CONTENTS

• Physical examination:
  • Wheeze
  • Stridor
  • Clubbing
• Bronchoalveolar lavage (BAL)
  • Lymphocytic
    • CD4/CD8 ratio
  • Neutrophilic
  • Eosinophilic ➡️
  • Mixed cellularity
  • Foamy macrophages
  • Hemosiderin-laden macrophages
  • Atypical hyperplastic type-II pneumocytes
• Questions & discussion

abbreviations used in the pulmonary section: 8

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid-fast bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• CF: Cystic fibrosis 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground-glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OHS: Obesity hypoventilation syndrome 📖
• OP: Organizing pneumonia 📖
• OSA: Obstructive sleep apnea 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans cell histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: Tumor necrosis factor
• UIP: Usual interstitial pneumonia 📖

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wheeze

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definition

• Wheeze is a musical sound that is generally louder on expiration.
• Wheeze generally requires a stethoscope to hear. If loud noises are grossly audible from across the room, these are more likely to represent stridor.

differential diagnosis includes:

• Intrathoracic upper airway lesion:
  • Tracheal stenosis.
  • Foreign body aspiration.
  • Benign or malignant tumors.
  • Tracheobronchomalacia.
• Lower airway:
  • Asthma, COPD.
  • Anaphylaxis.
  • Pulmonary edema (“cardiac wheeze”).
  • Pulmonary embolism.
  • Bronchiectasis (including cystic fibrosis).
  • Aspiration.
  • Bronchiolitis.

initial diagnostic approach

• Clearance after coughing: Suggests causation by airway secretions.
• Focal wheeze suggests endobronchial tumor, aspirated foreign body, mucus plug, or congenital anomaly. (Murray 2022) Focal wheeze is often monophonic (unlike polyphonic wheezing, which would be more consistent with a diffuse process such as asthma or COPD). (ERS handbook 3rd ed.)
• Mid-to-late inspiratory squeak: May suggest bronchiolar diseases (e.g., hypersensitivity pneumonia, bronchiolitis obliterans, or infectious bronchiolitis). (Murray 2022; ERS handbook 3rd ed.)

additional diagnostic tests

• Pulmonary function tests may help evaluate for airway obstruction of the small or large airways.
• CT scan may help evaluate for a range of pathologies involving the large or small airways.
  • Dynamic CT with inspiratory and expiratory imaging may assist in the diagnosis of small airway disease.
  • CT angiography may be required if the diagnosis of pulmonary embolism is a concern.

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stridor

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definition

• Stridor is a high-pitched sound heard synchronously with breathing, without a stethoscope.

clinical significance of stridor

• Stridor indicates a severe narrowing of the upper airway. To cause stridor at rest, the airway is usually profoundly narrowed (<5 mm).
• Stridor is usually louder on inspiration (inspiratory stridor), but not always: (ERS handbook 3rd ed.)
  • Inspiratory stridor suggests a variable obstruction of the extrathoracic airway (larynx or upper trachea). Stridor is louder on inspiration because negative pressure within the extrathoracic airway tends to pull the airway closed.
  • Expiratory stridor suggests a variable obstruction within the intrathoracic airway.
• 🛑 Stridor should generally be regarded as a medical emergency (unless it is known to be chronic).

common causes of stridor

• Foreign body aspiration.
• Vocal cord dysfunction.
• Laryngospasm.
• Laryngeal edema:
  • Angioedema.
  • Anaphylaxis.
  • Post-extubation laryngeal edema.
• Infection:
  • Epiglottitis.
  • Retropharyngeal or peritonsillar abscess.
  • Deep neck space infection (e.g., Ludwig angina).
• Tumor or chronic stenotic lesions, e.g.:
  • Goiter causing compression of the trachea.
  • Upper airway tumor.
  • Tracheal stenosis.
• Vocal cord paralysis.

bedside evaluation for additional findings:

• Glottic involvement suggested by:
  • Hoarseness or altered voice.
  • Inability to swallow; spontaneously drooling saliva.

evaluation

• Immediate bedside nasolaryngoscopy or bronchoscopy is the preferred approach if there is concern for acute pathology. This allows for evaluation of the etiology of stridor and planning regarding treatment and airway management.
• CT scan of the neck and thorax may be considered for patients with chronic or subacute stridor, who are not in respiratory distress.
• 🛑 Proceeding directly to rapid-sequence intubation may be dangerous, as patients may have anatomic lesions which render intubation difficult. If intubation is required, awake intubation including a double-setup is preferred (with immediate capability of performing a surgical airway should intubation fail).

management

• Management should ideally be directed towards a specific underlying etiology (e.g., anaphylaxis).
• Inhaled heliox is often an effective temporizing measure that may improve patient comfort and reduce the work of breathing (to buy time while gathering materials and personnel to proceed further in a controlled fashion). If heliox isn't available, CPAP or BiPAP may be used as a short-term approach to prevent inspiratory collapse of the upper airway.
• When in doubt, nebulized racemic epinephrine may be reasonable as a short-term supportive measure while urgently pursuing the etiology of the stridor.

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clubbing

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basics

• Clubbing may be stimulated by various angiogenic factors that result from pulmonary infection/inflammation, or shunting of blood past the liver or lungs.
• Clubbing can develop within two weeks among patients with new-onset empyema and it may reverse within a similar time frame. (Murray 2022) Although clubbing is generally a sign of chronic disease, it may be a stigmata of some subacute diseases as well.
• Clinical performance of clubbing:
  • Clubbing may be seen in ~1% of normal people, so patients should be asked whether this is a chronic or acute feature.
  • Among patients admitted to an internal medicine service, clubbing was associated with serious disease 40% of the time. Thus, new-onset clubbing warrants an appropriate investigation. (Murray 2022)

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clinical presentation

digital clubbing

• The angle between the nail and the cuticle is >190 degrees (hyponychial angle).

hypertrophic osteoarthropathy

• The same processes that cause clubbing may additionally cause hypertrophic osteoarthropathy. This is usually seen together with clubbing, but it can rarely occur without clubbing.
• Symptoms:
  • Joint pain involving the shoulders, wrists, knees, and/or ankles (which may be accompanied by joint effusions).
  • Erythema and edema of the overlying skin.
• Hypertrophic osteoarthropathy may be associated with subperiosteal bone formation on plain film, especially seen in the radius and ulna, or tibia and fibula (figure below).
• Technetium-99m bone scan is the most sensitive test for hypertrophic osteoarthropathy (since the radioisotope will be concentrated in areas of new bone formation). PET scanning will usually show hypermetabolic activity, but it's not as sensitive or specific as a technetium-99m bone scan.

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causes of generalized clubbing

lung disease

• Lung cancer:
  • Most common cause of clubbing.
  • Primary lung cancer is more often involved than pulmonary metastases (usually non-small cell lung cancer).
• Chronic infection:
  • Bronchiectasis (including cystic fibrosis).
  • Lung abscess.
  • Tuberculosis.
  • Fungal infection.
• Interstitial lung diseases:
  • Idiopathic pulmonary fibrosis (most commonly).
  • HP (hypersensitivity pneumonitis).
  • Sarcoidosis.
  • Lipoid pneumonia.
  • Asbestosis.
  • PLCH (pulmonary Langerhans cell histiocytosis).
  • LIP (lymphoid interstitial pneumonia).

pleural disease

• Empyema.
• Mesothelioma.
• Benign asbestos pleural disease.

cardiovascular

• Right-to-left shunt, e.g.:
  • Intracardiac shunting.
  • Pulmonary arteriovenous malformations.
• Endovascular infection, e.g.:
  • Endocarditis.
  • Infected intravascular device.

gastrointestinal

• Cirrhosis (especially patients with hepatopulmonary syndrome).
• Inflammatory bowel disease.
• Gastrointestinal tumors. (32033661)

other

• Hereditary (chronic, genetic, clinically significant only as a red herring).
• Other thoracic neoplasms (e.g., thymoma, mediastinal tumors, esophageal cancer).
• Graves hyperthyroidism.
• Hematologic disorders: POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes), thalassemia.
• Prostaglandin infusion.
• PVOD/PCH (pulmonary vaso-occlusive disease/pulmonary capillary hemangiomatosis).

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investigation may include

• Chest CT scan.
• Echocardiography including bubble study.
• Liver function tests.

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bronchoalveolar lavage (BAL)

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Bronchoalveolar lavage (BAL) may be used as a diagnostic tool that provides information on the differential cell count as well as other abnormalities. The literature regarding precise sensitivity and specificity of this data is often limited. Consequently, BAL data should generally be considered as a general guide to the diagnosis, rather than as a tool to definitively exclude various diagnoses. If the fluid return is poor, then the BAL may be contaminated with bronchial cells (rather than alveolar cells), leading to unreliable results. (ERS handbook 3rd ed.)

normal BAL differential

• Macrophages: >80% (smoking will tend to increase the number of macrophages, thereby decreasing the percent of lymphocytes).
• Lymphocytes: <15%.
• Neutrophils: <3%.
• Eosinophils: <1%.
• Mast cells: <0.5%
• Plasma cells: 0%
• Epithelial cells:
  • Ciliated bronchial epithelial cells <5%.
  • Squamous epithelial cells: none or rare.

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lymphocytosis 

In the context of interstitial lung disease, BAL lymphocytosis often suggests a likelihood to respond to immunosuppressive therapy (e.g., steroid).

cutoff to define BAL lymphocytosis?

• Lymphocyte percent is normally <15%.
• BAL lymphocytosis might be roughly regarded as >30% in a nonsmoker or >20% in a smoker.
• Lymphocytes of ~15-25% may suggest a granulomatous disease (e.g., hypersensitivity pneumonitis or sarcoidosis). (BTS 2020 guidelines)
• Lymphocytes >50% suggests hypersensitivity pneumonitis or cellular NSIP (nonspecific interstitial pneumonia). (BTS 2020 guidelines)

causes of BAL lymphocytosis

• Granulomatous disease:
  • Sarcoidosis, berylliosis, Crohn disease.
  • GLILD (granulomatous and lymphocytic interstitial lung disease).
  • Hypersensitivity pneumonitis.
  • Silicosis. (ERS handbook 3rd ed.)
• Cellular NSIP (including some connective tissue disease-related interstitial lung diseases). (22550210)
• OP (organizing pneumonia).
• Drug-induced pneumonitis (including checkpoint inhibitors).
• Radiation pneumonitis.
• LIP (lymphocytic interstitial pneumonitis).
• Connective tissue disease-related interstitial lung disease. (36630775)
• Pulmonary lymphoma.
• Infection:
  • Viral pneumonia.
  • Tuberculosis.
  • HIV infection.

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CD4/CD8 ratio 

The utility of the CD4/CD8 ratio is unclear (specifically, in terms of the value that it adds to other diagnostic studies). However, this may be useful to sort out the cause of BAL lymphocytosis. If it is obtained, a rough guide to interpretation is below. (ERS handbook 3rd edition)

CD4/CD8 ratio decreased (<~1.5)

• More frequent:
  • HP (hypersensitivity pneumonia).
  • OP (organizing pneumonia).
  • Drug-induced pneumonitis (including checkpoint inhibitor pneumonitis), wherein CD4/CD8 ratio is usually <1. (36865931)
• Less frequent:
  • Silicosis.
  • HIV.

CD4/CD8 ratio normal (~1.5-2)

• Tuberculosis.
• Lymphangitic carcinomatosis.

CD4/CD8 ratio elevated (>~2)

• Sarcoidosis, chronic beryllium disease, Crohn disease:
  • CD4/CD8 ratio <1 argues strongly against a diagnosis of sarcoidosis.
  • CD4/CD8 ratio >3.5 may support a diagnosis of sarcoidosis.
  • CD4/CD8 ratio >4 in the absence of an increased proportion of other inflammatory cell types is >95% specific for sarcoidosis as compared to other inflammatory interstitial lung diseases. (BTS 2020 guidelines)
  • Further discussion of the BAL in sarcoidosis: 📖
• Some forms of HP (e.g., hot tub lung, farmer's lung).
• Asbestos-induced alveolitis.
• Alveolar proteinosis.
• Connective-tissue disorders.

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neutrophilic (+/- eosinophilic) 

cutoff to define neutrophilic BAL?

• Normally, neutrophils are <3%.
• Substantially >5% neutrophils is abnormal.
• If neutrophils are >50% this suggests suppurative infection or DAD (diffuse alveolar damage).

causes of elevated BAL neutrophils

• Bacterial infection.
• DAD (diffuse alveolar damage), including:
  • AIP (acute interstitial pneumonia).
  • Acute exacerbation of IPF.
• Other interstitial lung diseases:
  • IPF (idiopathic pulmonary fibrosis).
  • Fibrotic HP (hypersensitivity pneumonitis).
  • Fibrotic NSIP.
  • Organizing pneumonia.
  • DIP (desquamative interstitial pneumonia).
• Some drug-induced pneumonitis.
• Asbestosis.
• GPA (granulomatosis with polyangiitis).
• Diffuse panbronchiolitis.
• Bronchiolitis obliterans.

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mixed cellularity 

• Organizing pneumonia.
• NSIP.
• Connective tissue disorders.
• Drug-induced pneumonitis.
• Inorganic dust disease. (ERS handbook 3rd ed.)

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lipid-laden (“foamy”) macrophages 

definition

• Foamy macrophages are the histologic correlate of lipid-laden macrophages.
• Lipid-laden macrophages may also be identified using specific stains (e.g., oil red O).

causes of lipid-laden (foamy) macrophages

• Exogenous lipoid pneumonia.
• Endogenous lipoid pneumonia:
  • Endogenous lipoid pneumonia is not a specific disorder, but rather it is a feature of diseases wherein surfactant clearance is impaired. This term is sometimes applied broadly (e.g., including many of the disorders below, such as pulmonary alveolar proteinosis).
  • The most common cause is an obstructed bronchus, leading to breakdown of cell membranes distally, with the generation of endogenous lipoid material.
• Fat embolism.
• PAP (pulmonary alveolar proteinosis).
• Drug reactions (including amiodarone).
• Metabolic storage disorders, which cause multisystem accumulation of lipid-laden macrophages:
  • Niemann-Pick disease.
  • Gaucher disease.
  • Erdheim-Chester disease (multisystem infiltration of lipid-laden macrophages, associated with granulomatous inflammation and fibrosis). (33563460; 35809945, 29626972)
• OP (organizing pneumonia).
• Recurrent pneumonia, or cystic fibrosis.

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hemosiderin-laden macrophages 

• >20% hemosiderin-laden macrophages support a diagnosis of DAH (diffuse alveolar hemorrhage). This is discussed further here: 📖

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atypical hyperplastic type II pneumocytes 

• This suggests the diagnosis of DAD (diffuse alveolar damage).

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questions & discussion

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