000 Hypersensitivity Pneumonitis (HP) Introduction

Hypersensitivity – aka (extrinsic allergic alveolitis)

TCV 000: Hypersensitivity Pneumonitis (HP)

The Environmental Detective Work. Clinical diagnosis of Hypersensitivity Pneumonitis often requires playing detective. The patient presents with respiratory symptoms (cough, dyspnea) that may mimic pneumonia or asthma, but the key lies in the history. Is there a parakeet at home? Do they use a hot tub? Do they work with hay? The classic “aha” moment comes when symptoms improve during a vacation (away from the antigen) and recur upon returning home. Unlike asthma (IgE-mediated), HP is a complex immune reaction involving T-cells and IgG. Imaging often reveals the tell-tale “Headcheese Sign” (mixed density), and the primary treatment is not just medication, but strict antigen avoidance.

Title	Details
Definition	Primary Definition: An immune-mediated granulomatous interstitial lung disease caused by repeated inhalation of and sensitization to a wide variety of organic dusts/antigens. Classification: Interstitial Lung Disease (ILD); specifically an Inhalational Lung Disease (distinct from Pneumoconiosis). Salisbury ML, Am J Respir Crit Care Med 2017 — PubMed Link
Cause	Etiology: Inhalation of organic antigens (bacteria, fungi, animal proteins). Specific Associations: “Bird Fancier’s Lung” (avian proteins), “Farmer’s Lung” (moldy hay/actinomycetes), “Hot Tub Lung” (Mycobacterium avium complex). Selman M, Am J Respir Crit Care Med 2012 — PubMed Link
Pathophysiology	Mechanism: Combined Type III (Immune Complex) and Type IV (T-cell mediated/Delayed) hypersensitivity reaction. Functional Consequence: Lymphocytic inflammation of the alveoli and bronchioles leading to gas exchange abnormalities and potentially irreversible fibrosis. Costabel U, Eur Respir J 2020 — PubMed Link
Structural Result	Morphology: Poorly formed non-necrotizing granulomas (loose clusters of giant cells) centered on the bronchioles. Compartment: Bronchiolocentric (involving the secondary lobule center) and Interstitial. Takemura T, Semin Respir Crit Care Med 2008 — PubMed Link
Clinical Features	Acute: Flu-like symptoms (fever, chills, cough) occurring 4–8 hours after heavy exposure. Chronic: Insidious onset of progressive dyspnea, fatigue, and weight loss (often mimics IPF). Lacasse Y, Lancet Respir Med 2021 — PubMed Link
Imaging	Key Diagnostic Features: Centrilobular ground-glass nodules (soft, fluffy) and mosaic attenuation (air trapping) on expiratory CT. Discriminator: The “Headcheese Sign” (combination of ground-glass opacity, normal lung, and air trapping) is highly suggestive of the fibrotic/chronic phase. Hirschmann JV, Radiographics 2009 — PubMed Link
Labs / Physiology	Serology: Positive serum precipitins (IgG antibodies) against specific antigens (e.g., Pigeon, Aspergillus). BAL: Lymphocytosis (>20–30%) with a low CD4/CD8 ratio (often <1.0), unlike Sarcoidosis. Meyer KC, Am J Respir Crit Care Med 2012 — PubMed Link
Treatment	First-line: Complete antigen avoidance (crucial for recovery). Pharmacologic: Systemic corticosteroids for symptomatic acute/subacute disease; antifibrotics (nintedanib) for progressive fibrotic HP. Raghu G, Am J Respir Crit Care Med 2020 — PubMed Link
Prognosis	Course: Excellent if antigen is identified and avoided early. Poor Factors: Continued exposure or development of fibrosis (fibrotic HP has a survival rate similar to IPF). Fernández Pérez ER, Am J Respir Crit Care Med 2013 — PubMed Link

Comparison: Acute vs. Chronic Hypersensitivity Pneumonitis (HP)

Note on LFTs: In this context, “LFTs” refers to Lung Function Tests (PFTs), specifically Spirometry and Diffusion Capacity (DLCO).

Feature	Acute / Inflammatory HP	Chronic / Fibrotic HP
Clinical Tempo	Abrupt onset (4–8 hours post-exposure). Recurrent “Flu-like” attacks (fever, chills, cough).	Insidious, slow progression over months or years. Often misdiagnosed initially as IPF or COPD.
History of Exposure	Intermittent, heavy antigen exposure (e.g., cleaning a pigeon coop once a week).	Continuous, low-level antigen exposure (e.g., one parakeet in the home, down comforters).
Reversibility	High: Symptoms and findings typically resolve completely with antigen avoidance.	Low: Lung damage is often permanent (fibrosis); goal is to stop progression.
Pathology	Cellular bronchiolitis. Poorly formed, non-necrotizing granulomas.	Fibrosis (collagen deposition). Bridging fibrosis and architectural distortion.

Deep Dive: Imaging & Lung Function (LFTs/PFTs)

Feature	Acute / Inflammatory HP	Chronic / Fibrotic HP
CT Pattern (Primary)	Ground-Glass Opacities (GGO): Bilateral, diffuse, or patchy haziness. Centrilobular Nodules: Soft, fluffy nodules (not solid) in the center of the secondary lobule.	Reticulation: Coarse lines indicating fibrosis. Volume Loss: Shrinking of the lungs due to scarring. Traction Bronchiectasis: Airways pulled open by scar tissue.
Key Radiological Sign	“Mosaic Attenuation”: Patchy areas of air trapping (dark) mixed with GGO (bright) on expiratory scans.	“Headcheese Sign”: A complex mix of three densities: Normal lung (Gray) Ground-glass inflammation (White) Air trapping/Cysts (Black)
Distribution	Diffuse or slightly lower-lobe predominant. Homogeneous texture.	Mid-to-Upper Lobe Predominance (often spares the extreme bases, unlike IPF). Heterogeneous texture.
Lung Function (PFTs)	Pattern: Restrictive (Reduced FVC, TLC). Diffusion (DLCO): Mildly reduced. Reversibility: PFTs often return to normal after antigen removal.	Pattern: Severe Restriction (Markedly reduced FVC). Diffusion (DLCO): Severely reduced (Hallmark of vascular destruction). Obstruction: May see mixed restriction/obstruction due to airway fibrosis.
Hypoxemia	Present during attacks or exertion. Improves with rest and steroids.	Chronic hypoxemia. Often requires permanent supplemental oxygen.

Hypersensitivity Pneumonitis is a disease that most commonly affects the midlung field Next in frequency are the upper lung field and lastly diffuse involvement. Anatomically the small airways and the alveoli are affected with inflammation and granulomas are present
Ashley Davidoff MD TheCommonvein.net lungs-0732b01

A normal bronchiole usually 1mm or less in diameter. The wall consists of ciliated cuboidal epithelium and a layer of smooth muscle. Bronchioles divide into even smaller bronchioles, called terminal bronchioles, which are 0.5 mm or less in diameter and are primarily lined by club cells, and accompanied by a small number of ciliated cuboidal cells.. Respiratory bronchioles are the final division of the bronchioles within the lung and they are .5mm or less in diameter and contain a simple non ciliated cuboidal epithelium and a thin layer of smooth muscle
Ashley Davidoff MD TheCommonVein.net lungs-0721

Smoking excites the Langerhans cell which in turn induces and attracts early cellular interstitial infiltrates which surround the bronchiole. The diagram shows a bronchiole surrounded by an acute cellular inflammatory response
Ashley Davidoff MD TheCommonVein.net lungs-0722

=
- Alveolitis
- Cellular Bronchiolitis
- Granulomas
- acute, subacute, and chronic/fibrotic
- Immune reaction – inflammation to an
- allergen
  - protein
    - microbe
    - animal protein
    - plant protein
    - hapten = low molecular wt protein combining with host protein becomes immunogenic
  - Smoking
    - 95% of pts with HP are non smokers
    - 5% smokers with HP have a high mortality
- Pneumonitis –
- Terminal bronchiole and alveoli
Nutshell Buzz
- Airway Thickening
- Alveolitis
Acute stage
- - - Diffuse Alveolar Damage
      - Increased permeability
      - Neutrophils
      - neutrophillic exudate
        
        air space opacity
        
        GGO
        
        consolidation
      - Exudate
        
        Fill Alveoli
        Early Events in the Pathophysiology of the ARDS
        The initial injury results in an acute severe inflammatory response consisting hyperemia , edema with migration initially of neutrophils in the first 6-24 hours followed by monocytes (24-48hours). The intra -alveolar macrophages are activated.
        Ashley Davidoff
        TheCommonVein.net
        
        Result of Cellular Response
        The cells of the immune system release cytokines, chemotactic agents and proteases. Immune cells , macrophages and fibroblasts are attracted to the interstitium. Some of proinflammatory agents are toxic to the cell lining causing damage to the surfactant, type 1 pneumocytes and the capillary endothelium. There is progressive edema.
        Ashley Davidoff
        TheCommonVein.net
        
        Result of Cellular Response and Associated Tissue Injury
        The damage to the endothelium of the capillary results in bleeding into the alveoli. The severe tissue damage and fluid exudation results in protein rich intra-alveolar fluid . The fibroblasts start to lay down collagen as part of the early repair process
        Ashley Davidoff
        TheCommonVein.net
        
        Hyaline Membrane
        A hyaline membrane evolves covering the damaged surface of the alveolus. This impedes gas exchange
        Ashley Davidoff
        TheCommonVein.net
        
        Exudative Diffuse Alveolar Damage (DAD) in early ARDS. Comparison between ARDS and normal lung tissue demonstrates the presence of alveolar collapse, neutrophil infiltration, areas of microscopic hemorrhage, hyaline membrane formation and alveolar edema in ARDS. Histopathology images were adapted and reproduced under Creative Commons licenses: ARDS histopathology component by Nephron (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons; and Normal lung alveoli component By Jpogi —Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=46568489.
        
        Acute exudative phase of diffuse alveolar damage with prominent hyaline membranes (DAD)
        Courtesy Dr Yale Rosen
        
        The Fluid in the Alveoli Can Result in
- Radiology
  - GGO’s
  - Consolidation
    - Position
      - bilateral
        
        midlung >upper lung >diffuse
        
        only lower lungs does not happen
    - Shape
      - Ill defined
      - Patchy and or
      - Nodular Infiltrates

Bird Fanciers Disease
Acute Hypersensitivity Pneumonitis
Upper and Mid Lung Field

Mild Ground Glass Changes
Acute Hypersensitivity Pneumonitis
54-year-old female who keeps parakeets present with mild dyspnea
Chest CT shows mild ground glass changes in the mid and upper lung fields consistent with acute hypersensitivity pneumonitis (HP)
Ashley Davidoff TheCommonVein.net 136571

- - - - Nodular
        
        Aspiration Pneumonia Pulmonary Edema and DAD
        54 year old male alcoholic with seizures presents with diffuse alveolar disease consistent with pulmonary edema (a). CT scan (b) shows bibasilar infiltrates consistent with aspiration.
        Follow up CXR 6 months later (c) shows resolution
        Ashley Davidoff MD TheCommonVein.net
- Non Fibrotic = Subacute Phase
  - Structurally
    - Small Airways
      - Poorly Defined Ground Glass Nodules
    - Alveoli – Alveolitis =
      - Mosaic Attenuation
    - Combined Small Airway and Alveoli
      - 3 density sign = head cheese sign
  - Disease
    - Inflammation
      - Cellular Infiltrate and Edema
        
        Around Bronchioles
        
        Bronchiolitis = Cellular Bronchiolitis
        
        Smoking excites the Langerhans cell which in turn induces and attracts early cellular interstitial infiltrates which surround the bronchiole. The diagram shows a bronchiole surrounded by an acute cellular inflammatory response
        Ashley Davidoff MD TheCommonVein.net lungs-0722
        
        Around Alveoli =
        
        Alveolitis –
        
        Inflamed Alveoli
        Ashley Davidoff MD TheCommonvein.net lungs-0021
        
        Inflammation in the Wall of the Alveoli = Interstitial Infiltrate
        
        High magnification photomicrograph of a lung biopsy taken showing chronic hypersensitivity pneumonitis (H&E), showing mild expansion of the alveolar septa (interstitium) by lymphocytes.[clarification needed] A multinucleated giant cell, seen within the interstitium to the right of the picture halfway down, is an important clue to the correct diagnosis.
        Courtesy Wikiwand web lungs 435
      - Granulomas around the bronchiole or arteriole
      - Impinging on the Lumen of a Centrilobular Bronchiole
      - Granuloma Impinges on the lumen of the centrilobular bronchiole The peri- bronchiole inflammation has receded in this subacute to chronic phase
        Ashley Davidoff MD TheCommonVein.net lungs-0729
        
        Granulomas around the bronchiole or arteriole
        
        Occluding the Lumen of a Centrilobular Bronchiole
        
        Granuloma occludes the lumen of the centrilobular bronchiole and the peri-bronchiole inflammation has receded in this subacute to chronic phase
        Ashley Davidoff MD TheCommonVein.net lungs-0731
- Diagnosis
  - Mid Lung Fields> Upper Lung Fields > Diffuse
  - Bronchiolitis
  - Alveolitis
    - GGO
      - Patchy
  - Granulomas
    - Nodules
  - GGO
  - reticlonodular
- Reticulation
- Ground Glass
- Heterogeneous
- Lobular sparing air trapping mosaic attenuation
- Head Cheese Sign

Head cheese or brawn is a cold cut terrine or meat jelly, often made with flesh from the head of a calf or pig (less commonly a sheep or cow), typically set in aspic, that originated in Europe. Usually eaten cold, at room temperature, or in a sandwich, the dish is, despite the name, not a dairy cheese. The parts of the head used in the dish vary, though commonly do not include the brain, eyes or ears of the animal. The tongue, and sometimes the feet and heart of the animal may be included; the dish is also made using trimmings from more commonly eaten cuts of pork and veal, with the addition of gelatin as a binding agent. Head cheese may also be made without using the flesh from the head of an animal.
Courtesy Rainer Zenz source Wiki

Structural focus

A normal bronchiole usually 1mm or less in diameter. The wall consists of ciliated cuboidal epithelium and a layer of smooth muscle. Bronchioles divide into even smaller bronchioles, called terminal bronchioles, which are 0.5 mm or less in diameter and are primarily lined by club cells, and accompanied by a small number of ciliated cuboidal cells.. Respiratory bronchioles are the final division of the bronchioles within the lung and they are .5mm or less in diameter and contain a simple non ciliated cuboidal epithelium and a thin layer of smooth muscle
Ashley Davidoff MD TheCommonVein.net lungs-0721

Normal Small Airways

The Acinus,
The Duct, and the Artery
The pulmonary arteriole accompanies the airway as it carries oxygen from the trachea to the alveoli. They part ways at the alveoli where the pulmonary venule then takes the oxygenated blood from capillary network around the alveoli back to the left atrium.
The intimate relationship of the airways and the pulmonary artery and their close approximation in size, is helpful in radiology, firstly to identify theese structures and secondly to define disease such as heart failure and bronchiectasis.
The acinus as shown in this image is defined as a unit of lung consisting of a single first order respiratory bronchiole that subtending a cluster of alveoli reminiscent of a bunch of grapes or berries (acinus in Latin means berry) . The lobular bronchiole (lb) branches into the terminal bronchiole (tb), which then branches into the first order respiratory bronchiole (rb). Subsequent branching after the respiratory bronchiole, includes in order, the alveolar duct (ad), alveolar sac (as), and then finally the berry like alveoli.
Courtesy Ashley Davidoff 2019
lungs-0033-low res

Respiratory Bronchioles
This slide shows the transition from a terminal bronchiole, with a low cuboidal epithelium, to respiratory bronchioles, with a squamous epithelium. Terminal bronchioles are last generation of conducting airways.
Respiratory bronchioles can be identified by the presence of some alveoli along their walls. The respiratory bronchiole splits into a number of alveolar ducts, which terminate in alveolar sacs and individual alveoli
Courtesy medcell.med.Yale.edu

Non-specific severe chronic inflammation of a terminal bronchiole.
Courtesy Dr Yale Rosen

The Alveolus –
The Buck Ends Here
The alveolus is lined by a simple epithelium – one cell layer thick. There are two types of lining cells; Type 1 pneumocytes are squamous cells that cover 90% of the surface of the inner lining of the lung , and type II cuboidal pneumocytes that are in fact much more numerous than Type I. They are involved in the production of surfactant . In the lumen there are resident macrophages which play a crucial role in the immune system. The mucosa is grounded by a basement membrane and a lamina propria, and connected to the lamina propria and basement membrane of the surrounding capillary. The alveolus is lined by a thin layer of surfactant. (teal blue)
Ashley Davidoff
TheCommonVein.net

Magnification of Normal Histology of the Lung
Lower magnification of the lung with H and E stain shows cup-shaped alveolar spaces outlined by delicate thin alveolar capillary membrane.
key words
lung, pulmonary, normal alveolus, alveoli, histology, interstitium, interstitial
Courtesy Armando Fraire MD. 32819

High magnification photomicrograph of a lung biopsy taken showing chronic hypersensitivity pneumonitis (H&E), showing mild expansion of the alveolar septa (interstitium) by lymphocytes.[clarification needed] A multinucleated giant cell, seen within the interstitium to the right of the picture halfway down, is an important clue to the correct diagnosis.
Courtesy Wikiwand
web lungs 435

Acute

Abrupt onset
Flu like symptoms
malaise

Note

patients with fibrotic HP often overlap with those described in patients with idiopathic interstitial pneumonias – UIP and NSIP

distinction between
- IPF and an inflammation-driven disorder such as fibrotic HP
- is crucial, because
  - immunosuppressive therapy is considered to be harmful in IPF
  - appropriate in fibrotic HP.
- On the other hand
  - anti-fibrotic treatment licensed for IPF,
  - not for fibrotic HP.