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A thirty three years-old man presented with dyspnea, fever and cough

Dr. Ahmet Bircan University of Suleyman DemirelFaculty of MedicineDept. of Pulmonary Medicine, Isparta

Turkish Thoracic Society 13th Annual Congress, 2010, Istanbul

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Case presentation

33 years-old, man Symptoms:

Dyspnea, fever, cough and weight loss History:

No complaints until 45 days before his admission Symptoms; had started 45 days ago Cough; nonproductive Fever; once every 2-3 nights, without taking his

temperature Weight loss; inappetence, malaise and weight loss (3

kg) (+) in the last 2 months

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No co-morbidity

Smoking: never

Family story: nothing special

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Physical Exam Good condition Blood pressure: 100/60 mmHg, Pulse: 94/min., Temperature: 36 0C, Respiratory rate: 24/min., Respiratory system exam:

In oscultation, fine crackles were found bilaterally at the base of hemithorax

All the other systems were normal

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Laboratory findings-1Hemogram Leukocyte: 12.000/mm3,

Neutrophile, 85.6%, Lymphocyte, 8.5%

Hemoglobin: 17.2 g/dl, Hematocrit: %47 Platelet: 307.000/mm3, ESR: 3 mm/h CRP: 34.8 mg/L

Biochemistry AST: 45 U/L (N:10-40) LDH: 517 U/L, (N:150-

290) All other biochemical

analyses were in normal limits

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Chest X-Ray

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Thorax HRCT

diffuse, multiple, small and ill-defined centrilobular-acinar nodules and patchy ground-glass opacities in both lungs

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Laboratory findings-2

ABG analysis, breathing in room airPulmonary function tests

measurement predicted

FVC 2.68 L 50%

FEV1 2.46 L 56%

FEV1/FVC 91.7% 110%

FEF25-75 3.66 L 80%

DLCO 15.7ml/Hg/dk 48%

DLCO/VA 3.45ml/Hg/dk/L

74%

measurement

pH 7.43

PaCO2 34.6 mmHg

PaO2 57 mmHg

HCO3 22.4 mEq/L

SaO2 90.4%

P(A-a)O2 49

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Laboratory findings-3

AFB smear (-) From inducted sputum and BAL

ANA: (-) RF: N Compleman: N ACE: N IgG: 2310 IgA, IgE ve IgM; N

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What is your diagnosis with these findings?

1. Atypical pneumonia

2. Miliary tuberculosis

3. Sarcoidosis

4. Hypersensitivity pneumonitis

5. Silicosis

6. Organic toxic dust sydrome

7. Silo filler’s disease

8. Reactive airway dysfunction syndrome (RADS)

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What is your next step in diagnostic approach?

1. More information about history

2. Serological tests for M.pneumoniae

3. Galium scintigraphy

4. Bronchoscopy (BAL,TBB)

5. Reversibility test

6. Surgical biopsy

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No tb contacts in his family Occupation:

10 years ago, he had worked in a textile factory for 2 years, with no respiratory symptoms

working as a security staff in a bank for 2 years

Hobby: A pigeon breeder for 7 years

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What is the next procedure?

1. FOB+BAL

2. FOB+TBNA

3. FOB+BAL+TBB

4. EBUS

5. Provocation tests

6. VATS biopsy

7. Open lung biopsy

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Bronchoscopic examination revealed no endobronchial patology

BAL was done TBBs were obtained from LLL Due to technical errors cytologic analyses of

the BAL fluid did not performed

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TBB material of our patient

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Hypersensitivity pneumonitis

extrinsic allergic alveolitis

Pigeon breeders disease

Pigeon, turkey, duck, parrots, cannaries, chickens, geese

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Diagnostic criteria

History of symptoms compatible with HP

Confirmation of exposure to the offending agent by history, serum and/or BAL fluid antibody.

Characteristic radiological findings

BAL fluid lymphocytosis Compatible histological changes Positive natural challenge or by

controlled inhalational challenge.

Basilar crackles. Decreased diffusion

capacity. Arterial hypoxaemia

Major (at least 4) Minor (at least 2)

Schuyler M. The diagnosis of hypersensitivity pneumonitis. Chest 1997; 111: 534–536.

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Predictors of Hypersensitivity pnömonitisVariables OR 95% CI

Exposure to a known offending antigen 38.8 (11.6-129.6)

Positive precipitating antibodies 5.3 (2.7-10.4)

Recurrent episodes of symptoms 3.3 (1.5-7.5)

Inspiratory crackles 4.5 (1.8-11.7)

Symptoms 4–8 h after exposure 7.2 (1.8-28.6)

Weight loss 2.0 (1.0-3.9)

Lacasse Y, et al. AJRCCM Lacasse Y, et al. AJRCCM 2003; 2003; 168: 168: 952-8.952-8.

Presence of all 6 probability of HP was 98%

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Aetiology

More than 200 types of HP were described Clinical, radiological and pathological

similarities of these types of HP suggest us an common pathogenesis.Thermophilic actinomyches..Farmers LungPenicillium spp… Humidifier LungAnimal proteins….Pigeon Breeders LungAnimal proteins…Bird Fancier’s LungFungus…Malt Workers LungMAC…..Hot Tub Lung And many many more……

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What is most common form of HP?

1. Farmer lung disease

2. Pigeon breeder disease

3. Bagassosis

4. Japanese summer type HP

5. Drug induced HP

6. HP due to chemical compounds

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Epidemiology Prevalance of HP is variable in different population

Geographical features, climate and production of industrial crops

In Turkey, FLD is more frequently seen in the region of East Anatolia (livestock) and Black Sea (production of nuts)

The most frequent types of HP in European countries are HPs seen in pigeon breeders and in farmers

Among farmers----- FLD 1-19%; Among pigeon breeders------ PBD 6-20%

80-95% of patients are nonsmoker. Prognosis is poor in smokers

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HistopathologyAcute HP

Inflammatory interstitial infiltrate Scattered poorly formed non-

caseating granulomas and multinucleated giant cells

Cellular Bronchiolitis These features seen in up to 75%

of cases Vasculitis and eosinophils are not

present Subacute HP

Interstitiel mononuclear infiltrate chronic HP

Interstitiel fibrosisTakemura T, et al. Curr Opinion Pulm Med 2008,14:440–54.

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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

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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 (a

key mediator) IL-10 (counter-regulatory mediator)

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

Pathogenesis

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Pathogenesis

Progression to fibrosis TGF-Beta

Fibroblast chemoattractant, collagen production TNF-alpha

Stimulate the proliferation of collagen producing fibroblasts in the interstitial space through TGF-B mediated pathways

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Clinical presentation Affected by multiple factors

Antigenic feature of organic particle, it’s size and concentration

Frequency and intensity of antigen exposure Host immune response Co-infections

Classically, consisted of acute, subacute and chronic forms.

Alternate classification schemes have been proposed because of: clinical course is so highly variable acute forms of HSP do not necessarily evolve into a

chronic form of the disease

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Classification Hypersensitivity Pneumonitis: A Hypothesis

Aktive (n=41)Aktive (n=41) Recurrent symptoms

Normal CXR

Sequela (n=127) Sequela (n=127) Clubbing Hypoxemia Restrictive PFT HRCT reveals fibrosis

Lacasse Y, et al. Classification of hypersensitivity pneumonitis: a hypothesis.Lacasse Y, et al. Classification of hypersensitivity pneumonitis: a hypothesis.

Int Arch Allergy Immunol 2009:149:161-6. Int Arch Allergy Immunol 2009:149:161-6.

Data obtained from a large prospective multicenter cohort study (the HP Study) 168 patients

P<0.0001

In each group, frequency of nodular opacities were similar Subacute HP is difficult to define

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Which clinical form is consistent with our case?

1. Acute form

2. Subacute form

3. Chronic form

Dyspnea, fever, cough and weight loss for a duration of six weeks

Bibasillar crackles Centrilobular nodulles

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Acute form Occur in previously sensitized

patients with intermittent high intensity antigenic exposure

Influenza like symptoms; dyspnea, nonproductive cough, fever, chills, myalgia and headache <1 month Begin 2-9 h after exposure Peak during 6-24 h Usually resolves 24-48 h

Bibasilar crakles(+)

47y, M, bird-related HP, bilaterally asymetric ground glass opacity

Silva, C. I. S. et al. Am. J. Roentgenol. 2007;188:334-344

Matar LD, AJR. 2000; 177: 1601-6.

38 y, W, antigen?

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Subacute form

Silva, C. I. S. et al. Am. J. Roentgenol. 2007;188:334-344

Small amounts of antigen exposure

for a long period More insidious onset (several weeks- month) Is marked by cough and dyspnea, leading to hospitalization P.E. reveals bibasilar crackles (+) and dyspnea on exertion (+) Removal of the patient from the offending environment

improves the symptoms

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Chronic form Occurs in 5% of HP patients

Slowly progressive dyspnea on exertion Cough, malaise, weight loss

Removal of the patient from the offending environment does not improve the symptoms

Precipitating Ab may or may not be present Interstitial fibrosis Clubbing (+), in 20-50 %, poor prognosis PHT, Cor pulmonale

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Chronic form

44y, M, FLD, emphysema

56y, M, isocyanate compound, traction

bronchiectasis,

77y, M, PBD, reticulonodular inf.

Silva CIS, et al. Am J Roentgenol. 2007; 188: 334-44.

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BAL 3-5 fold increase in cell count Neutrophils may predominate in lavage fluid if

performed within 48 hours of acute exposure Lymphocytic alveolitis (CD8+ T-lymphocytes ), >5 days CD4+/CD8+ < 1

Type of HP Duration of antigen exposure Time of taking BAL Cilinical presantation

in chronic form CD4+

in acute form CD8+

Smoking smokers CD4+

Increase IgG, IgM, IgA

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Lung biopsy TBB is of limited usefulness for the diagnosis Surgical Lung biopsy

Diagnostic yield 34-100 % Treatment alteration 46-75 %

Selection of patients Timing of the procedure Expertise of the attending pathologist

It should be reserved for rare cases with puzzling clinical presentation and when the clinical course or response to therapy is unusual Lung Biopsy (This recommendation is not based on evidence)

Girard M, Lacasse Y and Cormier Y. Allergy 2009: 64: 322–334 Girard M, Lacasse Y and Cormier Y. Allergy 2009: 64: 322–334

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What is the most appropriate treatment option for this patient?

1. Removal of patients from antigenic exposure is sufficient

2. Removal of patients from antigenic exposure + inhaled CS

3. Removal of patients from antigenic exposure + oral CS

4. Removal of patients from antigenic exposure + oral CS + immunosupressive treatment

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Treatment-preventing

The most important steps Making early diagnosis Avoiding recurrent exposures Decreasing the incidence of occupational risks;

Improved fresh air ventilation Medical surveillance/restriction

Adapting modern agricultural practices Cleaning habitat in home-related HP

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Treatment

Removal of patients from antigenic exposure is generally sufficient

Oral corticosteroids; Provides symptom control in acute/subacute forms Does not influence long-term prognosis 0.5-1 mg/kg/day prednisolone, until objective

improvement occurs 10-15 mg/day maintenance, for 6 months

Improvement has been reported with inhaled steroids in subacute HP, but studies are scanty

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Olgumuzun tedavi sonu grafisi

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Take home messages

HP is an immunologically mediated lung disease mediated primarily by T-cell responses to inhaled antigens.

The diagnosis requires careful history, appropriate laboratory tests, and lung biopsy in selected patients.

Avoidance of exposure is associated with a good prognosis and corticosteroids are indicated in severely symptomatic patients

Because of constantly changing environmental exposures, new examples of HP are being described, and represent an ongoing challenge in patients with ILD.