Upper respiratory tract and the lung

Dr. Laila Elbarghati

Upper respiratory tract

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Lesion of upper respiratory tract Acute infections:

1. Acute rhinitis2. Acute sinusitis3. Acute tonsillitis4. Acute pharyngitis5. Acute epiglottitis6. Acute laryngitis

Nasal polypsN.B: There are also chronic forms of such inflammations due to repeated attacks.

Acute rhinitis

Inflammation of the nasal mucosa. There are 2 types:

1. Common cold

2. Allergic rhinitis

Common cold (Coryza) Common disease caused by pathogens such as influenza viruses, rhinoviruses &

RSV. 40% unknown cause It cause fever nasal congestion, watery discharge & sore throat. It is either self

limited (week) or Complicated by otitis media & sinusitis.

This inflammation divided into 2 phases:1. Viral phase: virus adheres to cell surface protein, enter the cell & replicate causing

edema & congestion with no neutrophils exudation.2. Bacterial phase: where bacteria invade the damaged tissue & cause features of

acute inflammation.

Allergic rhinitis (hay fever)Atopic disease characterized by edema & eosinophils infiltrate. The patient is present with itching, sneezing & watery discharge.

Acute sinusitis Inflammation of the mucosa lining the sinuses (maxillary sinus). It occurs

as a complication of rhinitis or dental sepsis.

Caused by S. pneumoniae or S. aureus.

It may cause excessive mucous that obstructing the sinus cavities. Such mucous may become purulent & spread to the brain.

Acute tonsillitis

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Common disease caused by streptococcus hemolyticus.3 types:1. Catarrhal: enlarged & hyperemic tonsils2. Follicular: purulent exudate over lymph follicles.3. Membranous: purulent exudate forms a membrane that covers the tonsils.

It should be treated or Cause:1. Quinsy (peritonsillar abscess)2. Direct spread of infection3. Acute rheumatic fever4. Post streptococcal glomerulonephritis

Acute pharyngitis Pharyngitis caused by Ebstein-Barr virus (EBV) & adenovirus (70%) or by β-

hemolytic streptococci (30%). It accompanies cold or tonsillitis.

It may complicated by:1. Reteropharyngeal abscess.2. Adenoid: hyperplasia of the lymphoid tissue in the posterior pharyngeal wall

results in adenoid face (Narrow nostril, open mouth & short upper lip).

Acute epiglottitis Caused by H. influenza but vaccination against H. influenza reduce the

incidence.

Acute onset cause pain & airway obstruction (fatal).

Acute laryngitis Caused by inhalation of irritants gases (chlorine) or agents that cause common

cold. It is either tuberculous form where infected sputum coughed up or

diphtheric form in which exotoxin cause pseudomembrane formation..

Caused by Corynebacterium diaphtheria in children between 2-5 years, but it is rare due to immunization.

Complications of diaphteric laryngitis:1) Toxic myocarditis2) Peripheral neuropathy3) Sloughing & aspiration of the pseudomembrane cause major airway

obstruction.

Nasal polyps Recurrent infections of the nose lead to polypoid thickening of the mucosa. It is bilateral rounded masses that arise in the middle turbinate. Gelatinous with smooth surface, consist of loose edematous connective tissue

that covered by ciliated respiratory epithelium.

Upper respiratory tract tumors

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1. Nasopharyngeal carcinoma

2. Laryngeal tumors - Vocal cord polyps

- Squamous papilloma - Carcinoma of the larynx

Nasopharyngeal carcinomaCaused by EBV in Chinese population so it is viral oncogene of genetic susceptibility. More common in children & old age.

There are 3 types:1. Keratinizing squamous cell carcinoma

2. Non keratinizing squamous cell carcinoma

3. Undifferentiated carcinoma: common, large neoplastic cells with reactive lymphocytes.

Spread to cervical lymph node, then to the blood. It is a radiosensitive tumor & 5 years survival rate is 50%.

Laryngeal tumors

Non malignant lesions:

1. Vocal cord polyps

2. Squamous papilloma

Vocal cord polyps Occur in heavy smokers or singers (Singer’s nodes). Smooth round mass (0.5 cm). Consist of fibrous tissue covered with stratified squamous epithelium; the

epithelium may be ulcerated by contact trauma with other cord.

Squamous papilloma Benign tumor, caused by human papilloma virus. Single in adult& premalignant, multiple in children (Juvenile laryngeal

papilloma) that regress at puberty. Soft finger like projections (1 cm) consist of fibrovascular tissue covered by

stratified squamous epithelium. Ulceration & hemoptysis can occur, it recur after excision

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Carcinoma larynx 2% of all cancer, more in men (7:1), caused by asbestos, smoke & alcohol.

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95% are squamous cell. Glottic tumor in 70%, supraglottic in 25% & subglottic in 5%.

Appear as gray wrinkled plaques on mucosal surface that ulcerate. It Interfere with vocal cord mobility cause & cause persistent hoarseness.

The spread is rare in glottic tumor due to few lymphatics, unlike supraglottic & subglottic tumors that spread to cervical nodes.

Treated by surgery & radiation. 1/3 dies of the disease due to metastasis.

Causes of epistaxis

Local GeneralTrauma Hypertension

Tumors Leukemia

Nasal polyps Haemorrhagic blood disease

VitC&K deficiency

Normal lung Supplied by pulmonary and bronchial arteries (of aortic origin). Exchange gases between inspired air and blood. Right bronchus is more vertical in line with the trachea so, aspirated foreign

bodies, vomitus and blood enter the right lung than the left.

Bronchi bronchioles terminal bronchioles (2mm) acinus (7mm).

The acinus is composed of respiratory bronchioles which give rise to several alveoli (site of gas exchange). 3-5 terminal bronchioles with its acinus called pulmonary lobule.

Normal AcinusHistology

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The respiratory tree till the bronchus is lined by pseudostratified columnar ciliated epithelial cells, cartilaginous airways with mucus secreting goblet cells.The bronchioles unlike bronchi have no cartilage and submucosal glands .

With each division the epithelium become cubiodal to flat non ciliated epithelium.

Alveolar wall consist of:1. Capillary endothelium2. Type 1 pneumocytes: flattened cells cover 95% of the surface.3. Type 2 pneumocytes: rounded granular cells secrets surfactant and undergo

hyperplasia when type 1 cells are injured.4. Pulmonary interstitum: separate the basement membrane of epithelium and

endothelium. It contains fine elastic fibers, collagen, fibroblasts, smooth muscle cells, mast cells, monocytes & lymphocytes.

5. Alveolar macrophages: attached to epithelial cells or lying free within the alveolar space.

The alveolar walls are not solid but are perforated by numerous pores of kohn which permit the passage of bacteria and exudate between adjacent alveoli.Adjacent to alveolar cell membrane is the pulmonary surfactant layer.

Alveolar wall

Adequate respiration is maintained by:1. Adequate intake of air.2. Rapid diffusion along alveolar walls.3. Adequate perfusion of pulmonary circulation.

Atelectasis (collapse)

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Loss of lung volume caused by inadequate expansion of air spaces. This result in shunting of inadequate oxygenated blood from pulmonary arteries into veins. Thus give rise to ventilation-perfusion imbalance and hypoxia.

Atelectasis divided into 3 categories:

1) Resorption atelectasis (obstruction)

2) Compression atelectasis (passive or relaxation)

3) Contraction atelectasis (cicatrization)

4) Microatelectasis: It occurs in premature infants due to weak respiratory action and lack of surfactant.

Various forms of acquired atelectasis

Resorption atelectasisOccurs when an obstruction prevent air from reaching distal airway. It depend on the level of obstruction, an entire lung, a complete lobe, or one or more segment may be involved.

The causes of bronchus obstruction:1. Mucous or mucopurulent plug which occur postoperative or complicate bronchial

asthma, bronchiectasis or chronic bronchitis2. Foreign bodies in children3. Blood clots during oral surgery or anesthesia4. Bronchiogenic carcinoma5. Enlarged lymph node as from T.B

Compression atelectasis

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Accumulation of fluid, blood or air into pleural cavity that mechanically collapse the adjacent lung. Basal atelectasis result from elevated diaphragm as in bedridden patients, during and after surgery and ascites.

Contraction atelectasis -Occurs when either local or generalized fibrotic changes in the lung or pleural

prevent expansion.-Atelectasis except that caused by contraction is reversible and should be treated to

prevent hypoxemia and infection.

MorphologyMacroscopic:The affected area dark red, depressed with rubbery consistency.Microscopic:The alveolar walls are apposed to each other with narrow space.

Lung diseases

Obstructive lung diseases

Constrictive lung diseases

Obstructive lung diseases

Increase in resistance to air flow due to partial or complete obstruction at any level.

Obstructive diseases such as:Asthma, emphysema, chronic bronchitis, bronchiolitis & bronchiectasis.

Expiratory obstruction result from:1. Anatomic airway narrowing as in asthma2. Loss of elastic recoil as in emphysema

Chronic bronchitis and emphysema (persisting and irreversible airflow obstruction) are often coexist together so, they are called chronic obstructive pulmonary diseases (COPD).

Restrictive lung diseases

Restrictive diseases characterized by reduced expansion of lung parenchyma and decreased total lung capacity.

Restrictive diseases occur in 2 conditions:1. Extra pulmonary disorders that affect the ability of the chest wall act as bellow

(severe obesity, kyphoscoliosis and Guillian-Barre syndrome. 2. Acute or chronic interstitial lung diseases as acute respiratory distress syndrome

(ARDS), sarcoidosis, & idiopathic pulmonary fibrosis (IPF).

Obstructive lung disease:

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Asthma Emphysema Chronic bronchitis Bronchiolitis Bronchiectasis

Bronchial asthma -Episodic reversible bronchospasm result from increased bronchioconstrictor

response to different stimuli. It affects 5% of adult & 10% of children.

-It is believed to result from persistent bronchial inflammation so, considered as a chronic inflammatory disorder of the airway .

It is classified into 2 categories:

1. Extrinsic asthma

2. Intrinsic asthma

Extrinsic asthmaIs initiated by type 1 hypersensitivity reaction (allergic asthma), induced by exposure of an extrinsic antigen (3 types):

A- Atopic asthma B- Occupational asthma: due to fumes, gases & chemicals.

C- Allergic bronchopulmonary aspergillosis: Bronchial colonization with aspergillus organisms.

Atopic asthma - Most common

- Occurs in the first 2 decades of life - Associated with other allergic manifestations

- +ve family history - IgE and eosinophil count high in the blood

- It is driven by T helper 2 lymphocytes (TH2) subtype of CD4+T cells

Intrinsic asthma (asthmatic diathesis) Non immune mechanism, IgE is normal.

Different stimuli can trigger it such as:1. Cold 2. Exercise3. Aspirin4. Pulmonary infection5. Psychological stress

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Aspirin (drug induced asthma) It inhibits cyclooxygenase pathway of arachidonic acid metabolism without affecting the lipooxygenase route thus increase the level of the bronchioconstrictor leukotrienes.

In general, asthma develop early in life is of extrinsic type, while asthma that develop later is of intrinsic type. However, patients who have extrinsic asthma is also susceptible to develop asthma when exposed to factors of intrinsic type.

PathogenesisAirway hyperresponsiveness caused by increased sensitivity to bronchoconstrictive agents such as histamine, leukotrienes or methacholine (cholinergic agonist).

Chronic inflammation of bronchi showed bronchial epithelium damage and inflammatory cells aggregation (eosinophils, lymphocytes and mast cells).

Extrinsic asthma

Activation of TH2 lymphocytes

IL-5 IL-4 & -13

IgE synthesis &mast cells recruitment Eosinophils growth

Release of mediators as histamine, leukotrienes anProstaglandins

Smooth muscle contraction, bronchial edema and mucus plugging

Atopic asthma demonstrates 2 phases:1. Early phase: 30-60 minutes after antigen inhalation. Antigen bind to IgE

receptors on mast cells that release mediators to open the tight junctions between epithelial cells. Ag enter the mucosa to activate mast cells & eosinophils to release further mediators causing bronchospasm, increase vascular permeability & mucous.

2. Late phase: 4-8 hours later. Antigen bind to Ig trigger another round of response. Eosinophils factors release mediators from other inflammatory cells to cause epithelial damage.

Mast cells release primary and secondary mediators that function in both early and late phase.

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Acute asthma

Early phase mediators

EffectsMediator

Bronchospasm, increase vascular permeability and mucin secretion

Leukotrienes C4, D4

Bronchospam and increase vascular permeability

Histamine

Bronchospasm & vasodilatationProstaglandins D2

Platelet aggregation and histamine releasePlatelet-activating factor

Late phase mediators

EffectsMediator

Recruit eosinophils and neutrophilsEosinophilic and neutrophilic chemotactic factors

Augment TH2 cell response by increasing IgE synthesis and eosinophils

chemotaxis

IL-4 & -5

Upregulate adhesion molecules on vascular endothelium and inflammatory

cells

Tumor necrosis factor

Leukocytes aggregation result in:1. Release additional mediators that activate mast cells and intensify the initial

response.2. Cause epithelial cell damage that release endothelin & nitric oxide which cause

muscle contraction and relaxation. Therefore, sustain the inflammatory response without additional antigen exposure.

Eosinophils secret major basic protein (MBP), eosinophilic cationic protein (ECP) & eosinophil peroxidase that is toxic to epithelial cells. So it sustains the inflammatory response without additional Ag exposure.

Intrinsic asthmaThere is an overlap with the mechanism of extrinsic asthma for example:

Respiratory syncytial virus through TH2 cells activation. Aspirin induced asthma through leukotriene C4.

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MorphologyMacroscopically:

Lungs are overdistended due to over inflation. Bronchi and bronchioles are occluded by thick mucus with patchy areas of collapse,

Microscopically:Sputum examination shows:

1. Curschmann spirals: mucus plugs contain whorls of shed epithelium.2. Eosinophils & Charcot-Leyden crystals: crystalloid made of eosinophil

membrane protein.

Airway remodeling Thick basement membrane due to cytokine activation of myofibroblasts that lay

down collagen. Edema & inflammatory infiltrate (eosinophil & mast cells), Increase in the size of submucosal glands. Hypertrophy &/or hyperplasia of bronchial wall muscle.

Features of bronchial asthma

Clinical course Dyspnea, wheezing and chest tightness that last from 1 to several hours Relieve spontaneously or with treatment Status asthmaticus persist for days and result in severe cyanosis & death Diagnosed by high eosinophil count in the blood and Curschmann spirals &

Charcot –leyden crystals in the sputum

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EmphysemaPermanent enlargement of the air spaces distal to terminal bronchioles with destruction of their walls. Most cases are asymptomatic as 50% of cases diagnosed only at autopsy.

Normal alveoli

Types of Emphysema:1. Centriacinar (Centrilobular)

2. Distal acinar (Paraseptal)

3. Panacinar (Pan lobular)

4. Irregular emphysema

Centriacinar emphysema 95% of cases, it occurs in heavy smokers. Severe in the upper lobe, it involves the proximal or central part of the acini. Contain both normal and emphysematous air spaces. In severe cases the distal

part also involved so the differentiation become difficult.

Panacinar emphysema Occurs in patients with α1-antitrypsin deficiency. Involve the lower zone, it affect the entire acini (respiratory bronchiole,

alveolar duct & alveoli).

Distal acinar emphysema It involves the distal part of the acinus, adjacent to the pleura, at the margin of

the lobules. It occurs adjacent to fibrosis or scaring Range from 0.5 to 2 cm. Sometimes form cyst like structure called bullae It results in spontaneous pneumothorax.

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Irregular emphysema Common form related to scarring. Asymptomatic. So named because the acinus is irregularly involved.

Pathogenesis Protease-antiprotease imbalance

Oxidant-antioxidant imbalanceProtease-antiprotease imbalance

-α1 antitrypsin (AT) present in serum & macrophages. It is a major inhibitor of elastase secreted by neutrophils during inflammation. Patients with genetic deficiency of AT develop emphysema (1%).

-Any stimulus increase neutophils in lung and release their protease. With low level of AT enzyme, tissue destruction occurs & emphysema result .

In smokers: Nicotine attracts neutrophils in the alveoli. Neutrophils release elastase & proteinase result in tissue damage.

Oxidant-antioxidant imbalance Normally the lung contains antioxidants (superoxide dismutase,

glutathione). Tobacco smoke contains ROS (free radicals), thus result in tissue damage.

Oxidative injury also result in inactivation of AT even in patients without enzyme deficiency.

N.B: Centriacinar form seen in smokers as smoke particles impact at the bifurcation of respiratory bronchioles with influx of neutrophils and macrophages.

Emphysema pathogenesis

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MorphologyMacroscopic:

Panacinar: pale, voluminous lung that overlap the heart. Centriacinar: pink, less voluminous, affect the upper part of the lung.

In severe cases the emphysematous bullae become visible .Cross section spongy with empty spaces.

Microscopic:Thinning & destruction of the alveolar wall create large air spaces. The elastic tissue is lost in alveolar septa result in reduce traction on the small air way & collapse during expiration. There is evidence of accompanying bronchitis & bronchiolitis .

Clinical courseDyspnea, cough, wheezing & weight loss. Patients are barrel chested with prolonged expiration, sitting forward in a hunched-over position to squeeze air.

Patients fall into 2 groups depending on whether or not they tolerate hypoxia:1. Pink puffers2. Blue bloaters

Pink puffers:Do not tolerate hypoxia, severe breathlessness, hyperventilation & normal blood gases. In patient with pure emphysema.

Blue bloaters:Tolerate hypoxia, severe hypoxiaemia & hypercapnia, right ventricular hypertrophy & cor pulmonale. In patient with associated bronchitis (COPD).

All patients develop secondary pulmonary hypertension. Death is due to chronic respiratory failure & cor pulmonale.

Pulmonary hypertension: due to hypoxia induced pulmonary vascular spasm & loss of capillary surface area from alveolar destruction .

Cor pulmonale: right ventricular hypertrophy & right side heart failure.

Conditions related to emphysema:1. Compensatory emphysema: after surgical removal of a diseased lobe.2. Senile emphysema: overdistended lung related to aging (senile

hyperinflation).3. Obstructive overinflation: Lung expands due to trapped air as obstruction by

tumor or foreign bodies.4. Mediastinal emphysema (interstitial): entrance of air into connective tissue

stroma & mediastinumIt occurs with increase intra alveolar pressure as in:

1. Vomiting2. Violent coughing (Whooping cough)3. Patient on respirator4. Patients who have perforating injury (fractured rib)

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Chronic bronchitis Inflammation of the large & medium bronchi. Persistent productive cough for at least 3 consecutive months in at least 2 consecutive

years. Common among cigarette smokers. 20-25% of men between 40-65 years have the disease

due to the presence of ADAM33 gene.

Types1. Simple chronic bronchitis: cough with mucoid sputum but airflow is not

obstructed. 2. Chronic mucopurulent bronchitis: sputum contains pus due to secondary

infection.3. Chronic asthmatic bronchitis: hyperresponsive airways & intermittent attack of

asthma.4. Chronic obstructive bronchitis: chronic outflow obstruction measured by

pulmonary function tests.

Causes1. Cigarette smoking 2. Air pollutants such as sulfur dioxide & nitrogen dioxide

PathogenesisHypersecretion & hypertrophy of bronchial mucus glands and inflammation with infiltration of CD8+T cells, macrophages & neutrophils.

MorphologyMacroscopic:The lining of large airways, smaller bronchi & bronchioles are hyperemic, swollen by edema & covered by layer of mucinous or mucopurulent secretions.

Microscopic: - Enlargement of mucus secreting glands - Increase in goblet cells with loss of ciliated epithelium - Inflammatory cells infiltrate in the mucosa - Reid index: increase in submucosal thickness to that of the bronchial wall, RI: greater than 1:2 is significant

Chronic bronchiolitis1. Goblet cell metaplasia2. Smooth muscle hyperplasia 3. Inflammation & fibrosis result in airway obstruction

Clinical course Persistent productive cough Both emphysema & chronic bronchitis may coexist (COPD) causing

hypercapnia, hypoxemia & cyanosis Recurrent infections & respiratory failure Pulmonary hypertension & heart failure develop later

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Bronchiectasis

Permanent dilation of bronchi & bronchioles due to muscle & elastic tissue destruction.

Causes1. Bronchial obstruction: as tumors & foreign bodies2. Necrotizing pneumonia: as Klebsiella or S. aureus3. Congenital conditions: such as A. Cystic fibrosis: abnormal viscid mucus B. Ig deficiencies: repeated bacterial infectionC. Kartagener syndrome: abnormal cilia that impair mucociliary clearance result in

persistent infection.

Pathogenesis1. Obstruction impairs clearance of secretions result in superimposed infection.

2. Chronic infection cause obstructive secretion, inflammation & dilatation of airways.

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MorphologyMacroscopic:

Affect lower lobes bilaterally. Affect single segment of the lung if the cause is obstruction. Airways dilated 4 times of usual diameter to the pleura.

Microscopic: In acute cases, acute & chronic inflammatory exudate within the wall of bronchi

& bronchioles with desquamation of epithelium. In chronic cases, fibrosis, dilation & scaring of the bronchial wall. Sometimes

necrosis results in lung abscess.

Clinical course Productive cough of mucopurulent sputum, hemoptysis & finger clubbing.

Hypoxemia, pulmonary hypertension & cor pulmonale in severe cases.

Brain abscess and amyloidosis as a complications.

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Pathological changesSiteDisease

Smooth muscle hyperplasia, excess

mucus

BronchusAsthma

Mucus gland hyperplasia, excess

secretion

BronchusChronic bronchitis

Airway dilatation, & scaring

BronchusBronchiectasia

Inflammatory scarring, obliteration

BronchusBronchiolitis

Alveoli enlargement, wall destruction

AcinusEmphysema

Restrictive lung diseases

More pressure is required to expand the lung because they are stiff due to:1. Chest wall abnormalities2. Parenchymal causes*

The disease affects both type 1 & 2 pneumocytes. If chronic it affects the interstitium & called interstitial lung disease.Damage to alveolar epithelium & interstitium produce abnormalities in the ventilation perfusion ratio result in hypoxia & respiratory failure.

Restrictive lung disease can be :

1. Acute: associated with abrupt decrease in respiratory function & inflammation.2. Chronic: associated with insidious development of respiratory dysfunction,

chronic inflammation & fibrosis.

Acute restrictive lung disease (ARLD)

1. Acute lung injury (ALI) 2. Acute respiratory distress syndrome (ARDS)

Chronic restrictive lung disease (CRLD) 1. Idiopathic pulmonary fibrosis (IPF)2. Hypersensitivity pneumonitis3. Diffuse alveolar hemorrhage syndrome4. Sarcoidosis

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ARLDALI is an early stage of ARDS. They are caused by damage to alveolar capillary membrane called as diffuse alveolar damage (DAD). They are associated with:

1. Direct lung injury as pneumonia & acid aspiration.2. Indirect lung injury in systemic process as in sepsis & trauma..

PathogenesisDamage to alveolar capillary membrane cause:

1. Increase vascular permeability2. Loss of diffusion capacity3. Surfactant abnormalities caused by damage to type II pneumocytes

IL-1, 8 & TNF cause neutrophils activation. Such factors release oxidants, protease & leukotrienes that cause active tissue

damage. Macrophages release IL-1, TNF to sustain the inflammation. Macrophages release TGF-α & PDGF recruit fibroblast for the repair process.

MorphologyMacroscopic: Lung resembles the liver, dark red, firm, airless & heavy.

Microscopic:1. Exudative2. Proliferative3. Fibrotic

1. Exudative phase (0-7 days)1. Capillary congestion with neutrophils collection2. Necrosis of alveolar epithelial cells3. Collapsed alveoli4. Alveolar duct are dilated & lined with hyaline membrane

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Hyaline membrane consists of protein-rich edema fluid with remnants of necrotic epithelial cells.

2. Proliferative phase (1-3 weeks)1. Proliferation of type II pneumocytes then differentiate into type 1 pneumocytes2. Phagocytosis of remnant hyaline membrane3. Expansion of alveolar septa by proliferating fibroblasts

3. Fibrotic phase Progressive fibrosis involves the interstitium & alveolar spaces interspersed with dilated

& distorted airspace (honeycomb lung).

Clinical course 85% develop ALI & ARDS within 72 hours of acute insult Acute onset of dyspnea & hypoxemia Bilateral pulmonary infiltrate on X-ray May progress to multisystem organ failure

Poor prognosis in:1. Sepsis2. Old age3. Cardiac, renal or hepatic failure

Mortality rate is 40%

Chronic restrictive lung diseases

Unknown cause & pathogenesis Same signs & symptoms (group) End stage is diffuse interstitial pulmonary fibrosis

CRLD1. Idiopathic pulmonary fibrosis (IPF)2. Hypersensitivity pneumonitis3. Diffuse alveolar hemorrhage syndrome 4. Sarcoidosis

Other causes such as chemotherapeutic agents (methotrexate) or radiotherapy.

Idiopathic pulmonary fibrosis Also known as cryptogenic fibrosing alveolitis Male more affected 2/3 of the cases are older than 60 years Inflammatory response to injury that healed by fibrosis Same finding as in asbestosis so you have to rule other diseases

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Pathogenesis Activated macrophages secret IL-8 & LT that activate neutrophils result in

alveolar epithelial damage and connective tissue degradation.

Macrophage chemotactic protein-1 (MCP-1) by alveolar cells attracts macrophages & T cells result in fibrosis by secreting platelet derivative growth factor (PDGF) & transforming growth factor (TGF-β).

MorphologyMacroscopic:

-Dense yellow-white color of fibrosis. -Cystic spaces that result from gradual destruction of the normal architecture of the lung

(honeycomb lung) .

Microscopic: - Alveolar septal infiltrate of lymphocytes & plasma cells with type II cells

hyperplasia. - Fibrotic areas show dense collagen.

- Honeycomb lung.

Clinical course Slow onset, non productive cough & dyspnea Cyanosis & crackles during inspiration Computerized axial tomography & lung biopsy to exclude other causes Corticosteroid to suppress the inflammation Mean survival rate is 2-4 years

Hypersensitivity pneumonitis

Immunological mediated inflammatory disease that affects alveoli (allergic alveoli). Result from sensitivity to inhaled antigen (moldy hay & chemical agents).

Immunological disease because of:

1. Bronchoalveolar lavage show high level of MIP-1α, IL-8 &T lymphocytes2. Complement & Ig within vessel wall by immunofluorescence3. Non caseating granulomas (type IV hypersensitivity)

MorphologyNon caseating granulomas in 2/3 of cases consist of mononuclear cell infiltrate (lymphocytes) in pulmonary interstitium. Later diffuse interstitial fibrosis occurs.

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FindingsEtiologyLocationDisease

Granuloma formation, interstitial fibrosis

Type III & IV hypersensitivity reaction

AlveoliHypersensitivity pneumonitis

Bronchospasm & thick mucous

Type I hypersensitivity reaction

BronchiAsthma

Clinical course 4-8 hr after exposure the patient develop fever, cough & dyspnea Chronic cases: dyspnea, malaise & weight loss Presence of antibody in the serum Chronic cases resolve slowly. 5% respiratory failure occur

Diffuse alveolar hemorrhage syndrome

Immune mediated diseases that present as triad of hemoptysis, anemia & diffuse pulmonary infiltrate. 2 examples:

1. Good pasture syndrome2. Idiopathic pulmonary hemosiderosis: Unknown cause with spontaneous

remission

Good pasture syndrome

Rare, represented as interstitial pneumonitis & glomerulonephritis. It is an example of Type II reaction as it is caused by antibodies to antigen common to glomerular & pulmonary basement membrane .

Connective tissue disease as SLE, RA & scleroderma presented as IPF or diffuse alveolar hemorrhage.

MorphologyFibrous thickening of alveolar wall with focal necrosis and intraalveolar hemorrhage. Hemosiderin pigment accumulate extracellular or within the macrophage.

Clinical course IgG detected in renal biopsy & alveolar septa in 90% of cases.

Treated by plasma exchange to remove the antibodies & immunosuppressive drugs to inhibit antibody formation.

Renal transplant is required in severe cases.

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Sarcoidosis -Multi systemic disease of unknown cause, characterized by formation of non

caseating granuloma. -Affect adult younger than 40 years & it is high in non smokers.

-Danish, Swedish & US blacks 10 times more affected.

PathogenesisDisorder immune regulation in genetically predisposed persons exposed to certain environmental agents.

1. Immunological factors2. Genetic factors3. Environmental factors

Immunological factorsCell mediated response to an unidentified antigen include:

1. Intraalveolar & interstitial accumulation of CD4+ T cells. 2. Increased in IL-2 & IFN-γ causing macrophage activation.3. Increase in IL-8, TNF & MIP-1α that recruit T cells & macrophages to induce

granuloma formation.

Genetic factorsFamilial & racial factorAssociation with certain HLA genotypes (HLA-A1 & HLA-B8)

Environmental factorsSeveral antigens inciting sarcoidosis (viruses, mycobacteria, pollen).No evidence of infectious agents.

Morphology Mononuclear phagocytes rimmed by CD4+ helper T cells. Epitheliod histocytes with eosinophilic cytoplasm & vesicular nuclei Multinucleated giant cells Thin layer of fibroblasts

2 microscopic features:1. Shaumann bodies: laminated concretions of calcium & proteins2. Asteroid bodies: stellate inclusions enclosed within giant cells

Involve the lungs in 90% in the interstitum, connective tissue around bronchioles & pleura.

Involve the skin in 25% (erythema nodosum). Involve the eye & lacrimal glands occur in 50% (iritis, iridocyclitis, glucoma,

& retinitis). Spleen, liver & bone marrow also affected.

Clinical course Asymptomatic or enlarged hilar & paratracheal lymph nodes in x-ray &

autopsy in 90%. Nodes are painless, firm with rubbery texture (non matted) . Respiratory symptoms, fever & anorexia.

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70% of patients recover, 20% have lung dysfunction or visual impairment & 10% got pulmonary fibrosis & cor pulmonale.

Vascular lung diseases

Pulmonary thromboembolism, hemorrhage & infarction

Pulmonary hypertension & vascular sclerosis

Pulmonary thromboembolism, hemorrhage & infarction

Embolization of right side heart thrombi to the lung is a fatal disease. 95% arise from thrombi within the deep veins of the legs. Infarction results from pulmonary thromboembolism (10%).

Risk factors1. Leg surgery2. Severe trauma3. Prolonged bed rest 4. Contraceptive bills 5. Congestive heart failure6. Disseminated cancer

Pulmonary artery occlusion cause:1. Increase in pulmonary artery pressure2. Ischemia of downstream pulmonary parenchyma

Occlusion of major vessel result in sudden increase in pulmonary artery pressure, low cardiac output, right side heart failure (acute cor pulmonale) or death.

Morphology Emboli in the main pulmonary artery or its right or left branches called (saddle

embolus). Smaller emboli keep the vitality of the parenchyma, some time with hemorrhage in the alveolar space.

3/4 of infarcts affect the lower lobes. Multiple, wedge shaped, the base towards the hilus, hemorrhagic & appear as red blue areas.

The RBC lyses in 48 hr, the infarct become red brown due to hemosiderin. Then replaced by fibrous tissue.

Microscopically : Fresh infarct is a coagulative necrosis of the lung parenchyma.

Clinical course60-80% are silent removed by fibrinolysis.

10-15% cause pulmonary infarction.5% cause acute cor pulmonale & sudden death.

3% recurrent emboli cause pulmonary hypertension & chronic cor pulmonale (chance of recurrence is 30%).

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When 60% of pulmonary vasculature is obstructed death occur before patient feel chest pain or dyspnea.Prophylactic therapy:

1. Early ambulation2. Leg exercise3. Elastic stocking

Patient with pulmonary embolism need thrombolytic & anticoagulant therapy.

Non thrombotic forms of pulmonary embolism:1. Air embolism2. Fat embolism3. Amniotic fluid embolism4. Foreign body embolism

Pulmonary hypertension & vascular sclerosisCaused by:

-Decrease in pulmonary vascular bed (cross section)-Increase in pulmonary vascular bed flow

It is primary (idiopathic 5%) or secondary to:1. COPD2. Recurrent pulmonary emboli3. Heart disease4. Connective tissue disease as scleroderma

Primary pulmonar y hypertension The etiology is unknown; there is intimal & medial vascular hypertrophy. It resultfrom chronic vasoconstriction as 10% of patients suffer from vasoactive disorder as Raynaud phenomenon & vasodilators are able to reduce the vascular resistance.

Secondary pulmonary hypertension Hyperreactivity is secondary to endothelial dysfunction by reduction in NO &

increase in endothelin that cause vasoconstriction Endothelial cells release growth factors that cause smooth muscle proliferation

result in vascular thickening

MorphologyMain arteries: atheroma same as atherosclerosis.Medium size: proliferation of myointimal & smooth muscle cells result in thick intima & media.Small arteries: medial hypertrophy, narrow lumen.

Clinical coursePrimary pulmonary hypertension: affect young age women causing chest pain, dyspnea & fatigue. It causes death from right side heart failure.Secondary pulmonary hypertension: affect any age with features of underlying disease (cardiac, pulmonary).

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Treated by vasodilators to relieve respiratory distress. Lung transplantation in advanced cases.

Pulmonary infection (pneumonia)

1/6 of all death in United States. Epithelial surface of the lung are exposed to contaminated air. Pulmonary host defenses such as nasal hair, mucocilliary, cough, alveolar

macrophages & Ig production. Defects in cellular & humoral immunity result in increased incidence of

infection. Cigarette smoke affect mucocilliary & macrophage function. Alcohol impairs cough & neutrophil chemotaxis.

Defense mechanism1. Mucociliary removal of organism.2. Phagocytosis by alveolar macrophages.3. Phagocytosis by neutrophils recruited by macrophages.4. Complement activation.

Pneumonia

It is either acute or chronic inflammation of the lung parenchyma. Bronchopneumonia: more than one lobeLobar pneumonia: one lobe

Anatomic distinction is difficult due to:1. Many organisms present with either 2 patterns2. Confluent bronchopneumonia is hard to distinguish from lobar pneumonia in

x-ray

Classification1. Community acquired acute pneumonia2. Community acquired atypical pneumonia3. Nosocomial pneumonia4. Aspiration pneumonia5. Chronic pneumonia6. Lung abscess7. Immunocompromised pneumonia

Community acquired acute pneumoniaStreptococcus pneumonia is common. Aspiration of pharyngeal flora (20% of S. pneumonia in throat).

occur in 3 groups:1. Chronic diseases (COPD, D.M)2. Congenital or acquired Ig defects

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3. Absent splenic function

MorphologyLower lobe or right middle lobes are more affected.Lobar pneumonia goes through 4 stages:

1. Congestion2. Red hepatization 3. Gray hepatization 4. Resolution

Congestion: the affected lobe is heavy & red. Vascular congestion with neutrophils & bacteria.

Red hepatization: liver like consistency. Alveolar space filled with neutrophils, RBC & fibrin.

Gray hepatization: lung is dry, gray & firm as RBC lysed but fibrinous exudate persist.

Resolution: the exudate enzymatically digested, or expectorated leaving lung normal. The pleura resolve or leave fibrous thickening.

Bronchopneumonia : Inflammatory consolidation distributed through one or more lobes. If confluent give the

appearance of lobar pneumonia. The lesion is 3-4 cm elevated, gray red & surrounded by hyperemic lung. Suppurative

exudate fills the bronchi, bronchioles & alveoli.

Clinical course Fever, chills, chest pain & mucopurulent cough. Sputum show gram +ve organism & neutrophil contain lancet shaped

diplococci. Blood culture +ve in 30%. Treated by penicillin. Antibiotic sensitivity for resistant strains. Pneumococcal vaccine should be used for risk patients.

Complications1. Tissue destruction & necrosis abscess.2. Supprative material in pleura empyema. 3. Organization of alveolar exudate solid lung.4. Bacterial dissemination meningitis, arthritis or infective endocarditis.

Other organismsHemophilus influenzaStaphylococcus aureus Klebsiella pneumoniaPseudomonas aeruginosa Legionella pneumophila Moraxella catarrhalis

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Community acquired atypical pneumonia

Caused by Mycoplama pneumoniae & Chlamydia pneumoniae. Severe infection occurs in infancy, old age, malnourished & alcoholism. It causes pharyngitis, laryngitis, tracheobronchitis & pneumonia.

PathogenesisOrganism damage respiratory epithelium, inhibit mucociliary function causing inflammation & necrosis that extend to the alveoli.

MorphologyMacroscopically:

Unilateral or bilateral, patchy or whole lobe involved. The affected area is red blue & congested.

Microscopically:Alveolar septa are edematous with infiltrate of lymphocytes & plasma cells but no exudate. In severe cases diffuse alveolar damage with hyaline membrane develop.

Clinical course Acute onset with fever, headache & malaise. Later productive cough develop. X-ray show patches in the lower lobe. Mycoplasma antigen test & PCR for its DNA. Erythromycin effective against both causative organisms. The prognosis is good.

Nosocomial pneumonia

Hospital acquired pneumonia caused by Pseudomonas & S. aureus. It is common in immunosuppressed patients, or patient on ventilator (ventilator associated pneumonia).

Aspiration pneumonia

Occur when gastric content aspirate during vomiting especially in patients with abnormal swallowing reflexes. Pneumonia is chemical & bacterial by aerobic bacteria. It cause death but if the patient survive, abscess formation is common.

Chronic pneumonia

Occurs in chronic granulomatous disease such as Tuberculosis & Actinomycosis. T.B caused by Mycobacterium tuberculosis usually affects the lung. It is either primary or secondary types.

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In secondary type organism drain through lymphatic ducts to the venous return of right side of the heart then to pulmonary arteries.

Ghon focus: gray white inflammatory consolidation with caseous necrosis. Ghon complex: is a combination of parenchymal lesion with nodal involvement.Rank complex: when Ghon complex undergo fibrosis & calcification.Miliary T.B: 2 cm yellow white consolidation scattered throughout the lung.

Lung abscess

Localized area of suppurative necrosis in lung parenchyma. It is a mixed aerobic-anaerobic infection such as Fusobacterium, S. aureus & β-hemolytic streptococci.

Causes1. Aspiration of infective material: from infected teeth, sinuses & tonsils,

depressed cough reflexes, during oral surgery & coma2. Aspiration of gastric content: with infection organism from oropharynx.3. Complication of necrotizing bacterial pneumonia & bronchiectasis: especially

those caused by S. aureus, S. pyogenes & K. pneumonia.4. Bronchial obstruction: as with bronchogenic carcinoma. 10% develop abscess

from aspirated blood & tumor fragments.5. Septic embolism: from septic thrombophelibitis or infective endocarditis.6. Hematogenous spread of bacteria: in disseminated infections more in

staphylococcal bacteremia.

MorphologyCommon in the right side as the airways is vertical. The size range from few mm to 6 cm.Site depends on the cause:1. From infective material: single, in the lower part of upper lobe or upper part of

the lower lobe.2. From pneumonia or bronchiectasis: multiple & basal.3. From septic emboli or blood: multiple, any part.

Microscopically:Suppuration surrounded by fibrous scaring & mononuclear infiltrate (lymphocyte, plasma cells & macrophages).

Clinical course Cough with large amount of sputum (foul smelling, purulent, sanguineous). Fever, weight loss, anemia & finger clubbing. Air-fluid level in x-ray. Antibiotic therapy or surgical drainage. 10% mortality rate.

Complications1. Abscess rupture into airways to be drained.

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2. Rupture into pleural cavity causing bronchopleural fistula result in empyema.3. Embolization through blood to the brain cause meningitis or brain abscess.4. Secondary amyloidosis (AA) in chronic cases.

Immunocompromised pneumonia

Cytomegalovirus infections

Pneumocystis pneumonia

Cytomegalovirus infections (CMV)

A member of herpes virus family. It occurs in immunosuppressed adults (AIDS) & recipient of bone marrow transplant.

Mode of transmission1. Transplacentally (congenital CMV)2. Cervical or vaginal secretions at birth & breast milk (perinatal).3. Saliva in preschool years4. Venereal route after 15 years 5. Respiratory secretions6. Fecooral route7. Iatrogenic through organ transplant or blood transfusion

Clinical course1. Congenital CMV: 95% asymptomatic or classic cytomegalic inclusion disease cause intrauterine growth retardation (jaundice, bleeding & anemia) & microencephaly.

2. Perinatal CMV: failure to thrive, interstitial pneumonitis & hepatitis.Excrete the virus in the urine or saliva for months to years.

3. CMV mononucleosis: asymptomatic in young children with 50% show anti-CMV antibodies indicate previous exposure. The patients presented with fever, lymphadenopathy, hepatomegaly & atypical lymphocytosis. They recover with no complications.

Immunosuppressed CMV: in 3 groups:1. Recipient of organ transplant2. Recipient of allogeneic bone marrow transplant3. Patients with AIDS

In all serious CMV infections affect lung (pneumonitis), GIT (colitis), retina (retinitis).

Morphology Any organ can be affected as lung, kidney & brain.

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Interstitial mononuclear infiltrate with foci of necrosis in the lung. Cells infected show gigantism of both entire cells & nucleus (40µ). Enlarged

basophilic inclusion surrounded by a clear halo within the nucleus (owl’s eye).

Clinical courseViral culture, rising antiviral antibody titer & PCR detection of CMV DNA.Treated with antifungal drugs

Pneumocystis pneumonia

Caused by P. jiroveci (formally known as P. carinii) close to fungi than protozoan.

Latent infection that reactivated in immunocompromised host (AIDS, organ transplant, chemotherapy & corticosteriods).

.

Morphology Intra-alveolar foamy pink exudate with H&E called (cotton candy exudate). Thick septa & mononuclear infiltrate. Silver stain of tissue sections show cup shaped cyst wall.

Clinical course Fever, cough & dyspnea X-ray show bilateral hilar & basal infiltrate. Giemsa stain to show the organism in the sputum (4µ with long filopodia). Organism seen in bronchoalveolar lavage fluid. PCR assay. Recover with early treatment but relapse is common.

Lung tumors Primary

1- Benign: Fibroma, leiomypma, hamartoma2- Malignant: Bronchogenic carcinoma & bronchial carcinoid

Secondary

Hamartoma: Common benign tumour (75%). Spherical mass (3-4 cm). Consist of mature cartilage admixed with fat, fibrous tissue & blood vessels with

clefts lined by respiratory epithelium.

Bronchogenic carcinoma

First cause of cancer death Age 50-60 years, equal in both sex

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50% metastasize at time of diagnosis 5 year survival rate is 15%

Histological classification Non-small cell lung carcinoma (NSCLC) (70%)

1. Adenocarcinoma, bronchioloalveolar carcinoma 40%2. Squamous cell carcinoma 20%3. Large cell carcinoma 10%

Small cell lung carcinoma (SCLC) (20%) Combined pattern (10%).

Etiology Close related to smoking (90%) Exposure to asbestos increase risk of lung cancer 55 times in smokers.

However, some smokers have no cancer so it is conditioned by genetic factors.

Start with inactivation of tumor suppressor gene on 3p whereas TP53 mutation occurs late.

Morphology Begin as small mucosal mass (firm, gray white) to large mass that push the

lung parenchyma. It may undergo central necrosis & hemorrhage. The tumor extends to the pleura, chest wall, lymphatic & blood spread.

Non small cell lung carcinoma1. Adenocarcinomas

Common in non smoker women. Peripheral close to lung scar as in bronchiectasis (scar carcinomas). Grow slowly but metastasize at early stage

Microscopically: It is acinar, papillary or solid types. Arise from a precursor lesion called atypical

adenomatous hyperplasia (AAH). AAH is focus of epithelial proliferation of cuboidal cells resembling type II cells that show cytological atypia.

2. Adenocarcinoma in situ

Formally known as Bronchioloalveolar carcinomas (BAC). It forms a single or multiple nodules not more than 3 cm. Preserve alveolar architecture as they grow in monolayer on top of alveolar

septa (lepidic growth pattern) with no stromal invasion.

3. Squamous cell carcinoma Start with squamous metaplasia, dysplasia, carcinoma in situ then cancer. Rang from well differentiated (keratin pearls) to poorly differentiated neoplasm. Arise in major bronchi, obstruction cause distal atelectasis & infection.

4. Large cell carcinomas Represent squamous cell or glandular neoplasms that are undifferentiated.

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Large anaplastic cells with large vesicular nuclei & prominent nucleoli. May have giant cells (giant cell carcinoma) or spindle cells (spindle cell

carcinoma) or both. Poor prognosis as it spread early.

Small cell lung carcinomas It is also called (Oat cell carcinoma). Arise from neuroendocrine cells & express neuroendocrine markers. Gray central masses with early lymph node spread. Round cells with scant cytoplasm & mitotic nuclei. In cytology, nuclear molding result from close apposition of tumor cells with

scant cytoplasm.

Combined patternSquamous & adenocarcinomaSquamous & SCLC

Spread1. Pericardial or pleural spaces: haemorrhagic effusion2. L.N in the mediastinum & neck (clavicular). 3. Supraclavicular L.N (Virchow node).4. Superior vena cava.5. Brachial or cervical sympathetic plexus: cause severe pain in ulna nerve route to

produce Horner syndrome.6. Pancost syndrome: apical tumor with destruction of 1st & 2nd ribs & thoracic

vertebrae.

Clinical course Silent lesions. Chronic productive cough if localized. Hoarseness, chest pain, pericardial or pleural effusion & pneumonitis. Oran spread as brain (neurological symptoms), liver (hepatomegaly), bone

(pain) & adrenal (Addison disease). NSCLC is cured by surgery. Therefore it has a better prognosis than SCLC. SCLC spread at time of diagnosis so treated by chemotherapy with or without

radiation.

Paraneoplastic syndromes1. Hypercalcemia (parathyroid hormone) in squamous cell carcinoma.2. Cushing syndrome (ACTH)3. Hyponatrimao (ADH)4. Neuromuscular syndrome5. Finger clubbing6. Hematological manifestation as DIC in adenocarcinoma.

N.B: The others (2-5) more with small cell carcinoma.

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Features SCC NSCC

Site Central Peripheral

Mucin Present Present

Neuroendocrine markers(chromogrnain & synaptophysin)

Absent Absent

Treatment Chemotherapy Surgery

Prognosis Bad Good

The major differences between SCC & NSCC

Bronchial carcinoid

Arise from neuroendocrine cells that line the bronchial mucosa. It occurs in early age (40 years) & represents 5% of all tumors.

MorphologyMacroscopic:In main bronchi & grow as:1. An obstructing polypoid & spherical mass.2. Mucosal plaque penetrates the wall to fan out in peribronchial tissue (collar-

button lesion).

Microscopic:-Nests of uniform cells with round nuclei (salt & pepper chromatin), rare mitosis & little pleomorphism. -Cytoplasm contains dense neurosecretory granules.

Atypical carcinoid: high mitotic rate, high cytological variability. Focal necrosis, high lymph node & distant metastasis.

Clinical course Cough hemoptysis & recurrent infections. 5-15% spread to hilar lymph node, distant metastasis is rare. Resectable & curable tumors. 5-10 years survival rate is 50-90%.

Causes of heamopytsis:1. Diseases of the bronchi: bronchitis & bronchiectasis.2. Diseases of the lung: pneumonia, *tuberculosis, lung abscess, tumours & *chronic

venous congestion.

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3. Haemorrhagic blood diseases as leukemia & haemophilia.4. Scurvey.

Pleural lesions

Pleural effusion & pleuritis

Malignant mesothelioma

Pleural effusion & pleuritis

Pleural effusion: presence of fluids in the pleural space. It is either transduate or exudate with inflammatory cells (pleuritis).

Fibrinous, hemorrhagic & suppurative exudate leads to fibrous organization, adhesion & pleural thickening.

Causes of pleuritis1. Microbial invasion via pulmonary infection or blood seeding.2. Cancer (BAC, metastatic neoplasm & mesothelioma).3. Pulmonary infarction

Pneumothorax, hydropneumothorax, pyopneumothorax Hemothorax, chylothorax

Penumothorax: presence of air in the pleural sac. Spontaneous or secondary to emphysema, fractured rib, lung abscess & carcinoma.

Hydropneumothorax: presence of serous fluid in the pleural sac.

With infection empyema & pyopneumothorax develop.

Hemothorax: collection of blood in the pleural sac. Occur as a complication of ruptured aortic aneurysm & trauma.

Chylothorax: collection of milky lymphatic fluid with lipid in the pleural sac. It is caused by obstruction of lymphatic ducts by intrathoracic cancer.

Malignant mesothelioma

Occur in parietal or visceral pleura, less common in the pericardium or peritoneum. 50% of cases are due to asbestos exposure. It requires 25-40 years to develop the cancer this suggest multiple genetic events for tumorogenesis.

Asbestos not removed or metabolized. They gather near the mesothelial cells, generate ROS & cause DNA damage.

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Siman virus 40 (SV40) found in 80% of cases, it is a potent carcinogen that inactivate growth regulators such as TP53.

MorphologyThe tumor ensheathed by a yellow-white firm gelatinous layer that obliterate the pleural space.3 patterns:1. Epithelial: cuboidal cells line tubular & cystic spaces.2. Sarcomatoid: spindle cells3. Biphasis: both patterns.

Clinical course Pleural fibrosis & plaque in CT-scan. Invade the thoracic wall or subpleural lung tissue. Distant metastasis is rare.

Good luck

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