Idiopathic Pulmonary Fibrosis

 

Pulmonary Fibrosis

 PKGhatak,MD

Pulmonary fibrosis is a pathological term indicating the presence of abundant fibrous tissue in between the alveoli (air sacs) of the lungs. This entity is not just one condition but more or less 200 different conditions/ diseases that are included under this broad definition.

In the interest of patients, Pulmonary fibrosis may be considered just two entities. 1. Unknown causes. 2. Known or secondary to another illness the patient is suffering or had suffered recently.

Unknown causes of Pulmonary Fibrosis are called Idiopathic Pulmonary Fibrosis or IPF in short. In this article, an attempt will be made to summarize updated information on IPF.

The current covid pandemic has generated fear, interest, discussions on infections, immune responses, overactive immune system, resulting in a Cytokine storm, pneumonia, and the cause of death of unfortunate patients. The public has already acquired some information about them.

The protective system that keeps our body free of infections, cancers, parasites, etc. also has another important function is to repair the damaged tissue and make the body whole again.

The repair of danged tissue is undertaken in stages. In the initial stage, the dead cells and other foreign agents are removed from the site, then in the next stage, the damaged parts are stitched together by laying down fibrous tissue, like we repair torn fabrics with threads. And the final stage is the remodeling of the damaged site involving laying down various tissues by the respective Stem Cells.

In Idiopathic Pulmonary Fibrosis, the final stage does not happen, instead, the fibrous tissue keeps growing. This fibrous tissue has very little elasticity, unlike the healthy elastic tissue of the lung. We breathe in the air by expanding the chest wall unconsciously without effort by contacting the diaphragm and a group of breathing muscles. The fresh air from outside which is rich in oxygen enters the lungs and travels to the tiny air sacs, called alveoli. Carbon dioxide leaves the blood and oxygen enters the blood. Then inhalation stops, the lungs return to the initial state by the pull of the elastic tissue of the lung and the carbon dioxide containing air is forced out of the lungs.

Fibrosis of the lung disrupts this smooth respiration and the exchange of gases. More effort is required to inhale and exhale. Breathing becomes a laborious effort, the patients generally refer to shortness of breath.

What is the incidence of IPF.

In the USA the incidence is about 8 per 100,000 people per year, and the estimated worldwide rate is 20 per 100,000 people /year.

Is IPF a hereditary disease.

In general, IPF is seen as just one person in a family. When more than one person in a family has identified this disease then the illness is called Familial IPF. The incidence of Familial IPF is about 5 % of all IPF cases.

What are the known mutations of gene/ genes or abnormal DNA of chromosomes.

This field is expanding. As of now, in about 15 % of cases of IPF the TERE and TERT gene mutations are documented. These mutated genes are located in the Telomers of Chromosomes. As a result, the Telomerase enzyme decreases. In the end, the alveolar cells die and an increase in fibroblasts occurs. The fact that IPF patients are over 50 years of age when they notice shortness of breath supports this. It is postulated that the mutation of genes begins initially with a few genes and as time passes the population of mutated genes increases and the changes in the lung become significant enough to produce symptoms.

What are the presenting symptoms.

The most common symptoms are shortness of breath and persisting dry cough. Later on, breathlessness develops even at rest. Fatigue, decreased appetite and weight loss follow.

What physical abnormalities detected by examination.

The findings are: rapid rate of breathing, clubbing of fingers, bluish nail beds and lips, dry rales also called crackles detected by listening with a stethoscope over the bases of lungs. In more advanced cases signs of right ventricular hypertrophy and congestive heart failure are present.

 What other names of IPF were used before.

In the past IPF was called Hammond-Rich syndrome, Cryptogenic fibrosing alveolitis, Chronic idiopathic fibrosing alveolitis, Usual pulmonary fibrosis, immune pneumonia, desquamating interstitial pneumonia and now it is simply known as IPF.

What tests are considered diagnostic.

Until recently an open biopsy of the lung was required for a definitive diagnosis. A high-resolution CT (HRCT) demonstrating typical radiological findings and absence of other radiological signs of specific illnesses, in a clinical situation consists of patients over 50 years of age, presented with symptoms and signs listed above. This is enough to make a firm diagnosis of IPF. Lung biopsy is called for only when this method fails.

What are specific signs detected in HRCT.

The disease preferentially involves the lower lobes of the lung, and the degree of changes is variable from one location to the other, even varies within a given section. Changes begin in the distal parts of the lung and then spread toward the central part of the lung. Septal thickening, honeycombing pattern, traction bronchiectasis, subpleural and basal reticulations are diagnostic for IPF.

If a biopsy is performed, what are the diagnostic findings.

The pathological changes are variable because of the nature of IPF. However, these changes are present: alveolar cell damage, accumulation of fibroblasts, contraction and collapse of alveolar architecture, deposition of collagen I, collagen III and fibro mucin deposition in the extracellular matrix.

Why bronchoscopic biopsy of the lung is not advocated in IPF.

The tissue obtained in bronchoscopic biopsy is tiny, a larger piece of the lung is necessary for proper examination because of non-uniform pathology. Post biopsy pneumothorax generally follows because the lung is stiff and fails to contact and seal the opening made by biopsy.

Why right ventricular hypertrophy and congestive heart failure develop in IPF.

The right ventricle pumps out blood into the lungs via the pulmonary artery - one to the right and one to the left lung. The distortion of pulmonary architecture causes blood vessels to twist and the lumen becomes narrow and this change causes obstruction of easy blood flow to the lungs. Vascular resistance increases. This is called pulmonary hypertension. The hypertrophy of the right ventricle is just an attempt to increase the force of contraction to overcome pulmonary hypertension. When this compensatory mechanism fails congestive heart failure develops.

What are the fundamental abnormalities in IPF.

Leukotrienes (ILs), Prostaglandins (PGs) and Cytokines are important in the development of IPF. Many previously accepted theories, in the genesis of IPF, are discarded. Today the theory, that most researchers agree with, is highlighted here:

For reasons unknown, the alveolar type I cells die prematurely and steadily. The type II alveolar cells proliferate to cover the exposed basement membrane. In IPF the alveolar type II cells do not disappear, as type II cells should do in normal repairs. Instead, type II cells recruit Macrophages which in turn recruit fibroblasts and transform them into myofibroblasts. Myofibroblasts secrete collagen. In inherited cases, the DNA gene mutation encodes a defective protein, Surfactant C, an unfolded protein. The mutated genes are located in Telomerase coding areas. This protein also limits cell repair. The CD4TH1 cells stimulate the Macrophages of the lungs to transform into macrophage1 cells (M1). M1 expresses IL-12(interleukin-12), TNF (tissue necrosis factor) and Chemokine CXCL10. All of these lead to tissue destruction. In acquired IPF mutated gene preferentially stimulates CD4 helper T cells (CD4TH2) cells which in turn stimulate the growth of immune response cells and not the inflammatory cells. CD4TH2 cells stimulate the production of macrophage 2 cells (M2) that lead to the production of IL-4 and IL-13. Both are stimulants to fibroblast proliferation and angiogenesis.

What other IL (Leukotrienes) influence IPF.

IL-13 is an important mediator of pulmonary fibrosis. IL-1 contains 11 subunits, 4 of them act to suppress inflammation, whereas, the remaining 7 are proinflammatory.

Role of Prostaglandins (PDs) in IPF.

PD E2 normally inhibits fibroblast proliferation and its migration to the lungs. Also decreases collagen secretion and limits growth factor (TIF beta). In IPF the signaling of PD E2 is downgraded as a result fibroblast activities are not restricted. Prostaglandin D2 expresses the COX2 enzyme which enhances IPF.

Role of Cytokines in IPF.

The role of cytokines in IPF is complex. The balance between pro-inflammatory cytokines and profibrogenic cytokines is tilted in favor of angiogenesis and fibroblast proliferation. The pro-inflammatory cytokines are CCL17, CCL22, CCL2, and CCL3. The proangiogenic cytokines are CXCL8, CXCL5, and CXCL12 and antiangiogenic are CXCL9, CXCL10, and CXCL11. CXC chemokine is thought to promote aberrant neo-angiogenesis and lung recruitment of circulating fibrocytes, with the contribution of TGF-β. 

The fibroblast proliferation and extracellular matrix deposition induced by TNF-α include interleukin (IL)-1α, IL-1β, and TGF-β. All these cytokines exert their effects on lung fibroblasts through induction of the secretion of platelet derived growth factor PDGF. The platelet derived growth factor PDGF and connective tissue growth factor CTGF is the final movers in fibroblast recruitment and proliferation and in the end the alveolar cell proliferation and myofibroblast generation and collagen deposition in the matrix. 

What other tests are performed in IPF.

Two sets of tests are obtained before starting the treatment of IPF.

The first one consists of determining the lung volumes, diffusion capacity and pulse oximetry.

The other tests are a battery of tests to exclude any treatable disease that was overlooked at the time of final diagnosis. That part of the tests is left out in this discussion.

Lung volumes and diffusion capacity.

The vital capacity, total lung capacity, inspiratory reserve volume and functional residual capacity are all reduced. These tests are known as Pulmonary Function Studies. These pretreatment numbers are used for monitoring the disease. The diffusion capacity test is an indication of the severity of the functional consequences of IPF. Subsequently, repeated diffusion capacity tests are not necessary, that can be judged by pulse oximetry test alone.

Medications prescribed for IPF.

As we are experiencing controversy in the treatment of covid, this is also true in the IPF cases. However, it is going on outside social media. Until recently all new cases of IPF were prescribed prednisone, azathioprine and N-acetylcysteine. This protocol now is abandoned because of the lack of effectiveness.

What treatment modalities are helpful.

Oxygen therapy, in any and every way, to keep the oxygen saturation above 87 % at all times throughout 24 hours a day. Oxygen therapy delays the onset of Pulmonary hypertension and congestive heart failure. Lung transplantation, whenever possible, should be done. Lung transplant is considered curative therapy.

Are there any drugs to modify the immune response in IPF.

Several drugs are in the process of development. Two anti-fibrogenesis drugs have already been approved in order to slow down the formation of fibrous tissue. The results are encouraging but each one has significant side effects.

Names of Immunomodulators approved so far in the treatment of IPF.

Nintedanib (Ofev) is an oral medication given 3 times a day. It is a tyrosine kinase inhibitor. It slows down the progression of the disease mainly by stopping angiogenesis. Side effects are nausea, vomiting and anorexia. Early onset of drug resistance requiring discontinuation.

Pirfenidone (Esbriet). Given orally twice a day. The drug is an antifibrotic agent. Side effects include heartburn, nausea, diarrhea, anorexia and photosensitivity.

Is any Monoclonal Antibody drug available to treat IPF.

Pamrelumab, an anti-connective tissue growth factor (CTGF), has shown promise in the second stage of the trial. Several other monoclonal antibodies are in a development state.

Macrophage M2 antigen is isolated and currently, an antibody development against M2 is formulated.

What is the prognosis of IPF.

The disease is progressive and patients generally survive between 3 to 5 years from the time of the diagnosis.

The basic pathophysiology of IPF has gone through major revisions. The theory of inflammatory damage to the alveoli followed by fibrosis is no longer tenable. Inflammatory reactions, if any, in IPF are the result of damage of alveoli rather than the cause. The complex interactions between various cytokines, Leukotrienes, prostaglandins, immune cells and particularly the macrophages growth factor and platelet derived growth factor is complicated for easy understanding. IPF is a progressive and fatal disease and the treatment so far is not very satisfactory except for Lung Transplantation and continuous oxygen therapy.

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