IPF, also known as cryptogenic fibrosing alveolitis (CFA), occupies a special place among all forms of DPLD in that it is the condition with the worst prognosis and a generally rapidly progressive course that is refractory to treatment (mean survival after diagnosis approximately 3-5 years, or median of 28 months). An official statement from the respiratory societies (ATS/ERS/JRS/ALAT) regarding the diagnosis and management of IPF was published in 2011.
Definition / Diagnosis
Previously, histological evidence of the pattern of usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP) were compatible with the diagnosis of IPF. Careful monitoring of the progression in well-defined patient populations revealed, however, that the clinical progression as well as the response to steroid treatment differed considerably between patients with definite UIP and those with another histological pattern. In 2000, it was therefore specified that IPF is characterised by a pattern typical of UIP on an open lung biopsy, complemented by the exclusion of other possible causes, by evidence of the typical changes on HR-CT or chest X-ray, and demonstration of restrictive ventilatory impairment and/or signs of a disorder of gas exchange. According to the 2011 guideline, in many cases the diagnosis may now also be made without an open lung biopsy. Nevertheless, in uncertain cases an open lung biopsy should be attempted, bearing in mind the patient’s lung function and comorbidities.
IPF is a disease of middle to advanced age; patients are on average over 50 years of age (incidence of 2.7/100,000 in 35- to 44-year-olds; 175/100,000 in the over-75-year-olds). In view of the recently revised diagnostic criteria, the incidence data available to date must be regarded cautiously; an average incidence of 7-10/100,000 is likely. Males are somewhat more frequently affected by the disease than females.
The aetiology of IPF is largely unknown. Given that possibly up to 10% of all cases have a higher incidence in some families, a genetic component may be assumed. Indeed, recent studies identified mutations of surfactant protein C (SP-C; so far three large families), of surfactant protein A2 (SP-A2; two families) or of telemorase (approximately 8% of familial cases) in familial cases. The mutations identified at the carboxy terminal of pro-SP-C bring about abnormal protein folding and autoagglutination of the protein and, under certain circumstances (e.g. superimposed viral infection), lead to maladaptive stress on the endoplasmic reticulum (ER stress) and, as a result of this, to apoptosis of the epithelial cell. Interestingly, ER stress can also be demonstrated in sporadic forms of IPF. Also the identified mutations in SP-A2 alter the protein structure, so that the misfolded protein is retained in the endoplasmic reticulum and not secreted. The mutations of telomerase found in another portion of the familial forms of IPF lead to loss of the activity of the enzyme and thus to permanent shortening of chromosome length due to cell division. As a result of this, apoptosis of the type II cell also develops, via chronic DNA damage. Apoptosis is probably an essential element in the development of fibrosis and may also be regularly seen in spontaneous cases of IPF. Type II cell apoptosis and the abnormal reparatory response of the epithelium possibly associated with it is thus at the centre of the predominating pathogenetic mechanisms in IPF. Given the pedigrees and the very variable age of affected family members, an autosomal dominant mode of inheritance with low penetrance of the disease may be assumed. A not inconsiderable effect of secondary, exogenous factors in the form of a second hit is thus supposed. In keeping with this concept is the observation that smoking is an important risk factor for the disease and that respiratory infections often precede the onset of the disease.
Patients generally report a slowly evolving illness that often goes unrecognized for long periods of time, initially characterised by mild breathlessness on exertion. Patients quite often report a severe respiratory infection preceding the onset of the disease (“I have never been able to get over the infection”). Concomitantly, there is relatively often a dry non-productive cough that is frequently hard to treat. On clinical examination, there are usually prominent basal crepitations bilaterally, which subsequently can also be heard in the apices. About half of the patients have watch-glass nails and finger clubbing. Depending on the stage of the disease, there are also signs of chronic hypoxaemia (cyanosis of the lips, signs of cor pulmonale). Laboratory investigations may indicate a slightly raised LDH, an accelerated erythrocyte sedimentation rate (ESR) and, in isolated cases, even low titres of antinuclear antibodies or rheumatoid factor (10-20%).
On lung function tests, patients noticeably have restrictive ventilatory impairment with a reduction in forced vital capacity (FVC), signs of abnormal gas exchange with a greatly reduced CO diffusion, reduced capillary pO2 levels even at rest and more pronounced on exercise, and an increased alveolar-arterial oxygen gradient. The impaired diffusion capacity may precede the loss of FVC and should thus as far as possible be part of the lung function tests. Bronchoalveolar lavage (BAL) generally shows the picture of predominantly neutrophil alveolitis, often also accompanied by a slight increase in eosinophils. Lymphocyte counts above 15% or eosinophil counts above 20% of all cells, although not impossible, are very unusual for the diagnosis of IPF and should prompt a search for other diagnoses.
On the conventional chest X-ray, the prominent finding is marked basal reticular opacities, predominantly in subpleural areas. These changes are usually already evident at the time the diagnosis is made, but normal findings on the chest X-ray do not in any way exclude the presence of IPF. Here, the development of HRCT has helped to also reliably identify patients in an earlier stage of the disease. There are generally also symmetrical basal and subpleural increases in reticular markings bilaterally with a variable ground glass appearance albeit barely or discretely visible. Another characteristic finding is demonstration of traction bronchiectasis and subpleural honeycombing, which can be seen even in the early stages. Nodular changes, thickening of the bronchovascular bundle and mediastinal lymphadenopathy are not or only rarely found although hilar and/or mediastinal lymph nodes of up to 2 cm in size may not uncommonly be seen. The specificity of HRCT is relatively high but the sensitivity is low. If an experienced radiologist considers the diagnosis of IPF to be highly likely, the diagnosis of IPF is correct in about 90% of cases, while only two thirds of all patients with UIP demonstrated on biopsy, however, can be reliably identified radiologically. Collagen diseases and asbestosis are among the main radiological differential diagnoses. Extrinsic allergic alveolitis (EAA) must also be included in the differential diagnosis although in this condition the prominent basal findings are often absent. The finding of an extensive ground glass appearance should lead to other diagnoses being considered, especially RB-ILD, DIP, EAA, COP/BOOP and NSIP.
The histological picture of UIP is characterised by marked lack of homogeneity of the disease process in relation to age as well as the distribution of the changes. In immediate proximity to each other are areas with a normal alveolar structure, fibroblast nests and regions with a generally mild interstitial inflammatory reaction. A honeycomb pattern can also be seen microscopically, with cystically enlarged and bronchialised air spaces. UIP start near to the pleura and basally, with both sides being approximately the same, and progresses from there in a hilar and cranial direction. In cases with a rapidly progressive course, e.g. in the case of acceleration of the underlying disease, the changes typical of diffuse alveolar damage (DAD), organising pneumonia or capillaritis, may also be present. It is important to stress that a UIP pattern can also be seen in collagen diseases, asbestosis or chronic EAA.
To date, pirfenidone is licensed in the European Union as the only antifibrotic drug for the treatment of mild to moderate IPF. An enhancement of progression free survival could be shown for pirfenidone. Among others photosensitivity and gastrointestinal side effects are most commonly seen. Given the fatal course, early evaluation of lung transplantation currently appears to be the most important measure. Against the background of the current waiting times for a donor organ, an early, correct diagnosis thus takes on special importance. Especially in the case of a reduction in FVC of more than 10% in 6 months, a 6-minute walk test of less than 300 m and in the event of hypoxaemia at rest, the possibility of lung transplantation should urgently be evaluated. As part of a phase III study, high-dose N-acetyl cysteine (NAC) has been identified as a possible effective drug. In this study, there was noted to be at least a slowing of the progression of the disease with administration of this substance. A trial of treatment with NAC 3 × 600 mg appears justified, not least because of its generally very good tolerability. In the previous 2002 IPF consensus conference, a trial of treatment with steroids for at least 6 months combined with cyclophosphamide or azathioprine was also recommended, although there are no data from controlled studies in support of this. In a recent trial (PANTHER-IPF) the use of Azathioprine proved potentially harmful and should therefore no longer be considered. In the 2011 guideline a monotherapy with cortisone eis not anymore recommended. Based on our own previous experience, only 5-10% of all IPF patients may have had a slight and generally only transient improvement: as a rule, these are patients who have a marked ground glass appearance on the HRCT as well as lymphocytic or mixed cell alveolitis but who nevertheless have a UIP pattern on VATS. The suppression of the marked accompanying inflammatory reaction (regression of the ground glass appearance on HRCT) appears to be able to achieve an apparent halt in progression, only for a short period. However, further progression of the disease is also seen in these patients, generally after a few months. Increased numbers of clinical studies have been taking place very recently, and patients should be encouraged to take part in such studies. As before, the most robust and prognostically most important parameter for monitoring the course is the FVC. A reduction in this parameter of more than 10% in a year signals a more progressive course and thus an unfavourable prognosis.
Secondary pulmonary arterial hypertension may occur in advanced stages in patients with IPF and might contribute to a certain extent to the exertional dyspnoea. To what extent pharmacological correction of the pulmonary hypertension can result in an improvement in exercise tolerance or even in the prognosis must be investigated in future studies.