Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of unknown cause, affecting especially elderly, leading to death by respiratory failure in 3 to 5 years, if untreated. Current anti‐fibrotic treatments available manage to stabilize the course of the disease, providing the maintaining of the patient in the functional status and probably improving survival. The incidence of IPF is low and varies widely all over the world. In Romania the figures are not known, but the disease is severely underdiagnosed, probably due to confusion with other more prevalent diseases presenting with progressive exercise dyspnea. This paper aims to review the main clinical and investigational elements that should trigger the suspicion of IPF at the first presentation of the patient to any physician: family doctor, ambulatory or hospital pulmonologists or internal medicine doctors. The dyspnea present only during exercise, the absence of paroxysmal dyspnea, of wheezing, of orthopnea, the dry cough, the finger clubbing, the presence of dry bibasilar crackles in inspiration, the decrease in oxygen saturation during exercise, the restrictive syndrome on spirometry, and the bilateral reticular X-ray changes should determine the physician to suspect an interstitial lung disease and to refer the patient to an expert center for further investigations and an accurate diagnosis.
Idiopathic pulmonary fibrosis (IPF) is a rare disease, still it is the most prevalent of all idiopathic interstitial lung diseases (ILDs). IPF is a devastating disease: the development of scar tissue in the parenchyma of the lungs impairs the capacity of the lungs to do their main job in the body, that is to provide oxygen to the blood. Untreated, IPF induces respiratory failure and, due to its relentless and progressive course, leads to sufferance, limitation of the exercise capacity of the patient, inva-lidity, and a premature and painful death in 3 to 5 years after diagnosis(1).
The incidence of IPF in the world has increased con-stantly in the past decade, probably mainly as a conse-quence of an increase in diagnosis, due to a better understanding of the disease, to the use of complex imaging techniques and to the increase of the number of patients receiving a proper diagnosis and, eventually, treatment(2).
The numerous studies published offer a large range of incidence figures worldwide, according to the epidemiologic method used, to the diagnosis criteria, but also true regional differences may be present. The incidence of IPF varies between 36.6 per 100,000 population in California and 0.48 per 100,000 population in Brazil(2). The EMPIRE Registry for IPF, based in Prague, provides an incidence of 5.3 cases in 100,000 inhabitants for the Czech Republic(3).
In Romania there are no epidemiological studies aim-ing to identify the incidence of IPF. If the incidence in the Czech Republic were applied to the Romanian popu-lation, a simple calculation would estimate a number of about 1,060 IPF patients in our country. Currently, since the approval of anti‑fibrotic drugs for the treatment of IPF in 2017, the number of patients diagnosed and treat-ed is increasing, still it does not exceed 100 known patients. One should legitimately question: where are the others? IPF is not a disease that can be ignored, as the symptoms worsen in time, and the patient soon has severe limitations of his/her daily activities due to dysp-nea. The patient would certainly seek medical help at some point, and probably this is the moment when, in the absence of the physician’s suspicion of an interstitial lung disease, the patient would be given an alternative, more prevalent, more “at hand” diagnosis.
What are the hints for suspecting an interstitial lung disease at first hand? What details should trigger the attention of a doctor facing such a patient?
IPF, very similar to other ILDs, presents with two main symptoms: dyspnea and cough(1). These are com-mon to most chronic respiratory diseases, as well as to heart failure. But the features of the dyspnea in ILDs and especially in IPF are quite characteristic, and should suggest to the clinician the suspicion of an ILD.
The dyspnea is present only during exercise, worsen-ing over several months. Most patients present to the doctor when shortness of breath gets to be present when walking on flat ground at a speed that previously didn’t raise any problems. At rest, the patient feels perfect. This is related to the impaired diffusing capacity of the lung, that manifests initially only during exercise, when a higher need for oxygen is not matched by the impaired oxygenation of blood through the fibrotic lung paren-chyma. The dyspnea is chronic, with no paroxysmal moments, as we typically see in asthma. Also, wheezing is uncommon in ILDs. Unlike the dyspnea in heart fail-ure, there is no orthopnea in ILDs. The patient can lie down on his/her back without perceiving any supple-mental shortness of breath.
The cough in ILD is typically very dry, it may be trig-gered by deep inspiration or exercise, and is described by the patients as very uncomfortable and unable to relieve the trigger.
As for other symptoms, one of the main character-istics of IPF is that it affects the lungs only, and symp-toms outside the respiratory symptoms are absent in most cases.
Some patients complain of acid regurgitations, mark-er of a gastroesophageal reflux (GER). This is present in IPF patients more frequent than in general population, leading to the assumption that GER may play a patho-genic role in the development of lung fibrosis by chronic acid microaspiration. Still, it may be the other way around, the weakening of the cardial sphincter second-ary to the traction of the lower mediastinum due to the lung fibrosis may favor the acid reflux, explaining the high frequency of gastric reflux in these patients(4).
The clinical examination is very useful for the sus-picion of an ILD. At rest, like when the patient is sitting in the doctor’s office, the IPF patient has no overall characteristic features. It is usually an older individual, probably in his 60’s, probably a former smoker, with no particular sitting position, breathing pattern or facial signs, so “blitz diagnosis”, like in COPD, for example, is not an option.
Many ILD patients have clubbing of the fingers (observed typically in the moment when the physician uses the pulse oximeter to measure oxygen saturation).
The physical examination of the respiratory system shows no deformation of the chest, but the auscultation can find the typical crackles, very dry (described as “Velcro” sounds or like the sound of walking on snow in a freezing day), that can be heard at the bases of both lungs at the end of inspiration. Typically, no rhonchuses and no wheezes can be heard. There might be a problem to differentiate between the IPF crackles and the more “humid” basal rales of the heart failure. Anyway, a car-diac patient displaying these sounds would certainly also complain of orthopnea.
There are plenty of recordings of the “sounds of IPF” on the Internet(5). Still, the clinician should not expect to hear selected and amplified sounds in the usual clini-cal setting. Instead, the doctor should carefully look for the very dry crackles at the bases of the lungs at the end of inspiration, by a thorough and patient auscultation.
The exercise dyspnea corresponds to a decrease of oxygen saturation during an effort. This can be easily proven by a 6-minute walk test. The test involves the access to a long (at least 30 meters) and uncrowded cor-ridor, where the patient is invited to walk as fast as he can for 6 minutes. The distance walked in 6 minutes, the initial and final oxygen saturation and dyspnea (using the Borg scale) are measured. The results are influenced by a multitude of factors besides the perfor-mance of the respiration: cardiac performance, muscle training, joint problems(6). Still, the decrease of oxygen saturation during the test is extremely useful for sus-pecting a respiratory disease, given that a normal indi-vidual will experience an unchanged or an increased saturation during an effort.
In the typical ambulatory settings, it is difficult to perform a standardized 6-minute walk test. Anyway, less standardized methods can be used to objectify the decrease of oxygen saturation at exercise, like asking the patient to climb a flight of stairs or take a walk around and measure the saturation before and after.
The spirometry is mandatory for the assessment of a patient complaining of dyspnea. Typically, ILD patients will display a restriction, with a parallel decrease of vital capacity and FEV1, and a normal FEV1/FVC ratio(7). A hint for the presence of fibrosis is a slightly increased FEV1/FVC ratio. This is caused by the small airways being kept open during forced expiration by the extrin-sic traction determined by the fibrotic lung parenchyma.
Obstruction is uncommon in ILDs, and spirometry may be a very useful element of differentiation between an ILD and COPD in the ambulatory setting.
Of course, spirometry is useful if it is correctly per-formed, otherwise it can lead to more confusion (for example, a COPD patient who does not perform a com-plete expiration will display a false restriction, instead of the typical obstruction).
Chest X-ray may be useful for the diagnosis of ILD, and it is very useful for a differential diagnosis(1). In IPF, fine reticular opacities and sometimes thin-walled cysts can be seen diffuse bilaterally, and mainly in the lower lobes. Still, the chest X-ray may be normal, or the chang-es may be so discreet that are considered just the normal vascular pattern. A normal chest X-ray may be one of the main reasons for missing the diagnosis of an interstitial lung disease! Thus, the clinician should not discard the suspicion of an ILD based on a normal chest X-ray. A plain chest X-ray is far from being the gold standard for the diagnosis of IPF! A clinical and/or radiological sus-picion of an ILD should trigger the recommendation of a high resolution computer tomography of the chest (HRCT), which improves considerably the accuracy for the identification of interstitial imaging changes.
The X-ray is useful for identifying other causes of dyspnea, such as emphysema, infection (including tuberculosis), bronchiectasis, lung tumors, cardiac enlargement, and pleural effusion.
IPF resembles many other diseases with dyspnea and discreet bilateral radiologic changes, leading to confusion.
COPD: in both IPF and COPD, the patient is usually a current or former smoker, complains of progressive dyspnea at exercise and can have finger clubbing. But in COPD productive cough is frequent, the ausculta-tion reveals bronchial rales or diffuse diminished lung sounds due to emphysema, and the spirometry shows obstruction.
Asthma: older and chronic asthma patients may complain of exercise dyspnea, but they also have paroxystical dyspnea accompanied by wheezing, sometimes wake up during the night because of the shortness of breath, the auscultation of the lungs reveals wheezes, and the spirometry shows obstruc-tion reversible to bronchodilators.
Heart failure is a very common condition in the elderly, manifesting with dyspnea at exercise. These patients complain also of shortness of breath when lying down and prefer to use several pillows to help them keep an upper position of the thorax to allow them to sleep, which never happens in ILD patients. Other clinical signs can be present: cardiac arrhyth-mias, edema of the lower limbs, visible jugular veins, high blood pressure, the lung sounds are bibasilar but more “humid” than the typical IPF crackles. The chest X-ray may show an enlarged heart, minimal pleural effusion, and augmented vascular shadows.
Exercise dyspnea can be encountered also in physi-cal deconditioning or hysteria, accompanied by normal physical examination, chest X-ray, and spirometry.
The radiologic “interstitial syndrome”, characterized by bilateral diffuse reticular and/or micronodular changes, can be seen in different conditions:
carcinomatosis of the lungs;
infection (e.g., pneumocystosis, invasive aspergillosis);
IPF suspicion: summary
Here are, in summary, the “hints” for suspecting an IPF at the first presentation to a physician, no matter if this is a general practitioner, a pulmonologist or an internal medicine doctor, in an ambulatory setting or in hospital (Table 1).
What comes next?
It should be stressed that the diagnosis of “pulmo-nary fibrosis” is not enough at this stage. The so-called “pulmonary fibrosis” doesn’t exist as a distinctive dis-ease. The term is usually used as a surrogate for “inter-stitial lung disease”, but refers to a patient with a yet undefined interstitial disease, and more efforts are needed to assign the patient to one of the more than 200 different entities comprised in the group of ILDs.
Just sending the patient home with a diagnosis of “pulmonary fibrosis” and with various recommendations will just delay the moment of the accurate diagnosis and postpone a correct treatment. We frequently see patients diagnosed with “pulmonary fibrosis” based only on the aforementioned elements, and they are recommended oral corticosteroids, or inhaled corticosteroids, or inhaled com-bination therapy (corticosteroid + bronchodilator), or no treatment at all, and no other referral either.
The correct attitude when faced with a patient with suspected IPF is to refer the patient to a center with expertise in the diagnosis and treatment of ILDs.
Before referring the patient, some physicians would prefer to request a CT scan of the thorax, which is a very useful tool for obtaining supplemental information. Anyway, it should be stressed that this CT needs to be a high resolution exam (HRCT), with thin sections (ideally, 1 mm) and a lung algorithm(1). Otherwise, a standard exam with sections thicker than 3 mm is not enough to differentiate the fine changes of the lung parenchyma, that make the difference between IPF, NSIP and chronic hypersensitivity pneumonitis, for example. Typically, once arrived in an expert center, the patient will need to repeat the exam with high resolution, with an undesired repeated exposure to a high dose of radiation.
The expert centers have equipment for complex investigations, like measurement of diffusion capacity, bronchoscopy with broncho-alveolar lavage, HRCT, tho-racic surgery for lung biopsy and, most important, spe-cialists with expertise in the management of ILDs, comprising pulmonologists, radiologists and patholo-gists, all with interest and experience in ILDs.
This expertise is not easy to build up, when we are talking about a large group of quite rare diseases, with many similarities, almost each case being unique in its way. The expertise comes from specifically studying the literature in the field (which is not short and continuously changing), but mostly from dealing with a higher number of ILD patients, referred to a few centers by many physi-cians all over the country, and discussing the cases in a multidisciplinary team, comprising the clinicians (pulmo-nologists), the radiologists and the pathologists.
In the expert center
The ILD specialist will resume the medical history and will order complex investigations, on top of the basic ones already performed.
The medical history needs to look thoroughly for exposure to allergens, to toxic agents in the home or professional environment of the patient, to long-term
medication with potential toxicity for the lungs, and for signs and symptoms that may give hints for the diagno-sis. Typically, in the short time that a physician has to discuss with a new patient, these details are not revealed, as the patient will never think to declare he/ she has a pet canary in the house, or mold on the bath-room ceiling, or is a worker in a cheese factory, for exam-ple, unless the question is not specifically asked.
HRCT will reveal the presence of typical fibrotic changes of IPF, consisting of fine linear and reticular opacities distributed mostly at the bases of the lungs, next to the pleura, as well as traction bronchiectasis and thin‑wall subpleural cysts (called “honeycombing”), build-ing up the radiologic UIP pattern (UIP: usual interstitial pneumonia). HRCT is currently considered the hallmark investigation for ILD diagnosis, being capable of showing changes specific for a particular disease, like UIP pattern in IPF, mosaic ground‑glass opacities and nodules in hypersensitivity pneumonitis, mediastinal lymph node enlargement and nodules in sarcoidosis, and so on.
Complex lung function tests are performed, recon-firming the presence of a restriction, but adding the measurement of diffusing capacity. In IPF, the DLCO is impaired earlier than the vital capacity, and patients with spirometry parameters at the lower limit of normal may have severe decrease of DLCO(7).
Broncho-alveolar lavage (BAL) is extremely useful for the diagnosis of some ILDs (sarcoidosis, hypersen-sitivity pneumonitis, alveolar proteinosis, eosinophilic pneumonia) and for the differential diagnosis of some confounding diseases (tuberculosis, cancer, infection). Some centers do this investigation routinely, as part of the usual diagnosis work-up of all patients with ILD(8).
The search for autoantibodies and precipitins (IgG) in the serum should be directed by the clinical context, and these are important elements for the diag-nosis of collagen-tissue diseases associating pulmonary involvement and of hypersensitivity pneumonitis(9,10).
Lung biopsy is no longer considered the gold standard for the diagnosis of ILDs, since the technological progress of thoracic imaging. A lung biopsy can be useful if the clinical, imaging and BAL results didn’t end up in a spe-cific diagnosis. The lung biopsy should be performed if its result will lead to a specific choice in the case manage-ment. Also, very important, a lung biopsy should be per-formed only if the pathologist examining it has the expertise in lung pathology, and in interstitial lung pathol-ogy. The balance between the benefit and the risks should always be assessed(11). ILD patients, usually with severe restriction, have a risk of mortality between 3% and 5%, and IPF patients have a risk of developing an acute exac-erbation of the disease, that can also be deadly(12). Cryobiopsy, a bronchoscopy technique with a good diag-nostic yield, could be a better option for obtaining a lung fragment in these fragile patients, than a surgical lung biopsy(13). Finally, the result of the biopsy should be inter-preted in the clinical and imaging context. For many rea-sons, the biopsy will not completely change a diagnosis based on solid clinical and imaging grounds.
This is where the multidisciplinary team has the highest value: to “negotiate” the most appropriate diag-nosis for every patient, when the separate elements don’t match entirely.
As mentioned before, the entire package of information is re-discussed in the expert multidisciplinary team. Sometimes, the IPF diagnosis is straightforward, like an older male patient, former smoker, with progressive exer-cise dyspnea, lung crackles, restriction and reduced DLCO, hypoxemia at exercise, and typical UIP pattern on HRCT. But in many instances, things are not so clear. The patient may associate joint pain, or may have more ground‑glass on the HRCT than expected, or a possible exposure to aller-gens, or the BAL may give confusing results.
These are the cases that need discussion, and more brains working together can do a better job in balancing the pros and the cons for a specific diagnosis. Supplemental tests, the careful recommendation of a lung biopsy or the decision of a treatment based on a working diagnosis are the outcomes of such discussions(14).
Finally, in a patient with an ILD, the main question that needs to be answered is: IPF or not IPF? The con-sequence is huge: it has been proven that IPF patients benefit from anti‑fibrotic treatment, while the immu-nosuppressive treatment may be harmful(15). The days when any patient with “pulmonary fibrosis” was treated, anyway, with high doses of oral corticosteroids are long gone, and starting such a treatment without making all the efforts for an accurate diagnosis is a mistake.
Why should we do our best to identify and diagnose correctly IPF patients?
Because the disease is deadly, if left untreated, simi-lar to some cancers. The anti‑fibrotic treatment cur-rently at hand, pirfenidone or nintedanib, bring hope in
the patients’ lives. These drugs manage to stabilize the disease and stop the progression of fibrosis. The patient will not improve, but his status will be maintained for a long time, “frozen” in the state he/she was at the moment of diagnosis(16,17).
This means that it is worth to find and treat these patients and, moreover, it is worth to find these patients as early as possible in the evolution of their disease, in order to offer them the opportunity to “freeze” in a bet-ter status, when they are still active and independent, and preserve an acceptable quality of life for a long time. Any delay in the correct IPF diagnosis, like “pulmonary fibrosis”, asthma, COPD, heart failure, treatments with oral or inhaled steroids, will just allow the disease to further progress. It is of note that many patients referred to expert centers arrive here with an already severe restriction, very low DLCO and severe symptoms, limiting the possibility of invasive tests. Sometimes they are already excluded from the range of anti‑fibrotic treatment prescription criteria, and even if they can benefit from the prescription, they are condemned to maintain an impaired functional status.
The anti‑fibrotic drugs have been available in Romania for one year already. This fact – and also the more and more visible activity of the expert centers – leads to a slow but constant increase in the number of patients referred for a specific diagnosis. This is good news for IPF patients and, in parallel with the very active international research for new drugs, there is hope for a better care and better quality of life, provided that their first contact with a physician will lead to a suspicion of the disease and to a fast referral to a center capable to provide the correct diagnosis and treatment.
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