Upper and Lower Respiratory Tract

Question 1

List the broad clinical signs of respiratory disease in dogs and cats

Answer 1

1. Sneezing
2. Reverse sneezing
3. Nasal discharge
4. Open mouth / postural breathing
5. Audible respiratory sounds
   
   • Stridor
   • Stertor
   • Wheezes?
   • Crackles?
6. Coughing

Question 2

List the various abnormal respiratory sounds and describe how they help localise respiratory disease

Answer 2

1. Stertor - soft palate / nasopharynx
2. Stridor - inspiratory noise, continuous - larynx
3. Wheeze
   
   • low pitched versus high pitched
     
     • large airway versus small airway
   • Monophonic versus polyphonic
     
     • large airways vs smaller/multiple airways
4. Crackles
   
   • Loudest end inspiratory
   • Indicate alveolar or bronchiolar disease
5. Decrease / absent sounds
   
   • Pleural space
     
     • Dorsally reduced sounds - air
     • Ventral reduced sounds - fluid

Question 3

List the various imaging modalities to assess the respiratory tract.

Together with their major indication and limitation

Answer 3

1. Radiography
   
   • General assessment of heart size and lung/airway changes. Assess symmetry of the nose.
   • Nasal studies limited by complexity of the structure and difficulty identifying early lesions
2. Computed tomography
   
   • Indicated for nasal and thoracic imaging - Ideal for thoracic studies due to spatial definition, contrast and speed of acquisition
   • The need for sedation / general anaesthesia is the biggest limitation in thoracic investigations
3. MRI
   
   • Primarily indicated for assessment of nasal disease and other fixed soft tissue changes
   • Thoracic investigation limited by movement and bony change may be underestimated
4. Fluoroscopy
   
   • Dynamic airway disease and swallowing studies (pharyngeal and oesophageal function)
   • Limited by patient compliance primarily
5. Ultrasonography
   
   • Assessment of extra-luminal soft tissue structures. Descriptions of changes have been reported for laryngeal paralysis (insensitive for laryngeal collapse)
   • Limited by tissue/air interface and tissue/bone interface artefacts
6. Nuclear Imaging
   
   • Global assessment of lung perfusion and lung ventilation (IV versus nebulized technetium) including V/Q scans
   • Most sensitive for identifying PTE
   • CAn be used for assessment of mucocilliary clearance
   • Cumbersome and requires patient isolation
   • Poor spatial resolution

Question 4

List the options for sampling of the respiratory tract

Nose, large airways and lower airways

Answer 4

1. Nasal swab
2. Nasal flush
3. Nasal biopsy
4. Transtracheal wash
5. Bronchial brushing
6. Bronchoalveolar lavage
7. Transthoracic needle aspirate or biopsy
8. Surgical biopsy

Question 5

List major pros and cons of the various nasal sampling techniques

Answer 5

1. Nasal swabs
   
   • Cell collection is often superficial inflammation and cannot aid in distinguishing the underlying cause
   • Cultures typically respresent normal flora or secondary infection and do not identify a causual organism
   • Samples can be collected for PCR to test for viral / bacterial disease with some utility
   • Highly beneficial in diagnosing nasal cryptococcosis in cats
2. Nasal hydropropulsion
   
   • Large samples may be obtained
   • Minimal equipment required
   • May relieve obstruction
   • Care must be taken to avoid aspiration
3. Biopsy (guided or blind)
   
   • Can be guided by endoscopy or CT for smaller lesions
   • Blind samples can be useful for larger lesions
   • Samples can be obtained for histopath or culture
   • Bleeding is the major risk.

Question 6

Discuss and compare sampling techniques from the lower airways.

Tracheal wash samples vs BAL vs endobronchial brush samples

Answer 6

1. Tracheal wash
   
   • samples can be obtained via transtracheal approach or via a cuffed ET tube
   • Generally indicated for sampling from large airways or when there is diffuse disease.
   • TTW can be performed in an awake animal with preserved coughing reflex
   • TTW dogs >15 kgs
   • Sample volumes are typically small
   • Cannot be utilised if there is skin contamination
2. Bronchoalveolar lavage
   
   • Requires general anaesthesia
   • +/- endoscopic guidance. Necessary for targeted sampling of lobar disease
   • Sample at least two sites if there is diffuse disease
   • Fluid can be submitted for cytology, routine culture, fungal culture, mycoplasma culture or PCR.
   • VQ mismatch and hypoxia are common and usually self-limiting and managed by oxygen supplementation
3. Endobronchial Brush (or needle) samples
   
   • Requires general anaesthesia and bronchoscopy
   • Requires endoscopic brush and needle instruments
   • Can provide information on focal lesions
   • Good at detecting inflammation in larger airways
   • lymphocyte numbers may be underestimated
   • Clinical implication of the results has yet to be fully ellucidated

Question 7

Discuss the pathogenesis of Tracheal Collapse

Answer 7

• Multifactorial and likely degenerative
• Congenital forms do occur also
• Primary cartilage factors causing intrinsic weakness
  
  • Suspected reduction in glycosaminoglycans and chondroitin sulfate
  • Tracheal cartilage weakness leads to flattening of the rings and widening of the dorsal membrane
• Secondary factors capable of causing progression
  
  • Obesity, Irritant inhalation, Periodontal disease, Respiratory infection, ET intubation?
• Chronic obstruction can contribute to the degeneration including pulmonary fibrosis in WHWT
• Controversial if concurrent or subsequent airway inflammatory disease is relevant to the pathogenesis of airway collapse
• Worsening collapse can lead to further oedema and inflammation which may precipitate further degeneration or at least perpetuate the cough.

Question 8

List the options for pulmonary function testing in dogs and cats

Answer 8

Mechanical function

1. Spirometery - only for tidal volume measurement
2. Tidal breathing flow volume loops
3. Barometric whole body plethysmography
4. Lung compliance
5. Lung resistance

Pulmonary gas exchage

1. Arterial Blood Gas Analysis
2. Oxygen Tension based indices
3. Pulse oximetry
4. End tidal capnography

Question 9

Discuss the various forms of eosinophilic airways disease proposed in dogs

Answer 9

1. Eosinophilic Bronchitis
   
   • Mildest form of the disease
   • Airway hyperaemia with no to mild mucus accumulation
   • Radiographs may appear normal (17/28 - 61%)
   • Peripheral eosinophilia is rare
2. Eosinophilic Granuloma
   
   • Bronchiectasis and nodular masses common on rads
     
     • Radiographs uniformly abnormal
   • Mucus exudation and inspissated mucus expected
   • BAL eosinophilia almost universal
   • Septic suppurative inflammation uncommon
3. Eosinophilic bronchopneumopathy
   
   • BAL eosinophilia is almost universal
   • 60% have peripheral leukocytosis
4. Parasitic airway diseases that cause airway eosinophilia
   
   • Lung worm (Angiostrongylus Vasorum)
   • Heartworm (Dirofilaria immitis)
   • oslerus osleri, capillaria aerophila, others

Question 10

Eosinophilic airway disease

What is the proposed pathogenesis of eosinophilic airway disease?

Answer 10

• Unknown
• Presumed hypersensitivity reaction to inhaled allergen
• Increase in CD4+ T cells and decrease in CD8+ T cells in BALF
• Activated Th2 cells may accumulate at sites of inflammation
  
  • Th2 cytokine expression not different from control?
• Transcription of MCP-3, eotaxin-2, eotaxin-3 has been shown in dogs with EBP.
• Eotaxin release is induced by IL-4 and IL-13
• Eotaxin binds to C chemokine receptor 3 (CCR3)
• Eotaxin stimulates recruitment of eosinophils
• Pulmonary damage is in part mediated by increase collagenolysis and proteolysis
  
  • matrix metalloproteinase produced by epithelial cell and macrophages increases collagenolysis
  • markers of increased ECM turnover or collagen type III production are increase - procollagentype III amino terminal propeptide
    
    • PIIINP increased in EBP and pulmonary fibrosis

Question 11

Describe the aetiology and pathogenesis of primary ciliary dyskinesia

Answer 11

1. PCD is the result of dysmotility of cilia
2. Cilia abnormalities are ultrastructural and electron microscopy is required for diagnosis
3. Ineffective clearance of mucus from airways is a hallmark
4. Dysfunction of the monocilia on the embryonic node can lead to randomisation of left/right body symmetry
5. ~40 human genetic PCD causing mutations have been identified
6. Usually autosomal recessive inheritance
7. Gene has been identified in Old English Sheepdog and Alaskan Malamutes

Question 12

Cilia abnormalities

Note the normal cilia structure together with the various abnormalities seen in patients with PCD

Answer 12

Motile cilia: Microtubule backbone - axonema. The axonema comprises nine microtube doublets surrounding a certal pair. Arising from the doublets are inner and outer dynein arms together with a radial spoke. There is a nexin-dynein regulatory complex (nexin link)

PCD patients can have the following cilial defects:

• abnormal or absent inner dynein arms
• abnormal or absent outer dynein arms
• Defects in radial spokes
• Defective nexin links
• General axonemal disorganization
• microtubule transposition

Question 13

Define Bronchiectasis

Answer 13

• An abnormal and permanent dilatation and distortion of subsegmental airways

Question 14

List potential causes of bronchiectasis in dogs and cats

Answer 14

1. Congenital disorders
   
   • Primary ciliary dyskinesia
2. Acquired disorders
   
   • Bronchial foreign body
   • post-aspiration injury
   • Chronic infectious bronchitis / bronchopneumonia
     
     • including B. bronchoseptica and pneumocystis carinii
   • Eosinophilic bronchopneumopathy
   • Chronic bronchitis
   • Pulmonary fibrosis
   • Immune deficiency syndromes
   • bronchopulmonary aspergillosis
   • Neoplasia

Question 15

Describe the primary and secondary changes seen with bronchiectasis on radiographs or CT

Answer 15

Primary:

• Abnormal bronchial dilatation (increased bronchoarterial ratio)
• Lack of peripheral bronchial tapering
• Distinct airways within 1 cm of the lung periphery (people)

Secondary:

• Bronchial wall thickening
• Mucus plugging
• Peripheral air trapping (reduced pulmonary density)
• Lobar consolidation

Question 16

Discuss the pathogenesis of Feline Inflammatory Bronchial Disease

Answer 16

• Thought to arise secondary to previous airway insult
  
  • Prior infection or inhaled irritant
• Damage to the airways causes inflammation
  
  • Pirmarily non-degenerate neutrophilic inflammation
• Ongoing inflammation can cause permanent changes to the airways
  
  • Thickening of the bronchi
  • Secretions leading to air-trapping
• Bronchiectasis can result from chronic disease

Question 17

Discuss the pathogenesis of feline asthma

Answer 17

• Though to be allergic, similar to the human form disease
• Allergens (eg. house dust mites, bermuda grass) bind to dendritic cells in the airway lumen
• Presented via MHC II to naive TH0 cells
• In susceptible individuls, this can trigger a Th2 response
• T helper 2 cell mediated response
  
  • IL4 / IL5 mediated
  • Production of IgE
  • cytokines (detected in blood and BALF) including eotaxin drive recruitment of eosinophils, mast cells and basophils which avidly bind IgE
  • re-exposure to allergen causes cross linking of bound IgE leading to degranulation
• Eosinophilic airway inflammation
• Increased airway responsiveness (allergen specific)
• Airflow obstruction / remodelling
• Note that clinical signs can wax and wane despite persistance of airway inflammation.
• ~50% of cats clinically improved without medication
• Ongoing airway inflammation has been documented in cats receiving high dose oral glucocorticoids

Question 18

Differential diagnoses for feline asthma / inflammatory bronchial disease

Answer 18

1. Pulmonary parasitic disease
   
   1. Aerulostrongylus abstrusus
   2. Eucoleus aerophilus (formerly capillaria)
   3. Troglostrongylus brevior
   4. Dirofilaria Immitis
   5. Wolbachia
2. Infection with Toxacara Cati
3. Bacterial / mycoplasm infection
4. Pulmonary neoplasia

Question 19

List readily available diagnostic testing options for feline asthma

Note expected abnormalities or required changes to confirm a diagnosis

Answer 19

1. History and clinical examination
   
   • chronic cough versus acute respiratory difficulty
   • wheezing (expiratory) +/- end expiratory push
   • tachypnoea
2. CBC/biochemistry
   
   • peripheral eosinophilia in 17-46% (not correlated to airway eosinophilia

• Diagnostic imaging - radiographs or CT​
  
  • diffuse bronchial or bronchointerstitial pattern
    
    • Normal radiographs in ~ 25%
  • airway hyperinflation
  • collapse of right middle lung lobe - mucus obstruction
  • bronchial wall thickening
  • pulmonary infiltrates
  • bronchiectasis
• Bronchoscopy
  
  • non-specific
  • mucus accumulation, airway dilatation or stenosis, hyperaemia, mucosal abnormalities, airway collapse
• BAL
  
  • Eosinophilia > 17% cells is arbitrary cut off
  • Subclinial eosinophilia in apparently healthy cats
  • eosinophilia also seen with parasitic infections
  • May be submitted for PCR (bacterial, mycoplasma, viral, parasitic)
• Faecal test
  
  • Baerman technique to assess for lung worm
  • Faecal float for Toxacara cati

Question 20

Discuss adjunctive testing options for feline asthma

Answer 20

1. Allergen testing
   
   • IDST or IgE blood tests
   • results may not be reliable
2. Pulmonary function testing
   
   • Indirect measure of airway resistance in response to airway provocation
   • May help differentiate asthma from chronic bronchitis
3. Biomarker testing
   
   • endothelin-1 - increased in cats with asthma compated to controls.
     
     • endothelin 1 has not been assessed in cats with other respiratory disease
   • Exhaled Breath Concentrates - hydrogen peroxide and acetone increases correlated with eosinophilia on BALF.
     
     • Uncertain if EBC will become clinically useful biomarker

Question 21

List the therapeutic options available for treatment of feline asthma.

Discuss the potential utility of the ‘experimental’ treatment options

Answer 21

Mainstay

1. Glucocorticoids
2. Bronchodilators

Experimental

1. Allergen specific immunotherapy
   
   • Variable diagnostic utility of IDST and IgE ELISA
   • enzymoimmunometric assay inaccurate
   • Rush immunotherapy (RIT) has resulted in reduction in airway eosinophilia
     
     • Reductions have occurred even when allergens not inplicated in sensitization are used.
2. Omega 3 fatty acid with antioxidant luteolin
   
   • diminished airway hyper-responsiveness, but not airway eosinophilia
3. Inhaled lidocaine
   
   • decreased airway hyper-responsiveness in an experimental model
4. Tyrosine kinase inhibitors
5. Stem cells
   
   • May help reduce airway eosinophilia in the acute setting.
   • Commercially available stem cells have not been assessed

Question 22

Discuss the use of corticosteroids in the treatment of feline asthma

Answer 22

• Ongoing inflammation is expected despite variability and flutuation in clinical signs
• No prospective, controlled studies on oral corticosteroid use in spontaneous asthma!
  
  • Retrospective studies often document clincal improvement as sufficient for a positive response - not reduction in BALF eosinophilia or airway hyper-responsiveness
• Oral prednisolone, inhaled fluticasone, inhaled budesonide have all shown positive responses
• Inhaled budesonide - improved BWBP readings in naturally occurring asthma (Galler 2013)
  
  • 400 ug q 12 hour
  • 3/15 had HPPA suppression
• Fluticasone - 44 ug, 110 ug, 220 ug doses q 12 hours - equipotent (Cohn 2010)
  
  • no suppression of HPAA at either dosage

Question 23

Discuss the use of bronchodilators in the management of feline asthma

Answer 23

• Responsiveness to bronchodilators is a hallmark of the diagnosis of asthma
• Monotherapy is not recommended as the airway inflammation that contributes to hyper-responsiveness is not controlled
• Inhaled bronchodilators do not reduce the time to recovery from an early asthmatic reaction in an experimental model (Leemans 2009)
  
  • Therefore injectable terbutaline is often preferred in acute crisis and can be used long term
• Inhaled albuterol can reduce life threatening bronchoconstriction.
  
  • racemic mixture of R- and S-enatiomers with the S- version promoting bronchocontriction and having a longer half life.
  • Chronic use can worsen underlying airway inflammation
• Long acting Beta agonists are a mainstay of therapy