Current approach of idiopathic pulmonary fibrosis: considerations on diagnostic and treatment advances in Romania [311362]

Review

Current approach of idiopathic pulmonary fibrosis: considerations on diagnostic and treatment advances in Romania

Antigona Carmen Trofor1), Sorin Man*2), Irina Rodica Chiselita3), Elena Cristina Moldoveanu3), Milena Adina Man2)

1)University of Medicine and Pharmacy “Grigore T. Popa”, Iasi, Romania

2)University of Medicine and Pharmacy “Iuliu Hatieganu”, [anonimizat]

3)[anonimizat], a chronic, [anonimizat], [anonimizat] a [anonimizat]. Moreover, [anonimizat] 2017. [anonimizat], diagnostic and treatment in general terms. [anonimizat], overview of existing clinical practice guideline recommendations and to management principles shared in the literature. Finally, current recommended therapeutic approach for Romanian patients is revised with highlights on treatment enrollment and on treatment monitoring criteria.

Keywords: [anonimizat], [anonimizat], ant fibrotic

Disease definition and general context

Idiopathic pulmonary fibrosis (IPF) is a rare and severe disease that belongs to the vast group of interstitial lung diseases (ILD), [anonimizat]-competent hosts without infection or neoplasm [1]. [anonimizat], [anonimizat]. The ILDs tend to evolve over months to years and include disorders of both known and unknown origins.

[anonimizat] (CTD-ILD), and hypersensitivity pneumonitis (HP). Among the ILDs of unknown cause are sarcoidosis and idiopathic interstitial pneumonias (IIP), a far-[anonimizat] (IPF), nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis with interstitial lung disease (RBILD), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), and lymphoid interstitial pneumonia (LIP) [2].

Idiopathic pulmonary fibrosis is defined as a chronic, [anonimizat], [anonimizat], clinically revealed by exertion dyspnea and a life expectancy of 3-5 years from the moment of its diagnosis. [anonimizat]-smokers, age 45-65 and over 65. It only affects the lungs and unlike other interstitial idiopathic pneumonias, has radiological and histopathological pattern of common interstitial pneumonia.1 (UIP) [3].

Epidemiology and risk factors

Overall, the annual incidence of IPF is increasing and especially increases with age (4.6 and 16.3 per 100 000 people) and the prevalence is 13 to 20 cases per 100 000.2[3-6]. Despite its clinical relevant picture, few data are available about IPF’s prevalence, probably also to the numerous challenges in both recruiting patients for large scale epidemiological studies and in harmonizing criteria for diagnostic confirmation. Data from Europe suggest IPF prevalence ranged from 1.25 to 23.4 cases per 100 000 population while in the U.S., a higher prevalence: 14-27.9/100 000 population (by narrow case definition) to 42.7 – 63 per 100 000 population (by broad case definitions) was reported [7].

The overall prevalence of IPF estimated in 2006 by Raghu et al. [8] was 14.0 and 42.7 per 100 000 person-years using their narrow and broad definition, respectively, while the prevalence estimated by Fernandez-Perez et al. in 2010 [9] was 27.9 and 63.0 per 100 000 person-years by their narrow and broad definition criteria, respectively.

In Japan, only one study has been conducted to investigate the epidemiology of IPF [10], and the results suggested that the estimated prevalence and incidence in 2008 appear to range from 10.0 to 2.2 per 100 000 person-years.

In a large population based survey, in Italy, based on healthcare administrative databases of Lombardy Healthcare System and on adopting three algorithms, such as generic case definition (GCD), broad case definition (BCD), and narrow case definition (NCD), Harari and colleagues identified IPF cases according to diagnoses reported in inpatient and outpatient claims occurred during 2000-2010. They reported the estimated mean annual incidence rate of IPF variable between 2.3 and 5.3 per 100 000 person-years, and the estimated prevalence rate varying between 12.6 and 35.5 per 100 000 person-years, depending on the case definition used to identify IPF patients [11].

There is predominance in men versus women (1/5 to 1/7.1) [4]. A complex contribution of both environmental and host factors is thought to contribute to the development of IPF, although the inciting factors remain elusive and the disease pathogenesis is incompletely understood [12-14]. Most frequent invoked environmental factors are tobacco smoking, chronic silent micro aspiration [15] and exposure to metal and wood dust. Family related IPF and genetic transmission in 0.5-3.7 % [10] are also cited. Gene-expression signatures have indicated that matrix metalloproteinase 7 (MMP7), MMP1, and MMP2 are among the most highly expressed genes in IPF [16]. Several intriguing reports suggest the involvement of herpes virus and/or hepatitis C virus in the etiology of IPF [17].

Understanding the actual concept about IPF pathogenesis

Initially considered an inflammatory condition, pathogenesis of IPF has considerably advanced in the past ten years. In the past, it was thought that the mechanism responsable was the aberrant repair response of the injured alveolar cells resulting in scarring of the lung, architectural distortions and irreversible loss of lung function. 3Currently the inflammatory process is described as mild and consisting of a patchy interstitial infiltrate of lymphocytes and plasma cells [18, 19], and is not considered an important component of IPF pathology or a factor contributing to pathogenesis of the disease.

Epithelial injury and activation: genetic and environmental interactions

Cigarette smoking is an environmental factor that can determine epithelial injury and apoptosis, and there are more such factors 4 , but also chronic micro-aspiration [20].

Alterations in unfolded protein response occur in some familial cases of pulmonary fibrosis that have mutations in surfactant protein C, a hydrophobic protein expressed exclusively by AEC type II (AEC II) [21]. Short-deletion mutations of this protein result in epithelial cell injury. Familial interstitial pneumonia and sporadic IPF, has been associated with a common polymorphism in the promoter region of mucin 5B gene (MUC5B) 5[22].

Disregulated/unregular repair process is caused even though the primary stimulus isn't present because of the high activeness of the epithelial cell. 6

Procoagulant signaling is activated in IPF and that deficient function of alveolar fibrinolysis, particularly determined by the epithelial cells, play a role in the fibrotic lung response 7 [20].

In injured tissues, fibroblasts are activated and differentiate into myofibroblasts, which are specialized contractile cells with higher profibrotic potential than fibroblasts. In injured tissues, fibroblasts are activated and differentiate into myofibroblasts, which are specialized contractile cells with higher profibrotic potential than fibroblasts. The high extracellular matrix deposit (which causes the destruction of the lung structure) is caused by these cells, in the fibroblastic foci. The source of 8fibroblasts and myofibroblasts and the reasons why they organize in morphologically distinct foci in IPF is unclear. Pathological fibroblast foci within the IPF lesion may derive from differentiation of resident fibroblasts, recruitment of circulating fibroblast precursors and trans-differentiation of epithelial cells into pathological fibroblast phenotypes [23].

Epithelial and mesenchymal markers in histological specimens obtained from patients with IPF are suggesting a role for epithelial to mesenchimal transition in pulmonary fibrosis, in a process similar to cell differentiation occurred during embryogenesis [24].

Finally, an increased angiogenic activity was described, as such, an imbalance between angiogenic chemokines (IL-8 and ENA-78) and angiostatic chemokines (IP-10) has been proposed to explain angiogenesis in the development of progressive pulmonary fibrosis [25].

Depending on disease progression pattern, different pathological findings are described. In a study aiming to define clinical and functional progress in 73 IPF patients, referred for a possible transplant indication, Balestro and colleagues have noted important differences in lung pathology among slow and rapid progressing patients, consisting mainly on the presence of an extensive degree of innate and adaptive immune inflammation in the rapid group, more prominent than in the slow one [26].

Diagnostic approach

Usually, middle aged or elderly patients address for a disease limited to the lungs, with a radiological and histopathological picture resembling to an usual interstitial pneumonia (UIP). UIP pattern is defined by reticular opacities +/- traction bronchiectasis and honeycombing on the chest X ray, plus histological aspects of patchy interstitial fibrosis alternating with areas of normal lung tissue/ architectural distortions due to honeycombing/heterogeneity of fibrosis with scarring and “fibroblastic foci”. An accurate diagnosis of IPF needs exclusion of any other causes of fibrotic interstitial pneumonia, especially: collagen vascular disease, drug toxicity, chronic hypersensitivity pneumonitis and asbestosis, or any other related disorders [3, 27].

Clinical manifestations

In general, IPF patients accuse slowly (average six months to two years) progressive dyspnea on exertion and dry cough. Slow onset of symptoms, is causing a delayed diagnostic and frequent confusion with cardiovascular dyspnea, COPD or lung cancer is not uncommon. In 90% of cases, gastro-esophageal acid reflux is revealed, but symptomless. Other general symptoms like fever, weight loss, and diffuse joints pain are rare and not specific [28]. End-inspiratory (“velcro-like”) crackles at chest auscultation and digital clubbing are common findings at physical exam.

Most patients describe such slow, progressive disease course, still some follow an alternative pattern with stable disease stages followed by episodic acute exacerbations or even a quick progressive route [28].

Acute exacerbations

Worsening of dyspnea in the past 30 days, vital capacity or gas exchange deterioration and new pulmonary infiltrates detected at radiological exam describe an acute exacerbation of IPF, after careful exclusion of any other differential diagnosis like pulmonary embolism, pneumonia, acute heart failure etc. A disease exacerbation can intervene in both debut and in the long run.

Coexisting conditions

Most encountered morbid associations in IPF are pulmonary hypertension in 32-84% of cases [29], lung cancer, regarded as an independent risk factor for IPF and pulmonary emphysema in 35 % of IPF patients. Pulmonary hypertension during exercise is common even during the early stages of IPF. The normal value of the pulmonary artery pressure at rest ranges between 23 and 28 mm Hg. Prognosis is affected by a pressure greater than 30 mm Hg . 9[30].

The couple IPF – Pulmonary emphysema has smoking as a common ground risk factor and appears like upper lobe emphysema and lower lobe fibrosis, with pronounced decrease of the diffusion capacity [31].

Sleep disturbance. In the case of a patient with IPF and arterial oxygen saturation of less than 90% (particularly) plus/minus history of snoring during sleep, it has been pointed out that they have a higher chance of manifest sleep disturbances. Reduced REM sleep, less profound and hypoxemia during REM sleep, were symptoms found in these patients. 10. In such cases, supplemental oxygen during sleep is indicated [30].

Facts for optimizing approach of patients with idiopathic pulmonary fibrosis

How can clinicians better understand IPF patients’ needs and how could they better help them?

Duck and colleagues approached this aspect by assessing IPF patients’ needs, experiences and perceptions and found that they face three major problems: “struggling to get a diagnosis”, “loss of the life I previously had” and “living with idiopathic pulmonary fibrosis”. That’s why, these authors concluded on the urgent need to establish properly funded regional Idiopathic Pulmonary Fibrosis networks with experienced staff conducting multidisciplinary teams to secure a timely diagnosis and treatment opportunities for patients, but also to ease early access to specialists who can provide information about the disease, discuss prognosis realistically and support them till death [32].

Basic laboratory investigations

Except non-specific inflammation markers, there are only few abnormal findings at blood test examination, such as polycythemia in advanced stages of disease. For the rest, a high auto-antibodies ratio may exclude a connective tissue pathology, or any specific tests to identify differential diagnosis are welcomed.

Spirometry shows restrictive respiratory dysfunction, due to reduced pulmonary compliance determined by parenchyma fibrosis, with decreased values of forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), while ratio of FEV1/FVC is normal or increased.

Gas exchange at rest and during exercise. The DLCO is reduced and may actually precede the reduction of lung volume. The reduction in the DLCO is probably caused both by a contraction of the pulmonary capillary volume and by ventilation and perfusion abnormalities. With exercise, the alveolar–arterial O2 gradient (AaPO2) widens, and the arterial O2 pressure (PaO2) and arterial O2 saturation (SaO2) fall. The most sensitive parameter that can be used for assessing the disease clinical progression has been showed to be the gas exchange during exercise. 11 Patients with IPF have elevated minute ventilation during exercise that is in part related to the increase in dead space (VD) ventilation [30, 33].

If cardiovascular comorbidities or pulmonary hypertension is not associated, the electrocardiogram generally is normal 12 [30].

Imagistic investigations

Chest radiography and high resolution computed tomography are the key exams to diagnose idiopathic pulmonary fibrosis. A standard chest X-ray may reveal interpretable abnormalities in 50-70% of the patients (see Figures 1a and 1b), but a normal thoracic radiographies are encountered as well in approximately 10%. Radiologic aspect of the lungs in IPF shows linear-reticular, bilateral opacities, predominant in the lower lobes, asymmetrically disposed. In advanced stages of the disease, a honeycombing pattern of course reticular lines juxtaposed between areas of focal round translucency can be found [34].

The “gold standard” investigation to confirm an imagistic diagnosis of idiopathic pulmonary fibrosis is high resolution computed tomography (HRCT) that provides valuable details of the lung parenchyma transformations.

The HRCT picture in IPF consists of patchy, predominantly peripheral, predominantly sub-pleural and necessarily bibasilar reticular opacities (see Figures 2a and 2b). Other findings may consist of: ground glass infiltrates with various limited localizations, "traction bronchiectasis" and honeycombing (defined on HRCT as palisades of small, round translucencies). Traction bronchiectasis and thickened interlobular septae increases specificity for a diagnosis of IPF. Together, these findings constitute a radiographic pattern that is termed "confident" or "certain" IPF [35].

Usefulness of HRCT has been proved also to differentiate IPF pattern from other similar entities, such as heart failure (ground glass), hypersensitivity pneumonitis, granulomatous infection or lymphangitis (fine multiple nodules), sarcoidosis, lung infection or malignancy (hilar limphadenopathy), and pneumoconiosis, histiocytosis or rheumatoid nodules ( upper lobes affectation).

After identification of the radiographic pattern of "possible" IPF, a surgical lung biopsy will be necessary to confirm the diagnosis.

Bronchoscopic exam

A bronchoscopic examination will not reveal any macroscopic signs specific for idiopathic pulmonary fibrosis, but will prove very useful for three reasons: to exclude other diagnostics (cancer, sarcoidosis, pneumoconiosis etc. by demonstrating tumor, infection, Langerhans' cells or occupational dust exposures) and to perform bronchoalveolar lavage (BAL) or transbronchial biopsy (TBB). Occasionally, suggestive aspects are found even in bronchial aspirate (see Figure 3).

Bronchoalveolar lavage is a safe, well tolerated procedure and it gained more and more acceptance as IPF diagnostic tool, in the last two decades. Main BAL information useful in clinical practice refer to total cell count, type of cells and lymphocytes sub typing.

It has been recognized that only about 30% of IPF patients can undergo a lung biopsy procedure, due to certain limitations for the performance of a surgical biopsy, such as in the case of: elderly patients with IPF, including severely impaired pulmonary function, acute exacerbations or significant co-morbidities [36]. So, from this perspective, BAL analysis represents a potential tool to plead for a diagnosis of interstitial lung disease, mostly in situations when lung biopsy is impossible to be done.

Increases in polymorphonuclear leukocytes (PMNs), neutrophil products, eosinophils, eosinophil products, activated alveolar macrophages, alveolar macrophage products, cytokines, growth factors for fibroblasts, and immune complexes have been all noted in BAL of patients with IPF [37, 38].

In a study aiming to evaluate the diagnostic contribution of BAL cell differentials in patients with clinic-radiological suspected IPF, Ohshimo and colleagues showed that a cut-off level of 30% for lymphocytes in BAL demonstrated a favorable discriminative power for the diagnosis of IPF and that the absence of a lymphocytosis is consistent with the diagnosis of IPF [39].

As BAL testing may serve for differential diagnosis in various entities competing with a suspicion of IPF, for patients with suspected ILD who undergo BAL, the American Thoracic Society Clinical Practice Guideline recommends that a differential cell count be performed on the BAL fluid. This includes lymphocyte, neutrophil, eosinophil, and mast cell counts. The remaining sample may be used for microbes, viruses, and/or malignant cell cytology laboratory testing, if clinically indicated [40].

Transbronchial biopsy

Using TBBs does not confirm UIP although it is abnormal in many cases. Also, these exams should not be used to evaluate the degree of fibrosis or inflammation because the sample prelevated is small in size (2 to 5 mm). TBB can be used to identify a specific diagnosis other than UIP (malignancy, infections, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, eosinophilic pneumonia, or pulmonary histiocytosis X) in the right clinical setting or by using special histopathological methods or stains 13 [30].

In diffuse parenchyma lung disease, histological support for a specific diagnosis can be obtained using TBB n 29–79% of cases only, in majority UIP and IPF. A study by Votava et al [41] reveals that in two out of every three cases (67%), surgical lung biopsy (SLB) may change the diagnosis reached by TBB [42].

Histological diagnosis (surgical lung biopsy)

Surgical lung biopsy is considered gold standard for the diagnosis of diffuse lung diseases, while clinical and radiological criteria give a diagnosis in two thirds of subjects and HRCT in approximately 30-40% of cases. To attain the final diagnosis this procedure is needed in about one-third of cases, with multidisciplinary cooperation. Lung biopsy was conducted in about 30-60% of the cases, included in large clinical trials performed in the last decade. Mortality occurring 30 days after lung biopsy is the most serious complication (3-4%). The biopsy should be prelevated from minimum two lobes since there is a great histological variability. 14

The histopathological lesion associated with IPF is known as usual interstitial pneumonia (UIP) that features normal lung architecture alternating with patchy areas of histological apparent pulmonary parenchyma fibrosis, with a scar appearance. Fibrosis takes the form of alveolar septal thickening with marked involvement of the sub-pleural regions (see Figure 4), where often, sub-pleural nodules exist. Abundant smooth muscles are described together with fibrosis lesions.

The most severely involved areas of the lung demonstrate complete distortion of normal architecture, with sheets of dense collagen replacing normal lung tissue and occasional cystic structures known as microscopic honeycombs (see Figure 5).

Closer inspection reveals minute foci of immature fibroblastic proliferation at the edge of dense fibrosis where this interfaces with normal lung. These are referred to as fibroblast or fibroblastic foci, being frequently described in the UIP histopathological pattern. Fibroblast foci are pale-staining whirls of loose extracellular matrix molecules (see Figure 6), interspersed with numerous cells of the fibroblast type. The number of fibroblast foci in surgical lung biopsy has been shown to correlate with survival in several studies [43].

In former cigarette smokers with IPF disease, a certain level of chronic small airways remodeling is expected.

Diagnostic controversies and the need for a multidisciplinary diagnostic approach

There are many difficulties in confirming a IPF diagnostic, as required by the “gold standard” criteria. Interpretation of the HRCT may rise different positions in front of a radiological pattern suggestive for both IPF and non IPF lesions and literature describes an inter-observer agreement of 80% amongst radiologists [44]. But the most sensitive question is referring to histopathology confirmation, for which there is a much lower inter-observer agreement between pathologists, of only 50% [45]. The main controversy is related to the distinction between the NSIP (homogeneously thickened interstitial spaces that contain accumulated fibrosis and inflammation) and UIP aspect. Evidence showed that UIP and NSIP are different ends of a spectrum resulting from the same disease, or even that NSIP may represent an early stage of IPF [46]. It has been shown in one study that 26% of patients with IPF had in one lobe NSIP pathology while in a sample from another lobe exhibiting UIP. 15 [47].

Because the appearance of UIP pattern in lung biopsies is alone insufficient for establishing the diagnosis of IPF and some difficulties are encountered during differentiation from other interstitial pneumonias, a multidisciplinary approach with a specialist in chest diseases, pathology, and radiology is recommended for the diagnosis of IPF at present [48].

Differential diagnosis of IPF

The differential diagnosis of IPF includes other idiopathic interstitial pneumonias. HRCT is useful for excluding disease with predominantly ground glass opacity or nodular patterns. Non-specific interstitial pneumonia (NSIP) will always remain in the differential and, in some cases, can only be excluded by biopsy [23].

Connective tissue diseases such as systemic sclerosis (HRCT scan features more closely resembling NSIP), polymyositis or rheumatoid arthritis (specific symptoms and the measurement of autoantibodies) can mimic IPF, both clinically and radiologically [23, 49].

There are also forms frusta autoimmune disorders which can be difficult to recognize The undifferentiated connective tissue disease can resemble IPF and is defined by one or more symptoms (Raynaud's syndrome, proximal muscle weakness or sicca like symptoms) linked with systemic inflammation ( antinuclear and other specific autoantibodies) 16 [50].

Chronic hypersensitivity pneumonitis [51] and other environmental (sometimes occupational) exposures can also be difficult to differentiate. The clinical history can serve to discriminate this condition but is oftentimes equivocal. The clinical history can serve to discriminate this condition but is often ambiguous.

Through the initial assessment of IPF it should also by sought the exposure to asbestos, grain dust and mold.

When making the differential diagnosis the following diseases should be taken into account: Radiation pneumonitis, end-stage sarcoidosis, certain drug toxicities (e.g. amiodarone , bleomycin, methotrexate, nitrofurantoin) and several congenital disorders (e.g. dyskeratosis congenital) 17 [23].

Some prognostic landmarks

Early studies looking at the prognosis of IPF identified older age, male sex, significant dyspnea, severe physiologic abnormalities, advanced fibrosis and a poor response to therapy as factors predicting shortened survival [52].

Some investigators identified interval decline of forced vital capacity as a characteristic that is predictive of survival in IPF patients. The prognostic was poor for those patients with a 10% lower FVC, after six or twelve months and was more accurate than predictions using baseline physiologic parameters 18 [53].

When biopsy-proven IPF patients were followed for three years by HRCT, it was found that radiographic honeycombing predicted the worst survival [54].

Treatment of idiopathic pulmonary fibrosis

Since its recognition as a standalone entity, idiopathic pulmonary fibrosis has been subject for various therapeutic approaches, aiming to improve symptoms and survival, by addressing either inflammation, at first supposed to cause this disease, or fibrosis progression, afterwards, as progresses in understanding pathogenesis have been produced.

So, the ATS-ERS consensus in 2000 has recommended the use of corticosteroids (prednisone starting at 0.5 mg/kg and tapered to a maintenance level of 0.125 mg/kg), combined with a cytotoxic agent (either azathioprine or cyclophosphamide (the dose targeted to 2–3 mg/kg).for carefully selected IPF patients. More complex regimens are used as well, like corticosteroid + two immune-suppressive therapy (azathioprine, cyclophosphamide, or methotrexate) + N-acetylcysteine [48]. Combination therapy is suggested for a period of at least six months with clinical and physiological response used to guide further management [30]. Opinions towards single or combination use of corticosteroids have changed in the 2011 updated guideline about IPF approach, as it will be shown in the next chapter of our review.

N-acetylcysteine (NAC) is also a possible treatment for IPF and it is a molecular precursor to the antioxidant glutathione. It is known that glutathione is consumed in the lungs of patients with IPF 19 [55]. Theoretically, oral NAC should replete glutathione stores and restore natural oxidant/anti-oxidant balance to prevent oxidative injury that precedes fibroproliferation [56]. The regimen of prednisone/azathioprine/NAC was shown to be possibly superior to prednisone/azathioprine alone [23].

A lot of new drug therapies have been trialed in IPF over the years. Following innumerable therapeutic efforts with disappointing results, the year 2014 has been highlighted by the emergence of two promising drugs, namely pirfenidone and nintedanib [57].

Pirfenidone and nintedanib are newly licensed treatments for IPF and the first drugs to have shown convincing evidence of slowing disease progression [58].

One of the anti-fibrotic drug approved in EU is Pirfenidone and it is used in patients with mild-moderate IPF. Pirfenidone mechanism of action is not known, but it was demonstrated that it can reduce the production of key profibrotic cytokines like transforming growth factor-, interleukin-1 and fibroblast growth factor (FGF) in a murine model of fibrosis. Also, lung collagen content and fibrosis scores were demonstrated to drop, and proliferation of fibroblasts was attenuated, indicating that pirfenidone acts by inhibiting important fibrogenic pathways. 20

The development of pirfenidone for clinical use follows a decade of clinical trial work involving the recruitment of over 1,700 patients into five trials designed to test its safety and efficacy. After initial phase II and III studies undergoing in Japan, it was showed that pirfenidone significantly reduced the decline in FVC over a year compared to placebo [59]. Than, the CAPACITY trials recruited patients in the US, Europe and Australia to receive high or low-dose pirfenidone or placebo, for a 72-week period. Patients receiving high-dose treatment, attained a change in FVC from baseline (the primary end-point) and prolonged progression-free survival time. Pirfenidone was approved in Europe in 2011, while the US FDA approved pirfenidone for the treatment of IPF in October 2014. Commonly reported treatment related adverse events include nausea, diarrhoea, dyspepsia, tiredness and fatigue, rash, photosensitivity reaction, anorexia [60].

Nintedanib is an intracellular triple tyrosine kinase inhibitor that binds competitively to receptors to vascular endothelial growth factor, platelet-derived growth factor and FGF, blocking downstream signaling pathways. The inhibition of fibroblast function is thought to be the central mechanism that nintedanib uses to modulate the disease processes in IPF. There were three clinical trials in which have been assessed the safety and efficacy of, on approximately 1500 IPF patients receiving various doses of nintedanib versus placebo. 21

The primary outcome (slowing FVC decline over one year) was reached, so this medication was approved in use in the US, also in 2014. The most common adverse effects of nintedanib are: diarrhoea, which in most cases is mild to moderate and improves over time, nausea, vomiting and abdominal discomfort and liver function abnormalities, in rare cases.

The efficacy profile of pirfenidone and nintedanib are similar, with equivalent slowing of disease progression; so, the decision regarding which treatment to initiate requires careful judgement. Yet, currently, there are more data available on the long-term effects of pirfenidone, and while significant mortality benefits are becoming apparent, it is currently unknown whether similar findings will be seen with nintedanib as data emerge from extension studies. If one must decide which anti-fibrotic drug to indicate in IPF, consideration should be given to specific prescribing criteria, financial arguments and manageable side effects. For instance, diarrhoea is the major drawback for nintedanib, and patients need to be made aware of the very small risk of involuntary diarrhoea. In addition, as nintedanib potentially increases the risk of bleeding, it should be avoided in patients with bleeding tendencies, in those taking anti-coagulants and in patients planning major surgery [60].

Imatinib

Imatinib, an inhibitor of PDGF, which has been implicated in the pathogenesis of IPF, has an actual recommendation against its use [61].

Antiacid therapy (either proton-pump inhibitors or H2 blockers) is efficient for the abnormal gastro esophageal reflux (GER), including clinically silent GER, that is highly prevalent in patients with IPF [62].

Sildenafil, stabilizes the second messenger of nitric oxide determining pulmonary vasodilatation and is authorized to be used in monotherapy for the treatment of pulmonary arterial hypertension or in combination with other drugs with the same purpose 22 [63].

Anticoagulation

There is evidence that in IPF, there is a procoagulant state both systemically and in the lung tissue, and this led to investigations into the potential benefits of anticoagulation [64]. Studies have focused on anticoagulation with vitamin K antagonists and low molecular-weight heparins. Newer direct oral anticoagulants haven’t so far specifically been studied for use in IPF, but the role of coagulation, as well as the profibrotic effect of platelets, is being actively investigated [65].

Dual Endothelin Receptor Antagonists. Two of this drugs are bosentan and macitentan,and their effect in patients with IPF, has been examined in two RCTs and one RCT, respectively, 23and recommendations for use in IPF patients, regardless PH have been issued in the last IPF guideline edition, as shown below. Ambrisentan is a selective type A endothelin receptor blocker not recommended in IPF.

Other treatment indications

Co-morbidities like ischemic heart disease and heart failure might cause additional breathlessness that will need specific treatments. Patients may also have coexisting airways disease and inhaler therapy should be optimized.

Smoking cessation should be offered in those IPF patients continuing to smoke.

Lung transplant: early referral is recommended in appropriate patients. The most common indication for transplant, in the US, is IPF with the estimated survival rate, after five years, between 50 and 56.24%. According to the NICE guidelines, the option of lung transplant should be discussed with patients that do not have absolute contraindication in the first 3-6 months after diagnosis. NHS Blood and Transplant Authority set of absolute contraindications include: untreatable psychiatric conditions or poor social support network, severe dysfunction in other organs, cancer in the past five years, unstable critical condition, poor compliance with the treatment, substance dependency. 24-25 [66, 67].

Pulmonary rehabilitation has demonstrated a significant improvement was noted in 6 MWT distance following exercise [68].

Oxygen therapy

The recent British Thoracic Society oxygen therapy guidelines is suggesting that as a ‘good practice point’, the use of ambulatory oxygen may be beneficial as a palliative adjunct in IPF patients with severe dyspnea but without evidence of hypoxemia [69].

Acute exacerbations of IPF

Patients with IPF may experience an exacerbation of their disease, which is defined as new airspace changes on HRCT, a deterioration of dyspnea over 30 days or less, and by eliminating other causes such as heart failure, pulmonary emboli, and infection. 26This is resulting in increased breathlessness and hospital admission in the majority of cases [70].

Treatment for acute exacerbation is currently very limited and entirely without an evidence base. Antibiotics are invariably prescribed to treat possible infection, regardless of the clinical findings, and in the majority of cases, patients are treated with high-dose prednisolone, usually in the form of pulsed methylprednisolone for three days, to overcome any inflammatory component within the scarred lung. In most cases, the steroid therapy does not seem to modify the course of the disease, although in some cases patient have a good response to this therapy. This is way further research and clinical trials are necessary to improve the outcome of acute exacerbations. 27[59].

Overview of clinical practice guideline recommendations

The definition, diagnostic criteria and treatment recommendations have been subject for several consensuses of experts in the past two decades, the most important being the result of a collaborative effort from the American Thoracic Society (ATS), European Respiratory Society (ERS), and the American College of Chest Physicians (ACCP). As such, in 2000, a panel of experts, has approved a number of key recommendations [30], focusing on disease definition, clinical criteria, indications for surgical lung biopsy and best therapeutic approach. Due to small body of evidence at that time, these recommendations were mainly based on experts’ opinions consensus, without using standard procedures for guideline development. Even so, this guidance paper represented a reference point for future documents arising in this field, by setting a “gold standard “clinical-radiological-pathological “correlation diagnostic in IPF, based on:

• Surgical lung biopsy revealing a histological pattern for UIP

• Eliminating other causes of interstitial lung disease

• Abnormal pulmonary physiology, during exercise, showing signs of

restriction and/or impaired gas exchange

•A pattern of "confident" or "possible" IPF on HRCT. 28

Following next decade’s scientific progresses, an update in diagnostic and treatment recommendations for IPF patients was produced in 2011 by Raghu and colleagues [3]. Its major novelty consisted of guideline development based on GRADE (Grading of Recommendations Assessment, Development and Evaluation) evidence based approach, but also of providing first evidence-based treatment recommendations for this rare respiratory disease. The 2011 guide, named” An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management, draw six summary conclusions and recommendations about the followings:

1. IPF is defined as a chronic progressive form of 29, progressive fibrosis interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathology and/or radiologic pattern of UIP.

2. The diagnosis of IPF requires:

a. Exclusion of alternative causes of ILD (e.g. 30domestic and occupational environmental exposures, connective tissue disease, and drug toxicity).

b. The presence of a UIP pattern on high-resolution computed tomography (HRCT) in patients not subjected to surgical lung biopsy.

c. Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy.

3. The accuracy of the diagnosis of IPF enhance with 31multidisciplinary discussion between pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD.

4. IPF is a fatal lung disease; the natural history is variable and unpredictable:

a. Most patients with IPF demonstrate a gradual worsening of lung function over years; a minority of patients remains stable or declines rapidly.

b. Some patients may experience episodes of acute respiratory worsening despite previous stability.

5. Disease progression is manifested by increasing respiratory symptoms, worsening pulmonary function test results, progressive fibrosis on HRCT, acute respiratory decline, or death.

6. Patients with IPF may have sub-clinical or co-morbid conditions including pulmonary hypertension, gastro esophageal reflux, obstructive sleep apnea, obesity, and emphysema. The impact of these conditions on the outcome of patients with IPF is unclear.

In the same time, based on available evidence before 2011, treatment recommendations for and against specific therapies in IPF and its complications or co-morbid conditions were released for the first time. The document statement agreed that there was no specific pharmacological treatment in IPF, formulated strong recommendations against the following therapies in IPF: Corticosteroid mono therapy, Colchicine, Cyclosporine A, Combined corticosteroid and immune-modulator therapy, Interferon g, Bosentan and Etanercept and weak recommendations against the use of Combined acetylcysteine and azathioprine and prednisone, Acetylcysteine monotherapy, Anticoagulation and Pirfenidone in majority of IPF patients. As well, there were made weak recommendations for treating gastro esophageal reflux, for corticosteroids in IPF’s exacerbations and for pulmonary rehabilitation, weak recommendations against treating pulmonary hypertension (PH) and against mechanical ventilation for respiratory failure. Lung transplant and oxygen therapy in appropriate patients with IPF received a strong recommendation.

Finally, the most recent clinical practice guideline for the treatment of idiopathic pulmonary fibrosis was produced in 2015 as an update to the previous 2011 clinical practice guideline, being a result of several systematic reviews and meta-analyses summarizing all available evidences pertinent to the clinical questions raised by the precedent version.

There were 12 treatment recommendations, transcribed here below [71]:

Clinicians should not use warfarin anticoagulation in patients with IPF who do not have a known alternative indication for its use.

Clinicians should not use imatinib in patients with IPF.

Clinicians should not use the combination therapy of N-acetylcysteine, azathioprine, and prednisone in patients with IPF.

Clinicians should not use ambrisentan in patients with IPF, regardless of the presence or absence of PH.

Clinicians should use nintedanib in patients with IPF.

Clinicians should use pirfenidone in patients with IPF.

Clinicians are suggested to use regular anti-acid treatment for patients with IPF.

Clinicians are suggested not to use sildenafil for the treatment of IPF.

Clinicians are suggested not to use bosentan or macitentan for the treatment of IPF.

Clinicians are suggested not to use N-acetylcysteine monotherapy in patients with IPF.

In patients with IPF the committee did not make a recommendation regarding single versus bilateral lung transplant. Justification. To guide this clinical decision the committee established that there need to be obtained supplementary proof. 32

Regarding treatment of PH in patients with PF, the committee did not make a suggestion. Justification. The committee established that supplementary proof is needed and should be evaluated to guide this clinical decision. 33.

Overall management principles

Like in many other chronic illnesses, the healthcare needs of 34 an IPF patient must be addressed to an ILD specialist team including 35: a consultant physician with ILD expertise, a respiratory physiotherapist, a nurse specialist and a pharmacist. Close liaison with the general practitioner and involvement of community nursing and palliative care teams will impose, over time, especially during the later stages of illness.

Three approaches to management have been proposed [60]:

a)Watch and wait approach: Patients presenting with early disease, or who have combined emphysema and IPF, may have preserved lung function tests and therefore not qualify for anti-fibrotic therapy under NICE guidance, which currently advocates therapy if the forced vital capacity (FVC) is between 50 and 80% of predicted value. Other patients may have minimal symptoms and wish to delay treatment due to concerns about the impact that potential side effects could place on their quality of life. In these patients a careful monitoring strategy is advised and regular lung-function tests every 3–6 months enable the clinician to detect evidence of worsening disease. A fall in FVC of >10% or transfer factor for carbon monoxide (TLCO) of >15% is representative of significant disease progression.

b) Active disease-directed treatment

Pirfenidone is available in the UK and in many European countries to patients with an FVC of between 50 and 80% and in respect with national treatment inclusion criteria.

c) Symptom-based approach

A subset of patients present with advanced disease or have extensive co-morbidities that preclude the use of anti-fibrotic therapy. Symptomatic relief of breathlessness, low-dose corticosteroids or codeine for intractable cough and supportive care are essential, in addition with palliative care involvement.

Recent treatment advances for Romanian patients diagnosed with idiopathic pulmonary fibrosis

In the last decade, most reference pulmonary disease clinics in Romania have succeeded to create access to new, modern laboratory and imagistic investigations like HRCT, complete bronchoscopy evaluation with BAL and TBB, thoracic surgery diagnostic procedures, or full parameters lung function testing, all these being indispensable for an accurate diagnosis of IPF. These progresses have made possible to advance with IPF screening in the Romanian population and to shape first patients databases in few such reference centers like Bucharest and Timisoara.

Moreover, in 2016, three excellence centers for a standardized management of this category of patients have been approved, at a first stage in Bucharest, Timisoara and Iasi and hopefully new centers will follow in the immediate future.

Starting with 2017, Pirfenidone is available in Romania for IPF patients with mild-moderate forms of disease, under free of charge prescription, according to a national program orphan lung disease treatment protocol. As such, in accordance with ATS-ERS criteria, those IPF patients with either a histopathological diagnostic confirmed through lung or transbronchial biopsy, or a probable histopathological aspect of UIP + a HRCT aspect of UIP or even a typical HRCT aspect of UIP with or without a lung biopsy with an UIP aspect can qualify to receive this anti-fibrosis medication. Additionally, IPF patients must be over 40 years old, non-smokers or former smokers for at least 3 months and have the confirmation of the IPF diagnosis since no more than 5 years before treatment enrollment. Lung function must fit a FVC of 50-90% of predicted value, a DLco of 30-90% of predicted and a FEV/FVC ratio > 0.8.

Patients cannot benefit this treatment if they are: intolerant to Pirfenidonum, pregnant and breastfeeding women, carrying severe hepatic or renal chronic disease, concomitantly using fluvoxamine.

Pirfenidone administration is recommended orally, in association with food, to avoid digestive intolerance. The usual dose is of 3 capsules of 267 mg three times/day, at a minimum 8 hours interval. Initial dosing is of 1 capsule every 8 hours in the first week of treatment, than 2 capsules every 8 hours, in the second week of treatment, than treatment will be continued with the usual dose. Doses can be adjusted, in case of adverse effects and treatment duration is undefined. Still, an annual evaluation is requested, to prolong Pirfenidone prescriptions.

Treatment with Pirfenidone must be monitored by patient’s currant pulmonologist, as follows: clinically and biologically once /month in the first six months of treatment, than at every three months, by spirometry and DLco three times/year and by HRCT annually.

Pirfenidone can be discontinued at patient’s wish for or by currant physician’s medical decision [72, 73].

Shaping future research directions in idiopathic pulmonary fibrosis

Even if so many progresses were done in the past decade in the diagnostic methods and new therapeutic agents, still IPF remains a disease for which the etiology is unknown, the pathogenesis is not yet completely understood and disease clinical course may pose numerous dilemmas to clinicians. There is no definitive consensus for its treatment approach and large multi-center clinical trials to sustain effectiveness of targeted pharmacological therapy would much more ease management of this difficult category of patients.

In a comprehensive review of the pharmacological treatment of IPF, Kreuter and colleagues, after full overview of all therapeutic options up to date, formulated the following open questions:

Should We Start Antifibrotic Treatment as Early as Possible?

Answer: Once the diagnosis of IPF has been established, it conceptually makes sense to start treatment as early as possible in order to preserve pulmonary function and to prolong survival [74].

Which Drug Should We Use as First-Line Treatment for IPF?

Answer: Both pirfenidone and nintedanib have been demonstrated to slow the decline in FVC in IPF patients with mild to- moderate functional impairment with acceptable safety profiles.

How Do We Treat More Severe IPF?

Answer: FDA authorized pirfenidone and nintedanib [75] use irrespective of disease severity (and The European Medicines Agency authorized nintedanib with the same directive), but there are no studies regarding the use of pirfenidone and nintedanib safeness and efficiency in patient with more severe functional impairment (e.g. FVC<50%). 36 For patients with DLCO < 35% predicted, echocardiographic evidence of right ventricular dysfunction, and no contraindications to the drug, a trial of sildenafil may be a reasonable therapeutic option [76].

How Do We Treat Patients with IPF and Lung Cancer?37

Answer: It is well known that patients with IPF are at high risk of developing lung cancer. No specific guideline recommendations exist on this associations, so Kreuter and colleagues, suggest to make decisions on a case-by-case basis after careful assessment of the benefits and the risks 38 [77].

How Do We Treat Elderly IPF Patients?

Answer: Management of elderly patients with IPF should be as personalized as possible in order to prevent functional decline and disease progression but also for limiting the risk of treatment-related adverse events [78].

Conclusions and future perspectives

The future development of state-of-the-art management for idiopathic pulmonary fibrosis is directly linked to sustained and extensive efforts of the researchers to both developing more accurate and easily applied diagnostic tools [79], and to maximizing patient’s therapeutic benefits.

Until then, many physicians will take into account combination therapy because there are two drugs available. The combined therapy has been successfully used in other respiratory diseases such as asthma, chronic obstructive pulmonary disease, or lung cancer. 39 But in patients with IPF Combination therapy should be avoided until more studies are available to prove its efficacy and tolerability/safety 40 [76]. Recently, a randomized, double-blind, placebo-controlled phase II, dose escalation trial has been conducted to assess the safety, tolerability, and pharmacokinetics of nintedanib, alone and when added to ongoing pirfenidone therapy in Japanese patients with IPF. Investigators observed a trend toward lower exposure of nintedanib when added to pirfenidone and suggested that further study is needed to evaluate the safety and tolerability profile of pirfenidone and nintedanib combination in patients with IPF [80].

References

King TE Jr. Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med, 2005, 172:268–279.

American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med, 2002, 165:277–304.

Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med, 2011, 183(6):788-824.

Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2006, 174:810-16.

Hodgson U, Laitinen T, Tukiainen P. Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder eff ect among multiplex families in Finland. Thorax, 2002, 57(4):338-42.

Gribbin J, Hubbard RB, Le Jeune I, Smith CJ, West J, Tata LJ. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax, 2006, 61(11):980-85.

Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev, 2012, 21(126):355-61.

Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2006; 174(7):810-6.

Fernández Pérez ER, Daniels CE, Schroeder DR, St Sauver J, Hartman TE, Bartholmai BJ, Yi ES, Ryu JH. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest, 2010, 137(1):129–37.

Natsuizaka M, Chiba H, Kuronuma K, Otsuka M, Kudo K, Mori M, Bando M, Sugiyama Y, Takahashi H. Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med, 2014; 190(7):773–9.

Harari S, Madotto F, Caminati A, Conti S, Cesana G. Epidemiology of Idiopathic Pulmonary Fibrosis in Northern Italy. PLoS One, 2016, 11(2):e0147072.

Spagnolo P, Grunewald J, du Bois RM. Genetic determinants of pulmonary fibrosis: evolving concepts. Lancet Respir Med, 2014, 2(5):416–428.

Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol, 2014, 9:157–179.

Spagnolo P, Rossi G, Cavazza A. Pathogenesis of idiopathic pulmonary fibrosis and its clinical implications. Expert Rev Clin Immunol, 2014, 10(8):1005–1017.

Lee JS, Collard HR, Raghu G, Sweet MP, Hays SR, Campos GM, Golden JA, King TE Jr. Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med, 2010, 123(4):304−11.

Selman M, Pardo A, Barrera L, Estrad A, Watson SR, Wilson K, Aziz N, Kaminski N, Zlotnik A. Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med, 2006, 173(2):188−98.

Egan JJ, Stewart JP, Hasleton PS, Arrand JR, Carroll KB, Woodcock AA: Epstein-Barr virus replication within pulmonary epithelial cells in cryptogenic fibrosing alveolitis. Thorax, 1995, 50(12):1234-1239.

American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med, 2002, 165:277–304.

American Thoracic Society; European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med, 2000, 161(2 Pt 1):646–664.

King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet, 2011, 378(9807):1949–1961.

Thomas AQ, Lane K, Phillips J 3rd, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, Roberts R, Haines J, Stahlman M, Loyd JE. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med, 2002, 165(9): 1322–28.

Zhang Y, Noth I, Garcia JGN, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med, 2011, 364(16):1576–77.

Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis, 2008, 3:8.

Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, Borok Z: Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor- beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol, 2005, 166(5):1321-1332.

Strieter RM, Gomperts BN, Keane MP. The role of CXC chemokines in pulmonary fibrosis. J Clin Invest, 2007, 117(3):549-556.

Balestro E, Calabrese F, Turato G, Lunardi F, Bazzan E, Marulli G, Biondini D, Rossi E, Sanduzzi A, Rea F, Rigobello C, Gregori D, Baraldo S, Spagnolo P, Cosio MG, Saetta M. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis. PLoS One, 2016, 11(5):e0154516.

Nițu FM, Olteanu M, Streba CT, Jimborean G, Postolache P, Man MA, Trofor AC, Nemeș RO, Dragonu L, Olteanu M, Tuberculosis and its particularities in Romania and worldwide. Romanian Journal of Morphology & Embryology,2017, 58(2):385–392.

Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc, 2006, 3(4):285-292.

Nathan SD, Noble PW, Tuder RM: Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots. Am J Respir Crit Care Med, 2007, 175(9):875-880.

American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med, 2000, 161(2 Pt 1):646-64.

Wells AU, Desai SR, Rubens MB, Goh NS, Cramer D, Nicholson AG, Colby TV, du Bois RM, Hansell DM: Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography. Am J Respir Crit Care Med, 2003, 167(7):962-969.

Duck A, Spencer LG, Bailey S, Leonard C, Ormes J, Caress AL. Perceptions, experiences and needs of patients with idiopathic pulmonary fibrosis. J Adv Nurs, 2015, 71(5):1055–1065.

Fulmer, JD, Roberts WC, von Gal ER, Crystal RG. Morphologic–physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis. J Clin Invest, 1979, 63(4):665–676.

Crystal RG, Fulmer JD, Roberts WC, Moss ML, Line BR, Reynolds HY. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med, 1976, 85(6):769-788.

Hunninghake GW, Lynch DA, Galvin JR, Gross BH, Muller N, Schwartz DA, King TE Jr., Lynch JP 3rd, Hegele R, Waldron J, Colby TV, Hogg JC. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest, 2003, 124(4):1215-1223.

Peikert T, Daniels CE, Beebe TJ, Meyer KC, Ryu JH; Interstitial Lung Diseases Network of the American College of Chest Physicians. Assessment of current practice in the diagnosis and therapy of idiopathic pulmonary fibrosis. Respir Med, 2008, 102(9):1342–1348.

Klech H, Hutter C. Clinical guidelines and indications for bronchoalveolar lavage (BAL): report of the European Society of Pneumology Task Force on BAL. Eur Respir J, 1990, 3:937–974.

Goldstein RA, Rohatgi PK, Bergofsky EH, Block ER, Daniele RP, Dantzker DR, Davis GS, Hunninghake GW, King TE Jr, Metzger WJ, et al. Clinical role of bronchoalveolar lavage in adults with pulmonary disease. Am Rev Respir Dis, 1990, 142(2):481–486.

Ohshimo S, Bonella F, Cui A, Beume M, Kohno N, Guzman J, Costabel U. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2009, 179(11):1043-7.

Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, Drent M, Haslam PL, Kim DS, Nagai S, Rottoli P, Saltini C, Selman M, Strange C, Wood B; American Thoracic Society Committee on BAL in Interstitial Lung Disease. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med, 2012, 185(9):1004-14.

Votava J, Belpario J, Kazerooni EA, Lagstein A, Myers JL, Simon RH, et al. A22 Interstitial Lung Disease: Evaluation and Pathobiology. American Thoracic Society; 2013. [Last accessed on 2015 Sep 29]. Utility of Transbronchial Biopsy Versus Surgical Lung Biopsy in the Diagnosis of Patients with Suspected Idiopathic Interstitial Pneumonia; p. A1089. Available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccmconference. 2013.187.1_MeetingAbstracts.A1089.

Purohit S, Dutt N, Saini LK. Transbronchial lung biopsy in diffuse parenchymal lung disease – Question still remains whether to go for surgical lung biopsy or not? Lung India, 2016, 33(1):117–118.

Kaarteenaho R. The current position of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis. Respir Res, 2013, 14:43.

Collins CD, Wells AU, Hansell DM, Morgan RA, MacSweeney JE, du Bois RM, Rubens MB: Observer variation in pattern type and extent of disease in fibrosing alveolitis on thin section computed tomography and chest radiography. Clin Radiol, 1994, 49(4):236-240.

Lettieri CJ, Veerappan GR, Parker JM, Franks TJ, Hayden D, Travis WD, Shorr AF: Discordance between general and pulmonary pathologists in the diagnosis of interstitial lung disease. Respir Med, 2005, 99(11):1425-1430.

Strieter RM: Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel. Chest, 2005, 128(5 Suppl 1):526S-532S.

Flaherty KR, Travis WD, Colby TV, Toews GB, Kazerooni EA, Gross BH, Jain A, Strawderman RL, Flint A, Lynch JP, Martinez FJ: Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med, 2001, 164(9):1722-1727.

Anar C, Okutan O, Uzun O, Özsu S, Altınsoy B. Approaches in Diagnosis and Treatment of Patients with Idiopathic Pulmonary Fibrosis: A Questionnaire Study. Eurasian J Pulmonol, 2015, 17(2):85-91.

Desai SR, Veeraraghavan S, Hansell DM, Nikolakopolou A, Goh NS, Nicholson AG, Colby TV, Denton CP, Black CM, du Bois RM, Wells AU. CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology, 2004, 232(2):560-567.

Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, Jones KD, King TE Jr. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med, 2007, 176(7):691-697.

Man MA, Man SC, Motoc NS, Pop CM, Trofor AC, Fatal hypersensitivity pneumonitis after chemical occupational exposure, Romanian Journal of Morphology & Embryology, 2017, 58(2): 627–634.

Perez A, Rogers RM, Dauber JH: The prognosis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol, 2003, 29(3 Suppl):S19-26.

Collard HR, King TE Jr., Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2003,

168(5):538-542.

Gay SE, Kazerooni EA, Toews GB, Lynch JP 3rd, Gross BH, Cascade PN, Spizarny DL, Flint A, Schork MA, Whyte RI, Popovich J, Hyzy R, Martinez FJ. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med, 1998, 157(4 Pt 1):1063-1072.

Cantin AM, Hubbard RC, Crystal RG: Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis, 1989, 139(2):370-372.

Cantin AM, North SL, Fells GA, Hubbard RC, Crystal RG: Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J Clin Invest, 1987, 79(6):1665-1673.

Tzouvelekis A, Bonella F, Spagnolo P. Update on therapeutic management of idiopathic pulmonary fibrosis. Ther Clin Risk Manag, 2015, 11:359-70.

Trawinska MA, Rupesinghe RD, Hart SP. Patient considerations and drug selection in the treatment of idiopathic pulmonary fibrosis. Ther Clin Risk Manag, 2016, 12:563-74.

Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A Takeuchi M, Raghu G, Kudoh S, Nukiwa T, the Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J, 2010, 35(4):821-9.

Fraser E, Hoyles RK. Therapeutic advances in idiopathic pulmonary fibrosis. Clin Med (Lond), 2016, 16(1):42-51.

Antoniades HN, Bravo MA, Avila RE, Galanopoulos T, Neville-Golden J, Maxwell M, Selman M. Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest, 1990, 86(4):1055–1064.

Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, Sillery JK, Pope CE 2nd, Pellegrini CA. High prevalence of abnormal acid gastro-esophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J, 2006, 27(1):136-42.

Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J, 2015, 46(4):903–975.

Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2012, 186(1):88-95.

Crooks MG, Hart SP. Coagulation and anticoagulation in idiopathic pulmonary fibrosis. Eur Respir Rev, 2015, 24(137):392-399.

Wells AU. The revised ATS/ERS/JRS/ALAT diagnostic criteria for idiopathic pulmonary fibrosis (IPF) – practical implications. Respir Res, 2013; 14(Suppl 1):S2.

George TJ, Arnaoutakis GJ, Shah AS. Lung transplant in idiopathic pulmonary fibrosis. Arch Surg, 2011, 146(10):1204-9.

Dowman L, Hill CJ, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev, 2014, (10):CD006322.

Hardinge M, Annandale J, Bourne S, Cooper B, Evans A, Freeman D, Green A, Hippolyte S, Knowles V, MacNee W, McDonnell L, Pye K, Suntharalingam J, Vora V, Wilkinson T; British Thoracic Society Home Oxygen Guideline Development Group.; British Thoracic Society Standards of Care Committee. British Thoracic Society guidelines for home oxygen use in adults. Thorax, 2015, 70(Suppl 1):i1– 43.

Juarez MM, Chan AL, Norris AG, Morrissey BM, Albertson TE. Acute exacerbation of idiopathic pulmonary fibrosis-a review of current and novel pharmacotherapies. J Thorac Dis, 2015, 7:499-519.

Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, Brozek JL, Collard HR, Cunningham W, Homma S, Johkoh T, Martinez FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M, Theodore A, Wells AU, Hoogsteden H, Schünemann HJ; American Thoracic Society; European Respiratory society; Japanese Respiratory Society; Latin American Thoracic Association. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med, 2015, 192(2):e3-19.

Romanian Therapeutic Protocol Pirfenidone, published in Order No 1463/1036/2016 published in The Official Gazette, No 1050 bis/ 27-Dec-2016.

Esbriet Summary of Product Characteristics, http://www. ema.europa.eu/docs/en_GB/ document_library/EPAR_-_ Product_Information/human/ 002154/WC500103049.pdf, accessed on January 30, 2017.

King CS, Nathan SD. Practical considerations in the pharmacologic treatment of idiopathic pulmonary fibrosis. Curr Opin Pulm Med, 2015, 21(5):479-489.

Ofev Summary of Product Characteristics, http://www.ema. europa.eu/docs/en_GB/document_ library/EPAR_-_Product_ Information/human/003821/ WC500182474.pdf, accessed on January 30, 2017.

Spagnolo P, Wells AU, Collard HR. Pharmacological treatment of idiopathic pulmonary fibrosis: an update. Drug Discov Today, 2015, 20(5):514–524.

Kreuter M, Bonella F, Wijsenbeek M, Maher TM, Spagnolo P. Pharmacological Treatment of Idiopathic Pulmonary Fibrosis: Current Approaches, Unsolved Issues, and Future Perspectives. Biomed Res Int, 2015, 2015:329481.

Meyer KC, Danoff SK, Lancaster LH, Nathan SD. Management of idiopathic pulmonary fibrosis in the elderly patient. Chest, 2015, 148(1):242-252.

Man M, Domokos B, Motoc N, Pop M. How to investigate interstitial lung disease (ILD) or interstitial pneumonia: from sympthoms to diagnostic of interstitial lung fibrosis-guideline for practicioners. Pneumologia, 2016, 65(4):190-192.

Ogura T, Taniguchi H, Azuma A, Inoue Y, Kondoh Y, Hasegawa Y, Bando M, Abe S, Mochizuki Y, Chida K, Klüglich M, Fujimoto T, Okazaki K, Tadayasu Y, Sakamoto W, Sugiyama Y. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J, 2015, 45(5):1382–1392.

Corresponding author

Sorin Man………………………

Received:

Accepted:

FIGURES

Figure 1. a. – Anterior-Posterior Chest X-ray indicates bibasilar reticulomicronodular abnormality

Figure 1. b. – Lateral Chest X-ray indicates reticulonodular pattern predominant lower lung and posterior

Figure 2. a. – HRCT at the subcarinar level indicates reticular abnormality typical peripheral distribution, irregular interlobular septal thickening, traction bronchiectasis, areas of honeycombing, centrilobular and paraseptal emphysema

Figure. 2. b. – HRCT at the level of lower lung indicates extensive and marked reticular opacities abnormality, traction bronchiectasis and honeycomb cysts predominant lower lung

Figure 3 – Exfoliative cytologic specimen. Epithelial scuamos cells on an inflammatory background. Papanicolaou staining, x400

Figure 4 – Subpleural fibroblastic foci. Van Gieson staining, x200

Figure 5 – Honeycombing. Van Gieson staining, x100

Figure 6 – Pale fibroblastic foci. Atelectatic lung parenchima. Van Gieson staining, x100