Download Idiopathic pulmonary fibrosis

Eman Riad Hamed
Chest diseases and tuberculosis
Contents:
Normal
structure of the lung parenchyma.
Factors affecting gas diffusion.
Idiopathic pulmonary fibrosis:
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Definition.
Risk factors.
Diagnosis.
Complications.
Treatment (for IPF and for its complications).
Monitoring of IPF.
Normal
structure of the interstitium:
The interstitium is a thin membrane
between the alveolar walls and the
pulmonary capillary endothelium,
peribronchial, and perivascular.
 Its normal thickness is 0.2-.06 µm and it is
concerned with gas exchange.
 cells of the interstitium:
o The alveolar wall is composed of type 1
alveolar epithelial cells, type 2 alveolar
epithelial cells, alveolar macrophages, and
fibroblasts.
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The pulmonary capillary endothelial cells,
and the basement membrane of the
capillary endothelium and alveolar
epithelium.
o The interstitium also contains collagen,
elastin, proteoglycans and some nerve
endings.
o
Factors
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affecting gas diffusion:
The area of the interstitium.
Partial pressure difference of gases across
the interstitium.
Diffusion coefficient of gases.
Thickness of the interstitium.
Definition:
IPF is defined as a specific form of chronic,
progressive fibrosing interstitial pneumonia
of unknown cause. It occurs primarily in
older adults, limited to the lungs, and is
associated with the pathologic and/or
radiologic pattern of usual interstitial
pneumonia (UIP).
Diagnosis of IPF:
o Exclusion of other known causes of
interstitial lung diseases (ILDs), e.g.
occupational exposures and drug
toxicities.
o High resolution CT finding and surgical lung
biopsy (when done) show UIP.
o clinical diagnosis and lung function.
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IPF is a fatal disease. Most patients show a
gradual worsening of symptoms and lung
function. A minority of patients remain
stable or has a rapid fatal course. Some
patients may show exacerbations of their
disease.
o Patients with IPF may also have pulmonary
hypertension, emphysema, obstructive
sleep apnea, obesity, and other
comorbidities that should be considered in
the management of IPF patients.
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Acute exacerbations of IPF refer to
worsening of symptoms and pulmonary
function that is not caused by cardiac
failure, pneumothorax, pulmonary
embolism, or pneumonia.
Risk
factors of IPF:
IPF is, by definition, a disease of unknown
etiology, however, some potential risk
factors are:
o Cigarette smoking.
o Environmental exposure e.g. metal dusts
(lead, steel, and others), exposure to wood
dust, stone cutting and polishing, and
others.
Risk
factors of IPF; cont.
o Microbial agents:
Epstein-Barr virus, Hepatitis C virus, human
herpes virus-7, and human herpes virus-8
infections.
o Genetic factors:
 The
ELMOD2 gene on chromosome 4q31 (a
gene with an unknown biological function) has
been implicated in familial IPF.
 Mutations in the surfactant protein C and
surfactant protein A genes.
 Polymorphisms of genes encoding for
cytokines (IL-1, IL-4, IL-8, IL-10, and IL-12).
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Corticosteroid monotherapy has no survival
benefits and causes adverse effects.
However, in a minority of patients, it may
improve pulmonary function.
Colchicine inhibits fibroblast proliferation
and collagen synthesis in vitro. It has no
effect on survival.
Cyclosporine has no effect on pulmonary
function or on survival. It is an
immunosuppressive agent that inhibits
activation of T cells.
Side effects of cyclosporine include
nephrotoxicity, hypertension, hyperkalemia,
liver dysfunction and hyperglycemia.
 Combined corticosteroid therapy and
immuno modulator therapy(azathioprine
and cyclophosphamide):
cyclophosphamide when used with
corticosteroids may have a survival benefit.
However, adverse effects such as
pancytopenia, liver and kidney dysfunction
should be considered.
Azathioprine may induce leukopenia (and
anemia and thrombocytopenia), hepatic
dysfunction and skin rashes.
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Combination corticosteroid, azathioprine,
and acetylcysteine shows an effect on
pulmonary function, but has no effect on
survival, and complications of
corticosteroids and azathioprine are to be
considered.
Acetylcysteine monotherapy for 12 weeks in
one study, showed improved lung function,
however, it is not recommended for the
majority of patients.
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Interferon γ 1b 200 µg three times a week
subcutanously, combined with low dose
prednisone showed an effect on survival,
but side effects are to be considered.
Bosentan is an endothelin-1 (ET-1) receptor
antagonist. It has effects on the time to
disease progression, quality of life, and
improved symptoms. However, it is not
recommended for the majority of patients.
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Etanercept is a recombinant soluble tumor
necrosis factor receptor that binds and
inactivates tumor necrosis factor. it has no
effect on survival or on pulmonary function.
Anticoagulants combined with
corticosteroids showed reduced mortality
during hospitalization for acute
exacerbations of IPF.
Pirfenidone is an immunosuppressant that
acts on fibroblasts suppressing proliferation
and reducing the production of fibrosis
associated proteins and cytokines, and
inhibits transforming growth factor β
stimulated collagen production.
Pirfenidone has effects on pulmonary
function, but it is not recommended for use
in the majority of patients. side effects
include elevated liver enzymes,
photosensitivity, dyspepsia, nausea, and
vomiting. It is given orally after meals.
CYP1A2 inhibitors may increase toxicity of
pirfenidone. So, amiodarone, propafenone
(antiarrhythmics), paroxetine, and fluxetine
(selective serotonin reuptake inhibitors)
should be used with caution.
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Updated guidelines for management of IPF
(ATS – 2014):
Recommendations that is conditional may
be because of either that the benefits of
the treatment lacks a strong evidence or
because the cost is very high that it
becomes questionable whether the effect
of treatment outweighs the cost.
An informed discussion about the
treatment options should be done
between the physician and the patient.
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There is a strong recommendation against
regular use of warfarin in patients with IPF.
Patients with IPF who have an indication for
warfarin such as atrial fibrillation or venous
thrombo embolism should receive it.
This is because there was no significant
effect of warfarin on the FRC.
However, this recommendation applies
only to oral warfarin with a target INR of 2.0
– 3.0.
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There is a strong recommendation against
the use of imatinib, a selective tyrosine
kinase inhibitor against platelet derived
growth factor (PDGF).
No difference in mortality, no effect on
disease progression, and significant
increase in the risk of sdverse effects of
treatment.
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There is a strong recommendation against
the use of the triple regimen of prednisone,
azathioprine, and N- acetylcysteine.
No effect on mortality or on disease
progression.
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There is a strong recommendation against
the use of ambrisentan, a selective
endothelin receptor antagonist.
Ambrisentan treatment showed increased
mortality and increased disease
progression.
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There is a conditional recommendation for
the use of nintedanib, a tyrosine kinase
inhibitor that targets vascular endothelial
growth factor (VEGF), fibroblast growth
factor, and PDGF.
No effect on mortality and more adverse
effects.
The effect on disease progression was with
high doses.
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There is a conditional recommendation for
the use of pirfenidone.
Showed an effect on disease progression,
effect on the 6 – minute – test, a reduced
risk for acute exacerbation of the disease.
No effect on mortality.
The proper dose and proper duration of
treatment are not well defined yet.
Monitoring of adverse effects, especially
when the high doses are used.
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There is a recommendation for the regular
use of antacid treatment (PPI or H2RA).
IPF patients may have an abnormal
gastroesophageal reflux in about 90% of
cases.
This may cause microaspiration and lung
injury in symptomatic and asymptomatic
patients.
Disease progression and mortality may be
improved and there is a low cost.
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There is a recommendation against the use
of sildenafil in IPF patients.
It has a minor effect on the quality of life,
but it has no effect on mortality or on
disease progression.
High cost and the adverse effects of the
drug.
IPF patient who receive sildenafil for
pulmonary hypertension or for Right
ventricular dysfunction should continue it
and further randomized controlled trials
(RCT) are required.
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There is a recommendation against the
use of bosentan and macitentan (dual
endothelin receptor(ER) antagonists.
No effect on survival or on disease
progression.
High cost and side effects.
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There is a recommendation against the use
of N – acetylcysteine monotherapy in IPF.
No effect on mortality or on disease
progression.
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There is no specific recommendation for
bilateral lung versus single lung
transplantation and further RCT are
required.
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There is no specific recommendation for
the treatment of pulmonary hypertension
in IPF patients.
Further RCT using ER antagonist and
phosphodiesterase – 5 receptor
antagonists are required.
Non-pharmacologic
treatment for IPF:
 Long term oxygen therapy.
 Lung transplantation.
 Mechanical ventilation.
 Pulmonary rehabilitation.
Treatment of complications: