Hypersensitivity Pneumonitis

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Hypersensitivity Pneumonitis

• Susan M. Rohr, D.O.
• October 26, 2006
• Sioux Valley Clinic Symposium
• Pulmonary, Critical Care, and Sleep Medicine

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Objectives

• Describe the clinical and radiographic
  presentation of Hypersensitivity Pneumonitis (HP)
• List environmental and occupational exposures
  that may trigger HP

3
HP

• Extrinsic Allergic Alveolitis
• Farmers Lung
• Humidifier Lung
• Pigeon Breeders Lung
• Bird Fanciers Lung
• Malt Workers Lung
• Hot Tub Lung
• And many many more..

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Not HP

• Silo Fillers Disease
• Acute toxic lung injury due to inhalation of
  nitrogen dioxide.
• Organic Dust Toxic Syndrome
• Inflammatory pneumonitis produced by endotoxin,
  mycotoxin, and spores when a massive dose of
  organic dust is inhaled.
• Metal Fume Fever
• Related to exposure to zinc oxide
• Ornithosis
• Infectious disease from Chlyamydia psittaci
  related to exposure to contaminated droppings.

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HP

• Recognized as early as 1713
• By Ramazinni
• Wheat reapers
• Associated with a number of organic Ag
• Animal products
• Plant products
• Aerosolized microorganisms
• Organic chemicals
• And probably other antigens

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HP

• Epidemiology
• 5-15 of exposed population develop disease
• Surge on the verge?
• 95 of patients are NON-Smokers
• Decreased co-stimulatory molecules on cell
  surface of alveolar macrophages of smokers
• Smokers with HP have poorer 10 year survival
• Most common antigens
• Thermophilic actinomycetes
• Avian proteins

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HP

• Clinical Syndromes
• Acute HP
• Subacute HP
• Chronic HP

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Acute HP

• Occurs 4-8 hours after antigen exposure
• Influenza-like
• Non-productive cough, dyspnea, fevers, chills,
  myalgias, malaise
• Tachycardic, tachypneic, inspiratory rales
• Neutrophilic leukocytosis, normal IgE, RF (50),
  precipitating antigens
• Peak intensity 12-24 hours after exposure
• Episodes recur with increasing intensity

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Acute HP

• CXR
• Bilateral reticulonodular infiltrates
• Patchy or diffuse
• Lower lung field predominance

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Acute HP

• CT
• Ground glass opacities
• Micronodules
• Clear after 4-6 weeks of antigen avoidance

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Acute HP

• PFTs
• Restrictive ventilatory impairment
• Low DLCO
• Airway hyper-responsiveness (60)
• Also think about co-existing asthma (5-10)

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Subacute HP

• Repeated exposure to low dose of antigen
• Pigeon exposure
• Mexico
• Exertional dyspnea, fatigue, cough
• Fever or low grade temp elevations
• Risk of developing chronic HP

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Subacute HP

• CXR
• May be normal during episodes of subacute HP
• Months to years
• Persistent fine micronodular infiltrates
• HRCT
• Fine linear densities, mild fibrosis

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Subacute HP

• PFTs
• Restriction
• DLCO may be normal or decreased
• Exertional hypoxemia

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Chronic HP

• Occurs in 5 of HP patients
• Frequent or continuous exposure to Ag
• Characterized by the development of pulmonary
  fibrosis
• Progressive cough, mucous production, dyspnea,
  weight loss, anorexia, malaise
• Clubbing?poor prognosis
• Precipitating Ab may or may not be present
• Chronic HP from avian proteins carries a high
  risk of severe fibrotic lung disease and poor
  prognosis

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Chronic HP

• CXR
• Low lung volumes
• Reticulonodular opacities
• Linear densities of fibrosis in mid-upper lung
  fields

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Chronic HP

• HRCT
• Honeycombing/fibrosis (peribronchiolar)
• More upper lobe predominance
• Scattered areas of fibrosis
• IPF more peripheral and basal (subpleural
  paraseptal)
• Although 25 of HP indistinguishable from IPF
• Micronodules
• Strongly favor HP over IPF
• Traction bronchiectesis
• Ground glass opacities
• Hyperlucent areas reflecting air trapping (Mosaic
  pattern)

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HP

• Differential Diagnosis of Acute HP
• Atypical pneumonia
• Pulmonary edema
• Organic Toxic Dust Syndrome
• Bronchoalveolar cell carcinoma
• BOOP

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HP

• Differential Diagnosis of Subacute HP
• Chronic bronchitis
• Cough variant asthma
• Occupational asthma
• Vasomotor rhinitis
• Low-grade OTDS
• Sarcoidosis
• Collagen vascular disease
• ILD (RBILD, EG, DIP)
• Atypical mycobacterial infection
• Mycotoxin exposure
• Chronic fatigue syndrome
• Occult malignancies

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HP

• Differential Diagnosis of Chronic HP
• IPF/UIP
• NSIP
• LIP
• Sarcoidosis
• Pulmonary Langerhans cell Histiocytosis

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Now

• Some specific forms of HP

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Hot Tub Lung

• MAC
• Infection vs HP
• Arguments to support both
• BCG hypersensitivity
• Metal working fluids
• Resolution without pharmacologic therapy
• Exposure
• Hot tubs, shower heads, and bath water.
• Basically, anyone could be exposed from water
  exposure!

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Hot Tub Lung

• Treatment
• Avoidance is still KEY!
• Some have treated severe cases with steroids,
  with and without antimycobacterial therapy.
• Bottom Line
• Corticosteroids and antimycobacterial therapy may
  be helpful in severe cases, however most may be
  treated with avoidance of antigen exposure alone.

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HP (Farmers HP)

• Thermophilic actinomycetes
• Saccharopolyspora rectivirgula, T. vulgaris,
  Aspergillus
• Moldy hay, straw, and grain dust
• Key
• Differentiate from other farmer related pulmonary
  diseases
• OTDS, chronic bronchitis, asthma
• Normal lymphocyte count on BAL essentially rules
  out farmers HP

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HP (Bird Fanciers HP)

• Bird Ag
• Pigeon, turkey, duck, parrots, cannaries, doves,
  chickens, geese, owls
• Disease depends on intensity and duration of
  exposure
• High intensity, short duration? Acute HP
• Low intensity, long duration? Chronic HP
• Ag can persist in room for 18 months after
  removal of the bird

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HP (Building Related HP)

• Summer-type HP
• Japan
• Trichosporum cutaneum (imperfect yeast)
• Hot /humid weather
• El Nino Lung
• Southern CA
• Excess precipitation and flood damage
• Pezizia domiciliana (fungus)

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HP (Building Related HP)

• BRHP
• Difficult to predict and prevent
• Variety of molds
• Air tight houses
• Aluminum sashes
• Mattresses
• Cellulose based wall board
• Carpeting
• Humidifiers (flavobacterium endotoxin)
• Accusations of public hysteria by insurance
  industry
• Indoor molds date back to biblical times

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HP

• Diagnostic Approach
• History, history, history
• Work
• Home
• Pets
• Hobbies
• Travel
• Clinical course
• Similar symptoms in family members or co-workers
• Job satisfaction
• Site visit
• Industrial hygienist
• Air, water, soil samples

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HP

• Diagnostic Approach
• Lacasse et al
• Six factors identified as significant predictors
• Exposure to known antigen
• Positive precipitating Ab
• Recurrent episodes of symptoms
• Inspiratory crackles on PE
• Symptoms occurring 4-8 hours after exposure
• Weight loss
• Presence of all 6? probability of HP was 98

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HP

• Diagnostic Approach
• Precipitating Antibodies
• Ouchterlony double infusion technique
• False negative
• Lab error
• Poorly purified antigens
• Lack of specific antigen in the panel
• Failure to adequately concentrate serum
• Continued exposure to high levels of Ag
• Cessation of Ag exposure
• Smoking
• False Positive

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HP

• Diagnostic Approach
• BAL samples
• 3-5 fold increase in cell count
• Neutrophils may predominate in lavage fluid if
  performed within 48 hours of acute exposure
• Lymphocytes predominate
• CD8 antigen so that the CD4/CD8 lt 1
• May remain elevated for years even after
  cessation of exposure
• Increase IgG, IgM, IgA

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HP

• Diagnostic Approach
• Inhalation Provocation Tests
• Not recommended in the routine evaluation
• Respiratory symptoms
• Temperature changes
• Leukocytosis
• Increased A-a gradient, decrease DLCO
• Decreased VC
• Increase BAL neutrophils
• Infiltrates on CT Scan

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HP

• Diagnostic Approach
• Skin Testing
• Immediate wheal and flare within 10-15 minutes
• Late phase inflammatory reaction 4-6 hours
• Again, not currently recommended as part of
  routine work-up!

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HP

• Diagnostic Approach
• Lung Biopsy
• Usually not necessary in acute or subacute HP
  unless clinical, radiographic, and laboratory
  findings are insufficient to make a definitive
  diagnosis
• May be more useful in chronic HP
• To differentiate from other causes of diffuse ILD
• Although NSIP very similar to chronic HP, and
  granulomas are less likely to be found in chronic
  HP

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HP

• Histopathology
• Acute HP
• Inflammatory interstitial infiltrate with
  lymphocytes (CD8), plasma cells, mast cells, and
  macrophages
• Scattered poorly formed non-caseating granulomas
  and multinucleated giant cells
• Cellular Bronchiolitis
• Features of BOOP seen in up to 50 of cases
• Vasculitis and eosinophils are NOT present

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Histopathology
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HP

• Histopathology
• Subacute HP
• Interstitial mononuclear infiltrate
• Scattered epitheliod granulomas
• Interstitial infiltrate occurs BOTH adjacent to
  and distant from the granulomas

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HP

• Histopathology
• Chronic HP
• Interstitial fibrosis
• Lymphocytic interstitial infiltrate
• Constrictive bronchiolitis
• Noncaseating granulomas are infrequent and may or
  may not be present

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HP

• Pathogenesis
• Type III humoral mechanism
• IgG (IgA or IgM)
• Complex with inhaled antigen to fix complement
• Stimulate alveolar macrophages to secrete
  inflammatory mediators
• Neutrophilic chemotactic factors
• Proteases
• Reactive oxygen intermediates
• IL-8 (important role in attracting PMNs within
  hours of antigen exposure)

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HP

• Pathogenesis
• Type IV cell mediated response
• Occurs with ongoing exposure to Ag
• Activated macrophages secrete IL-12
• Promotes CD4 Th0 lymphocytes to Th1
• IL-1 and TNF-alpha stimulate Th1 cells to produce
  IFN-gamma
• IFN-gamma appears to be a key mediator in the
  development of HP
• IFN-gamma knockout mice do not develop HP when
  exposed to Ag
• IL-10 appears to be an important
  counter-regulatory mediator
• IL-10 knockout mice have a more severe
  granulomatous, inflammatory reaction

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HP

• Pathogenesis
• Other Chemokines
• IL-8 and MCP-1
• Produces by alveolar macrophages
• Chemoattractant to CD8 lymphocytes into the lung
• MIP-1
• Produced by CD8 lymphocytes activated
  macrophages
• Facilitate the differentiation of alveolar
  macrophages into epithelioid cells
  multinucleated giant cells

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HP

• Pathogenesis
• Progression to fibrosis
• TGF-Beta
• Fibroblast chemoattractant
• Potent stimulator of fibroblast collagen
  production
• TNF-alpha
• Stimulate the proliferation of collagen producing
  fibroblasts in the interstitial space through
  TGF-B mediated pathways

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HP

• Genetic Predisposition
• HLA-DRB11305
• HLA-DQB10501
• Increased frequency in pigeon fanciers
• HLA-BRB10802
• Decreased frequency in pigeon fanciers
• TNF-2 -308 polymorphism of TNF-alpha promoter
  gene
• High level of TNF-alpha production
• Increased frequency in HP

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HP

• Just part of the spectrum?
• Acute, subacute HP
• Asthma
• Sarcoidosis
• Chronic HP
• UIP
• All in the same work environment
• Theory
• Variable presentations of exposure to same
  antigen in genetically susceptible individuals

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HP

• Treatment
• AVOID ANTIGEN EXPOSURE!!!!!!!
• Prednisone
• Severe Acute Subacute HP
• Treat for 1-2 weeks then taper over 4-6 weeks
• Severe or Progressive Chronic HP
• Treat for 6 months and re-evaluate
• Respiratory Protective devices
• Environmental control measures
• Changing air filters and humidifier water,
  appropriate hot tub procedures, improved air
  ventilation

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References

• Bourke SJ, et al HP Current concepts. Eur Respir
  J 2001 18supp 32, 81s-92s.
• Cappetulli E et al A case of hot tub lung due to
  MAC in an immunocompetent host. Arch Intern Med.
  2003 Apr 14163(7)845-8.
• Hanak V etal Hot tub lungpresenting features and
  clinical course of 21 patients. Respir Med. 2006
  Apr100(4)610-615.
• Kupeli E, et al Clues for the differential
  diagnosis of HP as an expectant variant of
  diffuse parenchymal lung disease. Postgrad Med J
  200480339-345.
• Lacasse Y, Selman M, Costabel V, et al Clinical
  diagnosis of HP. Am J Respir Crit Care Med 2003,
  168952-958.
• Mohr L HP Curr Opin Pulm Med 10401-411.
• Pardo A, et al Increase of Lung Neutrophils in HP
  is associated with Lung Fibrosis. Am J Respir
  Crit Care Med Vol 161 pp 1698-1704, 2000.
• Seifert S, Von Essen S et al Organic Dust Toxic
  Syndrome A Review. Journal of Toxicology Vol 41,
  No 2, pp.185-193, 2003.
• Travaline JM HP associated with hot tub use. Arch
  Intern Med. 2003 Oct 13163 (18)2250.
• Yi E. Hypersensitivity Pneumonitis. Critical
  Reviews in Clinical Laboratory Sciences, 39
  (6)581-629 (2002).
• Zompatori M, et al Chronic HP or IPF? Diagnostic
  role of HRCT. Radiol Med (Torino). 2003
  Sep106(3)135-46.