Idiopathic pulmonary fibrosis and other forms of progressive fibrosing interstitial lung diseases

Symptoms and Diagnosis

Pulmonology is rapidly developing today, especially after the COVID-19 pandemic. With the overall increase in knowledge in the field of pulmonology, knowledge of interstitial lung diseases is also growing. Without good knowledge of pulmonology, a range of lung diseases cannot be diagnosed or treated.

With advances in diagnosis, an individualized approach to the patient is becoming increasingly important. It is still unknown why some patients develop a lung disease and others do not, even though we fully understand the mechanisms of these same diseases. For example, why does one worker who has worked with metal dust and was a smoker develop pulmonary fibrosis, while another worker in the same factory does not.

Therapeutic options have significantly improved. This is encouraging for pulmonologists, as we are witnessing changes in the individual’s life; from better quality of life (no frequent visits to emergency departments), increased ability to tolerate physical exertion, reduced absences from work, and other important everyday situations. Unpleasant symptoms, such as daily several-hour dry cough, difficulty climbing stairs, going to the store, and the like, drastically reduce the quality of life. The most common questions from patients in everyday practice are “Will I get better, and when?” and “When will I start to notice the effect of the medication?” Patients expect a quick effect of the treatment because their quality of life has been significantly compromised.

Idiopathic pulmonary fibrosis (IPF) and other fibrosing interstitial lung diseases (PF-ILDs) are diseases that worsen permanently. IPF manifests itself in older age (usually from 60 to 80 years of age), where soft and stretchy lung tissue turns into rigid and inelastic tissue full of small scars. When the lungs are not stretchy, they are difficult to fill with air, and that is precisely why patients have various problems. A permanent and mild inflammation in the lungs is the main cause of this disease. This inflammation is the reason why patients do not have a fever, and it can be caused by smoking, metal dust, gastric acid (in people with acid reflux and heartburn), and genetic predisposition. With an ever-increasing life expectancy, the number of patients with this diagnosis is expected to increase.

In the diagnosis of IPF, pulmonary function tests (spirometry, diffusion) are helpful. There is also a reduced amount of oxygen in the blood, especially during physical exertion. LDH values are elevated in the biochemical findings.

Patients with idiopathic pulmonary fibrosis (IPF) typically have a dry, non-productive cough that lasts for more than six months and does not respond to antitussives (medicines for dry cough) and worsens with shortness of breath during physical exertion (especially climbing stairs). Chest tightness is also a common symptom. Other nonspecific symptoms may include fatigue, muscle and joint pain, and weight loss. To confirm the diagnosis, a CT scan of the lungs is needed, where the radiologist’s report will state that the lungs look like “honeycomb.”

If doctors are unsure whether IPF is the diagnosis, they may also recommend a bronchoscopy, which involves flushing the lungs with small amounts of water, and samples of that water from the lungs can be sent for further analysis to rule out other diseases (sarcoidosis, berylliosis, hypersensitivity pneumonitis, eosinophilic pneumonias, lymphangioleiomyomatosis, and other diseases).

A holistic approach is always necessary when dealing with a patient to check for signs of other systemic diseases (rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis), which can also “attack the lungs.” This way, we can also rule out hypersensitivity pneumonitis caused by environmental allergens (birds, hay, dust, molds) and occupational lung diseases as a result of exposure in the workplace (asbestosis, berylliosis).


Accelerated development and new discoveries in pulmonology provide hope for our patients for better treatment outcomes and better prognosis. Unfortunately, many diseases in pulmonology and medicine, in general, do not have satisfactory control with existing drugs. For this disease, we currently use only one group of drugs, which are antifibrotics. Antifibrotics are taken orally. These are drugs that slow down the formation of small scar (fibrous) tissue that turns the lungs into a “honeycomb.” So, this group of drugs is aimed at the consequence of this disease, not the inflammation that is its cause. Unfortunately, antifibrotics (nintedanib, pirfenidone) do not provide completely satisfactory treatment results.

The mechanism of action of pirfenidone is not yet fully understood. It is assumed that it primarily regulates tumor necrosis factor (TNF) pathways and modulates cell oxidation. In this way, it reduces the proliferation of fibroblasts and reduces the accumulation of inflammatory cells. Nintedanib is a small molecule, a tyrosine kinase inhibitor that inhibits kinase activity to ultimately inhibit the proliferation and migration of lung fibroblasts. Like any drugs, antifibrotics have their profile of possible side effects. Given that the receptors on which antifibrotics act are also found in other cells, not just inflammatory cells, certain side effects may occur. The most common side effects occur in the form of gastrointestinal problems (frequent diarrhea, which often led to discontinuation of therapy), and skin changes, especially at the beginning of therapy, leading to discontinuation at the start. Nintedanib is also associated with the risk of drug-induced liver damage, especially within the first three months of therapy.

PDE4 inhibitors

Today, the hope for better treatment success for these diseases is focused on a new group of drugs, namely phosphodiesterase 4 (PDE4) enzyme inhibitors. PDE4 inhibitors are non-steroidal anti-inflammatory agents that target signaling pathways towards inflammatory cells. The mechanism of action is based on the inhibition of PDE4, the main enzyme that metabolizes cyclic adenosine monophosphate (cAMP) and is present in structural and inflammatory cells.

Non-selective PDE4 inhibitors that are currently available on the market inhibit various variants of PDE4 (e.g., PDE4A, 4B, and 4D variants in the nanomolar range). Different PDE4 inhibitors have been approved for the treatment of various diseases such as chronic obstructive pulmonary disease (COPD), psoriasis, psoriatic arthritis, Behçet’s disease, atopic dermatitis, amyotrophic lateral sclerosis (ALS), and Krabbe disease.

However, there are now also selective PDE4 inhibitors in the final stages of testing, such as PDE4B inhibitors that are much more selective for the B variant of PDE4. Because of their selectivity, unlike available antifibrotics, a significantly lower risk of potential side effects is expected. Selective PDE4B inhibitors have shown strong antifibrotic and anti-inflammatory effects to date, and are expected to have an enhanced effect in treatment when used together with available antifibrotics. The final phase of testing with the selective PDE4B inhibitor is about to begin, and we are excited to see the results. We have high hopes for improving the treatment of IPF and PF-ILD with selective PDE4B inhibitors.

Today, it is important to raise awareness of the diagnosis of fibrotic interstitial lung diseases (IPF and PF-ILD) because it is known that the earlier the disease is diagnosed, the more effective the treatment will be.

Assist. Prof. Marija Gomerčić Palčić, MD, pulmonology specialist

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