Immunologic Lung Diseases Flashcards
helper T lymphocytes
*important for:
-activation of macrophages
-inflammation
-activation of B lymphocytes
*2 types: Th1 and Th2
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
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
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)
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
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
asthma is what type of hypersensitivity reaction?
*type IV HSR (due to Th2 inflammation)
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
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
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
maintenance treatment for asthma
*identification and removal of triggers
*rescue/relief: short-acting bronchodilators
*maintenance: inhaled corticosteroids, plus long-acting bronchodilators
treatment of severe asthma
*biologic agents (anti-IL-5, anti-IL-13, anti-IgE, others)
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)
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)
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
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
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
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
hypersensitivity pneumonitis - chronic pathology
*dense fibrotic change
*may resemble UIP, with less honeycombing
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
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
- remove antibodies rapidly (plasmapheresis)
- 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
