30 Idiopathic Pulmonary Fibrosis and Other Interstitial Lung Diseases Flashcards
1
Q
Interstitial lung diseases
- Interstitial lung diseases
- Affect…
- Associated with…
- The process often spills over into…
- There is a long list of lung insults and injuries that can lead to the development of interstitial lung disease
A
- Interstitial lung diseases
- Affect the gas exchange surface of the lung
- Associated with the accumulation of inflammatory cells, fibroblasts, and fluid in the interstitial space
- The process often spills over into the alveoli and small airways, but it is the expansion of the interstitial space that is most prominent
- There is a long list of lung insults and injuries that can lead to the development of interstitial lung disease
- Infection: viral pneumonia, mycoplasma pneumonia
- Malignancies: lymphangitic carcinomatosis
- Sarcoidosis
- ARDS recovery (almost all will have varying degrees of ILD)
- Pharmacologic (drug-induced): Amiodarone, Bleomycin, Busulfan, etc.
- Hypersensitivity pneumonitis: Farmers lung, Pigeon breeders’ lung, etc.
- Collagen Vascular Diseases: Rheumatoid Arthritis, Scleroderma, DM/PM, SLE, etc.
- Occupational exposures: Asbestosis, Silicosis, Coal Workers
- Pneumoconiosis
- Eosinophilic Granuloma
2
Q
Interstitial lung diseases
- Idiopathic interstitial pneumonias (IIP)
- Members of this class include…
- Idiopathic pulmonary fibrosis (IPF)
A
- Idiopathic interstitial pneumonias (IIP)
- Interstitial lung diseases that have no evident cause
- A class of lung diseases characterized by the development of variable degrees of inflammation and fibrosis limited to the lung and involving principally the alveolar structures
- Members of this class include…
- Acute interstitial pneumonia (AIP)
- Nonspecific interstitial pneumonia (NSIP)
- Desquamative interstitial pneumonia/respiratory bronchiolitis with interstitial lung disease (DIP/RBILD)
- Cryptogenic organizing pneumonia (COP)
- Formerly called bronchiolitis obliterans with organizing pneumonia
- Idiopathic pulmonary fibrosis (IPF)
- Idiopathic pulmonary fibrosis (IPF)
- One of the more common of the idiopathic interstitial pneumonias
- Carries the poorest prognosis
3
Q
Idiopathic pulmonary fibrosis (IPF)
- General
- Gender
- Age
- Prevalence
- Geography and race
- Age-adjusted mortality rates
A
- General
- The most common IIP encountered
- Gender
- More males have been reported with IPF than females
- Age
- ~2/3 of patients with IPF are over the age of sixty at presentation
- The estimated prevalence of the disease in patients older than 75 years of age is approximately 175 cases per 100,000
- Prevalence
- Old data: ~20.2 cases per 100,000 in males and 13.2 cases in females
- More recent data: incidence in the U.S. is 220/100,000 or ~89,000 cases with 34,000 new cases per year
- The difference is most likely a consequence of the frequent use of Chest CT scans in the evaluation of patients with lung disease
- Geography and race
- No distinct geographical distribution or predilection for race or ethnicity
- Age-adjusted mortality rates
- Appear to be higher in whites than blacks, but this may reflect inadequate reporting, healthcare availability or utilization, or, possibly, real differences in disease course
4
Q
Idiopathic pulmonary fibrosis (IPF)
- Patients usually present with…
- Physical examination reveals…
- The chest radiograph reveals…
A
- Patients usually present with…
- Dyspnea on exertion that has been progressing slowly for months or even years
- Paroxysmal, non-productive cough that is usually provoked by exertion or exposure to irritants
- A small percentage will have cough productive of mucoid or whitish sputum
- More common in those who have also smoked
- Physical examination reveals…
- Loud (“Velcro”) inspiratory crackles at the lung bases in up to 80% of patients
- Clubbing of the fingers and toes is seen in 25-50%
- The chest radiograph reveals…
- Reticulonodular infiltrates in up to 90% of subjects with a predilection for the lung bases
5
Q
Idiopathic pulmonary fibrosis (IPF)
- The high-resolution CT scan
- Pulmonary function studies reveal…
- Patients usually experience…
A
- The high-resolution CT scan
- The most useful non-invasive test to diagnose idiopathic pulmonary fibrosis
- Typically demonstrates a sub-pleural distribution of infiltrates which usually consist of honeycombing fibrosis and areas of “traction bronchiectasis”
- Pulmonary function studies reveal a restrictive impairment.
- Decreased FVC and FEV1
- Normal to increased FEV1/FVC
- Decreased DLco
- Widened (A-a)PO2 gradient particularly with exertion
- Patients usually experience…
- Desaturation of arterial blood with modest exercise when the DLco is less than 50% of predicted
- Retention of carbon dioxide does not occur until the disease is very advanced
6
Q
Idiopathic pulmonary fibrosis (IPF):
Natural history
- Prognosis
- Survival is adversely affected by the presence of…
- Even in the absence of complicating disease, the median survival of biopsy-confirmed IPF is…
- Mortality
A
- Prognosis
- Progressive illness
- Median survival is unaffected by medical therapy
- Earlier estimates suggesting a longer survival (and better response to therapy) were complicated by the inclusion of other types of IIPs that carry a more favorable prognosis and response to anti-inflammatory and immunosuppressive therapies
- Survival is adversely affected by the presence of…
- Concomitant diseases in this elderly population, such as coronary atherosclerotic disease, smoking-related lung disease, chronic obstructive lung disease and bronchogenic carcinoma, and pulmonary infections
- Even in the absence of complicating disease, the median survival of biopsy-confirmed IPF is…
- ~3½ years
- Mortality
- Most frequently due to respiratory failure from progressive pulmonary fibrosis
- Ischemic heart disease, bronchogenic carcinoma, infection, and pulmonary emboli accounted for some of the deaths in one series
7
Q
Idiopathic pulmonary fibrosis (IPF):
Natural history
- Natural history
- Some patients experience a gradual decline characterized by…
- Serial CT scans in such patients generally show…
- Some patients experience long periods of…
- A small proportion of patients experience rapid decline in lung function associated with…
- Lung histology, when available, shows…
A
- Natural history
- Highly variable and largely unpredictable
- Some patients experience a gradual decline characterized by…
- Worsening dyspnea and diminished exercise capacity as a consequence of progressive interstitial fibrosis and loss of lung function
- Serial CT scans in such patients generally show…
- Progressive honeycomb changes extending centrally, with traction bronchiectasis and lung distortion
- Some patients experience long periods of…
- Relative stability of lung function, occasionally punctuated by brief periods of accelerated decline
- A small proportion of patients experience rapid decline in lung function associated with…
- Severe gas exchange impairment
- The appearance of ground glass infiltrates on CT scanning
- Death from respiratory failure within a few weeks to months
- Lung histology, when available, shows…
- Diffuse alveolar damage superimposed on the UIP pattern of injury (formerly called Hamman-Rich syndrome), a syndrome now referred to as an acute exacerbation of IPF
8
Q
Idiopathic pulmonary fibrosis (IPF):
Pathology
- Hallmarks of usual interstitial pneumonia (UIP)
- Other findings
- The most destructive lesions are found…
A
- Hallmarks of usual interstitial pneumonia (UIP)
- Geographic and temporal heterogeneity
- Geographic heterogeneity dictates that there are areas of lung with marked loss of normal architecture such as honeycombing fibrosis adjacent to areas of nearly normal lung
- Other findings
- Hyperplasia of smooth muscle within the interstitial space
- Hyperplasia and metaplasia of epithelial cells in the alveoli and small airways
- The most destructive lesions are found…
- In the subpleural and paraseptal areas of the lung
9
Q
Idiopathic pulmonary fibrosis (IPF):
Pathology
- Temporal heterogeneity implies that…
- Inflammation
- Principal inflammatory cells
A
- Temporal heterogeneity implies that…
- Areas of inflammation and advanced scarring are seen in the same specimen
- Inflammation
- An early event that progresses to fibrosis
- Principal inflammatory cells
- Mononuclear cells, macrophages, lymphocytes, and plasma cells
- There is a scattering of polymorphonuclear leukocytes, mainly neutrophils, within the interstitium
- Occasionally, clumps of neutrophils are seen in dilated airways
10
Q
Idiopathic pulmonary fibrosis (IPF):
Pathology:
Features that characterize the fibrotic response
A
- The earliest is the “fibroblastic focus” where fibroblasts are undergoing replication
- These foci usually occur at an air-tissue interface where there is a junction between normal and scarred lung
- They are felt to be the source of the fibroblasts that lay down immature and mature collagen
- A large number of fibroblastic foci seem to portend a worse prognosis since they are a marker for the severity of the fibrotic response
11
Q
Idiopathic pulmonary fibrosis (IPF):
Prognosis
- Mean survival after diagnosis of IPF vs. non-specific interstitial pneumonitis (NSIP)
- The traditional concept of how IPF progresses
- Previous hypothesis
- Two additional patterns of disease progression
A
- Mean survival after diagnosis of IPF vs. non-specific interstitial pneumonitis (NSIP)
- IPF: 3½ years (18% after 6 years, 5% after 17 years)
- NSIP: much better (75% after 6 years, 50% after 17 years)
- These differences highlight the importance of making a correct diagnosis
- The traditional concept of how IPF progresses
- Previous hypothesis
- Patients lost lung function is a linear manner over time
- Eventually they reached the point where they either…
- Developed terminal respiratory insufficiency with or without infection
- Died of other causes prior to respiratory failure
- Two additional patterns of disease progression
- Patients with well-documented IPF actually may have periods of relative stability interrupted by accelerated declines in lung function over a period of several months
- Approximately 15% of patients may also experience “acute exacerbations” where the decline in lung function is more precipitous (usually over a period of weeks)
- These patients are often hospitalized with signs of acute respiratory failure associated with airspace disease on CT scan and (when biopsied) histologic evidence of diffuse alveolar damage
- Previous hypothesis
12
Q
Idiopathic pulmonary fibrosis (IPF):
Pathogenesis
- Current theories
- The causes of the initial and recurrent injury
- The risk of IPF seems higher in…
A
- Current theories
- A repetitive injury to the alveolar microenvironment followed by abnormal wound healing
- Instead of the normal sequence leading to repair and restoration of structure and function, progressive loss of alveoli is due to scarring
- The causes of the initial and recurrent injury
- Oxidative stress probably plays a role
- The risk of IPF seems higher in…
- Some occupational groups particularly sheet metal workers and workers with heavy sawdust exposure
- But the majority of subjects with IPF have no occupational exposures
13
Q
Idiopathic pulmonary fibrosis (IPF):
Pathogenesis
- Tissue injury is often associated with inflammation
- Other roles
A
- Tissue injury is often associated with inflammation
- Innate immune mechanisms may initiate the response
- Adaptive immune mechanisms may also be recruited leading to release of immune lymphokines and cytokines
- Activation of the cellular or humoral immune system in IPF
- An imbalance between Th1 and Th2 cytokines may contribute to fibrosis.
- Other roles
- Angiogenesis
Growth factor production - Fibroblast phenotypes
- Recruitment and maintenance of the myofibroblast
- Abnormal turnover of extracellular matrix
- Loss of epithelial cells may also be due to increased apoptosis of this cell type from mediators that the myofibroblasts release
- Angiogenesis
14
Q
Idiopathic pulmonary fibrosis (IPF):
Pathogenesis
- Role of these factors in the IPF lung
- A familial form of IPF
- Accounts for…
- Inheritance
- Male to female ratio
- Mutation
A
- Role of these factors in the IPF lung
- Upregulation of genes for TGF-β
- Connective tissue growth factor (CTGF)
- Matrix metaloproteinases (MMP’s), particularly MMP-7
- The balance between angiostatic and angiogenic factors
- A familial form of IPF
- Accounts for 2-10% of cases
- An autosomal dominant gene with variable penetrance is the culprit
- The male to female ratio in familial IPF is about equal
- Recently a mutation of the gene for Surfactant C was detected in a kindred with…
- Familial IPF associated with histological UIP
- Nonspecific Interstitial Pneumonia (NSIP)
15
Q
Idiopathic pulmonary fibrosis (IPF):
Treatment
- Proven effective medical therapies for IPF
- Potentially promising medical therapies
- High dose corticosteroids
- Corticosteroids when combined with cyclophosphamide or azathioprine
- Idiopathic interstitial pneumonias
- Prednisone, azathioprine, and the antioxidant N-acetylcysteine
- The short-term efficacy of regimens that combine steroids with colchicine, D-penicillamine, or both
A
- Proven effective medical therapies for IPF
- At this time, there are no proven effective medical therapies for IPF
- Potentially promising medical therapies
- High dose corticosteroids
- Decrease mortality
- Associated with significant and often irreversible side effects
- Corticosteroids when combined with cyclophosphamide or azathioprine
- Questionable improved survival compared to corticosteroids alone
- Idiopathic interstitial pneumonias
- More steroid-responsive
- Prednisone, azathioprine, and the antioxidant N-acetylcysteine
- Increase in mortality
- The short-term efficacy of regimens that combine steroids with colchicine, D-penicillamine, or both
- No significant difference in measures of lung function, gas exchange, or survival at the end of 2 years
- High dose corticosteroids