NEW APPROACHES TO MANAGING IDIOPATHIC PULMONARY

					NEW APPROACHES TO
MANAGING
IDIOPATHIC
PULMONARY FIBROSIS
         Presented By:
 Magd Mohamed Galal
  Professor Of Chest Diseases
      Al Azhar University
  Faculty Of Medicine For Girls
    Interstitial Lung Disease
               (ILD)
    Diffuse parenchymal lung
        diseases (DPLDs).
 Definition:
  A group of disorders that involve
   the distal lung parenchyma,or
   space between the epithelial and
   endothelial basement membranes.
               Diffuse Parenchymal Lung Disease


 DPLD of known
                           Idiopathic          Granulomatous          Other forms of
 cause eg drugs
                           Interstitial           DPLDs eg                DPLD
Or association eg
                         Pneumonia (IIP)         sarcoidosis         Eg LAM ,HX ect.
Collagen vascular
    disease
                    Idiopathic pulmonary
                                                      IIP other than IPF
                        Fibrosis (IPF)

                          Desquamative interstitial          Respiratory bronchiolitis
                                pnumonia                      Interstitial lung disease


                              Acute interstitial             Cryptogenic organizing
                                pneumonia                          pneumonia


                          Non specific interstitial           Lymphocytic interstitial
                          Pneumonia (provisional)                 pneumonia
General Diagnostic
   Approach
   Of DPLDs
    IDIOPATHIC
    PULMONARY
      FIBROSIS
(Cryptogenic Pulmonary
       Fibrosis)
                OVERVIEW
 Prevalence: 13–20/100,000 in US
  (approximately 35,000-55,000 cases)
 Onset: Usually between 50 and 70 yr
 Clinical presentation
     Progressive dyspnea on exertion
     Paroxysmal cough, usually nonproductive
     Abnormal breath sounds on chest auscultation
     Abnormal chest x-ray or HRCT
     Restrictive pulmonary physiology with reduced
      lung volumes and DLCO and widened A-aPO2
                         Coultas DB et al. Am J Respir Crit Care Med. 1994;150:967.
                               ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.
     CLASSIFICATION OF IIP
     (IMMUNOCOMPETENT HOST)

                              Idiopathic
                              interstitial
                              pneumonia
                                 (IIP)


  Idiopathic                 Respiratory
  pulmonary    Desquamative bronchiolitis-        Acute                 Nonspecific
fibrosis/Usual  interstitial associated         interstitial             interstitial
  interstitial  pneumonia interstitial lung     pneumonia               pneumonia
  pneumonia        (DIP)       disease             (AIP)                   (NSIP)
     (UIP)                     (RBILD)



                                        ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.
INTERNATIONAL
CONSENSUS STATEMENT
ON IPF: HISTOLOGY
 UIP is essential to diagnosis of IPF
       Idiopathic, progressive, diffuse fibrosing
        inflammatory process
       Involves lung parenchyma
 Surgical lung biopsy recommended in
  patients with suspected IPF, especially those
  with atypical clinical or radiographic features
 Major purpose of histologic examination is to
  distinguish UIP from other histologic subsets
                             ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.
  of IIP
DIAGNOSIS OF IPF
 Major criteria
     Exclusion of other known causes of ILD
     Abnormal pulmonary function studies
     Bibasilar reticular abnormalities on HRCT
      scan
     No histologic or cytologic features on
      transbronchial lung biopsy or BAL analysis
      supporting another diagnosis



                            ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.
DIAGNOSIS OF IPF

Minor criteria
  Age  >50 yr
  Insidious onset of otherwise
   unexplained exertional dyspnea
  Duration of illness 3 mo
  Bibasilar, dry (“Velcro”) inspiratory
   crackles
Pulmonary Function
 Reduction in all lung volume
 Increased static elastic recoil
 Rapid shallow rapid breathing
 Impaired single –breath diffusing capacity (DLco)
 Impaired oxygenation at rest and exercise
 Exercise induced alveolar –arterial O2 gradient correlates
  better with histologic abnormalities than do lung volumes
  or DLco.
 Exercise testing with arterial cannulations:
    Widening A-aPo2
    Respiratory alkalosis
    Decreased O2 consumption
    Increased dead space (VD/VT)
    Increased MV for level of O2consumption
    Low O2 pulse
 6 walk test + oximetry easier ,better for disease
  progression and regression.
           HRCT in IPF
 Bibasilar interstitial and intra lobular
  reticular opacities.
 Interlobular septal thickening
 Sub pleural honeycomb changes ,
 Traction bronchiectasis in lower
  lobes,
 Without pleural abnormalities.
HRCT FINDINGS IN IPF




                   Slide courtesy of G Raghu, MD.
                           BAL
 Normally contains 95-98% macrophages and very few
    neutrophils, lymphocytes, or eosinophils.
   The predominance of certain subgroups of cells in patients
    with DPLD might be helpful in the differential diagnosis.
   Neutrophils are often predominant in smokers and in
    patients with IPF, Hypersensitivity pneumonitis, or Collagen
    vascular diseases
   Lymphocytic predominance is seen mainly in patients with
    sarcoidosis or Hypersensitivity pneumonitis.
   Eosinophils predominate in patients with chronic
    eosinophilic pneumonia, Loeffler syndrome, or Churg-
    Strauss angiitis
   .On the other hand, BAL may yield a specific diagnosis in
    DPLD, patients with certain findings such as:-
              Asbestos bodies (which indicate asbestosis).
              Silica-filled macrophages (silicosis).
              Periodic acid-Schiff (PAS)-stained
               lipoproteinaceous material (pulmonary alveolar
               proteinosis).
              X bodies (eosinophilic granuloma).
        HISTOPATHOLOGIC
        ELEMENTS OF UIP
 Heteroganous areas of end stage fibrosis
  and honeycombing, with areas of active
  proliferation of fibroblast (suggesting
  diffuse ongoing microscopic alveolar
  epithelial injury.
 Fibroblastic foci
 Minimal interstitial inflammation (primary
  proliferative process)
 Honey combing (common) cystic space is
  lined by bronchial epithelium.
UIP interstitial inflammation mild &patchy. The
fibro tic zones are composed mainly of dense
collagen, & oldest disease is seen peripherally in
lung lobule or acinus.




                                     Slide courtesy of KO Leslie, MD.
TEMPORAL
HETEROGENEITY OF UIP




                Slide courtesy of KO Leslie, MD.
INFLAMMATION AND
FIBROSIS IN UIP
Interstitial inflammation and fibrosis
     with alveolar wall thickening




                                                                                             Temporal
                                                                                           heterogeneity




                                                                       Slide courtesy of KO Leslie, MD.
                                         Peripheral accentuation of fibrosis
CHRONIC INTERSTITIAL
INFLAMMATION IN UIP
Alveolar septal infiltrate of lymphocytes
             & plasma cells




                                            Hyperplasia of type 2 pneumocytes. of KO Leslie, MD.
                                                                       Slide courtesy
FIBROBLASTIC FOCI IN UIP




                 Slide courtesy of KO Leslie, MD.
Evidence Of Pulmonary
Hypertension
CONTRASTING
PATHOLOGIC
FEATURES OF IIP


                  .
Feature                    UIP                 DIP/RBILD                 AIP              NSIP
Temporal appearance        Variegated          Uniform                   Uniform          Uniform
Interstitial inflammation Scant                Scant                     Scant Usuallyprominent
Collagen fibrosis          Patchy              Variable, diffuse No Variable, diffuse
                                               in DIP; focal, mild
                                               in RBILD
Fibroblast proliferation Fibroblastic foci No                        Diffuse Occasional, diffuse,
r                                                                          rare fibroblastic foci
Organizing pneumonia       No                  No                        No Occasional, focal
Honeycomb changes          Yes                 No                        No               Rare
Intraalveolar macrophage   Occasional, focal   Diffuse in DIP;           No Occasional, patchy
accumulation                                   peribronchiolar in
                                               RBILD
Hyaline membranes          No                  No                        Occasional,            No
                                                                         focal




                                         Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301.
                NSIP

 Either pure inflammatory or dense
  fibrosis (predominance of cellular
  pattern or fibro tic pattern).
 Must exclude (HSP, drug, and collagen
  vascular disease).
 Pathology, uniform of same age (as a
  result of single insult).
 Fibroblastic foci & Honey combing are
  rare
PATHOGENESIS OF
PULMONARY
FIBROSIS
            PATHOGENESIS AND
              COURSE OF UIP
                              UIP
Multiple microscopic foci of injury occurring over many years

       Focal fibroblast proliferation (fibroblastic foci)


                    Collagen deposition
                                            Recurrent microscopic injury

                Progressive clinical course


                            Death
                              Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301.
     MOLECULAR BIOLOGY OF
     PULMONARY REPAIR                                                             Triggering
         Cellular phase                   Fibrotic phase                             event

                                           Endothelial cell


                                           Angiostasis
                Monocyte
                           +                    ELR- CXC
                                                                                                    ELR- CXC
                          TNF-a                                  ELR+ CXC
                          IL-1                                              ELR- CXC
                MØ
                                                                                         ELR+ CXC
                      IL-1                       Extracellular
                     TNF-a                          matrix
                        +
                                   fibroblast
                                                                 Normal alveoli         Cellular phase
                             –             ELR+ CXC
                           IFN-g                 Angiogenesis

                               IL-12
             Lymphocyte        IL-18      Endothelial cell




                                                                 ELR+ CXC                           ELR- CXC
                                                                            ELR- CXC     ELR+ CXC


Slide courtesy of RM Strieter, MD.                               Homeostasis            Fibro tic phase
INFLAMMATORY RESPONSE OF
       THE LUNG
                   Circulating              Fixed
                   leukocyte                macrophage
  Recognition                    Capillary Antigen
                                 endothelial
                                 cell

       Capillary

                     Recruitment
   Monocyte



                                            Removal

                   Infiltrating     Phagocytic Fibrous matrix
                   leukocyte        leukocyte (scar issue)
                                    (macrophage)
                         Activated
                                                      Resolution
                         leukocyte
                              Chemotactic
                              cytokine wave      Fibroblast


                                                      Slide courtesy of RM Strieter, MD.
      Th1 AND Th2 RESPONSES
Th1                                               TISSUE
Increased IFN-g
   Increased IFN-g
   Increased IL-2
   Increased IL-2            Cell-Mediated     RESTORATION
   Increased IL-12
   Increased IL-12             Immunity
   Increased IL-18 IFN-g
   Increased IL-18
   Increased IL-2
   Increased IL-12
   Increased IL-18
                                               Fibroblast Activation
Th2                                                     and
   Increased IL-4                                Matrix Deposition
   Increased IL-5          Antibody-Mediated
   Increased IL-10              Immunity
   Increased IL-13
                                                   FIBROSIS
                                                Slide courtesy of RM Strieter, MD.
ROLE OF Th1 AND Th2
RESPONSES IN REPAIR
     PROCESS

Cytokine Activation        Fibrotic Phase
      Phase
      Th2 Type                  ExtracellularMatrix
          IL-4/IL-13                (Fibrosis)
              (+)
                 Chemokines
         IL-       Fibroblast
         10
         (-)
                 IFN-g
                 IL-12
                 IL-18
                   (-)

      Th1 Type                   Resolution




                                           Slide courtesy of RM Strieter, MD.
ROLE OF TGF-b AND IFN-g IN
REPAIR PROCESS
   TGF-b receptor                 IFN-g receptor


               Activation of Jak/STAT1

                Smad3-4
                           IFN-g inhibits
     Smad7                 activation of
                           Smad3-Smad4 and
                           induces Smad7




                           Increase of TGF-b–dependent
                           gene transcription

                Inhibition of TGF-b–dependent
                gene transcription
                                   Ulloa L et al. Nature. 1999;397:710.
MOLECULAR BIOLOGY OF
IPF: SUMMARY
 Shift to increased production of Th2
  cytokines and decreased production of Th1
  cytokines resulting from unknown lung injury
 Over expression of Th2 cytokine TGF-b
  stimulates angiogenesis, fibroblast activation,
  deposition of ECM, and fibro genesis
 Th1 cytokine IFN-g counters effects of TGF-b,
  but IFN-g production decreased in IPF
  IFN-g may have therapeutic role in
  management of IPF
PROGNOSTIC
FACTORS IN IPF
 Figure 4. Kaplan-Meier survival curves for patients grouped by combining
  HRCT and histopathologic features as follows: histopathologic pattern
  showing NSIP and HRCT interpreted as indeterminate or NSIP (n=23,
  dotted line); histopathologic pattern showing UIP and HRCT interpreted as
  indeterminate or NSIP (n=46, dashed line); and histopathologic pattern
  showing UIP and HRCT interpreted as UIP (n=27, solid line), p=0.001. + =
  last follow-up visit; circle = death.
             CAUSE OF DEATH
                           IPF
                          [N=543]

                       1-7 year FU


                       60% Died
                          [N=326]



Respiratory Lung Pulmonary Pulmonary Cardiovascular Other
  failure   cancer embolism infection   disease     18%
   39%       10%     3%        3%         27%
                                       Panos RJ et al. Am J Med. 1990;88:396.
RISK FACTORS FOR
PROGRESSIVE DISEASE
 Age: >50 yr
 Gender: male
 Dyspnea: moderate to severe with exertion
 History of cigarette smoking
 Lung function: moderate to severe loss
    (especially gas exchange with exercise)
   BAL fluid: neutrophilia or eosinophilia at
    presentation
   HRCT scan: reticular opacities or honeycomb
    changes
   Response to corticosteroids: poor
   Pathology: more fibrosis, fibroblastic foci
HRCT ABNORMALITIES AND
CHANGES IN LUNG FUNCTION
                              100
Frequency of Improvement in



                              75
     Lung Function (%)




                              50



                              25


                                        N=4         N=12                  N=11
                               0
                                    Ground Glass   Mixed             Reticular
                                              HRCT Appearance
                                                       Wells AU et al. Am Rev Respir Dis. 1993;148:1076.
HRCT APPEARANCE VS
SURVIVAL IN IPF
               100
                90

                                                          CT appearance atypical of CFA
Survival (%)



               70
                60
               50
                40
               30
               20
               10                                CT appearance typical of CFA
                 0
                     0   1      2   3    4   5      6         7
                             Time from Presentation (yr)
                                                        Daniil ZD et al. Am J Respir Crit Care Med.
                                                                                     1999;160:899.
BAL CELLULARITY AND
STEROID RESPONSIVENESS
                                    Responders (N=8)
                  100
                                                        *
                                    Non responders (N=19)
                                    * p<0.05
                             *
 Prevalence (%)

                   75

                                          *
                   50



                   25



                    0
                        Lymphocytes Neutrophils    Eosinophils
                           >11%        >4%            >3%

                                                       Rudd RM et al. Am Rev Respir Dis. 1981;124:1.
APPROACHES TO
THERAPY
The hope of achieving stability as
  scarred lung cannot regenerate.
Start treatment in patient who are
  symptomatic :
 In those with a 30-40% reduction in
  lung function indices.
 With evidence of disease progression
  on serial lung function testing.
THERAPEUTIC
APPROACHES TO IPF
 Corticosteroids          Antioxidant agents
 Other                       Glutathione
  immunosuppressives          N-acetylcysteine
      Azathioprine           Others
      Cyclophosphamide    Agents that block
 Antifibrotic agents       neutrophil adhesion
    Colchicine             molecules
    D-Penicillamine       Inhibitors of specific
    IFN-g                  fibrogenic cytokines
    IFN-b
                            and growth factors
    Pirfenidone

                           ATS/ERS. Am J Respir Crit Care Med. 2000;161:646
CLINICAL RESPONSE TO THERAPY
            IN IPF
                        100

    Stable or Improved (%)                              Prednisolone +
                                                        Cyclophosphamide
                                                        Prednisolone

                             50




                              0
                                  1   3     12     24      36
                                          Months
                                                           Johnson MA et al. Thorax. 1989;44:280.
EFFECT OF THERAPY ON
SURVIVAL IN IPF
                  100
                                                       Prednisone
                                                       Prednisone + Colchicine
                  80                                   Prednisone + D-Penicillamine
                                                       Prednisone + Colchicine
   Survival (%)

                                                       + D-Penicillamine
                   60


                  40



                  20



                    0
                        0   10   20    30   40   50   60    70
                                      Months
                                                           Selman M et al. Chest. 1998;114:507.
NEW TARGETS FOR
THERAPEUTIC
INTERVENTION
 Greater insight into pathogenesis of IPF using
  molecular biological approaches
 Wide range of potential mediators identified
 Targets might include
     Initial injurious agent
     Earliest pathogen tic event
     Final common pathway leading to fibrosis
Lung Transplantation
 Indication:
    Severe ,end stage lung disease.
    Medical therapy ineffective.
    Substantial limitation in activities of daily life.
    Limited life expectancy(<18 months)
 End stage lung disease:
    Severe dyspnoea
    Honeycombing or pulmonary hypertension.
    Severe physiologic derangement
        TLC<60%-

        (A-a)Po2 at rest >30

        Severe exercise desaturation or (A-a)Po2 widening.

        Clinical /radiological/physiologic score >70.
Treatment Of Complications

 Supportive therapy to minimize morbidity.
 O2 therapy
     Oxygen concentrators
     Portable liquid oxygen
 Diuretic therapy
 Opiate.
 Treatment of PE ,infection.

				
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