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Information for Patients

FIBROSING LUNG DISEASES – Information for patients

The term “fibrosing lung disease” covers a wide variety of different and frequently life-threatening illnesses, some of which are more common while others are extremely rare. Since lung fibrosis can have more than 100 different causes, both the correct diagnosis and treatment are difficult and require considerable effort on the part of doctors and affected patients.

Many patients are very anxious as a result of the large number of terms and the underlying diseases in question. This web-site is thus aimed at affected patients and their loved ones, but interested doctors as well. Over the following pages, we will give you useful clinical information, links to other web-sites and contact addresses – including our special outpatient clinics – and up-to-date scientific background information on “lung fibrosis”. Finally, the therapeutic measures that are currently available are listed.

We hope that many of the questions that concern you, as patients, will be answered by reading the information given here.

WHAT is lung fibrosis?

Fibrosing lung disease or lung fibrosis encompasses a large number of different clinical syndromes. These syndromes are all accompanied by a change in the delicate structure of the lung and disorders of gas exchange. They are diseases of the connective tissue of the lung (interstitium or parenchyma), from which the terms “interstitial lung disease” (ILD) or “diffuse parenchymal lung disease” are derived.

Some of these lung diseases start with a persistent inflammatory reaction which takes place in the air sacs (alveoli). In other forms, it is not so much the inflammatory reaction that is the prominent feature but, as we now believe, more the damage to the lining cells (epithelium) of the alveoli. Both processes subsequently result in increased formation of connective tissue and thus in fibrosis. This scar tissue forms both in the alveoli and between them, and in some forms around the airways (bronchi). Eventually there is also extensive loss of normally formed alveoli.

These processes make the lung stiffer with the result that more force needs to be used to stretch the lung and thus breathing becomes more strenuous(decrease in the elasticity or compliance of the lung). With the increase in the amount of connective tissue, the so-called diffusion distance increases. This is the distance that oxygen must cover when passing from the air side of the alveolus to the blood vessels (capillaries). As a result of this increase in the diffusion distance – as well as the loss of normally formed alveoli and thus the surface area for gas exchange overall – the uptake of oxygen into the bloodstream is made more difficult, giving rise to a decrease in exercise capacity.

HOW OFTEN does lung fibrosis occur?

There are still no reliable data for Europe on the proportion of the population with the disease (so-called prevalence) and on the number of new cases (so-called incidence).

A population based study from the USA that recorded data between 1988 and 1990 is currently the only reliable study on the incidence of fibrosing lung diseases. According to this study, the total number of patients is 67.2 (females) and 80.9 (males) per 100,000 inhabitants and the number of new cases of the disease per annum is 26.1 (females) and 31.5 (males) per 100,000 inhabitants.

Based on these figures, it is clear that fibrosing lung diseases occur much more frequently than has so far been assumed. Extrapolating to Europe, we estimate that approximately 750,000 patients have lung fibrosis.

HOW does lung fibrosis occur?

We are able to identify more than 100 different forms of lung fibrosis. In general, they can be divided into forms with a known cause and those with an unknown cause. However, there are a few that occur particularly frequently. In Europe, these include sarcoidosis, the group of idiopathic interstitial pneumonias and extrinsic allergic alveolitis.

Sarcoidosis and extrinsic allergic alveolitis are caused by chronic inflammation. In most cases, complete reversal of the changes is possible in the early stage. This occurs either spontaneously (that is, without treatment) or on treatment with steroids (e.g. cortisone). The group of idiopathic interstitial pneumonias is more difficult to evaluate in terms of its course and prognosis. This group currently includes 7 different subforms which can be differentiated on the basis of clinical, imaging and histological criteria. Within this group, idiopathic pulmonary fibrosis (IPF) has special significance because of its incidence and aggressive course. IPF can occur either sporadically or in increased numbers in certain families. The causes have so far not been discovered. In the last few years, however, a large amount of evidence has been found to suggest that chronic damage to the lining cells (epithelium) of the alveoli is involved in the occurrence of the disease.

As mentioned above, there are more than a hundred causes of the development of interstitial lung disease. The following list therefore does not claim to be complete:

  • Lung fibrosis as part of rheumatic-type diseases (collagen/vascular diseases)
    • - scleroderma
    • - rheumatoid arthritis
    • - mixed connective tissue disease
    • - polymyositis/dermatomyositis
    • - systemic lupus erythematosus
  • Lung fibrosis triggered by medical treatments
    • - antibiotics (e.g. nitrofurantoin)
    • - anti-arrhythmics (e.g. amiodarone)
    • - anti-inflammatory drugs
    • - anticonvulsants
    • - chemotherapy agents (e.g. bleomycin)
    • - radiotherapy
    • - oxygen
  • Lung fibrosis caused by inhaled dust particles
    • - inorganic dusts (asbestosis, silicosis [coal worker’s pneumoconiosis], talc pneumonia,)
    • - organic dusts (extrinsic allergic alveolitis)
  • Lung fibrosis in association with systemic diseases of unknown origin
    • - sarcoidosis
    • - amyloidosis
    • - Niemann-Pick/Gaucher’s disease
    • - Hermansky-Pudlak syndrome
  • Lung fibrosis of unknown origin
    • - idiopathic pulmonary fibrosis (IPF)
    • - non-specific interstitial pneumonia (NSIP)

WHAT symptoms occur?

The most common symptoms of lung fibrosis are breathlessness on exertion (exertional dyspnoea) and cough. The body’s exercise capacity decreases usually gradually and is thus often explained by affected individuals as normal limitations due to ageing. A reduction in the limit of performance during sporting activities is the most likely feature. In everyday life, the first problems usually occur when climbing stairs. If the disease progresses, the breathlessness may even occur at rest (dyspnoea at rest). The oxygen deficiency may also be seen as a dark blue colour (cyanosis) of the lips and fingers. Some patients may develop so-called finger clubbing (swollen ends of fingers) or watch-glass nails (swelling of the finger nails that resembles an hourglass).

A dry cough, a so-called non-productive cough, may be more marked on exercise, in the morning after getting up or during cold weather and is not easily tractable. In some patients, the cough is accompanied by clear to whitish sputum.

Patients with a fibrosing lung disease tend to have frequent infections of the airways and lung. Infection often results in the disease being diagnosed for the first time.

A rather rare symptom of the disease is the so-called door-stop phenomenon. In this, the patient notices that inspiration stops suddenly in a specific position, which the patient is then able to overcome again after a few breaths.

Furthermore, flu-like symptoms such as fatigue, mild fever, weight loss and muscle and joint pain may occur. The symptoms develop gradually over weeks and months and this distinguishes them from the similar symptoms of a cold.

If the lung fibrosis occurs as part of a systemic connective tissue disease (e.g. collagen vascular disease), other complaints and symptoms in other parts of the body and organs can be found, such as blue discolouration of the fingers (so-called Raynaud’s syndrome), dry eyes (sicca symptoms) or difficulties swallowing.

In specific syndromes, there may be an increase in symptoms due to environmental factors, such as in extrinsic allergic alveolitis. This disease is due to sensitisation of the body to certain organic substances (allergens). In this context, antibodies to these substances are formed. Frequent triggers are feathers of pigeons and canaries, fungal spores and certain bacteria. On contact with, or inhalation of, these substances, there is then an increase in symptoms. These symptoms (including watering of the eyes, fever, increased breathlessness) typically occur after a slight delay of about 4 to 8 hours after exposure.

HOW is lung fibrosis diagnosed?

If there is a well-founded suspicion of the presence of lung fibrosis, a range of investigations are necessary. It is important to take a very thorough history (questioning of the patient). In particular, this provides important information on what triggered the disease, e.g. through inhaled inorganic or organic dusts or medicines.

Questionnaires such as the Frankfurt Questionnaire, or the patient questionnaire used in the European IPF Registry may be helpful in this. These questionnaires cover all relevant aspects of the possible causes of lung and airways diseases, such as, in particular, contact with animals, occupational, family, drug, housing and environmental history.

Costly clinical and laboratory investigations (e.g. determination of rheumatoid factor or immunological investigations) are also generally necessary.

The basic diagnostic investigations include:

  • physical examination
  • lung function tests (with body plethysmography [measurement of lung function in a cabin resembling a telephone box], measurement of CO diffusion [measures how well oxygen from the air gets into the bloodstream via the alveoli] and analysis of capillary blood gases [determination of the blood oxygen and carbon dioxide content])
  • X-ray of the lung/high-resolution computed tomography

In the early stage of the disease, there may be no changes in lung function and X-ray findings, a fact that often leads to delay in making the diagnosis.

Among the clinical investigation methods, only the measurement of CO diffusion and so-called ergospirometry [measurement of lung function under stress] are sensitive enough to be able to reliably exclude the presence of lung fibrosis.

The situation is similar regarding imaging investigations; the X-ray is one of the first investigations. X rays are able to pass through fibrotically changed tissue to only a limited extent with the result that the X-ray film is not as black and therefore “whiter” than normal lung tissue at these sites. However, the X-ray may be unremarkable in up to 10% of patients with lung fibrosis or may not be specific for lung fibrosis. Thus, in most cases, a computed tomography (CT) scan of the lung is needed as a further investigation. It has the advantage of giving images that are not superimposed. From the point of view of technology, a high-resolution (so-called HRCT) scan should be performed for this. Compared to the clinical investigation findings, only after an HRCT has been performed is it possible to reliably exclude fibrosing lung disease.

In order to determine the cause and classify the lung fibrosis, in many cases a bronchoscopy (lung endoscopy) is also recommendable[D1] . During this procedure, bronchoalveolar lavage (BAL: rinsing an individual lung segment with saline), a differential cell count (examination of individual cells), a microbiological examination (examination for organisms and pathogens in the lung) and transbronchial as well as mucosal biopsies (removal of a sample of tissue from different parts of the lung using a small pair of forceps) are performed.

In quite a number of cases, a definitive diagnosis is not possible even despite the above-mentioned investigations, so removal of a larger tissue specimen is needed. In most cases, a minimally invasive procedure in the form of so-called video-assisted thoracoscopy (VATS) is undertaken. This procedure is now associated with a very low complication rate and in most cases allows reliable evaluation of the disease process.

The diagnosis cannot currently be made only based on so-called surrogate parameters (e.g. blood tests). However, these tests can result in important additional information that shows an association between the lung disease and another disease, for example.

Parameters to monitor the course of the disease are regular lung function tests, blood tests, stress tests and radiological investigations.

Given the complexity of the disease syndrome, the definitive diagnosis of lung fibrosis should be made through discussion between experienced lung specialists, pathologists and radiologists, following the recommendation of the American Thoracic Society (ATS) and the European Respiratory Society (ERS). In case of specific issues, it is worth consulting a specialist in occupational medicine. The diagnosis can be established with the best-possible reliability based on current knowledge only through interdisciplinary cooperation in the diagnostic process. Sometimes, however, even the
diagnosis made as part of such a collaborative discussion has a provisional nature as, for example, new aspects may be discovered after further diagnostic procedures. Also in the case of very advanced change in the lung tissue, it is sometimes no longer possible to reliably classify the changes. The doctors and hospitals participating in the European IPF network hold such interdisciplinary discussions at regular intervals.

WHAT is the prognosis?

The natural course of fibrosing lung diseases differs greatly depending on the underlying form. Spontaneous improvements or even complete reversal have been observed in some patients with sarcoidosis. If the disease has been triggered by noxious substances (e.g. cigarette smoking in the cases of respiratory bronchiolitis, RB-ILD) or allergens (e.g. bird feathers in extrinsic allergic alveolitis), the disease undergoes regression in the early stages if the triggering substance is avoided. Other forms respond to treatment with cortisone (if necessary in conjunction with other immunosuppressant substances). Complete regression on treatment is seen, for example, in the case of cryptogenic organising pneumonia (COP).

In the other forms, slow progression of the disease predominates. As a result of the processes causing the changes in the lung, gas exchange is increasingly impaired. Additional administration of oxygen is eventually required. Oxygen therapy is given either only during stress or in the form of long-term oxygen therapy (LOT) including at rest. Depending on the patient’s functional impairment, early retirement is necessary.

Patients with lung fibrosis have increased susceptibility to infections of the airways and lung, which should be treated early and systematically. Hospital admissions are frequently required during such infections.

By considering the prognosis, course to date, age, concomitant diseases and current impairment, lung transplantation is a possibility. This procedure involves not inconsiderable risks and stresses but in many cases can greatly improve the prognosis and quality of life of patients with fibrosing lung diseases.

In view of the relative frequency and aggressive course, so-called idiopathic pulmonary fibrosis (IPF) is of particular importance among the types of fibrosing lung disease. The life expectancy in this form of lung fibrosis is greatly reduced.

WHAT treatments are available?

Fibrosing lung diseases are accompanied by partly reversible and partly irreversible changes in lung tissue. The aim of treatment is therefore to cause the reversible changes to regress and to halt the irreversible changes.

Cortisone drugs are most frequently used in the treatment of fibrosing lung disease. These drugs have been successfully used in certain forms of sarcoidosis. In extrinsic allergic alveolitis, these drugs bring about accelerated regression of changes in the initial stages. If the lung fibrosis occurs within the context of rheumatic diseases, the cortisone therapy often needs to be augmented or replaced by other immunosuppressant drugs.

Based on previous recommendations cortisone and immunosuppressants (e.g. cyclophosphamide and azathioprine) have been frequently used for the treatment of patients with idiopathic pulmonary fibrosis (IPF). While the response to this treatment is somewhat rare and usually only means temporary stabilisation of the course and the use of azathioprine is meanwhile proven potentially harmful this treatment is no longer recommended.

To date the only anifibrotic substance that holds a market authorization within the EU is Pirfenidone. Pirfenidone is used for the treatment in mild to moderate IPF. Against this background, other medicines are currently being tested in clinical studies[D1] .

In addition to drug treatment, all patients benefit from stopping smoking, since smoking is associated with more rapid disease progression. Furthermore, despite the lack of studies on the benefit of physical exercise, the experts are unanimous that regular exercise improves the symptoms and quality of life. Infections of the airways should be treated early and generally with antibiotics. In the absence of a response, inpatient treatment is usually necessary.

Depending on more specific circumstances, the possibilities and risks of a lung transplantation should be discussed when IPF is diagnosed so as to be able to undertake the necessary preliminary examinations early on, for example.

Given the poor prognosis of IPF, alternative treatment approaches have recently been developed. Studies on these have been and are being conducted:

Phase II studies
 
Phase III studies (ongoing or completed)
  • inhaled heparin (DOSEFIB)
  • the leukotriene antagonist zileutin
  • antibodies to CTGF (connective tissue growth factor)
  • the TNF-α inhibitor etanercept

 
  • N-acetylcysteine (IFIGENIA)
  • Interferon-γ 1b (INSPIRE)
  • Pirfenidone (CAPACITY)
  • Glivec (imatinib mesylate)
  • Bosentan, Macitentan (BUILD 3, MUSIC)
  • Intedanib (BIBF1120)
  • Ambrisentan (ARTEMIS)
  • Sildenafil (STEP-IPF) 

In recent years, much new information has been obtained on how IPF occurs. Developing new treatments based on these findings and being able to offer these to patients will be a challenge of the next few years.