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

1
A thirty three years-old man presented with
dyspnea, fever and cough

• Dr. Ahmet Bircan
• University of Suleyman Demirel
• Faculty of Medicine
• Dept. of Pulmonary Medicine, Isparta

Turkish Thoracic Society 13th Annual Congress,
2010, Istanbul
2
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

3

• No co-morbidity
• Smoking never
• Family story nothing special

4
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

5
Laboratory findings-1

• Biochemistry
• AST 45 U/L (N10-40)
• LDH 517 U/L, (N150-290)
• All other biochemical analyses were in normal
  limits

• Hemogram
• 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

6
Chest X-Ray
7
What is your next step in diagnosis?

1. Microbiological examination of sputum (for ARB
   and nonspesific agents)
2. Thorax HRCT
3. PFT and ABG
4. Bronchoscopy (BAL, TBB)
5. Hepsi

8
Thorax HRCT
diffuse, multiple, small and ill-defined
centrilobular-acinar nodules and patchy
ground-glass opacities in both lungs
9
Laboratory findings-2

• ABG analysis, breathing in room air

• Pulmonary 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
10
Laboratory findings-3

• AFB smear (-)
• From inducted sputum and BAL
• ANA (-)
• RF N
• Compleman N
• ACE N
• IgG 2310
• IgA, IgE ve IgM N

11
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 fillers disease
8. Reactive airway dysfunction syndrome (RADS)

12
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

13

• 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

14
What is the next procedure?

1. FOBBAL
2. FOBTBNA
3. FOBBALTBB
4. EBUS
5. Provocation tests
6. VATS biopsy
7. Open lung biopsy

15

• 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

16
TBB material of our patient
17
Hypersensitivity pneumonitis extrinsic allergic
alveolitis

• Pigeon breeders disease

Pigeon, turkey, duck, parrots, cannaries,
chickens, geese
18
Diagnostic criteria
Major (at least 4) Minor
(at least 2)

• 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

Schuyler M. The diagnosis of hypersensitivity
pneumonitis. Chest 1997 111 534536.
19
Predictors of Hypersensitivity pnömonitis
Variables 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 48 h after exposure 7.2 (1.8-28.6)
Weight loss 2.0 (1.0-3.9)
Presence of all 6? probability of HP was 98
Lacasse Y, et al. AJRCCM 2003 168 952-8.
20
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
Lung Penicillium spp Humidifier Lung Animal
proteins.Pigeon Breeders Lung Animal
proteinsBird Fanciers Lung FungusMalt Workers
Lung MAC..Hot Tub Lung And many many more
21
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

22
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

23
Laboratory tests

• Leukocytosis (Neutrophilia and lymphopenia)
• ESR ?
• CRP ?
• PFT Restrictive ventilatory defect
• DLCO ?
• (A-a)PO2 ?
• Hypoxemia related with exercise
• Increased serum IgG and IgM
• Increased serum LDH
• RF()

Hastamizin laboratuvar bulgulari ile uyumlu
bulgular
24
Histopathology

• Acute 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 fibrosis

Takemura T, et al. Curr Opinion Pulm Med
2008,1444054.
25
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

26
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 (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

27
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

28
Clinical presentation

• Affected by multiple factors
• Antigenic feature of organic particle, its 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

29
Classification Hypersensitivity Pneumonitis A
Hypothesis
Data obtained from a large prospective
multicenter cohort study (the HP Study) 168
patients

• Aktive (n41)
• Recurrent symptoms
• Normal CXR

• Sequela (n127)
• Clubbing
• Hypoxemia
• Restrictive PFT
• HRCT reveals fibrosis

Plt0.0001

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

Lacasse Y, et al. Classification of
hypersensitivity pneumonitis a hypothesis. Int
Arch Allergy Immunol 2009149161-6.
30
Which clinical form is consistent with our case?

• Acute form
• Subacute form
• Chronic form

• Dyspnea, fever, cough and weight loss for a
  duration of six weeks
• Bibasillar crackles
• Centrilobular nodulles

31
Acute form

• Occur in previously sensitized patients with
  intermittent high intensity antigenic exposure
• Influenza like symptoms dyspnea, nonproductive
  cough, fever, chills, myalgia and headache lt1
  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.
2007188334-344
38 y, W, antigen?
Matar LD, AJR. 2000 177 1601-6.
32
Subacute form

• 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

Silva, C. I. S. et al. Am. J. Roentgenol.
2007188334-344
33
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

34
Chronic form
56y, M, isocyanate compound, traction
bronchiectasis,
77y, M, PBD, reticulonodular inf.
Silva CIS, et al. Am J Roentgenol. 2007 188
334-44.
44y, M, FLD, emphysema
35
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 ),
  gt5 days
• CD4/CD8 lt 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

36
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 322334
37
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

38
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

39
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

40
Olgumuzun tedavi sonu grafisi
41
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.