- Gas exchange between air and blood.
- Thin, delicate, air‑blood barrier, in walls of minute air cells (alveoli) - only in deepest (most distal) part of system; in respiratory bronchioles and alveolar ducts
- Functional or respiratory part of the system.
- Conducting region: protects fragile alveoli and ensures delivery of inspired air to them.
- Simple, delicate structure
- Capillary & scant connective tissue
- Simple squamous epithelium
- Effects of smokeless tobacco limited to oral mucosa
- Tobacco smoke
- - Exposes entire aerodigestive tract to carcinogens
- - Major role in COPD
- - Contributes to other lung conditions.
Conducting region defense mechanisms
- Vibrissae: long hairs in nasal vestibule filter foreign particles
- Large venous blood vessels in nose warm inspired air.
- Cartilage in walls of upper regions maintain patency of conducting passageways: Nasal cavity, Larynx, Trachea, and Bronchi
- Mucus secreted by glands and goblet cells traps foreign particles
- Wave‑like beating of cilia on surface of columnar epithelial cells removes particles
- Cough reflex
- - Muscle contraction narrows tracheal lumen
- - Smaller bore increases velocity of expired air, which clears passage
Alveoli (air cells)
Adjacent alveoli share common wall or septum.
DEFENSE IN ALVEOLI
- Alveolar macrophages phagocytose particles which reach alveoli
- Lymphoid tissue immune defense mechanisms: secretory IgA, serum IgM & IgG, and T lymphocytes.
- Surfactant (produced by type 2 alveolar cells) reduces surface tension
- Limited response to insults: alveolitis --> fibrosis; insults attacking alveolar septae -> inflammatory cells -> mediators -> tissue damage -> scarring, or fibrosis
- Shrunken, relatively airless pulmonary parenchyma
- Due to incomplete expansion or collapse of previously inflated parenchyma - Reduces oxygenation of blood; Predisposes to infection (secondary infection, nonmoving static tissue, fluid or solid).
- Often reversible.
- Distal to complete obstruction of airway
- Prevents passage of air.
- Air gradually resorbed from parenchyma supplied by obstructed airway.
- Alveoli in affected area (entire lung, lobe or patches) collapse.
- Obstructions include - Mucous plugs, Tumors, foreign bodies.
- Lung collapse due to pressure in pleural cavity:
- Fluid effusion 2nd to chronic heart failure
- Pneumothorax (leakage of air)
- Fibrosis in lung or pleura hamper expansion
ACUTE RESPIRATORY DISTRESS SYNDROME
- Acute, diffuse inflam response to direct insults:
- - Airway or chest trauma
- - Aspirated gastric contents
- - Toxic gases
- or to indirect insults:
- - Shock
- - Sepsis
- - Drugs
- Acute severe life-threatening respiratory insufficiency - Cyanosis & severe hypoxemia
- Refractory to O2 therapy (no response)
- May progress to multiple organ failure, in absence of primary left-sided heart failure.
- Chest films show diffuse alveolar infiltration, opacity
- DAD (diffuse alveolar damage) is histologic pattern.
Pathogenesis of ARDS
- During acute lung injury, variety of acute insults result in inflamed alveoli
- inflamed alveoli or MIF activates macrophages, which releases mediators during the acute stage, which are chemotactic for neutrophils
- neutrophils come in alveoli and release mediators like leukotrienes, PAF, proteases, which cause edema, destroy the type I cells, and releases fibrin from the edema, destroy type II cells, resulting in reduced surfactant
- tissue damage and reduced surfactant together cause the formation of a hyaline membrane, composed of necrotic cells and fibrin
- During the Organizing phase, macrophages release fibrogenic cytokines, which leads to fibrosis and formation of honeycomb lung
Acute stage DAD morphology
- Capillary congestion
- Interstitial and intra-alveolar edema & hemorrhage
- Inflam cells especially m’phages & neutrophils
- Some alveoli collapsed, others distended
- Hyaline membranes: necrotic epithelium + fibrin
Organizing stage DAD morphology
- Organization of exudate -> intra-alveolar fibrosis with very thick septa.
- Results in honeycomb lung (diffuse interstitial fibrosis interspersed with dilated and distorted airspaces)
Clinical course of ARDS
- Mortality rate is ~ 40% - secondary bronchopneumonia in fatal cases.
- Resolution in some cases.
- Regions of interstitial fibrosis in some survivors
- “ARDS” is often limited to patients needing ventilatory support on ICU.
- Acute lung injury (ALI) is less severe (with similar pathology).
RESPIRATORY DISTRESS SYNDROME OF THE NEWBORN
- Due to surfactant disturbance, which is only secondary in ARDS.
- Most common cause of respiratory distress in newborn.
- Premature infants - Type II cells not mature enough to produce surfactant
- Surfactant reduces alveolar surface tension and decreases pressure needed to keep alveoli open.
- Atelectasis without surfactant
- Hypoxia -> epithelial & endothelial damage
- Hyaline membranes (necrotic cells & fibrin) on luminal aspect of alveolar walls.
- Used to be fatal
- Current successful Tx
- - Antenatal corticosteroids (stimulate surfactant synthesis)
- - Exogenous surfactant and O2 at birth.
OBSTRUCTIVE LUNG DISEASES
- Chronic bronchitis
- Cystic fibrosis
OBSTRUCTIVE LUNG DISEASES
- Limitation of airflow due to partial or complete obstruction.
- Primary feature: decreased expiratory flow rate
- Expiratory airflow obstruction due to: Anatomic airway narrowing, as in asthma or loss of elastic recoil of lung, as in emphysema.
- Chronic obstructive pulmonary disease is often applied to chronic bronchitis and emphysema.
- In US, affects >10% of adult population; the 4th leading cause of death
- Abnormal permanent enlargement of air spaces distal to terminal bronchioles
- Destruction of walls, w/o obvious fibrosis.
- Inflate, swell up, blow up
- Spaces or holes in parenchyma due to fusion of adjacent alveoli when septum is destroyed.
- As disease advances, spaces enlarge -> huge bullae
- Very common disease
- Usually occurs with chronic bronchitis
- Cigarette smoking causes both
CENTRIACINAR (CENTRILOBULAR) EMPHYSEMA
- Most common form of emphysema
- Respiratory bronchioles (central or proximal part of lobule) destroyed and enlarged.
- “Holes” rimmed by spared tissue
- Holes are dilated air spaces where septae have been destroyed.
- As disease progresses, spread into distal structures - alveolar ducts, panacniar emphysema.
PANACINAR (PANLOBULAR) EMPHYSEMA
- All alveoli in affected area uniformly enlarged.
- Changes in alveoli lining respiratory bronchioles and full extent of alveolar ducts.
- Assoc w/ inherited a1-antitrypsin deficiency
- Normal balance betwn proteolytic agents and their antagonists is disturbed
- Smoking stims proteolytic agents (e.g. elastase)
- Septal destruction due to excessive proteolytic (mainly elastolytic) activity
- Smoking also destroys its inhibitors
- Enzyme a1-antitrypsin (in serum, tissue fluids & macrophages) is most important protease inhibitor
- Inherited serum a1-antitrypsin deficiency -> Panlobular emphysema and liver cirrhosis
- TGF-b1 polymorphisms -> reduced mesenchymal cell response to TGF-b signal -> reduced response to injury
Emphysema clinical features
- Typical patient - middle-aged, barrel-chested, heavy-smoker.
- Early, progressive dyspnea (shortness of breath), w/ expiratory airflow limitation (can't breathe out, key to diagnosis)
- Productive cough depends upon extent of associated chronic bronchitis.
- Usually loss of weight.
- Persistent cough with sputum production for at least 3 mos in 2 consecutive years
- Without any other identifiable cause.
- Coexistent emphysema almost always.
- Simple chronic bronchitis: productive cough, with mucoid sputum, but no physiologic evidence of airflow obstruction.
- Obstructive chronic bronchitis: chronic outflow obstruction
CHRONIC BRONCHITIS Pathogenesis
- Large airways
- Smoking etc -> mucus hypersecretion
- Infection is secondary.
- Smoking damages defense mechanisms (ciliary action etc.) -> contributes to infection.
SIMPLE BRONCHITIS - Trachea & large bronchi - Histology
- Hypertrophy of submucosal glands
- Hypersecretion of mucus
- Inflammatory infiltrate
- Reid index: ratio of thickness of mucous gland layer to thickness of wall betwn epithelium & cartilage, normally less than 0.4, increased in chronic bronchitis
CHRONIC BRONCHIOLITIS Pathogenesis
- Small airway disease
- Basis of airflow obstruction
- Smoking etc -> inflammation & fibrosis -> narrowing of bronchioles
- Coexistent emphysema adds to obstruction
Small airway disease histology
- Goblet cell metaplasia
- Mucus plugging lumen
- Inflam cell infiltration
- Fibrosis of walls
- Bronchiolitis obliterans in most severe cases
Chronic Bronchitis vs. Emphysema
- dyspnea: late - early
- infection: common - occasional
- cough: productive - not so much
- cor pulmonale: common - rare
- Elastic recoil: normal - low
- Appearance: blue bloater - pink puffer
Terminal COPD (emphysema and chronic bronchitis)
- DAMAGE TO ALVEOLAR SEPTAE
- Loss of alveoli and/or thick walls drastically impairs oxygenation of blood in alveolar septa and may eventually prove fatal.
- - Intermittent and reversible airway obstruction
- - Chronic bronchial inflammation
- - Smooth muscle hypertrophy & hyperactivity
- - Increased mucus secretion.
- Recurrent wheezing, breathlessness & cough
- Expiration is main difficulty.
- Lungs become hyperinflated.
EXTRINSIC (ATOPIC) ASTHMA - Pathogenesis
- Genetic predisposition to type I hypersensitivity reaction to extrinsic antigens
- Airway inflammation
- Bronchial hyper-responsiveness to stimuli
ASTHMA - Triggering
- Inhaled antigens elicit TH2-dominated response
- TH2 cells -> cytokines
- - IL-4 -> IgE production
- - IL-5 -> activates eosinophils.
- - IL-13 -> mucus product
- - IL-13 -> B cells -> IgE
- IgE production - Coats mast cells
- Eosinophil recruitment
ASTHMA - Early (immediate) response
- Ag reacts with pre-sensitized, IgE-coated mast cells - Cross-linking of IgE bound to its receptors on mast cell surface
- Mast cell mediators ->
- - Bronchospasm
- - increase vascular permeability
- - increase mucus production
- - increase inflam cell recruitment: Cells involved in late phase, Eosinophils etc
ASTHMA - Late Phase
- Fresh rounds of mediators from:
- - Recruited inflammatory cells
- - Endothelium
- - Lining epithelial cells
- Epithelial cells -> eotaxin - Recruit TH2 cells; Attracts eosinophils
- Eosinophils -> Major Basic Protein + Eosinophil Cationic Protein -> damage epithelium.
- Airway remodeling
EXTRINSIC ASTHMA -> Histology
- Lungs distended with air due to airway obstruction
- Bronchi and bronchioles filled with thick mucus
- Contains Curschmann’s spirals (strips of shed epith)
- Inflam cells including eosinophils and their Charcot-Leyden crystals (derived from eosinophil proteins)
EXTRINSIC ASTHMA - Airway Remodeling
- Increased goblet cells or hyperplastic submucosal glands -> mucus plugs
- Subepithelial fibrosis
- Basement membrane and smooth muscle markedly thickened.
ASTHMA - Clinical course
- Attacks usually subside spontaneously within a few hours or with treatment.
- Prognosis usually good.
- Very severe cases: some patients develop cor pulmonale and heart failure.
- “Status asthmaticus”: paroxysm persists and is occasionally fatal.
- Permanent abnormal dilatation of bronchi & bronchioles
- Chronic necrotizing infection -> destruction of muscle & elastic tissue
BRONCHIECTASIS - Pathogenesis
- Major factors:
- - Bronchial obstruction (tumors, foreign bodies or mucus plugs)
- - Infection (necrotizing pneumonias).
- - Both mechanisms in severe bronchiectasis.
CYSTIC FIBROSIS (AR) - Pathogenesis
- Defect due to abnormal function of an epithelial chloride channel protein
- Encoded by the CFTR cystic fibrosis transmembrane conductance regulator gene
- cAMP-dependent Cl- channels are defective in exocrine gland epithelium, excessive sodium absorption.
- Reduced Cl- secretion into respiratory tract lumen -> increased reabsorption of sodium and water.
- concentrated, viscid mucus -> obstruction
- Varies in severity.
- Pulmonary changes are most important problem
- Obstruction & 2nd infection -> severe pulmonary changes
CYSTIC FIBROSIS (AR) - Clinical features
- Chronic bronchitis
- Bronchiolitis obliterans
- Lung abscesses
- Cor pulmonale
CYSTIC FIBROSIS - Other organs
- Abnormally viscid mucous secretions -> obstruction of other organ passages -> clinical problems, eg Hepatic cirrhosis, Impaired intestinal digestion and absorption.
- Elevated chloride level in sweat is used in diagnosis: Decreased Cl- reabsorption from duct
RESTRICTIVE LUNG DISEASES
- - Severe obesity
- - Neuromuscular disorders
- - Acute
- -- ARDS: classic acute restrictive disease; organizing DAD resembles chronic interstitial diseases
- - Chronic
- -- IPF (idiopathic pulmonary fibrosis) 15%
- -- Pneumoconioses 25%
- -- Sarcoidosis 20%
- -- Collagen vascular diseases 10%: RA, SLE, System sclerosis, etc
CHRONIC INTERSTITIAL LUNG DISEASES
- Bilateral, often patchy, fibrosis of pulmonary connective tissue -> Mainly delicate alveolar wall interstitium
- Stiffness, reduced compliance -> increase effort of breathing (dyspnea)
- Damaged alveolar walls (epith & endoth)-> hypoxia
- Diffuse small nodules or “ground-glass” shadows.
- Often respiratory failure, with pulmonary hypertension and cor pulmonale.
- Later stages difficult to differentiate b/c scarring & gross destruction -> end-stage, “honeycomb” lung
IDIOPATHIC PULMONARY FIBROSIS (CRYPTOGENIC FIBROSING ALVEOLITIS)
- Radiologic & histologic pattern of fibrosis is UIP, Usual interstitial pneumonia, which is also shown in many other conditions.
- - DAD (organizing phase)
- - Collagen vascular diseases
- - Pneumoconioses
- - Sarcoidosis
- - Recurrent aspiration
- - Allergic alveolitis
- The others need to be excluded before applying the name "idiopathic".
IPF - Pathogenesis
- cause - unknown
- genetically predisposition - abnormal repair response to recurrent alveolar epithelial cell injuries caused by environmental factors (esp Cigarette smoking)
- genetic factors - mutations regarding telomerase, surfactant, increased secretion of a particular mucin.
- Injured type 1 pneumocytes -> TGF-b -> transform fibroblasts to myofibroblasts -> excessive collagen deposition, less cellular -> patchy interstitial fibrosis (UIP) -> collapse of alveolar walls, formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar epithelium, aka Honeycomb lung
IPF - Prognosis
- dry cough, progressive dyspnea
- Hypoxemia, cyanosis, and clubbing occur later
- Most patients deteriorate
- mean survival ranges from 2 to 4 years.
- Lung transplantation
- non-neoplastic lung reactions to inhalation of mineral dusts
- depend upon
- - amount of dust retained in the lungs
- - size and shape of the particles, 1 to 5um diameter most dangerous
- - solubility and physiochemical reactivity
- - concomitant tobacco smoking
PNEUMOCONIOSES - pathogenesis
- macrophages ingest Particles
- -> release toxic agents -> lung injury.
- -> release proinflammatory mediators and fibrogenic factors -> fibroblast proliferation and collagen deposition -> increasing pulmonary fibrosis
- Coal -> a spectrum of lung changes in coal workers; Silica increases risk.
- Asymptomatic pulmonary anthracosis
- - all urban dwellers and coal miners;
- - macrophages engulf inhaled carbon and accumulate in perilymphatic connective tissue and in lymph nodes w/ pigment accumulation;
- - no evident cellular reaction.
- Simple CWP (coal workers pneumoconiosis)
- - scattered coal macules & nodules throughout lungs
- - may cause centrilobular (early) emphysema.
- Progressive massive fibrosis (PMF) (“black lung disease”, complicated CWP)
- - Coalescence of enlarging nodules
- - Large black scars -> progressive respiratory dysfunction, pulmonary hypertension and cor pulmonale.
- Caused by crystalline forms of silica, especially quartz
- the most prevalent occupational disease in the world - mining, stone cutting, and production of ceramics.
- Macrophages ingest silica particles -> release fibrogenic mediators
- 1. Early stages - tiny nodules ->
- 2. Nodules coalesce into hard collagenous scars ->
- 3. Lesions expand and coalesce -> PMF; no shortness of breath until this stage.
- May progress after exposure has ceased
- Linked to
- - pulmonary hypertension
- - cor pulmonale
- - increased susceptibility to tuberculosis
- - possibly cancer
- Asbestos fibers, long thin silicate minerals - Asbestosis (pulmonary parenchymal interstitial fibrosis), lung carcinoma (much more common in asbestos workers who smoke tobacco), mesothelioma and other diseases.
- the worst - Straight, stiff and brittle fibers (amphiboles)
- Asbestos bodies - golden brown, fusiform or beaded rods composed of a core of asbestos fiber coated with iron-containing proteinaceous material. Clinically similar to other diffuse interstitial lung diseases.
- Some cases progress to cor pulmonale and death twenty years after initial exposure
- 20% lack a history of asbestos exposure
- occasionally in members of household of asbestos workers and in general public
- rare, rapidly fatal, cancer of mesothelial cells
- arises in the pleura and rapidly encases the lungs
- A multisystem disease
- Non-caseating granulomas in many organs
- Etiology - unknown; a disordered immune response to environmental challenges in genetically predisposed individuals
- In U.S., typically affects black people (mostly females; 20-40 yr).
- 90% of cases shows bilateral hilar lymphadenopathy or lung disease, visible on chest radiographs
- Other affected sites - skin and mucous membranes (including the nose and mouth), eyes in 25% of cases (blindness is rare), lymph nodes, bone marrow, spleen, liver, kidneys, heart, and CNS.
- Parotid glands enlarged in 10-20% -> xerostomia
Diagnosis of sarcoidosis
- Elevated angiotensin-converting enzyme, ESR, serum calcium, alkaline phosphatase, and vitamin D; not reliable
- Transbronchial lung biopsy - frequently used
- Non-caseating granulomas
- Schaumann bodies (laminated calcifications) and asteroid bodies in giant cells
- Positive Kveim-Siltzbach skin test (not often performed)
Prognosis of sarcoidosis
- treated with corticosteroids, steroid-sparing agents, and antimalarial agents
- Most recover with little residual effect
- A small percentage -> progressive fibrosis and cor pulmonale.
PRIMARY LUNG TUMORS
- carcinomas ~95%
- 5% are bronchial carcinoids, mesotheliomas, spindle cell malignancies and benign tumors
- The most common cause of cancer mortality worldwide and for both men and women in US
- Men:women is decreasing
- Peak incidence is in the 6th and 7th decades
Lung cancer in US
- The 2nd most common cancer in both men (next to prostate cancer) and women (next to breast cancer), excluding skin cancer.
- Accounts for ~ 13% of all new cancers.
- Accounts for ~ 27% of all cancer deaths
Etiology of lung carcinoma
- smoking, especially squamous cell carcinoma and small cell carcinoma
- other industrial hazards
- Smoking-related lung cancers - long sequence of genetic abnormalities, including mutations in tumor suppressor genes
- Inherited (genetic) factors condition the mutagenic effect of carcinogens.
Classification of lung carcinomas
- Four major histologic types
- - adenocarcinoma (now the most common)
- - squamous cell carcinoma
- - small cell carcinoma (compared with non-small cell carcinomas, metastasizes earlier and not amenable to surgery, more sensitive to chemo)
- - large cell carcinoma
- The 5-year survival rate for all stages of lung cancer combined is only 16%
- Mostly begin near the hilus in large (1st-3rd) bronchi; fewer arise in the periphery (mainly adenocarcinomas).
Squamous cell carcinoma
- Preceded by squamous metaplasia (pseudostratified collumnar epi -> stratified squamous epi), dysplasia and carcinoma in situ
- Well-differentiated: Sheets of paving stone-like epithelial cells w/ intercellular bridges and keratin (pearls).
- small focus -> tumor mass, obstructing lumen and invading parenchyma -> spread to lymph nodes occurs in most cases -> extend into the pleural cavity and chest wall
- Distant spread - via lymphatics or bloodstream
Small cell carcinoma
- Centrally located masses w/ extension into parenchyma and early hilar lymph node involvement
- High initial response to chemotherapy and radiotherapy
- The worst prognosis - median survival 1 yr
- Cells are small, fusiform (“oat cell”) or spherical with a relatively large dark-staining nucleus and scanty cytoplasm
- Some cells meet the criteria of neuroendocrine cells - dense-core granules and neuroendocrine markers such as neuron-specific enolase; some secrete hormones.
- the current most common lung cancer
- the most common in women and non-smokers
- Most arise in the periphery
- AAH (atypical adenomatous hyperplasia) is its precursor
- Irregular masses, mostly 2-5cm in diameter, but may replace an entire lobe.
- Adenocarcinoma in situ (AIS) - subtype; grows along alveolar walls.
Large cell carcinoma
- Anaplastic carcinoma
- May represent undifferentiated squamous cell carcinomas and adenocarcinomas.
- Prognosis is very poor.
- silent, insidious, aggressive, locally invasive, and widely metastasizing
- often spread to be unresectable before symptoms (cough, expectoration, dyspnea, chest pain, and weight loss).
- Metastatic sites include the adrenal gland, liver, brain and bone.
- Symptom complexes in patients with cancer, eg lung carcinoma, which cannot be readily explained by local or distant spread of the cancer or by the secretion of hormones indigenous to the site of origin of the tumor.
- Hormones produced - ADH and ACTH (mostly in small cell carcinomas), PTH and other hypercalcemic agents (mostly in squamous cell carcinomas)
Manifestations of bronchial carcinoma
- Others - digital clubbing
- warm, red, and enlarged or bulging ends of the fingers
- nails may curve downward like an upside-down spoon
- Sometimes occurs in people w/ pulmonary diseases, including lung cancer.
- May occur in association with hypertrophic osteoarthropathy - swollen and painful joints; strongly linked to lung carcinoma.
SECONDARY LUNG TUMORS
- Lung is the most common site of metastases
- The first vascular bed encountered by blood leaving most organs.
- Metastases are the most common tumors in the lung - evident at autopsy in ~1/3 fatal cancers.
- Typically multiple and circumscribed masses on chest radiographs.
- Any infection of the lung parenchyma.
- Classified on the basis of the specific etiologic agent (bacteria, viruses, mycoplasma and fungi) or the clinical setting.
- Mostly inhaled; overcome the elaborate respiratory system defenses.
- Occasional hematogenous origin.
COMMUNITY-ACQUIRED ACUTE PNEUMONIAS
- Intra-alveolar fluid exudate leading to solidification (consolidation) of the parenchyma characterizes bacterial invasion of the lungs.
- Streptococcus pneumoniae is the most common etiologic agent.
- Walls intact, full recovery possible.
- Traditionally, bronchopneumonia was separated from lobar pneumonia, but they overlap in the modern era.
- aka lobular pneumonia
- Patchy involvement of the parenchyma
- Lesions consist of a suppurative, neutrophil-rich exudate which fills bronchi, bronchioles and alveoli.
- Streptococcus pneumoniae tends to cause bronchopneumonia in the very young, the old and the debilitated.
- Acute bacterial infection of a large portion of a lobe or an entire lobe.
- The four classical stages are rarely seen today in US because the disease is altered by antibiotics.
- Stage one (congestion) - vascular dilatation and intra-alveolar fluid exudate.
- Stage two (red hepatization) - obliteration of alveolar spaces by red blood cells, neutrophils and fibrin.
- Stage three (grey hepatization) - fibrinosuppurative exudate persists while red cells disintegrate.
- Stage four (resolution) - exudate is digested.
- Epidemic and sporadic type of bacterial pneumonia caused by Legionella pneumophila.
- Flourishes in static water, causing dramatic outbreaks in large hotels, eg. American Legion meeting in Philadelphia 1976.
- Transmitted by inhalation or aspiration
- Acute bronchopneumonia in susceptible people
- Fatal in <50% of immunosuppressed people.
COMMUNITY-ACQUIRED VIRAL PNEUMONIAS
- Influenza viruses
- Human metapneumovirus
- Begin as upper respiratory infections.
- Factors favoring downward extension - extremes of age, alcoholism and debilitating illnesses. Previously classified as Community-Acquired Atypical (Interstitial) Pneumonias - significant differences
- Affect alveolar septae (widened by a chronic inflammatory cell infiltrate) but spaces are less involved (hence the term “atypical”).
- Sputum production is less
- Patchy or diffuse
- Prognosis is usually good
- severe cases - alveolar damage w/ hyaline membranes
- Epidemics may cause greater mortality
- Damage to pulmonary defenses predispose to secondary bacterial superinfections - can be more serious.
- Epidemics almost every winter in US - Influenza types A or B viruses
- Type C - mild respiratory illness
- Type A - subtypes based on surface proteins hemagglutinin (H) and neuraminidase (N); 3 known subtypes of human flu viruses: H1N1, H1N2, and H3N2.
- Type B - no subtypes.
- Mutations of H or N antigens - escape host antibodies.
- both H and N replaced through recombination with animal influenza viruses.
- In 2009, H1N1 -> the first flu pandemic in 40 years.
- H5N1 -> usually birds, not humans. However, when it spreads to humans it causes severe respiratory illness (50% death rate). While very rare, some avian influenza A viruses have caused illness in humans in North America.
- found worldwide
- associated with upper and lower respiratory tract infections, most often in young children, the elderly and immunocompromised people.
SARS-CoV (Sars-associated corona virus)
- spread to humans from civets, in China in 2002.
- severe acute respiratory syndrome in 2/3 patients
- Nearly 10% died
- ~800 deaths world-wide
- no confirmed cases since 2004
Middle East Respiratory Syndrome
- MERS-CoV viral respiratory illness
- first reported in Saudi Arabia in 2012
- Most people develop severe acute respiratory illness.
- spreads through close contact
- ~30% mortality
- In 2014, two cases in US in people traveling from Saudi Arabia
NOSOCOMIAL (HOSPITAL-ACQUIRED) PNEUMONIA
- Gram-negative rods and S. aureus
- Bacteria common to the hospital environment acquire resistance to antibiotics; invasive procedures (intubations and injections) are common and bacteria may contaminate equipment.
- Many patients with chronic diseases acquire terminal pneumonia while hospitalized.
- Ventilator-associated pneumonia - infections acquired by people requiring mechanical ventilation.
- Antibiotic-resistant bacteria that cause
- infections mainly in patients in healthcare settings. KPC (Klebsiella pneumoniae carbapenemase) and NDM (New Delhi Metallo-beta-lactamase) are enzymes that break down carbapenems and make them ineffective.
- Necrotizing, often fatal pneumonia
- very debilitated patients who aspirate gastric contents
- partly chemical (due to gastric acid) and partly bacterial (from oral flora)
- Aerobes are more common than anaerobes.
- Fatal abscess formation - common complication
- 1/3 world’s population is infected
- infection <> actual disease
- Two million people worldwide die each year from it
- flourishes where there are poverty, crowding and chronic debilitating illness.
- ~12 million people have both HIV and tuberculosis, a leading cause of death in AIDS.
- Mycobacterium tuberculosis, aerobic, acid-fast, slender rods, spreads from person to person via airborne droplets.
Pathogenesis of tuberculosis
- macrophages endocytosis -> replicates within phagosomes, impair endosome maturation and phagolysosome formation
- proliferate in alveolar macrophages in the earliest stage of primary tuberculosis (<3wks) - bacteremia and seeding of multiple sites; mostly asymptomatic or mildly ill.
- After 3 weeks, mycobacterial antigens (attached to APCs) stimulate TH1 cells -> IFN-gamma -> activates macrophages, bactericidal, resistance.
- Activated macrophages (hypersensitivity) -> TNF -> recruits monocytes -> differentiate into epithelioid cells -> ... -> epithelioid granulomas and tissue destruction, caseous necrosis
- Occurs in previously unexposed people
- Always involves the lungs
- A Ghon focus develops at the initial site of involvement, typically in the subpleural parenchyma.
- The tubercle or tuberculous granuloma - microscopic aggregation of plump round (epithelioid) histiocytes and Langhans giant cells surrounded by lymphocytes and fibroblasts.
- Central caseous necrosis usually present.
- The Ghon complex includes the focus and regional lymph nodes which drain the focus.
- Organisms disseminate widely to other organs.
- Granulomas do not form in immunosuppressed.
- In most cases (95%), development of cell-mediated immunity controls the infection.
- The Ghon complex heals and lesions eventually become localized, fibrocalcified nodules.
- The hypersensitivity and increased resistance induced by primary tuberculosis is reflected by a positive tuberculin (Mantoux) test.
- Organisms in the Ghon complex are usually non-viable.
- Vital organisms may remain dormant in latent lesions in the lungs and elsewhere.
- Progressive primary tuberculosis occurs in a few cases.
PRIMARY TUBERCULOSIS - Outcomes
- Healed lesions (organisms not viable)
- Latent lesions (dormant organisms)
- Progressive primary tuberculosis
- via airways -> acute bacterial pneumonia-like disease
- via lymphatics and vena cava -> miliary tuberculosis (multiple small pulmonary lesions)
- via systemic blood vessels (following erosion of pulmonary veins) -> miliary disease in multiple organs.
Progressive primary tuberculosis
- In ~5% cases (e.g. due to impaired immunity)
- May be fatal
Secondary (reactivation) tuberculosis
- reactivation of bacilli in dormant lesions (rarely exogenous reinfection) following reduced host resistance.
- more common
- Lesions begin in the apices of the upper lobes of the lungs.
- Localized disease may be asymptomatic.
PROGRESSIVE SECONDARY TUBERCULOSIS
- Apical lesion enlarges with expansion of the area of caseation.
- Erosion into a bronchus and discharge of caseous material produces a cavity.
- Higher oxygen tension -> growth of the organism.
SECONDARY TUBERCULOSIS - Clinical features
- Constitutional features
- • Fatigue
- • Weight loss
- • Low-grade fever
- • Night sweats.
- Pulmonary features
- • Productive cough
- • Hemoptysis
- • Pleuritic pain
Diagnosis of Pulmonary tuberculosis
- Definitive diagnosis - identification of tubercle bacilli.
- - physical and radiologic findings of apical cavitation or consolidation - suspect
- - Culture - gold-standard, allows testing of drug susceptibility; at least two weeks.
- - Newer molecular tests / Xpert - <2 hours, less reliable, expensive
- - Sputum/smear & Acid-fast stains - not definitive, can be other mycobacteria.
- - tuberculin test - subcutaneous injection of PPD; palpable induration within 72 hrs - active disease or previous exposure; not definitive.
- - Interferon-gamma release assays (IFGR) blood test - not affected by vaccination, no false positive due to vaccination.
Treatment of latent TB
- rifapentine and isoniazid taken as DOT (Directly Observed Treatment Shortcourse) over 3 months
- as effective as prevention
- as standard self-administered 9-mo daily regimen of isoniazid alone
- Cuts the doses from 270 daily doses to 12 weekly doses
- More compliance
Treatment of active TB
- 6-9 mo
- 10 drugs approved
- First line agents:
- - isoniazid (INH)
- - rifampin (RIF)
- - pyrazinamide (PZA)
- - ethambutol (EMB)
- Regimens have initial phase of 2mo
- Continuation phase of 4 or 7 mo (total 6 or 9 mo)
Multidrug-resistant strains (resistnat to isoniazid and rifampin) and immunosuppression are associated with a poor prognosis. Requires extensive chemo (up to 2yrs) w/ second-line drugs,
Extremely drug resistant (XDR) strains
- Rare type of MDR TB
- Also resistant to any fluoroquinolone and at least one of three injectable second-line drugs (or 3 of 6?)
- the consequence of inadequate drug therapy
- rapidly fatal
- Majority HIV+
- Bacille Calmette Guerin vaccine against TB
- Generally lasts for 15 yrs
- False positive for tuberculin test
- 2nd to pulmonary disease via infected sputum
- hematogenous is possible.
- Oral mucosal nodules: irregular, indurated, red or ulcerated, often painful
- Osteomyelitis: hematogenous or entry via tooth -> periapical tissues -> bone
MYCOBACTERIUM AVIUM-INTRACELLULARE COMPLEX
- Caused by M. avium and M. intracellulare
- Clinically significant disease mostly occurs in late
- stages of AIDS (CD4+ T-cell counts < 60 cells/mm3)
- Organisms proliferate in many organs, including lungs.
- Macrophages contain abundant acid-fast bacilli.
- 3 levels:
- Deep-seated mycoses caused by:
- •Pathogenic fungi
- •Opportunistic fungi
PATHOGENIC & OPPORTUNISTIC FUNGI
- Pathogenic fungi (e.g. Histoplasma capsulatum and Coccidioides immitis) of high virulence
- • Isolated pulmonary involvement in immunocompetent people
- • disseminated disease in immunosuppression
- Opportunistic fungi are low virulence
- • Cause disease in immunosuppression
- • Include invasive aspergillosis, Cryptococcus
- neoformans, and Pneumocystis jiroveci
- Histoplasma capsulatum infection by inhalation of soil
- particles contaminated by bird droppings
- Causes chronic disease in previously healthy people along Ohio and Mississippi rivers and Caribbean.
- Primary lung disease: self-limited, often latent with granulomas (like TB)
- 2nd lung disease: chronic, progressive starts in apices
- Wide dissemination in immunosuppression
- Fulminant disseminated histoplasmosis
- - No granulomas
- - Aggregates of m’phages throughout body
PNEUMOCYSTIS JIROVECI PNEUMONIA
- 100% AIDS sufferers, common cause of death.
- Correlates with CD4 cell count < 200 /ml.
- Cup-shaped organisms 5um diam
- Diffuse or patchy pneumonia
- Alveolar spaces filled w/ foamy material - organisms and cell debris.
- Interstitial inflammation w/ hyaline membrane
- Often, other bacterial, fungal and viral infections.
DIAGNOSIS of FUNGI
- • Culture - best
- • Morphology in tissue sections
- • Serologic tests for antibodies and antigens