The most clinically relevant genetic alterations are: mutations in the genes that maintain the length of the telomeres (TERT, TERC), which are more common in the familial forms, in the surfactant protein C gene and in the mucin 5B promoter region (MUC5B). There are no established genetic tests to assess predisposition to IPF.8,9

Smoking (>20 packs/year) and exposure to silicon, brass, steel, lead and wood dust, farming and agricultural work, and the construction of wooden houses are considered risk factors.8,10,11

Several studies have shown that gastroesophageal reflux is a risk factor for the predisposition and progression of IPF.12

There is insufficient evidence to consider that viral infections (hepatitis C virus, herpes virus, adenovirus) are etiological risk factors for IPF, although their contribution remains under study.

The possible autoimmune origin of IPF is based on the fact that the radiologic and/or histologic manifestations of UIP are associated with connective tissue diseases, although these usually present with histology typical of non-specific interstitial pneumonia.

The clinical presentation of IPF has an insidious onset, and is usually characterized by progressive dyspnea on exertion, often accompanied by non-productive cough. Symptom onset is slow, but worsens over time. The delay between the onset of symptoms and the final diagnosis is variable, and may be between 6 months and two years.14 The presence of systemic symptoms/signs should lead to suspicion of an alternative diagnosis. Crackles can be heard on auscultation in 90% of patients and acropachy is detected in 50%.3

There are no specific laboratory abnormalities for this disease. However, even in the absence of specific signs or symptoms of connective tissue diseases, serological autoimmune tests should be performed in all patients.2 In fact, positive anti-nuclear antibodies or rheumatoid factor can be detected in up to 20% of IPF cases.3 The presence of serum specific IgG against the antigens that can most often cause hypersensitivity pneumonitis should be assessed systematically, since its clinical manifestations are occasionally similar to those of IPF. If any of these are positive, in the context of plausible exposure and bronchoalveolar lavage (BAL) with an increased lymphocyte count, a provocation test against the antigen in question and/or surgical lung biopsy should be performed, in order to confirm or discard the diagnosis of chronic hypersensitivity pneumonia.3 The possibility of using new biomarkers in the diagnosis and characterization of this disease has also gained interest in recent years. Some such as KL-6, SP-A and SP-D, circulating fibrocytes and metalloproteinases 1 and 7 are currently being researched.15–18

Bronchoalveolar lavage (BAL) has been extensively used in the study of DILD. Its analysis in IPF usually shows discrete neutrophilia with or without eosinophilia, and is use has been classically related with its ability to rule out other entities.2,3 The last international consensus indicated that BAL cellular analysis should not be performed systematically in all patients in the diagnostic procedure, although it may be appropriate for a minority.2 Nevertheless, in certain cases, BAL may be very helpful in the differential diagnosis with other entities such as chronic hypersensitivity pneumonitis or non-specific interstitial pneumonia.

Transbronchial biopsy is useful in diseases with lymphatic and centrilobular distribution, or in those that present characteristic diagnostic features and which have a diffuse distribution.19 It is being increasingly used for the diagnosis of sarcoidosis, infections and tumors.19 In contrast, it is of no use in the diagnosis of IPF, since the distribution of the lesion cannot be observed due to the sample size. The incorporation of cryobiopsy to the procedure is very promising, but further studies are required to corroborate its usefulness in DILD.20

HRCT represents possibly the greatest diagnostic advance of the last two decades in the study of diffuse lung diseases. HRCT, either by sequential (slice-by-slice acquisition) or volumetric acquisition (continuous acquisition) is the undisputed technique in the diagnosis of IPF. Knowing the radiation dose used in HRCT is very important; the radiation dose used in volumetric HRCT is triple the values reached using sequential HRCT. The decision to use one or other technique will depend on the balance between the information expected and the individual risk due to the increased radiation received. Following established protocols is recommended, taking into account that the patient's age and sex are decisive factors (e.g. sequential HRCT, with 10mm intervals, in the initial assessment of patients under 40 years, and multi-detector computed tomography (MDCT) in patients aged 50 years or over).21

The objective is to identify findings typical of the UIP pattern (Fig. 3), and to distinguish them from the less specific patterns present in other idiopathic interstitial pneumonias. To prevent descriptive and conceptual errors, the radiological reading should use descriptive terminology based on the radiological–pathological correlation, as recommended by the Fleischner Society.22

Fig. 3.

HRCT at the level of the lung bases, showing a subpleural “reticular pattern” and the presence of multiple small cysts representing associated areas of honeycombing (arrows).

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The official 2011 ATS/ERS/JRS/ALAT consensus2 established that in HRCT, the definite diagnosis of UIP is based on the identification of four “typical” findings: (1) lung involvement should have subpleural and basal predominance, (2) presence of obvious reticulation, (3) existence of honeycombing with/without traction bronchiectasis/bronchiolectasis and (4) demonstrate the absence of findings considered to exclude a UIP pattern (Table 1, Fig. 3). The presence of ground glass opacities should be minimal or non-existent.

Honeycombing, made up of groups of thin-walled cysts, subpleural with a diameter between 3 and 10mm, is an essential finding for accurately diagnosing the UIP pattern. When there is no visible honeycombing, the diagnosis by HRCT will be that of a possible UIP pattern; in these cases, the definitive diagnosis of UIP should be made by biopsy. Lung biopsy can be avoided only when the HRCT shows a definitive pattern, typical of UIP. The positive predictive value of HRCT in the diagnosis of UIP is 90%–100%. A UIP pattern can also be identified in chronic hypersensitivity pneumonitis, asbestosis and some connective tissue diseases.23

HRCT also enables the presence of associated comorbidities (emphysema, pulmonary hypertension, lung cancer), which may determine the clinical progression of the disease, to be assessed. Other diffuse lung diseases, apart from idiopathic interstitial pneumonias, can also be suspected by HRCT.

The 2011 official ATS/ERS/JRS/ALAT consensus recommends that the diagnosis of idiopathic interstitial pneumonias be based on the consensus between the clinician, radiologist and pathologist.2

If the HRCT does not show a definitive pattern typical of UIP, the definitive diagnosis should be made by surgical lung biopsy.

Biopsies should be obtained in more than one lobe, and if possible, the middle lobe and lingula should be avoided, as they usually show non-specific changes that do not provide diagnostic information. Atelectasia due to the extraction can be minimized by gently instilling formaldehyde with a needle, or by shaking the tissue in the container with formaldehyde after removing the suture.

The histological pattern of UIP (Fig. 4) is defined by the fulfillment of four criteria: (a) evidence of marked fibrosis or distortion of the lung architecture, associated or not with honeycombing and predominantly subpleural and paraseptal; (b) presence of patchy lesions in which fibrotic areas are combined with areas of healthy lung; (c) presence of fibroblast foci in the areas of interface of fibrosis with healthy parenchyma and (d) absence of histopathological findings inconsistent with UIP. Among the characteristics not compatible with a UIP pattern are the presence of hyaline membranes, presence of foci with organizing pneumonia, granulomas, marked interstitial inflammatory cell infiltrate away from areas of honeycombing, predominantly airway centered changes, or the presence of other findings suggestive of an alternative diagnosis2 (Table 2).

Fig. 4.

Usual interstitial pneumonia pattern in lung biopsy: peripheral fibrosis (A) with foci of fibroblastic activity in interface areas (B) and microcystic honeycombing foci (C).

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A histological pattern indistinguishable from UIP can be observed in systemic diseases (e.g. rheumatoid arthritis and scleroderma), chronic hypersensitivity pneumonitis, drug-induced pneumonitis, asbestosis and familial fibrosis, so the presence of granulomas, asbestos bodies, specific infections or other exogenous agents must be discarded in the biopsy. These are the reasons a UIP pattern should not be interpreted directly as an IPF pattern without first having excluded all these diseases. The integration of the HRCT findings with the histological pattern is used to establish the diagnosis of IPF, exclude it or, if the data are inconclusive, maintain it as probable or possible (Table 3).

This is defined as the rapid deterioration of the disease in the absence of infection, heart failure, pulmonary embolism or other identifiable cause. The diagnosis is based on the combination of clinical (worsening of baseline dyspnea in less than 4 weeks) and radiological findings (ground glass opacities or consolidations superimposed on a typical UIP pattern on the HRCT).41 The histological findings usually correspond to diffuse alveolar damage patterns, although they are sometimes characterized by organizing pneumonia or fibroblastic foci, added to the UIP morphological pattern. Its incidence and mortality vary according to the series, depending on the diagnostic criteria and follow-up time, with an incidence at 1 year of 9%–14% and at 3 years of 21%–24%,38 and a mortality of up to 60%–70% in 3–6 months. Various studies have established possible risk factors for the development of acute exacerbations, such as low FVC and DLco, and the presence of emphysema and pulmonary hypertension.42

The pulmonary hypertension that appears in IPF is included within the clinical group of PH associated with interstitial lung disease (group 3) of the updated Dana Point classification, and is defined as a mean pulmonary artery pressure (PaPm) greater than 25mmHg.43 Its prevalence is estimated at 30%–45% in patients evaluated for lung transplant, but it is much higher in those with longer disease evolution and at the time of transplant. The development of PH worsens the quality of life and functional status in these patients, who present more dyspnea, lower DLco and reduced exercise capacity, with a shorter distance covered and greater desaturation in the 6MWT.43 It is also associated with lower survival, with a mortality at one year of 28% in patients with PH compared to 5.5% in its absence.44 Although one study reported high pulmonary vascular resistance (PVR) with early mortality in IPF,45 it remains to be defined which hemodynamic parameter has most prognostic significance in these patients. Patients with IPF may present other comorbidities that also contribute to the development of PH, such as emphysema, sleep apnea–hypopnea syndrome, venous thromboembolism, heart disease and diastolic dysfunction.

Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome with a diagnosis based on HRCT findings of centrilobular and paraseptal emphysema in the upper lobes and lesions compatible with UIP in lower lobes.46 Its prevalence is 30%–47% in patients with IPF and it usually appears in males with a history of smoking and major dyspnea. Spirometry and lung volumes are normal or minimally impaired (opposing effect between the hyperinflation due to the emphysema and the loss in volume due to the fibrosis), but there is a marked and disproportionate decrease in the DLco and significant exercise-induced hypoxemia (probably due to the additive effect of the emphysema, fibrosis and pulmonary vascular disease). In CPFE, the decrease in FVC and DLco is slower than in patients with IPF alone, and may cause an error in prognostic estimations. A recent study has demonstrated that the best predictor of mortality in these patients is the decrease in FEV1.47

In CPFE, precapillary PH appears more frequently, earlier and more pronounced than in patients with IPF without emphysema, which represents a poor prognosis and is the principal determinant of mortality. It remains to be determined whether CPFE represents a specific IPF phenotype in smokers, with different genetic predisposing factors and a different prognosis.

Various studies have documented the high prevalence (66%–87%) of GER in patients with IPF, which is asymptomatic in most of them.48 The existence of GER and hiatus hernia, also more common in patients with IPF, may represent a factor in the pathogenesis and progression of the disease in relation to the presence of microaspirations.

Patients with IPF have a high prevalence of sleep apnea-hypopnea syndrome (SAHS) and other breathing disorders during sleep.49 No correlation has been found between the severity of SAHS and physiological parameters such as FVC, DLco and lung volumes.49

There is a higher risk of developing bronchogenic carcinoma in patients with IPF. The prevalence is 5%–10% and increases with the duration of the disease and in patients with CPFE.50 As well as smoking as a predisposing factor, various genetic mutations have been described that could be associated with its onset in these patients. An increased risk of cardiovascular diseases (heart disease and venous thromboembolism) is also found in patients with IPF.51 Pneumothorax can result in worsening of IPF. Its incidence is 11%.2

The therapeutic approach in IPF began to change as of the new physiopathological hypothesis of the disease, in which the development of the condition was proposed as an epithelial–mesenchymal reparative abnormality that could commence without previous inflammation and where anti-inflammatory and immunomodulatory treatment had not been shown to modify the course of the disease.53,54 Based on this new concept, and following several advances in the understanding of the pathogenesis of pulmonary fibrosis, different research avenues were opened with the aim of inhibiting the fibrogenic process triggered, which was the beginning of the “anti-fibrotic” era. In the absence of other clinical therapeutic options, and despite the fact that the inefficacy of glucocorticoids in IPF had been known since 2003,53,55 the use of glucocorticoids±immunomodulators (azathioprine or cyclophosphamide)±N-Acetylcysteine was still considered in consensus guidelines as a treatment option. Table 5 specifies the recommendations and evidence for the pharmacological treatment of IPF.

Pirfenidone (Esbriet®)

Pirfenidone is a drug with anti-inflammatory and anti-fibrotic properties. It inhibits fibroblastic proliferation and the synthesis of pro-fibrogenic proteins and cytokines. Various experimental studies have demonstrated the anti-fibrotic effect of pirfenidone.58 Its clinical efficacy has been evaluated in three placebo-controlled, double-blind, randomized, multicentre, phase III studies in patients with IPF in Europe and the United States (CAPACITY studies) and Japan. The results of the CAPACITY studies have shown that pirfenidone, at doses of 2403mg/24h, reduces disease progression by 30%, and reduces the decline in FVC by 30%. Furthermore, a small percentage of patients presented rapid progression (20% pirfenidone with respect to 35% placebo) and a significant improvement was observed in the exercise capacity, determined by the distance covered in the 6MWT, as well as an increase in the progression-free interval (Fig. 5).55,59,60 To date, pirfenidone is the only drug with confirmed efficacy in the treatment of IPF. In March 2011, it was approved by the European Medicines Agency (EMA) for the treatment of mild-moderate IPF, defined as FVC>50% and DLco>35% (www.ema.europa.eu). At present, and as a result of the clinical trial results, its use is recommended in patients with FVC>50% and DLco>35%. Open-label studies are currently underway, in order to confirm the efficacy of the drug and to optimize its indications. The drug is available in several countries in the European Community, and will soon be available in Spain. It should be considered as a first line drug for the treatment of mild-moderate IPF (Table 4). The dose used is one 267mg capsule/8h for one week, 2 capsules/8h during the second week, and 3 capsules/8h from the third week onwards. The recommended treatment duration is at least 12 months. If there is improvement or stabilization of the disease, it seems logical that treatment should be continued. In the case of deterioration, the advisability of continuing treatment or instigating other therapeutic strategies should be considered for each patient. In this context, it should be pointed out that there are no data showing that the addition of NAC increases the efficacy of pirfenidone (Fig. 6). The main contraindications are drug hypersensitivity, concomitant use of fluvoxamine, severe liver disease or nephropathy, and pregnancy (its use in this population has not been confirmed). Pirfenidone interacts with omeprazole, so it is advisable to substitute this drug for pantoprazole. The most common side effects are dizziness, photosensitivity (skin and eye protection is essential), stomach upsets (administer the drug with food) and liver function abnormalities, generally reversible on reducing the dose.61

Fig. 5.

Beneficial effects of pirfenidone versus placebo in the meta-analysis of clinical trials in the CAPACITY Study. For abbreviations, see text.

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Fig. 6.

Pharmacological treatment of idiopathic pulmonary fibrosis.

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The complications of IPF and the co-existence of comorbidities play a determining role in the course of the disease, hence the importance of their early detection and treatment. The most relevant conditions due to their severity and prognostic implications are acute exacerbation, pulmonary hypertension and gastroesophageal reflux.2

At present, both cell therapy and gene therapy in IPF are in experimental study phases, so we will still have to wait some time to learn their effectiveness as an alternative treatment or combined with pharmacological treatments.

IPF is characterized by the death of alveolar epithelial cells, which are replaced by fibroblasts. Therefore, therapeutic approaches based on cell therapies are aimed at replacing the alveolar cells responsible for regenerating the alveolar epithelium. During the last decade, the transplant of stem cells with the ability to proliferate and differentiate into alveolar cells has been proposed as a therapeutic strategy. Mesenchymal stem cells are probably the cells that have been most widely studied and used, taking advantage of their capacity to differentiate into numerous different cell types. The results obtained on administering mesenchymal cells are contradictory. On the one side, it has been observed that they are capable of adhering to the alveolus and adopting an alveolar cell phenotype, but on the other, it has been reported that, contrary to expectations, they differentiate into fibroblasts, and thus would be increasing the intensity of the fibrosis rather then reducing it. This raises doubts about whether the administration of mesenchymal cells could be considered an ideal therapy in patients with IPF.77

To date, the best option proposed as cell therapy has been the administration of alveolar type II cells, which have managed to reverse the fibrogenesis process in an animal model of bleomycin-induced pulmonary fibrosis.78 These results indicate that the administration of alveolar type II cells could become a treatment for IPF. However, this will involve waiting for the results of currently ongoing clinical studies.

Although IPF is not a genetic disease, there are numerous studies showing that certain genetic polymorphisms may be associated with a higher susceptibility to developing IPF.8 Like cell therapies, gene therapy has only been carried out at experimental level, basically by inhibiting or administering different microRNAs that regulate the expression of different genes related with IPF.

The treatment of cough (especially nocturnal cough which makes it difficult to sleep) and dyspnea is a determining factor for maintaining an acceptable quality of life in patients with IPF. Codeine and other opiates and low-dose glucocorticoids (prednisone 5–10mg/day) have shown certain efficacy in the control of cough.78

In a clinical trial, it has been shown that thalidomide improves cough and respiratory quality of life (consistent recommendation, moderate quality evidence).79 Low doses of morphine can improve both the sensation of dyspnea and persistent cough in patients with advanced disease.78

Palliative care should be aimed at improving the quality of life of patients and their families facing the problems inherent in this progressive and so far incurable disease. Thus, the early identification, assessment and treatment of symptoms such as pain, dyspnea and uncontrollable coughing, as well as any other symptom related with disease progression, in both the physical and psychosocial sphere, is important.80 It is therefore recommended that palliative care be considered an integral part of the overall treatment of IPF (consistent recommendation, very low quality evidence).