hypersensitivity pneumonitis

Hypersensitivity pneumonitis

Yoavanit Srivaro M.D.

Outlines

• Historical perspective• Epidemiology• Pathogenesis and Etiology• Clinical and Radiological finding• Diagnosis• Treatment

Historical perspective

• 1st described in the early 1900s Farmer’s lung: “farmers who reported febrile episodes

after exposure to moldy grains, hay, or straw ”• Reed and Barbee in 1965 Pigeon breeder’s lung: “relationship between HP and

exposure to avian antigens”• Hendrick and colleagues in 1978 Budgerigar fancier’s lung

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Copyright © 2014 The Budgerigar Society

Budgerigar

Historical perspective

• In 1985, Cormier and Schuyler proposed that HP is

“an inappropriate immune response to inhaled antigens that causes shortness of breath, and a restrictive lung defect.”

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Epidemiology

• A landmark study of interstitial lung disease (ILD)

:ILD Prevalence of 30 per 100,000 population :HP Incidence less than 2%

Coultas DB, Zumwalt RE, Black WC,Sobonya RE. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med 1994;150:967-72.

Epidemiology

• Exposed farmers the prevalence ranges from 0.5% to 3.0%.

Richerson HB, Bernstein IL, Fink JN, et al. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity Pneumonitis. J Allergy Clin

Immunol 1989;84:839-44.

Epidemiology

• In a Spanish study on ILD incidence across 23 centers nationally with 511 patients registered

:estimated incidence of ILD was 7.6 per 100,000/year

Xaubet A, Ancochea J, Morell F, et al. Report on the incidence of interstitial lung diseases in

Spain. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21:64-70.

Epidemiology

• In a Spanish study on ILD incidence across 23 centers nationally with 511 patients registered

idiopathic pulmonary fibrosis 38.6% sarcoidosis 14.9% cryptogenic organizing pneumonia 10.4% ILD asso collagen vascular dis. 9.9% * hypersensitivity pneumonitis* 6.6%

Xaubet A, Ancochea J, Morell F, et al. Report on the incidence of interstitial lung diseases in

Spain. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21:64-70.

Pathogenesis and Etiology

• An abnormal immune response, mainly to antigens

:organic materials(fungal, bacterial, avian, vegetable) :inorganic materials• Many of the antigens in HP are immune stimulants

because :enzyme activity :growth patterns• Viral infection :initiation of HP, possibly increasing

antigen activation

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

-The exposure to aerosolized avian proteins, especially from feathers or bird droppings, is considered to be

the most common cause of HP.- Pigeons, doves, and parakeets are the birds most

often involved JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

DOVES

PIGEONS

PARAKEETSmkalty.org

Cockatoos

Cockateils

Parrot

Lovebird

Other birds of the order Psittaciformes have also been implicated as causes of HP

actinomycete

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Inorganic materials such as isocyanates and zinc, which serve as haptens and create antigenic complexes when combined with human serum albumin, are also able to

trigger HP.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Figure 61-4 Pathogenesis of hypersensitivity pneumonitis

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Figure 61-4 Pathogenesis of hypersensitivity pneumonitis

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Type IIIHypersensitivity

Type IVHypersensitivity

. Barrera L.et al. Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2008;177:44-55.

Figure 1(B) CD4:CD8ratio in BAL from control subjectsand subacute and chronic groups. Lines represent median values. *P , 0.01.

•Chronic HP (3.05, range 0.3 to 15)

• Subacute HP (1.3, range 0.1 to 10)

•Unaffected control subjects exposed to antigen (1.3, range 0.7 to 2.0)

. Barrera L.et al. Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2008;177:44-55.

Figure 9. Intracellular cytokine expression in patients with subacute HP &those with chronic HP. (A)Representative plots of IFN-g and IL-4 production within CD4 and CD8 T lymphocytes from bronchoalveolar lavage in patients with subacute HP and those with chronic HP. Results are presented as percentage of double-positive cytokine expressing CD4 T lymphocytes.

Chronic HP pts displayed Th2 cytokine pattern &Lower memory cell interferon-γ (IFN-γ) secretion. This Th2 skewing in chronic HP may be associated with the fibrotic responses observed in this condition

Barrera L, et al. Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2008;177:44-55.

Girard M. et al. Eur RespirJ 2011; 37:632-9

FIGURE 3. T-regulatory (Treg)-cell function test studies. a) Blood and b)bronchoalveolar lavage (BAL) activated T-cells (anti-CD3/CD28) were placed inculture with an equivalent number of blood or BAL Treg-cells from normalindividuals, asymptomatic subjects and hypersensitivity pneumonitis (HP) patients.

•Functional assays exploring the effects on T cell proliferation induced by CD3 and CD28 • Treg derived from HP pts showed absent regulatory capacity. • Subjects exposed to antigen but not exhibiting HP had normal Treg function. Girard M. et al. Eur RespirJ 2011; 37:632-9.

FIGURE 4. Concentration of interleukin (IL)-17 in a) serum and b) BAL from normal individuals, asymptomatic subjects & HP pts. Results are expressed as concentration(pg/mL-1) of IL-17. Data are presented as mean+/-SEM

HP Pt : increased IL-17 in serum & BAL fluidNormal subjects:noneExposed but not with HP: in between value

Girard M. et al. Eur RespirJ 2011; 37:632-9

Murine in a model of exposure to S. rectivirgula

CD34 restoreWild type

CD34 knockout mice

Did not develop HP Develop HP JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Clinical and Radiological finding

Type of Hypersensitivity pneumonitis

• Acute hypersensitivity pneumonitis• Subacute hypersensitivity pneumonitis• Chronic hypersensitivity pneumonitis

Acute Hypersensitivity pneumonitis

Symptoms• Cough• Fever• Sweating• Myalgia• Headache• Nausea

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Acute Hypersensitivity pneumonitis

Symptoms• Begin within 8 hr of exposure may persist up

to 1 months• Complete recovery within 1 month can be

expected when antigen exposure can be eliminated.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Acute Hypersensitivity pneumonitis

“Farmer’s lung” • S. rectivirgula• Episodic exposure to moldy hay or grain

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Acute Hypersensitivity pneumonitis

Physical Examination• May be normal • Wide spread crackles

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Acute Hypersensitivity pneumonitis

Chest X-ray• Normal (40% of cases) • May also reveal a diffuse nodularity, often

sparing the apices or bases.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Reproduced with permission from: Schuyler M.Hypersensitivitypneumonitis.In:Baum'sTextbook of Pulmonary Disease,7th ed,Crapo JD, Glassroth J, Karlinsky JB, King TE (Eds). LippincottWilliams & Wilkins, 2004. Copyright © 2004 Lippincott Williams & Wilkins.

•Chest radiograph of a patient with acute pigeon breeder's disease.

• Note bilateral lower lobe nodular opacities.

Acute Hypersensitivity pneumonitis

HRCT• Ground-glass opacities• Poorly defined centrilobular micronodules• Mosaic attenuation• Mediastinal lymphadenopathy

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Acute Hypersensitivity pneumonitis

Lung function test• Impaired diffusion• Possible restrictive lung defect

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Subacute Hypersensitivity pneumonitis

Symptoms• Usually develop gradually over days or weeks

Physical examination • Lung crackles

Lung function testing • Typically shows restriction with reduced gas

transfer

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Subacute hypersensitivity pneumonitis

HRCT• Micronodular pattern • Ground-glass attenuation• Often sparing the lung periphery• May progress to reticular or interstitial

patterns.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Figure 61-5 Radiologic findings in subacute HP Interstitial fibrosis (black arrows) & Emphysematous changes (white arrows) in chronic HP with superimposed subacute HP in a 77-year-old farmer.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Chronic hypersensitivity pneumonitis

• Low level chronic exposure & frequent• Bird fancier’s lung

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Chronic hypersensitivity pneumonitis

Symptoms & Signs**End-stage fibrotic lung disease** • Digital clubbing • Hypoxia• Respiratory failure

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Chronic hypersensitivity pneumonitis

Lung function test• Restrictive• Lower gas transfer measurements• Lower total lung capacity

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Chronic hypersensitivity pneumonitis

Chest X-ray• Interstitial pattern progressing to fibrosis or

honeycombing• Emphysematous change(smokers)

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Chronic hypersensitivity pneumonitis

HRCT• Fibrosis• Reticular pattern• Air trapping• Honeycombing• Traction bronchiectasis*dificult to distinguish from other forms of ILD *

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Chronic hypersensitivity pneumonitis

HRCT• Micronodules• Mosaic attenuation• Sparing of lung periphery**tend to favor HP as a diagnosis over other

interstitial diseases**

• Pleural disease is uncommon JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Figure 61-5 Radiologic findings in chronic (B) HP Ground-glass opacities (black arrows), Mosaic perfusion (white arrows)& Fibrosis (red arrow) in chronic HP caused by pigeon exposure.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Chronic HP is manifest as lung fibrosis- with areas of reticulation-traction bronchiectasis -architectural distortion -with a mid-lung predominance.(Courtesy of Dr. Michael Gotway.)

ส

Murray & Nadel’s Textbook of Respiratory Medicine 5th edition

Diagnosis

Clinical history

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Specific Antibodies

• Demonstration of Ab against suspected causative Ag :Important for Dx HP

• IgG Ab to putative Ag :Immunodiffusion(Precipitataing Ab) :Immunoelectrophoresis :ELISA

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Lung Function

• Normal :small proportion• Typically reveal :Restrictive defect :Reduced gas transfer measurements• Typical of emphysema :Obstructive defect : chronic phenotype.

Lung Function

• Pulmonary inhalational challenge :Occupational context :Not routinely used

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Bronchoalveolar Larvage

• Important diagnostic tool. • An alveolar lymphocytosis :supports the dx of HP :pts with characteristic clinical features &

pulmonary abn.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Bronchoalveolar Larvage

• Alveolar lymphocytosis may also be found in :Exposed to antigens but who are asymptomatic :Sarcoidosis :Collagen vascular diseases :Silicosis :Bronchiolitis obliterans with organizing

pneumonia (cryptogenic organizing pneumonia) :Drug reactions

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Bronchoalveolar Larvage

• Acute form HP :Predominance of CD8+ T lymphocytes :CD4+/CD8+ ratio lower than 1 • Chronic form HP :High CD4+/ CD8+ ratio

Lung Biopsy

• Transbronchial biopsy :Not particularly useful in the dx of HP :Provide evidence of graulomatous disease

suggestive of the diagnosis :At least six biopsies are required• Open-lung or thoracoscopic lung biopsy :Gold standard

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Lung Biopsy

• Diagnostic yield 34% to 100% • Should be performed for ILD of uncertain

diagnosis • Conservative approach :Clinicoradiologic findings in addition to BAL

results to make a diagnosis

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Differential Diagnosis

• Acute form HP :Infection-like symptoms. :Bacterial and viral infections *Cytomegalovirus pneumonitis*

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Differential Diagnosis

• Chronic HP :Sarcoidosis :Nonspecific interstitial pneumonitis (NSIP) :Lymphoid interstitial pneumonitis :Cryptogenic organizing pneumonia (COP) :ILD associated with collagen vascular disease

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Pathologic findings

• Acute HP :alveolar infiltration with neutrophils & eosinophils &

small-vessel vasculitis• Subacute HP : Triad of 1.A lymphocytic interstitial inflammatory cell infiltrate 2.Small nonnecrotizing granulomata 3.Bronchiolitis.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Figure 3. Surgical lung biopsy of a patient with subacute hypersensitivity pneumonitis from hot tub exposure (hematoxylin and eosin stain). The pathology shows predominantly an interstitial lymphoplasmocytic infiltrate (thick arrow), with cellular bronchiolitis (thin arrow) and some giant cells (arrow head). (Courtesy of Dr. Carol Farver.)

Pathologic findings

• Chronic HP

:Significant lung architecture distortion :Centrilobular fibrosis :Bridging fibrosis :Atelectatic fibrosis in the lobule :Giant cells are often seen in the

interstitium. JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Figure 5. Surgical lung biopsy of a patient with chronic hypersensitivity pneumonitis from exposure to birds (hematoxylin and eosin stain). The pathology shows predominantly a fibrotic pattern (thick arrow). (Courtesy of Dr. Carol Farver.)

 1. Known exposure to offending antigen(s) identified by: A. History of appropriate exposure. B. Aerobiologic or microbiologic investigations of the environment that confirm the presence of an inciting antigen C. The presence of specific IgG antibodies in serum against the identified antigen (serum precipitins). 2. Compatible clinical, radiographic, or physiologic findings: A. Respiratory (± constitutional) symptoms and signs, such as crackles on chest exam, weight loss, cough, breathlessness, febrile episodes, wheezing, and fatigue. These findings are especially suggestive if present, appearing or worsening several hours after antigen exposure B. Reticular, nodular, or ground glass opacity on chest radiograph or HRCT C. Altered spirometry and/or lung volumes (may be restrictive, obstructive, or mixed pattern), reduced DLCO, altered gas exchange either at rest or with exercise testing. 3. BAL with lymphocytosis: A. Usually with low CD4 to CD8 ratio B. Positive specific immune response to the antigen by lymphocyte transformation testing (currently not available in most centers) 4. Positive inhalation challenge testing by: A. Reexposure to the environment B. Inhalation challenge to the suspected antigen in a hospital setting 5. Histopathology showing compatible changes: A. Poorly formed, noncaseating granulomas OR B. Mononuclear cell infiltrate

The proposed diagnostic criteria for HP are based upon the presence of some or all of the following

Cormier, Y, Lacasse, Y. Keys to the diagnosis of hypersensitivity pneumonitis: The role of serum precipitins, lung biopsy, and high-resolution computed tomography. Clin Pulm Med 1996; 3:72.

Richerson HB, Bernstein IL, Fink JN, et al. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity Pneumonitis. J Allergy Clin Immunol 1989; 84:839.

 1. Known exposure to offending antigen(s) identified by: A. History of appropriate exposure. B. Aerobiologic or microbiologic investigations of the environment that confirm the presence of an inciting antigen C. The presence of specific IgG antibodies in serum against the identified antigen (serum precipitins). 2. Compatible clinical, radiographic, or physiologic findings: A. Respiratory (± constitutional) symptoms and signs, such as crackles on chest exam, weight loss, cough, breathlessness, febrile episodes, wheezing, and fatigue. These findings are especially suggestive if present, appearing or worsening several hours after antigen exposure B. Reticular, nodular, or ground glass opacity on chest radiograph or HRCT C. Altered spirometry and/or lung volumes (may be restrictive, obstructive, or mixed pattern), reduced DLCO, altered gas exchange either at rest or with exercise testing. 3. BAL with lymphocytosis: A. Usually with low CD4 to CD8 ratio B. Positive specific immune response to the antigen by lymphocyte transformation testing (currently not available in most centers) 4. Positive inhalation challenge testing by: A. Reexposure to the environment B. Inhalation challenge to the suspected antigen in a hospital setting 5. Histopathology showing compatible changes: A. Poorly formed, noncaseating granulomas OR B. Mononuclear cell infiltrate

The proposed diagnostic criteria for HP are based upon the presence of some or all of the following

Cormier, Y, Lacasse, Y. Keys to the diagnosis of hypersensitivity pneumonitis: The role of serum precipitins, lung biopsy, and high-resolution computed tomography. Clin Pulm Med 1996; 3:72.

Richerson HB, Bernstein IL, Fink JN, et al. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity Pneumonitis. J Allergy Clin Immunol 1989; 84:839.

Definite HP:●Criteria 1, 2, and 3 are met ●Criteria 1, 2, and 4A are met ●Criteria 1, 2A, 3, and 5 are met ●Criteria 2, 3, and 5 are met Probable HPcriteria 1, 2A, and 3 are presentSubclinical HP criteria 1 and 3A are present.

Treatment

• Acute and subacute HP are reversible with removal of the patient from antigen exposure

• Chronic changes of HP are less likely to be reversed.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Treatment

• Oral Corticosteroid :Used to suppress the lymphocytic

inflammation :These do not appear to improve prognosis in

pts with the chronic form :Best avoided unless acute life-threatening

complications are evident.

JO A. DOUGLASS .et al .Middleton’s allergy ; 8th edition 2013:1000-13

Treatment

• More severe attacks :Prednisone 60 mg/day :Supplemental oxygen for hypoxemia :Supportive measures. **Prednisone usually is continued until there

is significant symptomatic and functional improvement**

Murray & Nadel’s Textbook of Respiratory Medicine 5th edition

Treatment

• Cytotoxic agents :refractory progressive HP :Cyclophosphamide :Cyclosporin A :Azathioprine • Lung transplantation

Murray & Nadel’s Textbook of Respiratory Medicine 5th edition

Take home message

• HP results from an exacerbated immunologic response to inhaled antigens

• Manifestations ranging from infection-like acute symptoms to subacute &chronic interstitial dis.

• When exposure to the antigen persists, permanent lung damage may ensue.

• 1st line tx for HP is withdrawal of contact with the offending Ag.

• Oral corticosteroids, depending on the severity of presentation.

Thank You