, ethionamide, cycloserine, fluoroquinolones, kanamycin, amikacin, capreomycin, streptomycin

Three major forms of MAC pulmonary disease:

Slowly evolving cavitary disease that resembles tuberculosis on chest radiography -most commonly seen in middle-age or older men with a history of smoking and underlying pulmonary disease 'Lady Windermere syndrome' - observed in elderly, female non-smokers -chronic cough, shortness of breath, fatigue and other less specific symptoms -lingular or middle lobe infiltrates with a patchy, nodular appearance on radiography and associated bronchiectasis (chronically dilated bronchi) Formation of a solitary pulmonary nodule

Types of smallpox, rabies, and diphtheria vaccine

Smallpox -Variolation: live attenuated virus -Vaccination: live cowpox/vaccina virus Rabies -Inactivated (dead) virus -Live (attenuated) virus Diptheria -Passive immunization (antibody therapy)

14 Infectious Diseases Mostly Controlled by Vaccines

Smallpox Diptheria Tetanus Yellow fever Polio Measles Mumps Rubella Pertussis H.influenzae, type b Typhoid Rotavirus Hepatitis B

The removal of soluble and insoluble proteins in the alveoli in ARDS occurs primarily via:

Soluble protein appears to be removed primarily by diffusion between alveolar epithelial cells. Insoluble protein may be removed by endocytosis and transcytosis by alveolar epithelial cells and by phagocytosis by macrophages

Resorption atelectasis

Sometimes an obstruction in a central airway (due to tumor or mucous plug) can prevent any air from getting to the distal lung or lobe. Blood flow continues to the now isolated area leading to gradual uptake (resorption) of oxygen and nitrogen, resulting in atelectasis. The air in the isolated lobe/lung is slowly taken up by the blood leading to resorptive atelectasis. Since the central bronchi is obstructed, no sounds are transmitted to the area and therefore, tactile fremitus should be decreased in this type of atelectasis.

Influenza signs and symptoms

Sore throat, Headache, myalgia, fever, dry cough and malaise Fever between 100-104F Develops within days of exposure Tachycardia Rarely a runny nose Can't get out of bed CXR - bilateral nodular opacities WBC usually normal

M (microfold) cells

Specialized epithelial cells Have a folded lumenal surface to increase surface area Microbes and antigens can pass through (endocytosis or phagocytosis) into the associated lymphoid tissue

What are some identification test for the different species of mycobacteria?

Species-specific molecular probes are the most useful means of identifying commonly isolated mycobacteria (e.g., M. tuberculosis, M. avium, M. kansasii) -commercially prepared probe identification systems currently used are rapid (test time 2 hours), sensitive and specific Biochemical tests including analysis of cell wall lipids

What is the most commonly affected organ in blunt trauma

Spleen, may often require a splenectomy

Tools required for prophylaxis of TB (treating those who are infected latently but not actively)

Standardized skin test to reliably detect infection CXR Drugs for chemotherapy (streptomycin, PAS (1944))

43 year old man recently diagnosed with HIV. His CD4 count is 693. He is not on anti-retroviral therapy. He presents with fever, cough, and right-sided pleuritic chest pain. The Patient's Medical History Puts Him at a Particularly Increased Risk for Which Of The Following Organisms? -Streptococcus pneumoniae -Pneumocystis jiroveci -Mycobacterium avium intracellulare -Cytomegalovirus

Streptococcus pneumoniae This is an example of an encapsulated bacteria that is best cleared via antibody response. CD4 T cells are needed for the generation of these antibodies 11.3 cases per 100,000 person-years in adult patients without known HIV infection 677 cases per 100,000 person-years in HIV-infected patients - Half had CD4 counts > 200

What is the most common community acquired pneumonia organism?

Streptococcus pneumoniae Though other types include: - S. aureus - H. influenza - M. catarrhalis - Anaerobes (bad dentition)

A 53 year-old man with non-insulin-dependent diabetes and hypertension presents with symptoms of fever, chills, and a cough with green sputum. He also complains of right side pleuritic pain. PE reveals crackles in right lung. He is a long term cigarette smoker. Lab results are shown below: CXR shows infiltrate in upper right lobe Culture: -catalase negative -alpha hemolytic - blood culture negative

Streptococcus pneumoniae (number one cause of community acquired pneumonia)

Treatment of Hantavirus pulmonary syndrome

Supportive No antiviral: 30-50% die (though ribovarin has a slight effect)

ARDS treatment

Supportive Infection control Nutrition Prevention of GI bleeding and thromboembolism

Adhesive atelectasis

Surfactant in the alveoli reduces surface tension preventing alveolar collapse; its inactivation or inadequate production leads to an increase in surface tension which can cause alveolar collapse. Conditions that inactivate surfactant: ARDS, hyaline membrane disease, pulmonary embolism leading to loss of CO2 to an area, and prolonged shallow breathing (frequently due to post-operative pain) can all lead to adhesive atelectasis. In these cases, the major bronchi to the area is patent so sound is transmitted to the area, unlike the case of a central tumor when sounds are not transmitted. Thus tactile fremitus should be increased in adhesive atelectasis.

Diagnosis of Streptococcus pneumoniae

Symptomology Leukocytosis Culture from sputum or pleural fluid G+ diplococci, Catalase neg, alpha hemolytic, Capsule typing Urine test for shed bacterial cell wall polysaccharide (not capsule)

Bacillus anthracis diagnosis

Symptoms (high fever, severe SOB, tachypnea, cyanosis, profuse diaphoresis, hematemesis, chest pain which may mimic acute MI) Leukocytosis Culture organism from pleural fluid, blood culture Can use PCR to detect bacteria or spores, Reference lab does this.

Diagnosis of influenza

Symptoms and knowledge of community outbreak (clincher) Serology RT-PCR Immunochromatography: rapid test detects nucleoprotein antigens in nasal or throat swabs.

Mycoplasma pneumoniae symptoms

Symptoms at onset- fever, headache, chills, general malaise, possible scratchy throat Rare, if any, Myalgia Non productive (dry) cough Fever <102F Ambulatory, do not usually appear seriously ill Lung X-ray - patchy pneumonitis WBC - can be normal or elevated General symptoms disappear after week, but persistent cough and positive X-ray results may remain for months. Rarely fatal

Diagnosis of Respiratory syncytial virus

Symptoms, age (<3 yo) CBC Normal, but may have slightly elevated bands Test secretions by RT-PCR Detecting viral antigens (ELIZA or Immunochrom.)

Is acute respiratory distress syndrome (ARDS) a syndrome or a disease?

Syndrome which is defined as a group of symptoms that consistently occur together, or a condition characterized by a set of associated symptoms Note: disease is defined as a disorder of structure or function in a human, animal, or plant especially one that produces specific signs or symptoms or that affects a specific location and is nor simply a direct result of physical injury

Control of ventilation ascribed to the teleology of the respiratory system

Take up O2 (from external environment) and remove CO2 (from internal environment) to maintain rapid homeostasis of PaO2, PaCO2, and pH The mechanism involves periodic inflation (inspiration) and deflation (expiration) of the lung The driving signal is CO2 which is maintained in a tight range despite its production O2 is a driving signal only when levels are extremely low (e.g., PaO2 < 60 mmHg)

Complications of altitude

Temperature Humidity Solar radiation Ionizing radiation Hypoxia

C(a-v)O2

The amount of oxygen extracted from the blood by the tissues normally around 5 ml O2 / 100 ml blood

What is the role of conjugates in polysaccharide vaccines?

The antigen is attached covalently attached to these conjugates which are stronger antigens which illicit a stronger immunological response to the weak antigen

Aspergillosis virulence factors and pathogenesis

Thermo-tolerant to 50C It produces several enzymes considered to be virulence factors and include elastase, phospholipase, protease, and catalase The conidia themselves can bind to fibrinogen and laminin Invasive disease is depend on impaired neutrophil function (the neutrophil is unable to generate the oxidative burst to kill it)

Does heart size matter for cardiac output and thus VO2 max

The heart size to body weight ratio is pretty conserved at about 0.6% However, trained individuals and species might have a higher heart size to body ratio around 0.8% Therefore, larger hearts can have an effect on the cardiac output and VO2 max

Active immunity

The individual develops their own immune response against a pathogen due to either infection or vaccination

Passive immunity

The individual receives protective (neutralizing) antibodies from other sources Before the antibiotic era, passive immunity with antibody (serum) administration was the only therapeutic option against many bacterial diseases Example are maternal antibodies (You begin with immunity to various things such as mumps/measles but it quickly wanes)

In shunts, there is an overall hypoxemia. What compensates?

The low PO2 is sensed by the peripheral chemoreceptors and minute ventilation is increased. By definition, the increased ventilation goes to the normal lung and PCO2 decreases where as the PO2 increases from the blood leaving that lung . However this slight increase in PO2 has almost no effect on SaO2. Therefore all the extra work to increase the PO2 has very little effect on improving arterial oxygenatio However, PCO2 to CO2 content is linear over the human range. Therefore the decrease in PCO2 coming from the unaffected lung helps to compensate any increase in PaCO2Therefore when faced with a large shunt (or V/Q mismatch) the unaffected lung can compensate for the elevated CO2 coming from the blood perfusing the diseased lung by increasing minute ventilation; however the unaffected (normal) lung cannot compensate for the decreased oxygen saturation in the shunted blood even if minute ventilation is increased dramatically. Therefore low V/Q mismatch and shunt rarely produce abnormalities in arterial CO2 levels, but do produce systemic hypoxemia.

________ of O2 in the Alveolus Is Critical In Determining Oxygen Content and Delivery

The partial pressure (PAO2)

General idea for latent TB infection formation

There is seeding of the bacilli to the lung apex and remains at a dormant level Anything that can drop the cell mediated immunity (medications, HIV, malignancy, alcoholism) can lead to break down of granulomas and the escape of some of the bacilli and the formation of the active disease. In the worse case, you can have cavitary pulmonary TB housing about 10^13 cfu

Recovery phase of ARDS

The recovery phase is characterized by the gradual resolution of hypoxemia and improved lung compliance. Typically, the radiographic abnormalities resolve completely. The degree of histologic resolution of fibrosis has not been well characterized, although in many patients pulmonary function returns to normal

West zone 1

The region where PA exceed Pa which in turn exceeds Pv (PA> Pa> Pv). In this zone the pulmonary microvasculature iscompressed because the (positive)alveolar pressure exceeds the arterial driving pressure. Blood flow in zone 1 is minimal. In an upright person this is usually found in the apical parts of the lung.

Disseminated cryptococcus

The skin and bone are the most frequent sites of disseminated disease Skin lesions are sometimes the presenting sing and are often remarkable for their lack of inflammation The diagnosis can often be made via lesion biopsy

Antigen recognition in airways by innate immunity and immune consequences

The upper airway contains cilia and mucus which allows them to move particles out. They also have innate immune cells such as dendritic cells that sample the environment. These can then instruct the immune response to be tolerate those organisms or particles to help prevent inflammation when you dont need it In the alveolus, there are surfactants, alveolar macrophages, DCs all help to take in particles and can help lead to tonic suppression and prevent inflammation Some pathogens however, have PAMPs which engage PRRs which lead to activation of innate immune cells which expresses various stimulatory molecules and travel to the lymph nodes where they can activate a cell mediated response. In the alveolus, alveolar macrophages, neutrophils, etc can lead to this as well.

Live attenuated virus vaccines

The virus is isolated, grown in non human cells such that it mutates to grow well in this new cell type. It is then removed and grows poorly in humans Attenuated Strains held by CDC/CBER Expanded by Vaccine Manufacturers Tested for titer, infectivity Provided alone or in combination with other attenuated viruses Examples: -Polio (Sabin) -Mumps -Measles -Rubella -Influenza -Varicella (Chicken Pox) -Varicella (Zoster) -BCG -Anthrax -Yellow Fever -Cholera -Variola

What is anatomic dead space?

The volume of the conducting airways - i.e., the respiratory anatomy that can't participate in gas exchange Note: there won't be a PACO2 in this space

Central hypoventilation: Odine's curse

The voluntary control of respiration is intact but there is an absence of involuntary control

TNF-α inhibitors as therapeutics

There are soluble inhibitors such as etanercept (ENBREL) There are also monoclonal anti-TNFα antibodies

Possible outcomes of M. tuberculosis infection

There could be a low bacterial burden and the bacteria are destroyed with minimal tissue damage. The lesions here heal by fibrosis If there is a high bacterial burden, there are cellular immune responses. This results in tissue necrosis and ultimately granuloma formation that prevents further spread of bacteria. This containment can be in small granulomas where intracellular bacteria are killed; or large necrotic/caseous granuloma which effectively protects bacteria from macrophage killing. Note: this can lead to dormancy or reactivation Overall, effective immune réponse can lead to spontaneous healing. Ineffective immune response can lead to acute disease. You can also get containment (>90%)

In non-steady state exercise, we utilize

There is more of a shift of pyruvate generating lactate, H+, NAD+ via lactate dehydrogenase instead of traveling to the mitochondria for oxidative phosphorylation Note: lactic acid is only generated when pH drops below 4, therefore generally you will only see lactate and H+ Note: Lactate and H+ are transported out of the muscle via a cotransporter (MCT4)

Definitive identification of Coccidioides immitis

Thermal conversion, not that cannot be done you could use ExoAg or Nucleic acid probe confirmation

Surfactants

These are key soluble PRRs in the alveolar spaces and produced by pneumocytes They are a collectin family of molecules MBL is produced in the liver (acute phase) whereas SP-A/D are expressed in distal lung They interact with a variety of PAMPs and function as opsonins Note: they interact with alveolar macrophages and help to maintain the function of them

What are avian flu and swine flu

They are influenza A strains with different host specificities Key to host specificity are the sialic acid residues on host cell surfaces to which HA binds In one set of receptors sialic acid binds to galactose using a α2,3 linkage. The other receptors have an α2,6 linkage Birds predominantly have α2,3 linkage receptors (gut) -Birds have no symptoms Pigs have α 2,3 and 2,6 linkage receptors (Lungs and trachea) -Pigs develop symptoms

High risk immigrants are treated in the US if ______

They have been in the US for less than 5 years

Recombinant protein vaccines

They take a gene that produces a highly antigenic such as the surface antigen. This gene is added to a plasmid to generate recombinant DNA. This recombinant DNA is this added to a yeast cell. The yeast beings to multiply and produces the target antigen. This is extracted and purified to be added into the vaccine Examples: -Hepatitis B -Anthrax

Describe this electron micrograph

This is a capillary that shows endothelial cells that are swollen that has lost its apposition with the basement membrane There are also noticeable gaps

Disseminated invasive aspergillosis

This is the most severe form of aspergillosis Beings as pulmonary infection where the conidia germinate and form hyphae and invade tissue They can pretty easily cross the vasculature barrier in the lungs where they can gain access and spread to other parts of the body

Humoral immunity

This is triggered by extracellular microbes causing B lymphocytes to respond and being secretion antibodies These block infections and help in the elimination of extracellular microbes

Secondary lung infections

Those individuals with a primary infection that becomes more susceptible to a secondary infection Ex: Viral influenza is a seasonal infection that can lead to pneumonia Pneumonia can lead to death: -ARDS, virus or secondary bacterial infection ->90% of deaths from 1918 pandemic (Spanish flu, H5N1) resulted from pneumococcal pneumonia -~75% of cases in 1957-58 Asian influenza pandemic had histological evidence of bacterial pneumonia -2009 "swine flue" pandemic (H1N1), >50% of autopsy tissue showed bacterial pneumonia ~90,000 deaths in USA/year due to bacterial infections deaths due to MRSA > deaths due to HIV

Who is at risk for aspergillosis?

Those individuals with severe neutropenia, leukemia, and lymphoma

Which patients with latent tuberculosis infections should be treated?

Those who are PPD (+)/IFRA positive and age <35 yrs or any age who is a/has a: -Recent skin test conversion (>10 mm in past 2 years) -Recent immigrant (within 5 years) from a high-risk country -Homeless -Medical conditions which increase the risk of progression from latent to active tuberculosis infection -CXR with apical scarring consistent with old healed tuberculosis (Calcified granulomas and calcified lymph nodes do not significantly increased risk of re-activation and do not need to be treated)

Acute lung injury criteria

Timing: acute onset Oxygenation: PaO2/FiO2 ≤ 300 mmHg (regardless of PEEP) Chest radiograph: bilateral infiltrates PA wedge pressure: ≤ 18 mmHg Note: this was from the 1994 study and they removed compliance

ARDS criteria

Timing: acute onset Oxygenation: PaO2/FiO2≤ 200 mmHg (regardless of PEEP) Chest radiograph: bilateral infiltrates PA wedge pressure: ≤ 18 mmHg Note: this was from the 1994 study and they removed compliance

Partial pressure of O2 in venous blood is decreased due to _____

Tissue extraction Note: it generally comes in the right ventricle at about 40 mmHg

Decrease in flow (cardiac output) leads to ______

Tissue hypoxia Note: even if it is above the 250 ccO2/min required, it can be pathologic and can lead to lactic acidosis because of inadequate oxygen delivery

Zygomycosis virulence factors and pathogenesis

Tissue necrosis suggests tissue destructive enzymes Debilitated and immunocompromised -especially diabetic ketoacidosis -leukemias and lymphomas

Why would normal people retain carbon dioxide?

To compensate for a metabolic alkalosis - (I.e. a pathologic increase in HCO3-) - compensation limited by development of hypoxia - least predictable fo all compensations

PaCO2 correlates to _____

Total CO2 Note: even though this is only the amount dissolved

Toxoid vaccines

Toxigenic bacterial strains and centrifuged and purified The toxin is collected and formalin is added to inactive it forming a toxoid Examples: -Diptheria -Tetanus

M. tuberculosis immunodiagnosis

Tuberculin skin test (TST, Mantoux) -tuberculin antigen is a purified protein derivative (PPD) from the mycobacterial cell wall; second-generation assays use more specific antigens (e.g. ESAT-6, CFP-10) -tests reactivity to an intradermal injection of mycobacterial antigens: PPD injected under skin, measure diameter 48-72h later -a positive PPD reaction usually develops 3 to 4 weeks after exposure to M. tuberculosis -patients with severe disseminated disease, those on immunosuppressive drug, or with immunosuppressive diseases (e.g. AIDS) may fail to react due to anergy in vitro IFN-γ release assays -a blood test; sensitive, more specific alternative to the PPD skin test -immunoassays (ELISA) to measure IFN-γ produced by sensitized T cells stimulated by M. tuberculosis antigens (e.g. QuantiFERON-TB Gold or T-SPOT.TB) -the technical complexity of the assays currently limit their use

What eliminated bovine transmission of TB?

Tuberculin testing of cows and the pasteurization of milk

TB in homeless population

Tuberculosis case rate among homeless (in Denver, not sure about Mobile) is estimated to be 50-60 cases/100,000 High rate likely due to risk of recent exposure/infection rather than to underlying medical conditions Homeless individuals with a positive PPD (> 10 mm) are presumed to be recently infected and treated regardless of age

Cells within the carotid and aortic bodies

Type 1 (gloms cells) and 2 (sustentacular glial cells) Type-1 glomus cells are sensitive to: - PO2: Decreases in PaO2 causes O2-sensitive K+ channels to close leading to cell depolarization - H+ and PCO2: CO2 → CA → H+ + HCO3-→ → H+/Na+ exchanger leading to intracellular Na+ increases and cell depolarization →H+/Ca++ exchanger leading to intracellular Ca++ increases and neurotransmitter release → HCO3- → soluble adenylyl cyclase activation → increases cAMP → enhances intracellular Ca++ increases and neurotransmitter release

Whta is indicated by arrow

Type II pneumocyte (has lamellar bodies full of surfactant; and also ciliated extensions)

Determinants of Vaccine Response in Healthy People

Type of Vaccine -Live versus inactivated -Adjuvants Antigen Nature -Polysaccharide antigen -Protein antigen (quality of epitopes) -Antigen dose Vaccine Schedule -Delay between doses -Age -Genetic factors

Miliary Tuberculosis

Type of tuberculosis caused by hematogenous spread of the disease, with a characteristic appearance similar to millet seeds, which are small, white grains

Prevention of Streptococcus pneumoniae

Type- Specific anticapsular Antibodies are protective! Of the 80 strains, 23 are responsible for more than 90% of disease. Polyvalent Vaccine - pneumococcal polysaccharide vaccine [PPSV- primarily for elderly (>65 yo) - pneumovax] Pneumococcal Conjugate vaccine, PCV (13 valent) for children

Cryptococcus diagnosis

Typical CSF findings in cryptococcal meningitis -Increased pressure -pleocytosis of lymphocytes -depression of glucose levels -cryptococcal capsules are demonstrable in CSF in roughly 50% of caste by riding centrifuged sediment with India ink and microscopy Culture: -the volume of CSF sampled is important. The number of organisms present may be small enough to require a substantial volume of fluid (more than 30mL) to yield a positive culture Serology: -GXM polysaccharide antigen in the CSF or serum by latex agglutination or enzyme immunoassay methods is recommended (very sensitive and specific) -A rising antigen level indicates progression and a declining titer is a favorable sign

Symptoms of Haemophilus influenzae

Typical of pneumonia

Zygomycosis epidemiology

Ubiquitous Usually- Rhizopus spp. - others: Mucor, Absidia, Rhizomucor, and Cunninghamella

Cryptococcous neoformans epidemiology

Ubiquitous throughout the world Particularly in soil contaminated with avian droppings and decaying vegetable matter One environmental niche is the hollowed out area of trees, where lactase is involved in the degradation of wood Infectious form is thought to be either desiccated yeast cells or basidiospores stirred up from these sites and inhaled Occurs most when there is a defect in T-lymphocyte

Important questions to ask someone with pneumonia

Underlying medical problems that put pt in constant contact with health facility -Dialysis, chronic wound care, recent hospitlizations Any sick contacts? Any animal exposure? -Hunting, exposure to dead animals, goats, sheep, cattle -Pet birds Travel history Exposure to unusual water sources - recent stays in hotels Exposure to people with TB (past or present)

What is the presumed mechanism of high altitude pulmonary edema?

Uneven hypoxic pulmonary vasoconstriction This leads to increased permeability edema which will be high in protein There is also intracellular disruptions of capillary endo and/or alveolar epithelium the occurs with increases in wall stress -Circumferential tension (via increased transmural pressure) -Longitudinal tensions (via lung overinflation) -surface tension

Pulmonary stretch receptors (slowly adapting)

Unmyelinated nerve endings located between the smooth muscle of large and small airways Slowly adapting Signal via X cranial nerve Stimulated by changes in the shape of airways Responsible for the Hering-Breuer reflex

Oseltamivir and zanamivir

Use: Treatment and prophylaxis of influenza A and B. Reduce duration of illness if given within 2 days of onset of symptoms. Mechanism of action: Both of these drugs inhibit the viral neuraminidase, blocking release of viral particles from infected cells. Resistance: Neuraminidase mutations.

Fick equation

Used to determine VO2 max (oxygen consumption) VO2 = Q (CaO2 - CvO2) Q= cardiac output CaO2= content of arterial oxygen (= [(1.34 x [Hb] x SaO2) + (0.003 x PaO2)] ) CvO2= content of venous oxygen (= [(1.34 x [Hb] x SvO2) + (0.003 x PvO2)] )

Co-oximeter

Uses several wavelengths to analyze blood and determine the amount of oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methemoglobin Note: a pulse oximeter cannot distinguish carboxyhemoglobin from oxyhemoglobin!

What the average P50?

Usually around 27 mmHg

What might the PO2 be atop Everest

Usually the barometric pressure here will be about 215 mmHg Oxygen makes up about 21% so therefore it will be about 45 mmHg

What might the PO2 be at 1/2 atmosphere (about 16000 ft)

Usually the barometric pressure here will be about 378 mmHg Oxygen makes up about 21% so therefore it will be about 79 mmHg

What might the PO2 be within Leadville (highest altitude city)

Usually the barometric pressure here will be about 492 mmHg Oxygen makes up about 21% so therefore it will be about 103 mmHg

What might the PO2 be within an airplane?

Usually the barometric pressure here will be about 536 mmHg Oxygen makes up about 21% so therefore it will be about 113 mmHg

Shunt is an extreme _____

V/Q mismatch

minute ventilation (Ve) =

VA (alveolar ventilation) + VD (dead space)

Minute ventilation

VE = RR x VT (tidal volume) Normal Ve= 4 to 6 L/min Note: it could also be VE = VA + VD

How do exercise physiologist estimate gas exchange?

VO2 VCO2 Units= ml/kg/min

Prevention of influenza

Vaccine (made from antigens of viruses grown in tissue culture or chicken eggs) Contains the 2 types of A and 1 or 2 types of B circulating over the past year. Recommended for everyone. Nasal -live attenuated (not for immunocompromised) Injection - killed

Bacillus anthracis prevention

Vaccine: A culture filtrate of nonencapsulated, avirulent strain (PA toxin component) Military, only 2 years protection.

______ is not normal in Bronchiectasis

Ventilation

_______ is not normal in Bronchiolitis Obliterans

Ventilation

Macrolide drug interactions

Via CYP3A inhibition, more of a problem with the older drugs than with azithromycin

Mechanisms for increased susceptibility to secondary bacterial infection after influenza virus

Virus-induced damage to pulmonary epithelium Influenza neuraminidase and upregulation of platelet-activating factor receptor expression Cytokines (e.g. interferons) -Preexisting infection causes alveolar macrophages less able to recognize those new bacteria which can be due to a shift to Th1 response and INF induced downregulation of certain PRRs on the surface of the macrophages

The patients steroid use puts her at a particularly increased risk for:

Viruses -herpes zoster virus -herpes simplex virus -cytomegalovirus -Epstein-Barr virus -adenovirus -Influenza -parainfluenza virus Nocardia Intracellular pathogens -Listeria monocytogenes -Salmonella species -Brucella -Legionella

trachea pulled toward affected side

Volume loss due to focal scarring/fibrosis, or atelectasis

M. tuberculosis epidemiology

WHO estimates that a third of the world's population is infected with M. tuberculosis and that there are 30 million cases of active TB Almost 9 million new cases and 1.5 million TB-related deaths annually (2013) Regions with the highest incidence of disease are Southeast Asia, sub-Saharan Africa, Eastern Europe and Latin America In 2014 in the US, 9412 TB cases were reported (a rate of 3.0 cases per 100,000 persons) -Lowest number of cases recorded since national reporting began in 1953 -66.5% of these were in foreign born persons (rate ~13.4 times higher than that for US-born persons) -536 deaths from TB in the US in 2011 TB is the leading killer of people who are HIV infected -1/4 of all HIV-related deaths

Classic characteristics of apneic events

Watch for respiratory attempts against a closed upper airway (no air movement). Then watch for snoring during inspiration as the person is arousing from sleep and developing increased pharyngeal patency. The classic apnea ends with a visibly obvious arousal as limbs jerk, the body moves, and post-apneic hyperventilation is present. This is typically followed by another apneic event

community acquired pneumonia

When individuals who have not recently been hospitalized develop pneumonia Streptococcus pneumoniae (gram positive, lancet shaped, diplococcus) Moraxella catarrhalis (gram negative diplococcus) Haemophilus influenzae (gram negative rod) Mycoplasma pneumoniae (atypical pneumonia) (cell wall less bacteria, no gram reaction) Note: immunocompromised patients are susceptible to all the above plus fungi (e.g. Aspergillus) and Viruses

Proprioceptors in osteoarthritis-muscular system

When stimulated by movement, they lead to increased ventilation

When does dissemination of TB occur?

While CMI/DTH controls the initial infection The distal disease progresses while primary focus is controlled

Is mortality rate higher in those infections with antibiotic resistance organisms?

YES, about 2 fold higher The problem is there are few new antibiotics being developed in the market

A patient admitted to a nursing home one week prior is found to have smear positive TB. Three 45 y/o workers are exposed and tested immediately: - Worker 1: initial S.T. (-), repeat S.T. (-) @ 3 mos. - Worker 2: initial S.T. (-), repeat S.T.: 12 mm - Worker 3: initial S.T.: 18 mm (no previous Tx) All are ASX with normal CXR's. For each worker should they be treated or not treated?

Worker 1: This is a non-converter so no treatment is indicated Worker 2: This represents a converter with high risk of developing active TB so treatment is indicated Worker 3: They are not treated because he is at low risk for developing active disease, because his initial test indicated he was previously infected.

Are many antibiotics natural products that bacteria encounter in nature?

YES

Are the majority (84%) of all reported TB cases in the US occurring within racial and ethnic minorities?

YES

Can younger children who are immunocompromised by immunized with the pneumococcal polysaccharide vaccine?

YES

Do antibiotics "selectively" kill bacteria that do not have resistance?

YES

Do commensals ward off virulent infections?

YES

Does Carbon monoxide decrease oxygen content?

YES

Does influenza carry its own RNA polymerase?

YES

Does longer prophylaxis decrease active TB in patients with Fibrotic lesions?

YES

Does previous infection with TB appear to protect against Re-infection?

YES

For a given PaCO2, does exercise lead to an increase in minute ventilation?

YES

If a chest x ray shows a lot of scarring in the apex, even though culture were negative, are these individuals at a high risk for progression to active TB?

YES

Is fixed systemic hypertension measured during wakefulness at least twice as common in the untreated apnea population than in obese, nonapneic controls

YES

Is the partial pressure of O2 in capillary (PcO2) identical to partial pressure in alveolus (PAO2)

YES

Is there an increased hypercapnia ventilatory response with acclimatization at altitude?

YES

Is there an increased risk of developing tuberculosis immediately following PPD conversion?

YES

Is there decreased oxygen uptake with increasing altitude?

YES

Are the lungs exposed to the environment?

YES A typical adult human inhales about 11,000 liters of air per day The upper and lower airways are the largest exposed epithelial surface and exposed to all of this inhaled air This air can be rich in contaminants including infectious microbes. Microbes located in the upper airways can also be aspirated into the lungs

Does CO compete with oxygen for hemoglobin binding?

YES CO is about 200x more avid than O2

Is cardiac output a critical determinant of VO2 max?

YES HR - how close to your HR max? SV - Preload, contractility, afterload?

Is hypoxic pulmonary vasoconstriction present even in acclimated populations?

YES However, there are some populations that have lived in tibet for thousands of years that have some blunting of hypoxic pulmonary vasoconstriction helping to protect against pulmonary edema

Can patients with severe apnea present with CHF or cor pulmonale?

YES Most of these individuals have hypercapnia and hypoxemia during wakefulness, a blood gas derangement not see in typical untreated obstructive sleep apnea patients

Is there an acute increase in cardiac output at altitude?

YES Note: this is not sustained, if you accumulate for long periods of time, the cardiac output is not significantly increased

Do CD8 T cells require 2 signals to be activated?

YES One through the TCR and the other through co-stimulatory molecules However, once it is activated, it only requires 1 signal!

Is MAC complex relatively resistant to anti-tuberculosis drugs?

YES Recommended treatment regimen: clarithromycin or azithromycin combined with ethambutol and rifampin

Is there rapid equilibration of PO2 in capillary bed?

YES The PcO2 and the PAO2 rapidly equilibrate to about 100 mmHg within about 0.25 seconds

Is there diffusion limitation of oxygen uptake at altitude?

YES The venous PO2 comes in much lower and there is no equilibration with the alveoli after its passes through the capillary Note: cardiac output can also play a role of this, might need to decrease the cardiac output to slow the RBC down and give it more time to bind O2

Did isoniazid prophylaxis decrease incidence of progression of active TB?

YES This study used patients who were infected by were not an active TB case

Is passive immunity time dependent?

YES When used as a therapy (opposed to maternal antibodies) Best time for passive immunity is pre-exposure or partially into the post exposure time. The longer you wait, the less protection provided by passive immunity

Does intensity of exercise matter in regard to oxygen deficit and debt?

YES With higher intensity, both can extend for longer periods of time With higher O2 requirements, we cannot sustain the level of exercise intensity for extensive periods of time and thus a non-steady state exercise

Is the Partial pressure of O2 in arterial blood (PaO2) less than alveolar (PAO2) and capillary (PcO2) O2?

YES, it is generally around 90 mmHg Note: this is the PAO2 -PaO2 (A-a) gradient! This decrease I due to venous blood dumping into the pulmonary veins such as the bronchial veins and thebesian veins

Does PaCO2 stimulate peripheral chemoreceptors 5x faster than central ones and potentiate sensitivity to low PaO2?

YES, note that it is not a potent activator though

Does lactate accumulate in the blood?

YES, once the lactate threshold is reach (time at which the metabolic requirements of muscle are related to an increase in fermentation) Therefore, lactate can decrease blood pH, due to the H+ being buffered by bicarbonate system. Lactate and proton gives rise to "non-metabolic" CO2

Do acclimated individuals have an augmented hypoxic drive?

YES, there is a chronic adaptation that causes you to be more responsive to carbon dioxide

After a patient awakens from an axenic event, do blood gasses return to normal?

YES, they acquire pharyngeal potency, hyperventilate and return the blood gases back to normal sleeping values

Does corticosteroids have a net anti-inflammatory effect?

YES, this leads to weekend cell-mediated immunity

Can acute mountain sickness recur?

YES, upon ascent to higher altitude Long time residents of altitude (Leadville) can develop acute mountain sickness if they leave for > 10 days

Is there a higher titer of antibody and an earlier presentation of antibodies upon re-exposure to antigen?

YES, within 2-3 days

Histoplasmosis Virulence factors and pathogenesis

Yeast modulate pH of phagosome, survive & grow Facultative intracellular parasite of mononuclear cells May kill macrophage, releasing daughter cells; or just remain dormant Defects in CMI predispose to systemic disease

Pneumonic plague

Yersinia pestis

Is more oxygen delivered than needed?

Yes Oxygen delivery is 1000 ccO2/min Oxygen consumption is only 250 ccO2/min

Does Mycoplasma pneumoniae have specialized attachment tips?

Yes they binds to sialated glycoprotein receptors at the base of cilia of ciliated epithelial cells Leads to ciliostasis and death of the host cell

Is Isoniazid induced hepatitis age related?

Yes! There are more cases in the older population

Is there a correlation with VO2 max and Cardiac output?

Yes, a direct correlation

28 y/o woman from Mexico has a 12 mm induration on immigration screen. She had received BCG vaccination at age 2. She denied any known exposure to TB. She is well with a normal CXR. Do you treat or not?

Yes, regardless of her BCG status, with an induration of 12 mm and coming from a high risk location such as Mexico, she should be treated

Does a decrease in pH and an increase PO2 further increase ventilation?

Yes, ventilation will increase with changes in these factors if PCO2 levels are kept the same

45 y/o nurse who after years of non-reactive skin tests develops a 12 mm induration on her annual screen. She works at a county hospital which treats patients with tuberculosis. She is ASX and has a normal CXR. She has no other medical problems. Do you treat or not?

Yes, with a induration of 12mm she represents a recent converter (≥10 mm increase within 2 years) and she also works in an environment where there is a higher risk for exposure There is also a fairly high risk of progressing to active disease because she is a new conversion

45 y/o man immigrating from Vietnam has 14 mm of induration on his initial skin test. He has not had a prior skin test but his father died of tuberculosis 30 years prior. He has no symptoms and his CXR is normal. He has no other medical problems. Do you treat or not?

Yes, with a induration of 14mm and coming from Vietnam which has a high prevalence of TB Also he has a high risk for progressing to active disease because immigrants have the same rate of progression to active TB as that of their native country for the first 5 years.

A 52 y/o woman whose husband has smear-positive Mycobacterium tuberculosis has a PPD of 8 mm induration. She does not remember the results of her old skin test 20 years prior. She is asymptomatic with a normal chest radiograph. Do you treat or not?

Yes, with a induration of 8 mm and in close contact with someone she should be tested There is also a fairly high risk of progressing to active disease because she is a new conversion

What is the easy way to calculate VO2 max

[Distance covered (meters) in 12 min-504.9] / 44.73

Bohr effect

a decrease in the amount of oxygen associated with hemoglobin and other respiratory compounds in response to a lowered blood pH resulting from an increased concentration of carbon dioxide in the blood. Note: shift oxygen-hemoglobin curve to the right

Ghon focus

a primary lesion caused by M. tuberculosis It is small area of granulomatous inflammation, detectable by chest X-ray if it calcifies When lymph nodes fibrose and sometimes calcify they can produce a characteristic lesions known as a "Ghon complex"

Wheezes are associated with ____

acute or chronic bronchitis

Aminoglycosides affects:

aerobic gram negative bacteria

The degree of ______ is an important predictor of the outcome of ARDS

alveolar epithelial injury The loss of epithelial integrity in acute lung injury and the acute respiratory distress syndrome has a number of consequences. First, under normal conditions, the epithelial barrier is much less permeable than the endothelial barrier. Thus, epithelial injury can contribute to alveolar flooding. Second, the loss of epithelial integrity and injury to type II cells disrupt normal epithelial fluid transport, impairing the removal of edema fluid from the alveolar space. Third, injury to type II cells reduces the production and turnover of surfactant, contributing to the characteristic surfactant abnormalities. Fourth, loss of the epithelial barrier can lead to septic shock in patients with bacterial pneumonia. Finally, if injury to the alveolar epithelium is severe, disorganized or insufficient epithelial repair may lead to fibrosis

High risk immigrants in US greater than 5 years are only treated if _____

another risk is present

Early protection is due to induction of antigen-specific ______

antibodies

Shunts and low V/Q units contribute to _____

arterial hypoxemia

Each apnea event results in ____

arterial hypoxemia and hypercapnia This can lead to sympathetic hyper excitation and numerous cardiovascular changes Peripheral vascular resistance increases during an apnea event leading to transient systemic HTN Hypoxemia may also cause precapillary pulmonary vasoconstriction and its accompanying pulmonary HTN Vagal tone also increases during an apnea resulting in bradycardia that, along with the other cardiovascular events is worsened by prolonged apnea with increasingly severe hypoxemia

Intact communities of commensals can prevent colonization with multidrug resistant organisms through ______

both competition for space and resources and the complex immunologic and biochemical interactions that have developed between commensal and host Thus, Current antimicrobials exert tremendous collateral damage to the human microbiome through overuse and broadening spectrum, which has likely been the driving force behind the introduction and proliferation of multidrug resistant organisms

Peripheral chemoreceptors are located in ______

carotid and aortic bodies They signal the central controllers via the IX and X cranial nerves respectively

Primary sensing of arterial PO2 is done by the ______

carotid bodies located at the bifurcation of the common carotid artery into its external and internal branches Note: it is not simulated by a drop in oxygen content! (therefore anemia or carbon monoxide wouldn't affect it) Note: The carotid body is only minimally stimulated by elevations in PaCO2 but the combination of low PaO2 and elevated PaCO2 (i.e. respiratory arrest/failure) has a synergistic excitatory effect on the carotid body

Experimentally, removal of pulmonary edema fluid from the alveolar space can be enhanced by both:

catecholamine-dependent and catecholamine-independent mechanisms, including those increased by inhaled and systemic beta-agonists.

Granuloma

central core of alveolar macrophages, epithelioid cells and Langhans giant cells (fused epitheloid cells) with intracellular M. tuberculosis; surrounded by a dense wall of NK, CD4 and CD8 T cells and macrophages; i.e. an organized structure

Crackles are associated with ___

chronic bronchitis and consolidation as in pneumonia

Choroid plexus regulates _____

chronically carbonic anhydrase (CA) and thus HCO- and pH

M. tuberculosis microscopy

clinical specimens are stained with carbolfuchsin (Ziehl-Neelsen or Kinyoun methods) or fluorescent auramine-rhodamine dyes (Truant fluorochrome method), decolorized with an acid-alcohol solution, and then counterstained

Wheezes

continuous high pitched, musical sound heard during inspiration or expiration. Caused by high airflow through a narrowed airway. Diffuse wheezes suggest widespread airway narrowing such as asthma or bronchiolitis whereas fixed wheezing suggests a focal obstruction that needs to be evaluated.

When are bronchial and bronchovesicular breath sounds abnormal?

f heard over the peripheral lung tissue (i.e. anywhere other than over the main bronchi). Bronchovesicular and bronchial breath sounds heard in the peripheral lung suggest the replacement of air-filled lung with solid tissue (atelectasis usually) or fluid. Bronchial breath sounds also indicate that the bronchus supplying the affected area is patent. Post operative atelectasis (i.e. from lying in bed or splinting due to pain) usually presents as bronchovesicular and bronchial breath sounds over the lower lobes.

Flu like symptoms

fever, malaise, headache, myalgia, progressive cough, nausea, Severe sore throat (usual reason patient seeks medical attention)

After the acute phase, some do not heal and progress to ____

fibrosing alveolitis with persistent hypoxemia, increased alveolar dead space, and a further decrease in pulmonary compliance. Pulmonary hypertension, owing to obliteration of the pulmonary- capillary bed, may be severe and may lead to right ventricular failure. Chest radiographs show linear opacities, consistent with the presence of evolving fibrosis Pneumothorax may occur, but the incidence is only 10 to 13 percent and is not clearly related to airway pressures or the level of positive end-expiratory pressure. Computed tomography of the chest shows diffuse interstitial opacities and bullae Histologically, there is fibrosis along with acute and chronic inflammatory cells and partial resHTolution of the pulmonary edema

Pontiac fever ( milder form)

flu-like illness No lung involvement 2 to 3 day incubation Fever, chills, myalgia, headaches Not fatal Pt. recovers in 2 to 5 days

Therapy for obstructive sleep apnea

focuses on the maintenance of pharyngeal patency during sleep. Weight loss Surgery and dental devices designed to move the mandible forward or pull the tongue forward have also been variably successful Tracheostomy, which effectively bypasses the obstructing segment. However, its risk and cosmetic impact makes this approach unacceptable for most patients. The most common form of therapy is nasal continues positive airway pressure (CPAP), a simple device worn during sleep that delivers positive pressure through the nares into the nasal and oral pharynx pushing the tongue forward and dilating the collapsing lateral and posterior pharyngeal walls. This simple device is effective when applied during sleep, but falls far short of eliminating all apnea activity because many patients find the CPAP mask to be uncomfortable and use it on average less than four hours per night.

Eosinophilic pneumonia CXR

gradual onset, asthma-like sx for several days. diffuse wheezes and fine inspiratory crackles. bronchial and interstitial involvement. Peripheral eosinophilia present.

Bronchial breath sounds

high pitched and ordinarily heard over the trachea.

In peripheral chemoreceptors, the lower the levels of O2, the ___ the action potential firing, and the ___ the ventilation rate

higher higher Note: these responses are notable as PO2 < 60 mmHg

Elements that block O2 binding to cytochrome C oxidase cause _____

histologic hypoxia Big ones that do this is CO, CN-, and NH3+ This is a type b lactic acidosis the oxygen delivery is okay but its metabolism is not

The disease caused by M. tuberculosis primarily results from ______

host response to infection

Hypoxia

inadequate tissue oxygen Difficult to directly assess/measure

respiratory compensation for metabolic acidosis is fast but ____

incomplete

If you increase pH, minute ventilation will _____

increase

VO2 _______ with increased workload

increase linearly Note: at some pint, increased exercise intensity will not increase VO2= VO2 max

A decrease in alveolar ventilation leads to ______ PaCO2

increased

Ventilator-induced lung injury (VILI) __________ contributes to mortality

independently Therefore tidal volume set point on the ventilator is important such that you don't induce injury

Latent tuberculosis infection

infected with Mycobacterium tuberculosis, but no active disease. usually PPD (+) or positive interferon release assay, but without symptoms

Influenza infection leads to ______

inflammatory cell response of mucosal membrane --> monocytes and lymphocytes

In the lungs, how is the curve shifted

it is shifted to the left due to the low PaCO2 levels. This helps augment oxygen loading

Acute hypoxia can cause _____

loss of consciousness

Acute (exudative) phase of ARDS

manifested by the rapid onset of respiratory failure in a patient with a risk factor for the condition. Arterial hypoxemia that is refractory to treatment with supplemental oxygen is a characteristic feature. Radiographically, the findings are indistinguishable from those of cardiogenic pulmonary edema. Bilateral infiltrates may be patchy or asymmetric and may include pleural effusions Computed tomographic scanning has demonstrated that alveolar filling, consolidation, and atelectasis occur predominantly in dependent lung zones, whereas other areas may be relatively spared. However, bronchoalveolar-lavage studies indicate that even radiographically spared, nondependent areas may have substantial inflammation. Pathological findings include diffuse alveolar damage, with neutrophils, macrophages, erythrocytes, hyaline membranes, and protein-rich edema fluid in the alveolar spaces, capillary injury, and disruption of the alveolar epithelium

If you increase CO2, minute ventilation will ____

markedly increase

Bronchovesicular breath sounds

moderate in pitch and intensity. Heard during inspiration and expiration with a brief silent gap between inspiration and expiration. Can be heard over the major bronchi.

metabolic compensation for respiratory acidosis is slow, but ____

more complete

Most non-infected people vaccinated with BCG are PPD _____

negative, however it can still lead to false positives (25%)

Relaxation atelectasis

occurs when the interaction between the lung and the chest wall is interrupted. The lung is held close to the chest wall because of the negative pressure in the pleural space. Once the negative pressure is lost, the lung tends to recoil due to elastic properties and becomes atelectatic. This occurs in patients with pneumothorax and pleural effusions. In this instance, the loss of negative pressure in the pleura permits the lung to relax, due to elastic recoil. In this type of atelectais (i.e. due to pneumothorax or pleural effusion), there is a decrease in tactile fremitus (because of the effect of the pneumothorax or pleural effusion).

Innate immunity

occurs within hours and includes: -epithelial barriers -phagocytes -dendritic cells -complement - NK cells These respond to a variety of antigens

40% of Respiratory syncytial virus patients also present with______

otitis media

Information obtained directly or indirectly from arterial blood gasses

pH (measured) PaCO2 (measured) PaO2 (measured) HCO3- (calculated) P(A-a)O2 gradient (you need to calculate) SaO2 -calculated based on pH and PCO2 or -directly measured using co-oximeter CaO2 (you need to calculate) Other gases or abnormal hemoglobin - co-oximeter

Henderson-Hasselbalch equation

pH = 6.1 + log [HCO3-]/(.03*PaCO2)

Uncompensated respiratory alkalosis

pH = ↑ PaCO2 = ↓ HCO3- = ↔

Uncompensated metabolic alkalosis

pH = ↑ PaCO2 =↔ HCO3- = ↑

Uncompensated respiratory acidosis

pH = ↓ PaCO2 = ↑ HCO3- = ↔

Uncompensated metabolic acidosis

pH = ↓ PaCO2 = ↔ HCO3- = ↓

Order of the arterial blood gasses

pH/ PCO2/ PO2/ SaO2 Then HCO3- (must be calculated from the HH equation) Then calculate the P(A-a) O2 gradient

West zone 3

part of the lung in which pulmonary arterial and venous pressure exceeds alveolar pressure (Pa> Pv> PA). The driving pressure is the difference between arterial and venous pressure without contribution from alveolar pressure. You can now picture a solid uninterrupted column of fluid (blood) from the arterial side across the gas exchange units and into the venous side. In this way the use of a pulmonary artery (Swan-Ganz) catheter can estimate left atrial pressure. In zone 1 or 2 a catheter would be measuring alveolar not venous (and thus indirectly left atrial) pressure. Note that these are physiologic zones, not anatomic zones. That is if position changes (lying supine or standing on your head) the location of the zones will change.

The acute phase of acute lung injury and the acute respiratory distress syndrome is characterized by the influx of _______

protein-rich edema fluid into the air spaces as a consequence of increased permeability of the alveolar-capillary barrier

Pulmonary arterial hypertension can lead to ______

pulmonary artery and arteriole dropout (rarefication)

During steady state conditions (outside the oxygen deficit), we utilize ___

pyruvate from glycolysis and move it to the mitochondria of oxidative phosphorylation Can also utilize fat (palmitate) and move it to the mitochondria for ß oxidation These help meet the oxygen demands during steady state exercise

CO ____ oxygen saturation

reduces

Increasing alveolar ventilation ____ PaCO2

reduces

Re-infection tuberculosis

refers to active disease that develops as a result of re-exposure to tuberculosis in a person with known previous infection.

Re-activation tuberculosis

refers to active disease that develops in person with previous known infection without additional exposure.

What affects ventilation more, increases in frequency or the amplitude?

remember the difference between VE and VA

Rhonchi

rumbling sounds that are more continuous. They are caused by passage of air through large and medium-sized airways partially obstucted by mucous or secretions.

Vesicular breath sounds

soft and low pitched. They are heard through inspiration, continue through expiration and stop about one third through expiration. These are heard throughout the normal chest. Vesicular breath sounds are always normal

Hantavirus

ssRNA, neg sense, segmented (3), enveloped virus Replicates in cytoplasm, buds thru golgi Spread by aerosolized mouse urine NOT ARTHROPOD-BORNE

The most effective way to ventilate is with _____

steady deep tidal volumes!

Central controllers located in the pons and the medulla oblongata are under the influence of ______

supra-pontine signals from: - brain cortex - limbic system - thalamus/hypothalamus - midbrain - RTN ( central chemoreceptor signals) and NTS (peripheral signals)

The partial pressure of H2O is only determined by_____

temperature

PEEP (positive end expiratory pressure)

the pressure in the lungs (alveolar pressure) above atmospheric pressure (the pressure outside of the body) that exists at the end of expiration. Its goal is to prevent closure of atelectatic alveoli at end expiration

Antigenic shift

the re-assortment of genomes from two different flu strains coinfecting the same animal cell (usually pig). The new virus has mixed genome segments from each original virus. The chimeric virus can be transferred from animals to humans living in close proximity (sometimes in the same room some). Associated with major epidemics / pandemics.

Goal of the PPD skin test and the interferon gamma release assay is to ______

try to identify patents infected with mycobacterium tuberculosis PPD -Inexpensive -Does not require blood draw or lab -Relatively easy to perform -Long history Interferon gamma release assay -Does not require return patient visit -Results within 24 hours -Is not affected by prior BCG vaccination Note that neither test can reliably predict who will eventually develop active disease and both can loos sensitivity in immunosuppressed individuals Regardless, a negative test does not rule out active tuberculosis

Trimethoprim-sulfamethoxazole

two drugs that synergistically inhibit sequential steps in folate synthesis Resistance arise with mutations in dihydrofolate reductase Covers many bacteria, such as Pneumocystis jirovecii Used as empiric therapy of respiratory tract infections. As well as the treatment and prophylaxis of Pneumocystis jirovecii infections

Dead space represents ______

wasted ventilation (work without benefit) Note: dead space does not directly alter gas-exchange and does not lead to arterial gas abnormalities unless severe. Nonetheless the increase in work does pose a clinical problem.

M. tuberculosis Reactivation/Adult/Post-primary TB

~10% of patients with LTBI → reactivation disease later in life Disease is usually restricted to lower respiratory tract; although less commonly, can occur in other organs Non-specific symptoms including malaise, fatigue, weight loss, cough and fever/night sweats; progressive with continuing disease Cough is universal symptom, usually for > 3 weeks -initially a dry cough, but becomes productive, sputum may be bloody or purulent -hemoptysis is associated with tissue destruction Infiltrates appear in the apices of the lung, coalesce to form cavities with progressive destruction of lung tissue → cavitary disease

Avian flu viruses bind the _____ receptor

α2,3 This replicates in the bird gut, but can also infect pigs Note: Humans also carry both sialic acid receptors. Thus, swine and avian flu strains can infect humans

Swine flu viruses bind the _____ receptor

α2,6 This infects upper and lower respiratory tracts Note: Humans also carry both sialic acid receptors. Thus, swine and avian flu strains can infect humans

Extrapulmonary Tuberculosis

→ disseminated or miliary TB -bacteria spread via the lymphatics and bloodstream to other parts of the body or by extension to a neighboring part of the lung (e.g. tubercle erodes into a bronchus or the pleural cavity, and then discharges its contents) Can affect organs including kidneys, bones, lymph nodes, brain, meninges, bone marrow and bowel → disease ranges from localized tumor-like granulomas (tuberculoma) to fatal chronic meningitis

VO2 max with those with cardiomyopathy

≤ 15 ml/kg/min For patients with cardiac disease, a low VO2 max is the single most powerful predictor of mortality, regardless of the underlying cardiac diagnosis

What is the plateau pressure goal for ARDS patients

≤ 30 cmH2O (pH < 7.30)

What is considered to be a positive skin test?

≥ 5 mm - HIV infected or at risk -close contacts of newly diagnosed tuberculosis -fibrotic lesion on CXR consistent with old healed TB ≥10 mm -IVDU known to be HIV (-) -foreign born from high prevalence countries (Mexico, Vietnam, Philippines, Korea) -medical conditions increasing risk of TB -medically underserved low income -High-risk racial groups (hispanics, blacks, native Americans) - Recent converters (≥ 10mm increase within 2 years) ≥ 15 mm - Low risk groups Note: low risk groups should not be skin tested.