Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a disease of the elderly.

A chronic, progressive pulmonary disease characterized by interstitial pneumonia, which progresses to end-stage respiratory insufficiency and death within five years after the onset of symptoms.

A local and systemic immune response occurs with disease progression contributing to review acute exacerbations, hospitalizations and decreased survival.

Broncoalveoli lavage have shown that a high bacterial load is associated with

It is suspected innate iimmune responses may be abnormal in IPF, potentially increasing susceptibility to infection.

Survival rate of people with IPF has increased slightly in recent years with the median survival time after the diagnosis 3-5 years, which is worse than most malignancies

Characterized by the histopathological or radiologic patterns of interstitial pneumonia.

Has a complex phenotype manifested by clinical, etiological and molecular heterogeneity.

Gene heterogeneity in the radiograph and pathologic features is required for a definitive diagnosis of IPF.

Reduced levels of nitric oxide, a potent pulmonary vasodilator, is reduced. In this process and is associated with pulmonary vasoconstriction and impaired gas exchange (Giaid A).

Pathologic findings are those of interstitial pneumonia.

Most common of 7 idiopathic interstitial pneumonias classified by the American Thoracic Society.

Unknown cause with no effective treatment.

Proposed mechanism of cause related to repeated ling injury with aberrant fibrotic reaction.

Disease apparently the result of abnormal alveolar epithelial cell behavior causing the migration, proliferation, and activation of mesenchymal cells forming fibroblast and myofibroblast foci.

Activated myofibroblasts secrete extracellular matrix molecules which results in lung damage and destruction.

Associated with disordered fibroproliferation and alveolar epithelial cell function.

Diffuse interstitial fibrosis, honeycomb cystic changes and accumulation of connective tissue and fibroblasts.

Main histopathological features are areas of subpleural and paraseptal fibrosis and honeycombing, alternating with areas of less affected or normal tissue.

Honeycombing refers to cystic fibrosis of airspaces lined with bronchiolar epithelium and frequently filled with mucin and variable numbers of inlammatory cells.

Honeycombing with subpleural, clustered cystic airspaces with walls typically 3-10 mm in diameter is a critical finding for definitive diagnosis on CT scan.

Areas of active fibrosis are present in the background of collagen deposition.

Inflammatory changes are mild and consist of patchy areas of lymphoplasmacytic interstitial infiltrates.

Patients with IPF have a progressive course that is either gradual and predictable and may be defined by sudden episodes of acute worsening.

Chronic condition with insidious onset of dyspnea and cough over several months with a mean survival times ranging from 15 months to 5.6 years.

Associated with smoking, infections, environmental pollution, drugs and gastrointestinal reflux disease.

Genetic evidence substantial with familial aggregation in twins, siblings, and multigenerational families.

Inheritance suggestive of an autosomal dominant process with variable penetrance, but the genetic basis of familial disease is not understood.

In most affected families there appears to be an autosomal dominance, with vertical transmission pattern with reduced penetrance.

Genetic transmission occurs in about 0.5-3.7% of cases (van Moorsel CH et al).

Associated with mutations in surfactant protein A2, and genes maintaining telomere length.

A polymorphism in promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis (Seibold MA et al).

Mucin 5B is the strongest genetic risk factor for idiopathic pulmonary fibrosis and is observed at least 50% of patients with idiopathic pulmonary fibrosis and accounts with 30% of the risk of developing this disease.

Rare and common variants in seven genes, including MUC5B, at least 12 loci have been associated with IPF, as have environmental exposures searches as asbestos and microorganisms and autoimmune conditions such as rheumatoid arthritis and scleroderma.

Each of the above associated factors increases the risk of development of radiographic and pathologic features of usual interstitial pneumonia.

Common risk factors of IPF such as older age, male sex, cigarette smoking, and the MUC5B promoter variant also confer a predisposition to the development of IPF-like disease including rheumatoid arthritis-associated interstitial lung disease and chronic hypersensitivity pneumonitis.

The biologic heterogeneity has multiple emerging epigenetic and transcriptional molecular phenotypes so that the collective clinical, etiologic, and molecular heterogeneity suggested disease represents a response to recurrent environmental and endogenous injury in a susceptible host, in whom the progressive fibrotic response cannot resolve because of defects in one or several key mechanisms involved in lung homeostasis.

The key risk factors of genetic susceptibility, environmental exposures, and autoimmunity with known mechanisms of disease, such as host defense, cell senescence, bronchoalveolar cell function, and lung repair.

Median age at diagnosis 66 years, as it occurs in middle aged and elderly adults.

Median life expectancy after diagnosis about 3 years.

Disease process confined to the lungs.

Classic x-ray findings are peripheral honeycombing changes that are the most prominent in the bases of the lung, traction bronchiectasis and absence of ground-glass changes.

High resolution CT of the chest can establish the diagnosis with the findings of interstitial pneumonitis and a specificity approaching that of open lung biopsy.

High resolution CT scan can help in guiding lung biopsies by identifying the most profoundly affected area.

High resolution CT scan can reveal bilateral ground glass opacities and increased interstitial markings at the lung bases.

Restricted impairment on pulmonary function tests with reduced gas exchange.

Process results in diffuse epithelial cell activation, impaired epithelial cell repair, cytokine activity and apoptosis with secondary overproduction of collagen and fibronectin by fibroblasts.

The cycle of injury of abnormal epithelial healing causes progressive fibrosis and architectural distortion of the lung.

It is suggested that epithelial damage and abnormal wound repair contribute to its pathogenesis.

It is proposed that IPF is a result of chronic epithelial micro injury resulting in dysregulated wound healing response,  characterized by aberrant bidirectional epithelial-mesenchymal cross talk in genetically predisposed older persons.

The accumulation in persistence of hypersynthetic mesenchymal populations are derived from multiple cellular sources including local proliferation and differentiation of resident lung fibroblasts  influenced by fibroblast mitogens and differentiation factors with emergence of fibrotic foci and progression of fibrotic remodeling.

Profibrotic macrophages also promote a fibrogenic microenvironment.

The role of information in IPF remains controversial.

Patients seek care because of chronic and progressive dyspnea and cough.

50,000-70,000 cases per year.

Incidence of 6.8-16 cases per 100,000.

Prevalence ranges from 14-42 cases per 100,000 persons.

Higher predominance in males 1.5-1.7:1, then in women.

Incidence increases with age.

Cigarette smoking and exposure to metal and wood dust almost important environmental risk factors.

2-20% of patients have a positive family history of the disease.

Estimated 50 deaths per million persons per year.

Mortality increased with advancing age.

Mortality rates higher in men than women.

Median survival 2-4 years from the time diagnosis.

20-40% 5 year survival.

Worse prognosis exists for patients over the age of 70 years, those with a smoking history, individuals with low body mass index, severe physiological dysfunction, extensive radiographic evidence of disease and the presence of pulmonary hypertension.

A subgroup made up of mainly men cigarette smokers have a rapidly progressive process with a shortened survival, referred to as accelerated idiopathic pulmonary fibrosis.

Accelerated IPF has upregulation of pathways MAPK-EGR1-HSP70 that operate on epithelial and mesenchymal elements of the lung, and regulate cigarette smoke induced inflammation.

The mean annual rate of decline in forced vital capacity ranges from 0.13 m to 0.21 L (Ley B et al).

Corticosteroids considered the mainstay of therapy, but has minimal or no beneficial effect.

Immunosuppressive therapies of no benefit.

Prednisone plus azathioprine vs. prednisone, azathioprine plus acetylcysteine resulted in non significant clinical improvement in vital capacity and carbon dioxide diffusing capacity after one year of treatment in the latter group, with no benefit on survival.

The addition of acetylcysteine 600 mg three times a day to standard therapy of prednisone and azathioprine may slow the rate of deterioration and disease progression.

Interferon gamma-1b therapy may be useful in early stage disease but is not helpful in patients with advanced disease.

Sildenafil, a phosphodiesterase-5 inhibitor stabilizes the second messenger of nitric oxide, cyclic guanosine monophosphate, which leads to pulmonary vasodilataion,

Sildenafil increases vasodilatation in well ventilated lung tissue.

In the Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis, a double-blind, randomized, placebo-controlled trial did not show benefit in the first 12 weeks: only 10% of patients in the sildenafil group and 7% in the placebo group had an improvement of 20% or more in a six minute walk distance ( The Idiopathic Pulmonary Fibrosis Clinical Research Network ).

In the Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis treated patients had better arterial blood gases and carbon monoxide diffusing capacity compared to the placebo group.

5-year survival after lung transplant approximately 35%.

Pathologic disease associated with rales in 70-90% of patients.

Bilateral inspiratory crackles commonly found as is clubbing.

Generally, a steady and slowly progressive process although new clinical phenotypes suggests a more heterogeneous disease process.

Patients have depleted levels of glutathione in the lung and this depletion can be corrected by treating patients with acetylcysteine.

IPF may be acutely exacerbated with rapid clinical deterioration in the absence of infection, CHF, pulmonary embolism, or other processes.

Acute exacerbation of IPF occurs in 5-20% of cases, and is associated with mortality rate of 60% acutely and 90% by 6 months.

In acute exacerbation of idiopathic pulmonary fibrosis Torque teno virus has been detected in 27% of such cases (Wooten SC et al).

Acetylcysteine offers no benefit in preserving FVC in patients with IPF with mild-moderate impairment in lung function.

Presently no pharmocologic therapy improves survival.

Pirfenidone and nintedanib have shown in phase III trials to reduce the progression of disease.

Pirfenidone (Esbriet) and nintedanib approved for IPF.

Pirfenidone and nintedanib are associated with a decline in forced vital capacity, neither treatment halts disease progression or improves any objective measurements of disease status.

These two agents can slow process disease progression, but do not stop or reverse lung fibrosis.

Both drugs are poorly,p tolerated by substantial numbers of patients and have high cost, and lack perceived benefit on symptoms and quality of life.

Treatment with the anti-fibrotic preferential phosphodiesterase 4 B inhibitors prevents a decrease in lung function in patients with IPF.