Respiratory system

Normal Anatomy

Trachea divides into right and left mainstem bronchi.

Each main bronchus divides into lobar bronchi, then into segmental bronchi

Lobar bronchi are usually called secondary bronchi and segmental bronchi are called tertiary bronchi.

Bronchioles lack cartilage and submucosal glands

Right bronchus more vertical than left, thus aspirated material tends to enter right lung

Lung has double arterial supply - pulmonary and bronchial

Normal histology

Alveolar capillary basement membrane fuses with alveolar epithelium to form a single membrane for oxygen and carbon dioxide diffusion.

Acinus contains 3-5 terminal bronchioles, alveolar ducts and alveoli

Alveoli are lined by pseudostratified, columnar epithelium

Alveoli contain type I and II pneumocytes

Type I pneumocytes: 95%, flattened

Type II pneumocytes: 5%, produce surfactant, involved in repair if type I destroyed

Bronchial-bronchiolar epithelium contains goblet cells, neuroendocrine (Kultschitsky’s) cells, serous cells, basal cells, Clara cells and ciliated cells

CONGENITAL

Agenesis/Hypoplasia

Tracheal/bronchial anomalies, i.e., Tracheo-Esophageal (TE) fistula

Vascular anomalies

Congenital Emphysema

Foregut cysts

Pulmonary Artery Malformations (CPAM)

Sequestration (no connection to airways)

PULMONARY INFECTIONS

PULMONARY INFECTIONS

Pulmonary infections in the form of pneumonia are one of the leading causes of death all around the world.

This is due to – (1) the epithelial surfaces of the lung are constantly

exposed to liters of variously contaminated air – (2) nasopharyngeal flora are regularly aspirated

during sleep, even by healthy persons; and – (3) other common lung diseases render the lung

parenchyma vulnerable to virulent organisms.

PNEUMONIA

Definition– Broadly defined as any infection in the lung parenc

hyma.

It may present as acute, fulminant clinical disease or as chronic disease.

Pathogenesis : Inflammation caused by organisms.

PNEUMONIA

The histologic spectrum of pneumonia may vary from a

Fibrinopurulent alveolar exudate seen in

acute bacterial pneumonias.

Mononuclear interstitial infiltrates in viral

and other atypical pneumonias.

Granulomas and cavitation seen in many of

the chronic pneumonias.

PNEUMONIA

Classification – Anatomical

Acute bacterial pneumonias can present as one of two anatomic and radiographic patterns,

- Bronchopneumonia and - Lobar pneumonia.

– Aetiological or according to clinical setting Community-Acquired Acute Pneumonia

Community-Acquired Atypical Pneumonia

Nosocomial Pneumonia

Aspiration Pneumonia

Chronic Pneumonia

Necrotizing Pneumonia and Lung Abscess

Pneumonia in the Immunocompromised Host

PNEUMONIA

Community-Acquired Acute Pneumonias

– Community-acquired acute pneumonias are bacterial in origin.

– Onset is usually abrupt, with high fever, shaking chills, pleuritic chest pain, and a productive mucopurulent cough; occasional patients may have haemoptysis.

– S. pneumoniae (or pneumococcus) is the most common cause of community-acquired acute pneumonia.

PNEUMONIA

Pneumococcal pneumonia– Caused by Streptococcus pneumoniae

– Is responsible for more than 90% of lobar pneumonias.

– Can present as Lobar pneumonia Bronchopneumonia

PNEUMONIA

PNEUMONIA

Pneumococcal pneumonia

Lobar pneumonia

– In lobar pneumonia the contiguous airspaces of part or all of a lobe are homogeneously filled with an exudate that can be visualized on radiographs as a lobar or segmental consolidation.

Bronchopneumonia

– Implies a patchy distribution of inflammation that generally involves more than one lobe.

– This pattern results from an initial infection

of the bronchi and bronchioles with extension into the adjacent alveoli.

PNEUMONIA

Lobar pneumonia– Inflammation involves a lobe diffusely.

– 4 pathological stages identified in the progress of untreated infection.

1. Stage I- Acute congestion2. Stage II- Red hepatization3. Stage III- Gray hepatization 4. Stage IV- Resolution

PNEUMONIA

Acute congestionLasts for 1-2 daysAcute congestion and oedema

Macroscopy– Lung is heavy and firm– Dark red– Abundant frothy red fluid can be squeezed from it

PNEUMONIA

Acute congestion

Microscopy

– Alveolar spaces filled with inflammatory exudates and organisms

– Neutrophils are abundant

– Fibrin will be present

– Gram stained smear show large number of gram positive diplococci

PNEUMONIA

Red hepatization

Lasts for 2-4 days

Macroscopy

– Pleural surface have fibrinous tags of fibrin.

– Cut surface appear dry, firm red granules , feel like liver ( liver-like consistency).

– Affected lung tissue airless and sink in water.

PNEUMONIA

Red hepatization

Microscopy

– Capillary engorgement persists.

– Alveolar spaces are packed with neutrophils, red cells, and fibrin

– Organisms are almost disappeared, if present only few

RED HEPATIZATION

PNEUMONIA

Gray hepatization Lasts for 4-8 days

Macroscopy– Cut surface is dry, granules and gray.– Fibrinosuppurative exudate persist within the alveoli.

Microscopy

– Capillary engorgement resolved– Alveolar spaces are distended and filled with dense fibrin and with

dead and dying polymorphs.– Occasional degenerating red cells are seen.

PNEUMONIA

Resolution8th day onwards

Macroscopy– Fibrinous or fibrinopurulent pleuritis (pleural exudat

e) may resolve or undergo organization, leaving fibrous thickening or permanent adhesions.

– Lung parenchyma appear normal

ResolutionTransformation of exudates to mucoid masses richly infiltrated by macrophages and fibroblasts

PNEUMONIA

Resolution

Microscopy

– Capillaries will be normal

– Alveolar space will have macrophages. Exudates within the alveoli are enzymatically digested to produce granular, semifluid debris that is resorbed, ingested by macrophages, coughed up, or organized by fibroblasts growing into it.

PNEUMONIA

Bronchopneumonia

Commonly seen among infancy, old age , patients with debilitating diseases and patients with prolonged bed rest.

Organisms colonize the bronchiole and extend through the walls into surrounding alveoli.

PNEUMONIA

Bronchopneumonia Macroscopy

– Foci of inflammatory consolidation are distributed in patches throughout one or several lobes, most frequently bilateral and basal.

– Well-developed lesions up to 3 or 4 cm in diameter are slightly elevated and are gray-red to yellow .

– The lung substance immediately surrounding areas of consolidation is usually hyperemic and edematous.

– Confluence of these foci may occur in severe cases, producing the appearance of a lobar consolidation.

PNEUMONIA

Bronchopneumonia

Pleural involvement is less common than in lobar pneumonia.

Microscopy

– The reaction consists of focal suppurative exudate that fills the bronchi, bronchioles, and adjacent alveolar spaces.

– Ciliated epithelium is destroyed.

– Vascular congestion

Clinical Course

High grade fever, and productive cough. (Interleukin (IL) 1 and tumor necrosis factor (TNF), re

sults in fever. IL-8 and granulocyte CSF, stimulate the release of neutrophils and their attraction to the lung)

Pleuritic pain and pleural friction rub.

The whole lobe is radiopaque in lobar pneumonia, whereas there are focal opacities in bronchopneumonia.

PNEUMONIA

Sequalae and complications– Complete restitution of the lung is the rule for both forms.

– Complications may occur

– (1) Tissue destruction and necrosis may lead to

abscess formation;– (2) Suppurative material may accumulate in the

pleural cavity, producing an empyema;

– (3) Organization of the intra-alveolar exudate may

convert areas of the lung into solid fibrous tissue; – (4) Bacteremic dissemination may lead to

meningitis, arthritis, or infective endocarditis.

Community-acquired atypical pneumonias

The term atypical denotes the moderate amount of sputum, no physical findings of consolidation, only moderate elevation of white cell count, and lack of alveolar exudate.

Mycoplasma pneumoniae

Viruses: Influenza virus, the RSV, adenovirus, rhinoviruses, rubeola, and varicella

Chlamydia pneumoniae; and Coxiella burnetii

Morphology

All causal agents produce essentially similar morphologic patterns.

The lung involvement may be quite patchy or may involve laterally or unilaterally.

The affected areas are congested. The pleura is smooth, and pleuritis or pleural effusions are infrequent.

Morphology

Microscopically :

The alveolar septa are widened and edematous and usually have a mononuclear inflammatory infiltrate of lymphocytes, macrophages, and occasionally plasma cells.

Frequently “interstitial”, NOT alveolar

Severe Acute Respiratory Syndrome (SARS)

CORONA-VIRUS

SARS first appeared in November 2002 in the Guangdong Province of China

Like most other NON-bacterial pneumonias confirmed by PCR

Like most viral pneumonias, interstitium infiltrated, some giant cells often present.

S

A

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HOSPITAL-ACQUIRED PNEUMONIA

Pulmonary infections acquired in the course of a hospital stay.

They are common in patients with– DEBILITATION– CATHETERS, VENTILATORS– Enterobacteriaceae, pseudomonas– staph (MRSA)– MRSA (MR=Methicillin Resistant)

Hospital-acquired infections are serious and often lifethreatening complications.

ASPIRATION PNEUMONIA

Occurs in markedly debilitated patients or UNCONSCIOUS PATIENTS.

These patients have abnormal gag and swallowing reflexes that predispose to aspiration.

The resultant pneumonia is partly chemical because of the extremely irritating effects of the gastric content/acid.

This type of pneumonia is often necrotizing.

In those who survive, Often lead to lung ABSCESSES

CHRONIC PNEUMONIA

USUALLY NOT persistences of the community or nosocomial bacterial infections.

Often SYNONYMOUS with the 4 classic systemic fungal or granulomatous pulmonary infections, i.e., TB, Histo-, Blasto-, Coccidio-

If you see pulmonary granulomas, think of a CHRONIC process, often years

CHRONIC Pneumonias

TBHISTO-PLASMOSISBLASTO-MYCOSIS

COCCIDIO-MYCOSIS

LUNG ABSCESS

The term “pulmonary abscess” describes a local suppurative process within the lung, characterized by necrosis of lung tissue.

Oropharyngeal surgical procedures, sinobronchial infections, dental sepsis, and bronchiectasis play important roles in their development

Etiology and Pathogenesis

ASPIRATION of infective material SEPTIC EMBOLIZATION NEOPLASIA, sec. infection is common From NEIGHBORING structures:

– ESOPHAGUS– SPINE– PLEURA– DIAPHRAGM

ANY pneumonia which is severe and destructive, and inadequate treatment

Morphology

Abscesses: a few millimeters to large cavities of 5 to 6 cm, single or multiple.

Pulmonary abscesses due to aspiration are more common on the right and are most often single.

Abscesses that develop in the course of pneumonia or bronchiectasis are usually multiple, basal, and diffusely scattered.

Septic emboli and pyemic abscesses are multiple and may affect any region of the lungs.

Morphology

The cardinal histologic change in all abscesses is suppurative destruction of the lung parenchyma within the central area of cavitation.

In chronic cases considerable fibroblastic proliferation produces a fibrous wall.

Pneumonia in the immunocompromised host

Haemophilus influenzae

Major cause of life-threatening acute LRT infections, otitis media, and meningitis in young children.

In adults- Most common cause of acute exacerbation of COPD in adults

Exists in two forms: encapsulated (5%) and unencapsulated (95%).

Cause of secondary bacterial pneumonia in children and healthy adults following viral respiratory illnesses

MRSA, of course, is usually NOT “community” acquired

Complications: lung abscess and empyema. I/V drug abusers are at high risk of developing st

aphylococcal pneumonia in association with endocarditis.

Staphylococcus aureus

Klebsiella pneumoniae

Afflicts debilitated and malnourished people, particularly chronic alcoholics.

ALCOHOLICS with pneumonia are often thought of as having Klebsiella until proven otherwise

Thick and gelatinous sputum is characteristic, because the organism produces an abundant viscid capsular polysaccharide, which the patient may have difficulty expectorating.

OBSTRUCTIVE vs. RESTRICTIVE AIRWAY DISEASE

OBSTRUCTIVE vs. RESTRICTIVE AIRWAY DISEASE

Obstructive airway disease: increase in resistance to airflow due to obstruction at any level; includes emphysema, chronic bronchitis, bronchiectasis, asthma; reduced maximal airflow rates (FEV1)

Restrictive airway disease: reduced expansion of lung parenchyma with decrease in total lung capacity; normal FEV1; due to chest wall disorders (polio, obesity, pleural disease, kyphoscoliosis), interstitial / infiltrative diseases

Common abstructive and restrictive diseases

Obstructive   Asthma   COPD (Chronic bronchitis+emphysema)   Bronchiectasis   Cystic fibrosis   Bronchiolitis Restrictive—Parenchymal   Sarcoidosis   Idiopathic or drug induced pulmonary fibrosis   Pneumoconiosis

Restrictive—Extraparenchymal   Neuromuscular     Diaphragmatic weakness/paralysis     Myasthenia gravis     Guillain-Barré syndrome     Muscular dystrophies     Cervical spine injury   Chest wall     Kyphoscoliosis     Ankylosing spondylitis

Patterns of Abnormal Function

Overlap between chronic obstructive lung diseases

Site of disease

Bronchi-chronic bronchitis, bronchiectasis, asthma

Bronchioles-bronchiolitis

Acini-emphysema

Chronic obstructive pulmonary disease (COPD)

Also called chronic obstructive lung disease (COLD)

Two sub types: Chronic bronchitis and emphysema, coexist to variable degree in most patients

Characterized by gradual decrease in FEV1 over a period of time with a acute episode of acute exacerbation.

Risk factors: smoking, air pollution, respiratory infection, positive family history

Natural progression of COPD

40s: chronic productive cough, wheeze occasionally

50s: 1st acute chest illness 60s: Dyspnea on exertion, increasing cou

gh/sputum production, frequent exacerbation

Late stage: Hypoxemia with cyanosis, corpulmonale

Chronic bronchitis

Definition: defined clinically as persistent cough with sputum for at least 3 months for at least 2 consecutive years

Pathogenesis

Tobacco smoke (90%) and dust from grain, cotton, and silica.

Hypersecretion of mucus in the large airways, associated with hypertrophy of the submucosal glands in the trachea and bronchi.

Proteases released from neutrophils, and matrix metalloproteinases, stimulate mucus hypersecretion.

Pathogenesis

Secondary infection- producing acute exacerbations.

(Cigarette smoke interferes with ciliary action of the respiratory epithelium, it may cause direct damage to airway epithelium, and it inhibits the ability of bronchial and alveolar leukocytes to clear bacteria).

Morphology

Gross: hyperemia, swelling, and edema of the mucous membranes, frequently accompanied by excessive mucinous or mucopurulent secretions.

Microscopic: chronic inflammation of the airways and enlargement of the mucus-secreting glands of the trachea and bronchi, mucous gland hyperplasia.

Morphology

Reid index: ratio of thickness of mucus gland layer to thickness of wall between epithelium and cartilage ( normal is 0.4), increased in chronic bronchitis.

The bronchial epithelium may exhibit squamous metaplasia and dysplasia

Chronic bronchitis

Clinical Features

Persistent productive cough Dyspnea on exertion Hypercapnia, hypoxemia, and cyanosis (“blue bl

oaters”), polycythemia CXR: Increased bronchovascular marking Longstanding cases- leads to cor pulmonale with

cardiac failure. Death may also result from further impairment of

respiratory function due to superimposed acute infections

Emphysema

Definition: Abnormal permanent enlargement and destruction of air spaces distal to terminal bronchiole without obvious fibrosis

Differs from overinflation, which is not due to wall destruction (example: due to loss of opposite lung)

Acinar and airspace enlargement is usually due to tobacco related wall destruction.

Type of emphysema

Emphysema is classified according to its anatomic distribution within the lobule.

There are four major types: (1) centriacinar (> 95% of cases) (2) panacinar (3) paraseptal (distal), and (4) irregular. The first two cause clinically significant airflow o

bstruction.

Pattern of emphysema

Type of emphysema

Centriacinar emphysema: affects proximal (central) part of acini, sparing distal alveoli; worse in upper lobes, particularly apices

Seen in heavy smokers, coal worker pneumoconiosis

Clinically significant at age 40+ in smokers, although ventilatory deficits seen earlier

Type of emphysema

Panacinar emphysema: acini uniformly enlarged from respiratory bronchiole to terminal alveoli; usually lower lungs; associated with alpha-1-antitrypsin deficiency

Paraseptal (distal acinar) emphysema: distal acini affected, multiple continuous airspaces are affected; may be source of spontaneous pneumothorax

Irregular emphysema: minor clinically; invariably associated with scarring, irregular involvement of acini

Pathogenesis

Macrophages, CD8+ and CD4+ T lymphocytes, and neutrophils are increased in lung.

Activated inflammatory cells release a variety of mediators, including leukotriene B4, IL-8, TNF, that are capable of damaging lung structures or sustaining neutrophilic inflammation.

Protease-antiprotease imbalance, aided abetted by imbalance of oxidants and antioxidants

Pathogenesis

The protease-antiprotease imbalance hypothesis is based on the observation that patients with a genetic deficiency of the α1-antitrypsin have a markedly enhanced tendency to develop pulmonary emphysema.

α1-antitrypsin, normally present in serum, tissue fluids, and macrophages, is a major inhibitor of proteases.

α1-antitrypsin is encoded by codominantly expressed genes on the proteinase inhibitor (Pi) locus on chromosome 14.

Pathogenesis

The following sequence is postulated:   1. Neutrophils are normally sequestered in perip

heral capillaries, and a few gain access to the alveolar spaces.

2. Any stimulus that increases either the number neutrophils and macrophages in the lung or the release of their protease-containing granules increases proteolytic activity. 

 3. With low levels of serum α1-antitrypsin, elastic tissue destruction is unchecked and emphysema results.

Pathogenesis

In smokers, neutrophils and macrophages accumulate in alveoli.

Direct chemoattractant effects of nicotine as well as the effects of reactive oxygen species (ROS) contained in smoke.

These activate the transcription factor NF-κB, which switches on genes that encode TNF and chemokines, including IL-8. These, in turn, attract and activate neutrophils

Pathogenesis

Accumulated neutrophils are activated and release their granules, rich in a variety of cellular proteases (neutrophil elastase, proteinase 3, and cathepsin G), resulting in tissue damage. 

In addition to elastase, matrix metalloproteinases derived from macrophages and neutrophils have a role in tissue destruction

Pathogenesis

Morphology

Gross: voluminous lungs, generally, the upper two thirds of the lungs.

Large apical blebs or bullae are more characteristic of irregular emphysema secondary to scarring and of distal acinar emphysema.

Centriacinar Panacinar

Bullae, or “peripheral blebs”Bullae, or “peripheral blebs”

Microscopic: abnormally large alveoli separated by thin septa with only focal centriacinar fibrosis.

The pores of Kohn are so large that septa appear to be floating or protrude blindly into alveolar spaces with a club-shaped end.

Destruction of alveolar walls With advanced disease, larger abnormal airspaces,

blebs or bullae, which often deform and compress the respiratory bronchioles and vasculature of the lung.

Morphology

The loss of alveolar walls with emphysema

Clinical Course

The clinical manifestations of emphysema do not appear until at least one third of the functioning pulmonary parenchyma is damaged.

Dyspnea Cough or wheezing is the chief complaint. Weight loss Barrel-shaped chest, dyspnea, sits forward in a h

unched-over position, and breathes through pursed lips.

Pink puffers

Complication

Cor pulmonale and eventually CCF, related to secondary pulmonary vascular hypertension.

Death is due to – respiratory acidosis and coma, right-sided heart failur

e, and massive collapse of the lungs secondary to pneumothorax.

Treatment: bronchodilators, steroids, bullectomy, and, in selected patients, lung volume reduction surgery and lung transplantation.

Substitution therapy with α1-AT is being evaluated.

Summary

Asthma

Definition: Asthma is a chronic but reversi

ble inflammatory disorder of the airways characterized by recurrent episodes of wheezing, breathlessness, chest tightness, and coughing.

Asthma

Asthma

The hallmarks of the disease are hyperresponsiveness of airway to a variety of stimuli, resulting in – episodic bronchoconstriction– inflammation of the bronchial walls and – increased mucus secretion

Asthma, type

Atopic Asthma Type I IgE-mediated hypersensitivity reaction . T

he disease usually begins in childhood and is triggered by environmental allergens (dust, pollens, animal dander and food).

A positive family history of asthma is common. Serum radioallergosorbent tests (called RAST) id

entify the presence of IgE specific for a panel of allergens.

Asthma, type

Non-Atopic Asthma : Non-immune, respiratory infections due to viruses (e.g., rhinovirus, parainfluenza virus) are common triggers.

IgE-normal, no positive family history It is thought that virus-induced inflammati

on of the respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants.

Asthma, type

Drug-Induced Asthma Aspirin-sensitive asthma occurs in individuals w

ith recurrent rhinitis and nasal polyps. Occupational Asthma This form of asthma is stimulated by fumes, orga

nic and chemical dusts (wood, cotton, platinum), gases (toluene), and other chemicals (formaldehyde, penicillin products).

Pathogenesis (atopic asthma)

The major etiologic factors in atopic asthma are a genetic predisposition to type I IgE mediated hypersensitivity reaction

Initial sensitization affects T helper 2 cells, which release IL-4/5, which promote IgE release by B cells, that binds to mucosal mast cells and eosinophils.

Reexposure to allergen leads to mediator release from mucosal mast cells

IL-4-production of IgE, Il-5-activates locally recruited eosinophils, IL-13-mucus secretion

Pathogenesis

Acute/immediate phase response (minutes): release of preformed mediators-bronchoconstriction, edema, mucus secretion

Late phase reaction (hours): due to release of major basic protein from eosinophils, which causes epithelial damage and airway constriction.

Potent mediators: leukotrienes C4, D4, E4 (bronchoconstriction, increased vascular permeability, increased mucus secretion) and acetylcholine (cause airway smooth muscle constriction by directly stimulating muscarinic receptors)

Minor mediators: histamine, prostaglandin D2 (bronchoconstrictor)

Others: IL-1, TNF, and IL-6, chemokines (e.g., eotaxin), neuropeptides, nitric oxide, bradykinin, and endothelins.

Mediators

Morphology

Gross: overdistended lung, with small areas of atelectasis, occlusion of bronchi and bronchioles by thick, tenacious mucus plugs.

Micro: the mucus plugs contain whorls of shed epithelium, which give rise to the well-known spiral shaped mucus plugs called Curschmann spirals

Numerous eosinophils and Charcot-Leyden crystals (crystalloid mad up of galactin-10)

Morphology,microscopic

Overall thickening of airway wall  Sub-basement membrane fibrosis (deposition of

type 1 and III collagen beneath the classic BM composed of type IV collagen and laminin)

An increase in size of the submucosal glands and mucous metaplasia of airway epithelial cells 

Bronchial smooth muscle hyperplasia and hypertrophy

Microscopic

Eosinophils

Charcot-Leyden crystals

Clinical Course

Acute asthmatic attack lasts up to several hours.

Chest tightness, dyspnea, wheezing, and cough with or without sputum production

Cyanosis and even death. With appropriate therapy to relieve the att

acks, most individuals with asthma are able to maintain a productive life.

Summary

Begins in childhood, triggered by environmental allergens , often positive family history (atopic)

Skin test causes wheel and flare reaction Classic example of Type I IgE mediated hypersen

sitivity reaction Initial sensitization affects T helper 2 cells, which

release IL-4/5, which promote IgE release by B cells, mast cells and eosinophils

Summary

Reexposure to allergen-mediator release from mucosal mast cells

Acute response: bronchoconstriction, edema, mucus secretion, hypotension

Late phase reaction: epithelial damage and airway constriction

Putative mediators: leukotrienes C4, D4, E4 and acetylcholine; minor mediators: histamine, prostaglandin D2

Blood eosinophilia, sputum eosinophils