CHAPTER

8: RESPIRATORY
A-a gradient A-a gradient: defined as the gradient between the alveolar O2 and arterial O2 Normally, alveolar O2 is 100 and the arterial pO2 is 95. A normal A-a gradient is about 5 mmHg. The upper limit of normal is 30 mmHg (set high to achieve a high specificity/PPV) Why are the two different? Because of physiologic V/Q mismatch o When standing up the ventilation is better than perfusion in the apex, whereas perfusion is better than ventilation at lower lobes. o This explains why almost all pulmonary infarctions are in the lower lobes perfusion is greater there. o Also, this explains why reactivation TB is in the apex TB is a strict aerobe and needs as more O2, and there is more ventilation in the upper lobes (higher O2 content). A high A-a gradient means hypoxemia is due to V/Q defect in the lungs, and a normal A-a gradient means hypoxemia is due to something outside the lungs Hypoxemia + high A-a gradient (indicative of primary lung disease) o Ventilation defects: produces hypoxemia, and therefore prolongs the gradient dropping the PO2 and subtracting, and therefore a greater difference between the two o Perfusion defect: e.g., PE o Diffusion defect Hypoxemia + normal A-a gradient (indicative of a problem outside the lungs): o Depression of the medullary respiratory center (as with barbiturates) o Nerve problems: Guillain Barre syndrome, ALS o Obstruction of the upper airway from epiglottitis, laryngeotracheobronchitis o Paralysis of diaphragm Calculation: (0.21 x 713) pCO2/0.8= 100 (0.21 is the atmospheric O2; 760 minus the water vapor=713; pCO2 is normally 40, given in ABG; 0.8 is the RQ). Measured arterial pO2 100 = A-a difference

Upper Respiratory Disease Nasal Polyps: Most common is allergic polyp (develops in adults with long-standing allergic rhinitis) Polyps in nose of children = CF Triad asthma (ASA-intolerant asthma): triad of asthma, aspirin induced bronchospasm, and nasal polyps. Classic is 35 yo woman with chronic pain (headaches or fibromyalgia, etc.) with occasional asthma (they wont tell you she is taking an NSAID, or that she has a polyp!). Mechanism: COX block = lipoxygenase pathway dominance LT C4, D4, and E4 bronchoconstriction. This is NOT a type I hypersensitivity reaction; rather it is chemical mediated Laryngeal carcinoma A squamous cell carcinoma Major risk factors for squamous cancers in mouth, esophagus and larynx: smoking, alcohol, smoking and alcohol has synergistic effect Presents with hoarseness of the throat Laryngectomy specimen Epiglottitis Infection caused by H. influenzae Presents with insiratory stridor X-ray of lateral neck: thumbprint sign of acute epiglottitis due to Hemophilus influenzae Another cause of airway obstruction is croup (PIV) in young children causes tracheal inflammation

Respiratory Distress Syndromes Neonatal Respiratory Distress Syndrome/Hyaline membrane Disease Collapsing pressure in the airways = surface tension/radius of airway. o On expiration, normally the airway will be smaller b/c there is a postive intrathoracic pressure. o Surfactant is there to decrease surface tension and keep airways open on expiration. o If there is no surfactant, atelectasis will occur Pink hyaline membranes are due to degeneration of type II pneumocytes and leakage of fibrinogen which congeals to form the membrane Pathophysiology of hypoxemia: massive intrapulmonary shunt Babies with RDS commonly have PDA because of hypoxemia (normal breathing is required to close PDA) murmur Tx: PEEP therapy positive end expiratory pressure to prevent airway collapse, administration of surfactant Type II pneumocyte (progenitor cell of the lung) has lamellar bodies (look like onion) containing surfactant ; do not confuse with a macrophage, which has junk in the cytosol Three causes of iRDS Prematurity: surfactant begins syn early, but it peaks at 32-35 week, so if you are born prematurely, you will not have enough surfactant, and baby will develop increased risk of developing RDS. o Administration of antenatal glucocorticoids stimulates surfactant synthesis. o Thyroxine and prolactin can theoretically also do the same o Complications of prematurity: superoxide free radical damage seen in retinopathy of prematurity and blindness and bronchopulmonary dysplasia Gestational Diabetes: gestational diabetes glucose crosses the placenta stimulates insulin synthesis in the baby insulin has a negative effect on surfactant synthesis o Marosomia - insulin will increase storage of triglyceride in adipose, and increase the uptake of amino acids into muscle (like growth hormone) o These babies are frequently hypoglycemic when they are born because the glucose supply is cut off but the baby still has hyperinsulinemia

Adult Respiratory Distress Syndrome (ARDS) Similar to iRDS, but the injury is due to neutrophilic inflammatory infiltrate Most common cause is septic shock (and the most common cause of septic shock is E. coli from an indwelling catheter) For ICU patients o The first day they have septic shock, the second day they get ARDS, the third day they get DIC. Pathogenesis: Neutrophils destroy pneumocytes of the lung, decreasing surfactant production massive atelectasis (collapse). o Hyaline membranes arise from holes that neutrophils punch in the pulmonary capillaries as they extravasate, allowing protein and fibrinogen to enter and cause hyaline membrane formation; leaky capillary syndrome Pathophysiology: intrapulmonary shunting Really bad prognosis compared to iRDS

C section: the stress of vaginal delivery leads to release of ACTH and cortisol are not released, and surfactant is not made.

Pneumothorax Spontaneous pneumothorax Major cause is a ruptured subpleural bleb (i.e. an airpocket under the pleura that pops, causing a hole in the pleura) Lung stays inflated because of the negative intrathoracic pressure, but breaking the pleura disrupts the pressure gradient collapse o Diaphragmatic elevation on that side to fill up the space o Deviation of the trachea to the side of the collapse Usually seen in tall male or in a scuba divers when they come up too quickly Tension pneumothorax Major cause due to puncture injuries to the lung Cause: a tear in the pleura means that with every inspiration, air is pulled into the pleural cavity, and with expiration the flap closes as the air builds up, it pushes the lung and mediastinum to the opposite side of the thorax, leading to compression atelectasis There is no deflation, but rather a positive intrathoracic pressure in the pleural cavity bearing down on the rest of the thorax This compression can affect the SVC, right ventricle, right atrium medical emergency. With the positive intrathroacic pressure, the diaphragm will go down

Pulmonary Infection Pneumonia Typical PNA acute onset fever, chills productive cough o Productive cough exudate (pus) o Lobar PNA consolidation in the lung, leading to increased tactile/vocal fremitus, decreased resonance of percussion, egophony, whispered pectoriloquy o If there is a pleural effusion overlying the lung the only finding you would have is decreased percussion Atypical PNA subacute onset of nonproductive cough without high fever o This is interstitial inflammation without exudate and signs of consolidation Community acquired PNA o Typical form: S. pneumoniae (gram + diplococcus) Old tx: PCN G New tx: azithromycin o Atypical form: Mycoplasma pneumoniae, followed by Chlamydia pneumoniae Nosocomial PNA could be E. coli, P. aeruginosa or S. aureus Bronchopneumonia Most commonly due to S. pneumoniae (community acquired):

Lobar Pneumonia Most commonly due to S. pneumoniae Note the consolidation in the right upper lobe

Viral PNA Rhinovirus o The most common cause of the common cold o Acid labile destroyed by gastric acid (not a tummy bug!) o Never will have a vaccine because there are >100 serotypes RSV o The most common cause of bronchiolitis o Presents with wheezing (small airway inflammation) and PNA in a small child Influenza o Hemagglutinins help attach the virus to the mucosa o Neuraminidase bores a hole through the mucosa o Antigenic drift = minor mutation in HA or NA; no need for a new vaccine o Antigenic shift = major change in HA or NA need a new vaccine. o The flu shot is against A antigen Bacterial PNA Chlamydia psittacosis from birds (ie parrots, turkeys). Chlamydia trachomatis wheezing at 1 week of age, PNA, increased AP diameter, tympanic percussion sounds, no fever, bilateral conjunctivitis, staccato cough. o Mocst common cause of conjunctivitis in the 2nd week of life is Chlamydia trachomatis (although overall most common cause of conjunctivitis is inflammation due to erythromycin drops Hospital-acquired gram-negative PNA Pseudomonas o Water loving bacteria o Ventilator infections o Green productive cough Klebsiella o Famous in the alcoholic - high spiking fevers, productive cough with mucoid sputum (Klebsiella has a capsule) o Alcoholics can also get S. pneumonia. o Klebsiella lives in the upper lobes and can cavitate, therefore can cbe onfused with TB. Legionella o Atypical, nonproductive cough o Deadly o Spreads from water coolers or in mists in groceries or at restaurants. o Legionella can also cause liver disease, interstial nephritis (juxtaglomerlur cell disease low renin hyponatremia) o Tx = erythromycin

Fungal Infections Candida o Indwelling catheters, usually those in the subclavian o Candida sepsis is the systemic form Histoplasmosis o Midwest (Ohio/Tennessee valley) o Histoplasma capsulatum is carried by dung of starlings and bats o Presents as a non-productive cough in spelunkers/cave explorers o Histoplasma is the only systemic fungus that has yeast forms phagocytosed by alveolar macrophages o Note the yeast forms of Histoplasma in this macrophage in the bone marrow o Infection can be systemic Cryptococcus o Pigeons i.e., NYC executive with pigeons roosting in his A/C unit develops non-productive cough o Looks like mickey mouse yeast forms are narrow based buds. o Tx: Amphotericin B o Field stain shows Cryptococcus species in lung tissue Blastomycosis o Southeast USA o Skin and lung infections o Broad based budding o Verrucous skin lesion (raised, wart- like) on the face: Blastomyces dermatitidis

Coccidioidomycosis o Southwest USA (New Mexico, Arizona, SoCal o Spherule with endospores is Coccidioides immitis o LA earthquake followed by nonproductive cough: the arthrospore (the infectious form) is in the dust. o Or, spelunker deveops nonproductive cough in the sonaran desert - Coccidiomycosis (not Histo b/c this is not in the midwest) Aspergillosis o Aspergilloma aspergillus loves to inhabit abandoned TB fungus cavities Presents with massive hemoptysis Fungus balls in bilateral upper lobe cavitary lesions o Invasive aspergillus: invasion of the vessels in lung, leading to thrombosis and infarction o Allergies the mold, leading to extrinsic asthma and type I hypersensitivity o Corona (looks like a crown) by PAS stain - septate hyphae (unlike mucor) with narrow-angle branching (unlike mucor) Pneumocystitis carinii PNA o Fungus (used to be a protozoa) o This is the most common AIDS- defining lesion (CD4 < 200) o Prophylaxis with TMP-SMZ has prevented both PCP and toxoplasmosis, which is the most common cause of space occupying lesion within the HIV+ brain o Lung with PCP - note the foamy exudate in the alveoli o Silver stain reveals round and crushed ping-pong ball-like cysts in BAL specimens from alveoli, leading to foamy bubbly alveolar infiltrate o Presents with dyspnea, tachypnea, white-out on CXR o May be found in LN of HIV+ patients

 Tuberculosis Primary TB occurs in the lower part of the upper lobe or the upper part of the lower lobe and close to the pleura o Primary TB has a Ghon focus and a Ghon complex. o Most patients recover Reactivation TB occurs in ICH, and goe to the apex, producing a cavitary lesion. o Cavitary lesion lined by caseous material o No Ghon focus or complex Acid fast stain in TB - mycolic acid in the cell wall is responsible for acid-fastness

o Other organisms only seen with silver stain: Bartonella henselae (bacillary angiomatosis), Legionella

CXR with miliary TB:

Other things that cavitate in upper lobes: o Which systemic fungus is the TB of the lungs? Histoplasmosis o Which cancer can cavitate in the lung? Squamous cell lung carcinoma o Which bacteria can produce cavitations in the upper lobe? K. pneumoniae

Foreign Bodies If you are standing or sitting up, foreign body will go to posterobasal segment of the right lower lobe (i.e., the most posterior segment of the right lower lobe) If you are lying down (most common way to aspirate things), foreign body will go to superior segment of the right lower lobe. If you are lying on the right side, foreign body will go to either o Middle lobe of right lung o Posterior segment of right upper lobe (this is the only one that is in the upper lobe. If you are lying down on the left side, foreign body will go to the lingula. Abscess Most common cause of abscess is aspiration of oropharyngeal material o Risk factors: poor dentition, alcoholism o Aspirate consists of aerobes and anaerobes, fusobacterium, bacteroides (putrid smell) A secondary cause of lung abscess is PNA: S. aureus, Klebsiella CXR will show fluid-filled cavities in the lung Lung abscess in superior segment of the right lower lobe (patient must have been lying down)

Pulmonary Vascular Disease Pulmonary Embolus Small emboli produce wedge shaped hemorrhagic infarcts, only if you have underlying lung idsease o 85% of the time embolus will not produce infarct Large emboli (saddle embolus) lodging in the pulmonary artery o If this embolus blocks at least 3 out of the 5 orifices, you are dead in a millisecond acute right heart strain sudden death Most common site for thrombosis is the deep veins of the lower leg. The most common site for embolization to the lung is the femoral vein Screening test of choice: ventilation perfusion scan showing ventilation, but no perfusion o Observe PE to the right lower lobe (RLL) Confirmatory test is pulmonary angiogram.

Restrictive Pulmonary Disease Overview of Restrictive Disease Restriction difficulty filling, mostly due to fibrosis o Compliance (filling/inspiration term) low compliance in restrictive disease o Elasticity (recoil/expiration term) increased elasticity in restrictive disease Lung capacities are decreased: TLC, RV, TV FEV1/FVC normal or increased because a higher fraction of air is blown out at the beginning of expiration, even despite the overall decreased FVC. Pneumoconioses Airborne/dust-borne diseases Coal workers pneumoconiosis o Esp. in West Virginia/Penn o Anthrocotic pigment that causes a fibrous rxn in the lung, leading to restrictive lung disease o Increased incidence of TB, but not cancer o The dilated spaces represent centrilobular emphysema Silicosis o Sandblasters and rock-workers o Large, hard nodules of quartz in the lung occur when SiO2 makes it into the lung o Increased incidence of TB, but not cancer Caplan syndrome: rheumatoid nodules in the lung + pneumoconiosis Asbestosis Asbestos fibers (ferruginous bodies) look like rusty dumbbells because they are coated with iron The most common pulmonary lesion associated with asbestos is not cancer, but rather a benign fibrous plaque of a pleura Most common cancer associated with asbestos is primary lung cancer, and the second most common is mesothelioma, which is a malignancy of the serosal lining of the lungs

o Smoking + asbestos = greatly increased risk of primary lung cancer o No increased incidence of mesothelioma with smoking (not synergistic) Note that o Mesothelioma takes 25-30 years to develop most people die before they get to mesothelioma! o Lung cancers take about 10 years to develop o Lung cancers are more common, and you die earlier Main causes of asbestos exposure: roofers, people working in a naval shipyard (all the pipes in the ship are insulated with asbestos), also in brake lining of cars and headgear Mesothelioma - entire lung is encased by thickened pleura, a highly malignant tumor

Sacroidosis A granulomatous disease of unknown etiology The 2nd most common restrictive lung disease More common in black people Classic CXR: enlarged hilar LNs (potato nodes), haziness of interstitial fibrosis (along both lung bases there is a very fine reticulonodular pattern) Non-caseating granuloma in a hilar lymph node in a patient with sarcoidosis - note the multinucleated giant cells and the pink staining epithelioid cells representing activated macrophages:

Presents with dyspnea, uveitis (blurry vision) due to inflammation in the uveal tract), involvement of salivary glands or lacrimal glands, nodular skin lesions with noncaseating granulomas o Also, hypercalcemia: macrophages (epitheloid cells) make 1-alpha- hydroxylase hypervitaminosis D absorption of Ca++ from gut, reabsorption of Ca++ in kidneys Diagnosis of exclusion rule out other causes of granuloma (TB, histo)

Diagnose via high ACE (good marker of disease activity and response to tx) o ACE is elevated because of granulomas in the kidney Tx: steroids Sarcoid is the most common noninfectious cause of granulomatous hepatitis (TB is the the most common cause of infectious hepatitis) Hypersensitivity Pneumonitides Farmers lung o Thermophilic actinomyces (a mold) is blown up in the air o Hypersensitivity and dyspnea Silofillers Disease o Fermentation in the silo nitrogen dioxide wheezing and dyspnea. o Silos explode because of gas production from fermentation Byssinosis o Workers in textile industry (linen, cotton, hemp) o Dyspnea during the week, and Monday morning blues when they have to go back to work on Monday Goodpasture syndrome Begins in the lungs with a restrictive lung disease hemoptysis Proceeds to renal disease

Obstructive Lung Disease Overview of Obstructive Disease Obstruction difficulty expiring o Compliance (filling/inspiration term) high compliance in obstructive disease, because elastic tissue support is destroyed (floppy lung makes it easy to get air in) o Elasticity (recoil/expiration term) decrease elasticity in obstructive disease because the lung collapses on expiration Hyperinflation o Increased residual volume and TLC o Diaphragmatic depression and AP diameter increase o As air trapping gets worse and worse, other volumes are compressed down: tidal volume, vital capacity, and other volumes decrease o So, TLC and RV increases, everything else decreases FEV1/FVC way decreased, clearly distinguishing restrictive from obstructive lung disease o FEV1 is very low; can take ages to expire all the air o FVC is also decreased Chronic Bronchitis Defined clinically as productive cough for 3 months out of the year for 2 consecutive years. A disease of the terminal bronchioles o Anatomy: main stem bronchus, segmental bronchi, terminal bronchioles, resp bronchioles, alveolar ducts, alveoli. Airflow changes form turbulent to laminar at the terminal bronchioles o Small airway disease; presents with wheezing A disease of the mucus glands o Mucus gland hyperplasia in proximal airway o Goblet cell metaplasia o Mucous plugs Result: V/Q mismatch o Blue bloaters cyanosis because of inability to ventilate clogged airways Pink puffer (left) vs blue bloater (right) o Pink puffers predominantly have emphysema, which involves the respiratory unit, while blue bloaters have chronic bronchitis

Emphysema A disease of the respiratory unit (i.e., non-respiratory bronchiole) distal to where chronic bronchitis hits o Even destruction of respiratory unit and vasculature surrounding it o Even loss of V and Q no CO2 retention pink puffer phenotype respiratory alkalosis Presents with expiratory wheeze COPD CXR: hard to see the heart, depressed diaphragms increased AP diameter Other CXRs like this occur in other obstructive diseases with air-trapping: 3 month old with RSV, newborn with C. trachomatis PNA Types of emphysema: centrilobular and panacinar Centrilobular Emphysema o Associated with smoking o Involves upper lobes o Primarily destructionof respiratory bronchiole by neutrophils (PMNs chemotax in response to cigarette smoke) o Smokers have denatured alpha-1 antitrypsin o Trigger happy neutrophils destroy the elastic tissue support of the respiratory bronchioles no elastic recoil cystic spaces with air- trapping Panacinar Emphysema o Destruction of the entire respiratory unit (panacinar) o Genetic absence of alpha-1 antitrypsin o Presents at a young age with destruction of the lower lobes o Smokers with acquire A1AT deficiency can also have an element of panacinar emphysema Bronchiectasis Abnormal dilations of bronchi further than the hilum, abutting the pleura Mechanism: infection, destruction of elastic tissue support, dilatation of the airways. Segmental bronchi fill with pus Presentation: cupfulls of sputum Causes o Most commonly in the US: cystic fibrosis

o Most commonly in 3rd world: TB o Kartageners syndrome Immotile cilia Cilia have a 9+2 configuration arrangement with cilia and microtubules Absent dynein arm absence of arms keeping the 9 microtubules on the outside together Presents with sinusitis, bronchiectasis, infertility (sperm and fallopian tube cilia) and dextrocardia without transposition of great vessels, or situs inversus Main-stem bronchus cancer associated with bronchiectasis. At the top of the slide there is a white colored mass that has completely obstructed the main- stem bronchus:

Asthma Can be extrinsic (type 1 HPY) or intrinsic (chemicals) two separate entities! Intrinsic asthma: o Triad asthma in patients taking NSAIDs o Exercise-induced asthma tx with cromolyn sodium o Cold temperature can cause asthma. The wheezing is due to inflammation of the terminal bronchioles because LT C4, D4, E4 and PGs causing inflammation and narrowing of the airways Increased AP diameter in chronial asthma Sputum with Charcot-Leyden crystals in a patient with bronchial asthma

Lung Cancer Location CXRs: left x-ray with a primary peripheral adenocarcinoma, right x-ray with primary centrally located cancer

Centrally located o Have the highest association with smoking. o Include squamous cell carcinoma (more common) and small cell carcinoma (less common) o Generally located around the mainstem bronchus o Primary main-stem bronchus cancer note that toothpicks are necessary to keep the lumen open. Note the white material encircling and invading into the lumen of the main-stem bronchi. This could be either a squamous or small cell cancer

o Well differentiated squamous cell carcinoma of lungs - note the concentric areas of eosinophilic staining cells on the lower margin of the side. These are malignant squamous cells with keratin formation (called squamous pearls)

Cytology: Pap smear stains keratin bright red Squamous cell carcinoma in sputum specimen:

Peripherally located o Adenocarcinomas: the most common primary lung cancer, more common than squamous - more peripheral than central. o Shifted to the periphery b/c of the filters on the cigarettes - the filters prevented the large carcinogens from passing in, but the small carcinogens still passed through, and they are not trapped in the main stem, but trapped in the periphery. Thus, filters in cigarettes are responsible for the increase in peripherally located adenocarcinoma o There are at least 3 or 4 types of adenocarcinoma. One obviously does have a smoking relationship The ones that do not have a smoking relationship include bronchiolar alveolar carcinoma, and large cell adenocarcinoma of the lung, scar cancers

Pap smear with a malignant squamous pearl - note the concentric appearance of this malignant cell containing keratin

Small cell carcinoma - small cells that look like lymphocytes; this is the most malignant cancer of the lung. Tx via Ctx/RT (for SCLC surgery is ineffective). These tumors have neurosecretory granules (can make ADH and ACTH) and are S-100 Ag positive Biopsy and pap smear shown to the right

Metastatic Disease The most common cancer of the lung breast is the most common Note the multifocal nature of metastasis (left); can spread to the visceral pleura (white nodular masses, middle), and lymphatics (white tumor encircling small airways throughout the lungs, right)

A slightly less malignant tumor with APUD origin is bronchiocarcinoid. o Low grade malignancy of the same types of cells that produce small cell carcinoma. o They can invade, metastasize, and even produce carcinoid syndrome (make 5-HT) o Very uncommon

Horners syndrome Pancoast tumor/superior sulcus tumor tumors that are in the upper lobe posteriorly (in post mediastinum) o Most of the time is caused by squamous carcinoma in that area Tumor invades locally into the lower trunk of the brachial plexus, so can get lower trunk brachial plexus findings Tumor invades locally into the superior cervical ganglion knock out sympathetic activity o Ptosis (eyelid droop) o Anhydrosis (lack of sweating) o Miosis (pinpoint pupil) Pleural Effusion Exudate vs. transudate o Exudate: protein > 3 grams, and has cells in it (PNA, pulmonary infarction) o Transudate: < 3 grams, without many cells in it (most commonly heart failure) Mediastinum Thymoma - myasthenia gravis