Immunologic Lung Diseases Flashcards by Kyra Porter

helper T lymphocytes

*important for:
-activation of macrophages
-inflammation
-activation of B lymphocytes
*2 types: Th1 and Th2

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Th1 cells

*defining cytokine(s): IFN-gamma
*principles targets: macrophages
*major immune reactions: macrophage activation
*host defense: intracellular pathogens
*role in disease: autoimmunity; chronic inflammation

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Th2 cells

*defining cytokine(s): IL-4, IL-5, IL-13
*principles targets: eosinophils
*major immune reactions: eosinophil & mast cell activation; alternative macrophage activation
*host defense: helminths
*role in disease: allergy

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hypersensitivity reactions (HSR) - big picture

*4 types: ACID
-type I HSR: Anaphylactic & Atopic
-type II HSR: Cytotoxic (antibody-mediated)
-type III HSR: Immune complex
-type IV HSR: Delayed (cell-mediated)

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asthma - general

*a disease of airway smooth muscle and hyperresponsiveness
*2 presentations:
1. early onset (childhood) asthma:
-ALLERGIC asthma
-atopy often present
2. late onset (adulthood) asthma:
-typically more severe than childhood asthma
-allergic and non-allergic
-Th2-high (most people) or Th2-low phenotypes

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clinical presentation of asthma

*chronic symptoms - due to Th2 inflammation (type IV HSR):
-wheezing, shortness of breath
-nocturnal occur
-sometimes exercise-induced or cough-variant
-environmental triggers (allergens such as pollen, animal dander, odors, etc)

*acute exacerbations - due to type 1 HSR:
-immediate phase: IgE cross-linking, mast cells, histamine release
-delayed phase: recruitment and activation of Th2 cells, eosinophils, basophils, and neutrophils

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asthma is what type of hypersensitivity reaction?

*type IV HSR (due to Th2 inflammation)

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an acute exacerbation of asthma is what type of hypersensitivity reaction?

type 1 HSR
*2 phases:
-immediate phase: IgE cross-linking, mast cells, histamine release
-delayed phase: recruitment and activation of Th2 cells, eosinophils, basophils, and neutrophils

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pathophysiology of type 1 hypersensitivity reactions

initial allergen exposure (IL-4 and IL-13) → IgE production → IgE binds to mast cells → allergen cross-link IgE on mast cells → mast cells release mediators (degranulate) on second exposure (histamine, PGE, LT, PAF, cytokines) → early phase effects and promotion of last phase response

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treatment of asthma exacerbation

address immediate phase (type 1 HSR):
-short acting bronchodilators
-IV magnesium
address delayed phase (type 2 HSR):
-systemic corticosteroids for 1-2 weeks

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maintenance treatment for asthma

*identification and removal of triggers
*rescue/relief: short-acting bronchodilators
*maintenance: inhaled corticosteroids, plus long-acting bronchodilators

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treatment of severe asthma

*biologic agents (anti-IL-5, anti-IL-13, anti-IgE, others)

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allergic bronchopulmonary aspergillosis (ABPA) - clinical presentation

*asthma with peripheral blood eosinophilia
*central BRONCHIECTASIS and coughing of brown mucus plugs
*“FINGER IN GLOVE” change in bronchiectasis (mucus filling the bronchiectatic airway)
*allergic fungal sensitivity:
-high total IgE
-specific IgE to Aspergillus (serum or skin-prick testing)

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allergic bronchopulmonary aspergillosis (ABPA) - immunology

*a type IV Th2 hypersensitivity disease
*exaggerated response to fungal antigens (typically Aspergillus fumigatus)
*influx of eosinophils and mast cells, increase in IgE
*like asthma, has an immediate phase response (IgE) and delayed phase (IgG, IgA)

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allergic bronchopulmonary aspergillosis (ABPA) - treatment

*conventional treatment for the patient’s asthma
*systemic steroids (prednisone) tapering over 3-12 months
*sometimes, antifungal therapy is added (itraonazole); but note, this is not an infection with aspergillus, but rather an allergic reaction to it

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hypersensitivity pneumonitis - general

*spectrum of granulomatous, interstitial, bronchiolar, and alveolar filling lung disease
*caused by repeated exposure and sensitization to organic aerosol and low molecular weight chemical antigens
*antigens can be divided into several categories: microbial, animal protein, chemical sanitizers

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clinical presentation of hypersensitivity pneumonitis

*acute phase:
-4 to 12 hours after exposure to a previously sensitized antigen
-abrupt onset of fever, chills, dyspnea, cough, myalgias, and malaise
-decreased pulse ox
-leukocytosis
-chest imaging with nodular opacities
-CT = centrilobular nodules, representing active alveolitis
-PFT may be normal or RESTRICTIVE

*subacute phase: add weight loss, fatigue

*chronic phase: irreversible fibrotic change begins, can be disabling

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hypersensitivity pneumonitis - acute/subacute pathology

*POORLY FORMED INTERSTITIAL GRANULOMAS and marked LYMPHOCYTIC INFLAMMATION
-can appear similar to NSIP, distinguished by the presence of granulomas, and exposure history

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hypersensitivity pneumonitis - chronic pathology

*dense fibrotic change
*may resemble UIP, with less honeycombing

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immunology of hypersensitivity pneumonitis

*Th1 polarization (IFN-gamma and IL-12)
*mainly type IV HSR
*lymphocytosis (CD4/CD8 ratio < 1, indicating high CD8 infiltrate)
*neutrophilia
*precipitating IgG antibodies to the offending agent

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treatment of hypersensitivity pneumonitis

avoid repeat exposure to the antigen (systemic steroids if necessary)

granulomatosis with polyangiitis (GPA) - general

*formerly known as Wegener granulomatosis
*triad: necrotizing granulomatous inflammation, necrosis, and small vessel vasculitis
*usually involves some kind of SINUSITIS/PERFORATED NASAL SEPTUM
*affects the upper and lower airways
*kidney involvement is common (Pulmonary-Renal syndrome)
*aberrant cell-mediated response to exogenous or endogenous antigen

granulomatosis with polyangiitis (GPA) - clinical presentation

*general: fever, fatigue, arthralgias
*upper airway:
-paranasal sinus pain
-purulent drainage
-bloody nasal discharge
-nasal mucosal ulceration
-septal perforation
-SADDLE NOSE DEFORMITY
-ABSENCE OF NASAL SEPTUM
*lower airway:
-HEMOPTYSIS
-COUGH
-DYSPNEA
-chest discomfort

granulomatosis with polyangiitis (GPA) - immunology

*positive c-ANCA (anti-proteinase-3)
*Th1/Th17 pattern of cytokine production (IFN-gamma, IL-12, TNF, IL-17)
*neutrophilic production of reactive oxygen species

which condition has a positive c-ANCA

granulomatosis with polyangiitis (GPA) note - c-ANCA is anti-PR3

granulomatosis with polyangiitis (GPA) - diagnosis

*necrotizing granulomatous inflammation with vasculitis *c-ANCA positive (anti-PR3 positive)

granulomatosis with polyangiitis (GPA) - treatment

*intensive immunosuppression: -cyclophosphamide & high dose glucocorticoids initially -ongoing methotrexate or azathioprine

eosinophilic granulomatosis with polyangiitis (EGPA) - general

*formerly known as Churg-Strauss disease, or Allergic Angiitis *triad of findings: 1. asthma (+/- allergic rhinitis) 2. allergic ganulomatosis 3. vasculitis

eosinophilic granulomatosis with polyangiitis (EGPA) - clinical presentation

*general: fever, malaise, anorexia *pulmonary: -**asthma** precedes vasculitis -lung parenchyma is involved -peripheral pulmonary infiltrates -lung nodules -granulomatous mass lesions *EXTRAPULMONARY: -mononeuritis multiplex -heart disease -eosinophilic gastroenteritis or mesenteric vasculitis -renal disease

eosinophilic granulomatosis with polyangiitis (EGPA) - diagnosis

*peripheral blood eosinophilia *elevated ESR *positive p-ANCA (anti-MPO) *BIOPSY showing EOSINOPHILIA and vasculitis

which condition has a positive p-ANCA

eosinophilic granulomatosis with polyangiitis (EGPA)

eosinophilic granulomatosis with polyangiitis (EGPA) - immunology

*eosinophilia *Th2 disease (IL-4, IL-5, IL-13) *p-ANCA (myeloperoxidase)

eosinophilic granulomatosis with polyangiitis (EGPA) - pathology

*necrotizing granulomatous inflammation (allergic granuloma) *tissue infiltration by eosinophils *small vessel vasculitis: -fibrinoid necrosis -eosinophilic infiltrate -granuloma formation adjacent to vessel

eosinophilic granulomatosis with polyangiitis (EGPA) - treatment

*target Th2 response and eosinophils: -glucocorticoids -mepolizumab (anti-IL-5) -rituximab (anti-CD20)

anti-glomerular basement membrane disease (anti-GBM) - general

*formerly known as Goodpasture syndrome *anti-glomerular basement membrane antibodies, diffuse pulmonary hemorrhage, and glomerulonephritis

what disease is associated with this?

anti-glomerular basement membrane disease (anti-GBM)

clinical presentation of anti-glomerular basement membrane disease (anti-GMB)

*smoking is a risk factor *dyspnea *hemoptysis *cough *fatigue

anti-glomerular basement membrane disease (anti-GMB) - initial testing

***POSITIVE anti-GBM SERUM ANTIBODIES** *25-35% are ANCA positive *restrictive lung disease *KIDNEY BIOPSY is diagnostic (see image)

anti-glomerular basement membrane disease (anti-GMB) - immunology

*type II hypersensitivity ***autoantibody to glomerular basement membrane: -collagen type IV** -cryptic epitope -IgG1 and IgG4 -activation of complement -recruitment of neutrophils and macrophages -collage type 4 specific CD4 T cells

anti-glomerular basement membrane disease (anti-GMB) - histology

*all have glomerulonephritis *50-80% have alveolar hemorrhage *pathology: -kidney biopsy: crescentic glomerulonephritis, **linear staining for IgG and complement** (see image) -lung biopsy: neutrophilic capillaritis, hemosiderin-laden macrophages, hyperplasia of type II pneumocytes, alveolar interstitial thickening

anti-glomerular basement membrane disease (anti-GMB) - treatment

1. remove antibodies rapidly (plasmapheresis) 2. reduce production of antibodies (prednisone, oral cyclophosphamide)

sarcoidosis - general

*a disorder of granulomatous inflammation *most commonly affects the lung, but can affect any organ *a challenging diagnosis to make (a diagnosis of exclusion) *many patients do not require treatment, and yet some will develop severe disabling disease

sarcoidosis - clinical presentation

*can present in many ways *asymptomatic BILATERAL HILAR LYMPHADENOPATHY (BHL) (see image) *lupus pernio *LOFGREN SYNDROME = fever + erythema nodosum + BHL *PFTs, when abnormal, typically are RESTRICTIVE and can include reduced diffusing capacity

sarcoidosis - immunology

*Th1 response with granulomatous inflammation *the inciting agent is unknown *non-necrotizing granulomas can form in any organ (lung is most common)

sarcoidosis - classic lab findings

*hypercalcemia *elevated angiotensin-converting enzyme (ACE) level in blood

sarcoidosis - histology

*non-necrotizing granulomatous inflammation ***well-formed "tight" granulomas** *multinucleated giant cells *asteroid bodies or Schaumann bodies *absence of acid-fast bacilli *negative cultures for organisms

sarcoidosis - treatment

*if asymptomatic, treatment not needed *symptomatic patients or high-risk organ involvement (heart, brain, eye): -systemic steroids -methotrexate -infliximab

chronic granulomatous disease (CGD) - general

*a disorder of innate immunity *rare *X-linked (in most cases)

chronic granulomatous disease (CGD) - clinical presentation

*typically children around 4 years of age *recurrent bacterial or fungal infections and granulomatous inflammation: -abscesses, hepatomegaly, lymphadenopathy, scaly rash -invasive aspergillosis is a frequent cause of death *high mortality if unrecognized, or without aggressive antimicrobial therapy

chronic granulomatous disease (CGD) - immunology

*mutation affects the PHOX membrane protein, part of **NADPH oxidase** *defective production of ROS **so failure to create the "oxidative burst" use in host defense** *inability to clear infections, which stimulates a Th1 response: -results in extensive granuloma formation

chronic granulomatous disease (CGD) - treatment

*early antibiotic treatment for any infection *treatment with IFN-gamma therapy may improve superoxide production