Information for Clinicians
DIFFUSE PARENCHYMAL LUNG DISEASES – Information for clinicians
Diffuse parenchymal lung diseases (DPLD) encompass over 140 different non-infectious and non-malignant diseases of the lung parenchyma that can basically affect all three compartments of the lung (endothelium – interstitium – epithelium) and eventually lead to increased cellularity and/or to an increased amount of connective tissue in the terminal portion of the lung. Although the prevalence of DPLD is rather rare (67.5/100,000 for females and 80.9/100,000 for males), many more patients die each year as a result of DPLD as compared to asthma, which is approximately a hundred times more common. We can crudely differentiate between DPLD of known aetiology (e.g. extrinsic allergic alveolitis) and those of unknown aetiology (e.g. idiopathic interstitial pneumonia). Furthermore, it is possible to distinguish between primarily inflammatory forms (e.g. extrinsic allergic alveolitis, sarcoidosis) and forms in which the initial stage of the pathogenic sequence is chronic epithelial damage followed by an abnormal reparatory response (e.g. idiopathic pulmonary fibrosis). DPLD also occur as part of systemic connective tissue diseases (e.g. lupus), chronic inflammatory hepatic or bowel disease (e.g. Crohn’s disease) or vasculitic diseases (e.g. Wegener’s granulomatosis). Not uncommonly, medical treatments also result in DPLD being triggered (e.g. amiodarone, bleomycin). Lastly, the lung, given its large contact surface area with the environment, may be exposed to a very large number of inorganic (e.g. asbestos) or organic (e.g. fungal spores) dust particles, which can trigger DPLD.
The term DPLD which is now increasingly being used, will eventually supersede the term “interstitial lung diseases” (ILD). Moreover the terms “fibrosing lung diseases” amd “lung fibrosis” are used synonymously. In this article, we want to give an overview of all forms of DPLD with the exception of interstitial lung diseases in systemic diseases and sarcoidosis.
Despite the wide variety of underlying diseases, DPLD ultimately have many features in common: these include, firstly, the principal clinical symptom of exertional dyspnoea and later, in addition, dyspnoea at rest, the restrictive ventilatory impairment, the diffusion disorder and arterial hypoxaemia on exertion and later at rest, and finally demonstration of the typical changes on high-resolution computed tomography (HR-CT). Correct classification of the actual underlying disease requires considerable effort on the part of the patient and doctor alike and represents one of the most challenging differential diagnoses in internal medicine. It is contingent upon an appropriately thorough history, careful physical examination, lung function tests with characterisation of gas exchange at rest, complemented if necessary by stress tests (6-minute walk test, ergospirometry), serological tests, an HR-CT examination and, in most cases, bronchoscopy with bronchoalveolar lavage (BAL). Even after these procedures have been undertaken, for a considerable number of patients it is possible to narrow down the range of causes but not to clearly identify it. In these cases, depending on the patient’s age and comorbidities, an open lung biopsy (nowadays usually as minimally invasive video assisted thoracic surgery, VATS) should be attempted for a definitive clarification.
The treatment of DPLD must be directed at the primary underlying disease: in extrinsic allergic alveolitis, therefore, strict avoidance of the inhalational antigen is the most effective and most important measure. In some forms of DPLD, in which excessive nicotine abuse is believed to be an important trigger (e.g. pulmonary Langerhans cell histiocytosis, respiratory bronchiolitis ILD), the patient must be advised to categorically give up smoking or be supported in this pharmacologically. Regarding the high rate of spontaneous remissions an initial wait-and-see approach can be adopted in sarcoidosis. Pharmacologically, the treatment of ILD is still characterised by a limited range of effective drugs. Steroids are the gold standard in primary inflammatory forms of DPLD, complemented by immunosuppressant agents such as azathioprine or cyclophosphamide in order to reduce steroid toxicity. However, among the so called idiopathic interstitial pneumonias, especially in idiopathic pulmonary fibrosis (IPF) the previously recommended immunosuppressant treatment regimen revealed potentially harmful (PANTHER-IPF trial) and is no longer advisable. Novel antifibrotic drugs (pirfenidone) may bring about a reduced progression rate in some patients with mild to moderate IPF. Still, lung transplantation represents the only causal treatment option, but this also involves considerable side effects. In some forms of DPLD (e.g. sarcoidosis), pulmonary arterial hypertension (PAH), occasionally severe, may also develop over time, whilst in other forms PAH may be a prominent feature from the outset (e.g. pulmonary involvement in scleroderma). This being cause to perform initial screening procedures for PAH in every patient and to also check for this on a regular basis during the long-term course. If PAH is present, the appropriate treatment should be initiated. Experience shows that a clinically appreciable, significant treatment outcome is more likely to be achieved the greater the severity of the PAH and the less severe the degree of restriction.
In summary, the prognosis of DPLD varies enormously depending on the underlying disease and ranges from complete remission (spontaneous or on therapy), relatively stable long-term courses (spontaneous or on therapy), severe progressive forms to fulminant courses.
Idiopathic interstitial pneumonia
Idiopathic interstitial pneumonias (IIP), whose pathogenetic mechanisms are still largely unknown, represent a significant portion of the complex spectrum of DPLD. A classification based on histological criteria was first undertaken by Liebow and Carrington in 1969; the current classification was published in 2002 by the American Thoracic Society (ATS) and the European Respiratory Society (ERS). This latter classification is also essentially based on clinical, radiological and histopathological criteria. Overlaps between the histopathological patterns are very much a feature. If the molecular causes for the development of IIP are discovered, a further revision of this classification will be expected. Besides the defined entities of IIP described below, there is also a category called “unclassifiable interstitial pneumonia,” a term that should always be used if a clear classification (e.g. in the case of terminally altered lung tissue) is no longer possible.
Idiopathic pulmonary fibrosis (IPF)
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.
Non-specific interstitial pneumonia (NSIP)
Definition / diagnosis
According to the consensus conference, the group of NSIP is provisional. Originally conceived as an umbrella term for all otherwise non-classifiable forms of IIP, NSIP has been an entity in its own right since the last consensus conference and is based on the histopathological demonstration of an NSIP pattern, which shows a wide spectrum ranging from predominance of a chronic interstitial inflammation (cellular NSIP) to predominance of interstitial fibrosis (fibrotic NSIP). In contradistinction to the UIP pattern, the changes all appear to have the same age, with a predominantly homogeneous interstitial fibrosis of variable density. Intra-alveolar fibrotic processes are found in about one third of cases; fibrosis nests, as seen in UIP, are completely absent. Patients with a predominantly fibrosing reaction have a much worse prognosis compared with patients with a predominant inflammatory reaction. An additional complication is that the NSIP pattern is not specific for (idiopathic) NSIP but can also be seen in other syndromes, e.g. in collagen diseases, drug-induced pulmonary fibrosis and EAA. Thus, in pure clinical terms, it is much more difficult to classify than, for example, IPF and is based on the progression, cell findings on BAL and the HRCT.
There are currently no reliable data on the incidence, but it is probably lower than the incidence of IPF. NSIP patients are usually between 40 and 50 years old at the time of the initial diagnosis and thus almost 10 years younger than patients with IPF. There is no sex difference in the incidence of NSIP.
The aetiology of NSIP is currently completely unknown but it is worth stressing that in the above-mentioned cases of familial IPF isolated mutation carriers predominantly have an NSIP pattern. A discordant picture is also found time and again in IPF patients with evidence of an NSIP pattern as well as a UIP pattern in one and the same lung (in which cases they should, by definition, be considered as IPF). Lastly, cases have also occasionally been described where initially as part of VATS there is an NSIP pattern and then later at the time of transplantation a UIP pattern. It is thus not currently excluded that NSIP is a somewhat different response by the lung to one and the same triggering mechanism. This is also supported by the differentiation already discussed between the cellular and fibrotic NSIP, in which fibrotic NISP may indeed have a clinical course that resembles IPF, while cellular NSIP often responds to steroids and prognostically is much more favourable.
For NSIP, there is also mainly an insidious onset but courses with subacute forms are also occasionally possible. In addition to the initially prominent symptoms that are also found in IPF (exertional dyspnoea, cough), NSIP patients also have fatigue and, in at least 50%, weight loss. Fever is also present in a small percentage. Watch-glass nails and finger clubbing also occur but overall are less common than in IPF. Smokers are not disproportionately affected by the development of NSIP. Otherwise, the symptoms are similar to the clinical examination findings and also the results of lung function tests found for IPF. The heterogeneity of this patient group can be followed in many ways. BAL shows either a neutrophilic or lymphocytic alveolitis (the incidence for each being approximately 50%). Radiologically, NSIP patients noticeably have above all a ground glass appearance as the main finding on the HRCT; these are generally predominantly symmetrical and in a subpleural location. Irregular lines and increased reticular markings are found in about half of all patients; traction bronchiectasis then also occurs. Consolidation is not very typical but may well occur in the later course. Depending on the presence of fibrosing changes, a honeycomb pattern on HRCT may also be seen and the radiological picture is then difficult to differentiate from that of UIP. Accordingly, not even experienced radiologists can reliably differentiate it from UIP (32% of cases), EAA (20% of cases), organising pneumonia (14%) and other diagnoses (12%).
In NSIP patients with a progressive course a trial of treatment with steroids combined with azathioprine or cyclophosphamide should be undertaken in a similar way to the recommendations for IPF. NSIP patients with lymphocytic alveolitis and a predominant ground glass appearance (cellular NSIP) generally respond well to this type of treatment. As with IPF, secondary pulmonary hypertension may also be observed in the advanced stage of NSIP. Its pharmacological correction needs to be the subject of future studies.
Cryptogenic organising pneumonia (COP)
Definition / diagnosis
The currently valid term COP (cryptogenic organising pneumonitis) describes, like the term BOOP (bronchiolitis obliterans organizing pneumonia) still current in German-speaking countries, one and the same clinical syndrome which is characterised histologically by an organising pneumonia with intraluminal organising fibrosis in the alveolar ducts and alveolar spaces. There is also a variable degree of bronchiolar intra-luminal polyps of granulation tissue (bronchiolitis obliterans) as well as an interstitial inflammatory reaction. The lesions show a patchy distribution with an apparently similar temporal development pattern. These histopathological changes may be seen in several pulmonary or extrapulmonary processes and may even be idiopathic. Among the diseases in which this histopathological pattern occurs are organising bacterial and non-bacterial infections, organising aspiration pneumonia, collagen disease and vasculitis, EAA, eosinophilic lung diseases, post–bone marrow transplantation, drug effects, organisation after the inhalation of toxic substances and chronic inflammatory bowel diseases.
Exact figures on the incidence and prevalence are not currently available. COP affects men and women to the same extent, the mean age of onset of the disease is 55 years and non-smokers are affected almost twice as often as smokers.
The aetiology of COP is not currently known but an abnormal reparatory response to an initially inflammatory triggering mechanism is assumed.
The patients often report a respiratory infection that precedes their current symptoms and that did not disappear after repeat administration of different antibiotics. There are accompanying vegetative symptoms such as fever, weight loss, night sweats and myalgia. On laboratory investigations, the ESR, CRP and neutrophil count are often raised. On auscultation, crepitations may be heard either over a circumscribed area or, more likely, throughout the lungs. Lung function tests show restrictive ventilatory impairment to be the main finding, while in a minority of patients there is also obstructive ventilatory impairment. There is a variable degree of abnormal gas exchange with correspondingly impaired diffusion of CO and arterial hypoxaemia. The main radiological finding in COP is bilateral or unilateral, mainly patchy alveolar consolidation with corresponding demonstration of a positive air bronchogram. Nodular changes are also very common, while reticulonodular changes are rare. On HRCT, there is a subpleural or peribronchiolar distribution in 50% of all cases. The so-called tree-in-bud phenomonen is classically seen: a nodular condensation of centrilobular branching structure resembling a branch with blossoms. A ground glass appearance is also common. Bronchial carcinoma is an important differential diagnosis. The cellular differentiation of BAL often shows the picture of a CD8-dominant lymphocytosis, often with increased cell counts of neutrophil and eosinophil granulocytes. Alveolar macrophages often show foamy changes.
The treatment of choice is steroids, and in most cases this will allow a return to the original state. Similar to the regimen shown for IPF, but taking into consideration the often higher steroid requirement in COP and a notoriously high recurrence rate if the steroids are tapered off too quickly (depending on the publication, in up to 50% of cases), the initial dose should be 1.0-1.5 mg/kg body weight of prednisone equivalent (maximum 100 mg/day) for 4-8 weeks. If there is a response, the dose can be reduced slowly to 0.5-1.0 mg/kg body weight over a period of 4-6 weeks. This maintenance dose should then be slowly reduced further no earlier than after 3 to 6 months. If there is no primary response or if high steroid doses are not tolerated, steroid-sparing additional medication (such as cyclophosphamide or azathioprine) should be given, preferably in combination with 0.25 mg/kg body weight of prednisone.
Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-ILD (RB-ILD)
The term RB-ILD covers a form of IIP which is also termed “condensation or smoker’s pneumonia” in German. Here, the cause is generally excessive smoking, with the development of bronchiolitis (respiratory bronchiolitis, RB). In pure RB, patients only have collapse of the small airways. In some patients the disease can take on more severe forms, however, in which case there are numerous pigmented macrophages intraluminally and mild to moderate clinical symptoms (dyspnoea, hypoxaemia). We then talk of RB-ILD. DIP was originally interpreted by Liebow as an expression of desquamation of the alveolar epithelium and thus it is also termed desquamative interstitial pneumonia. We now know that the accumulation of cells in the distal airways and alveoli in this form is of macrophages, as in RB-ILD. Histologically, the picture of DIP is similar to RB-ILD, but the distribution pattern is much more homogeneous and does not even have the bronchiolocentric distribution. There is also mild peribronchial fibrosis and extensive hyperplasia of the alveolar type II cells. The bronchiolocentric lesions are usually combined with centrilobular emphysema. DIP thus very likely represents one spectrum and RB-ILD another spectrum of a common disease which only differs in the degree to which the different compartments are accentuated (like bronchiolitis obliterans and organising pneumonia).
There are no exact figures on the incidence. RB-ILD and DIP patients show long-term and persistent nicotine abuse and are between 40-50 years old.
The aetiology has not been elucidated although it is very likely a process directly triggered by smoking.
The clinical symptoms consist of slowly developing dyspnoea and dry cough, and approximately half the patients have finger clubbing. On lung function tests, restrictive ventilatory impairment and abnormal diffusion are prominent findings.
On HRCT, there is a ground glass appearance, being most prominent in the lower fields and periphery and are sometimes patchy and sometimes homogeneous. There are also centrilobular nodes and condensations of the central and peripheral airways. Centrilobular emphysema which is most marked in the upper lung fields is often also an accompanying feature. Simultaneously there are often patchily distributed hypodensities, which represent local air trapping. Although reticular markings are common, they are usually only mild.
On BAL, the lavage fluid itself often shows yellow-brownish discoloration, the alveolar macrophages seen in increased numbers have yellow, gold, brown or black pigments; eosinophils, neutrophils and lymphocytes may be present to a slightly increased extent.
The clinical symptoms and lung function disorder generally undergo marked regression although there are still no systematic studies on this issue in large populations. Steroids may also be administered as an adjunctive measure.
Acute interstitial pneumonia (AIP)
Acute interstitial pneumonia, first described by Hamman and Rich, is a rapidly deteriorating interstitial lung disease which even today still has a fatal course in at least 50%. Histologically, these patients are found to have the pattern of diffuse alveolar damage (DAD), characterised by hyaline membranes, alveolar oedema and a marked interstitial and alveolar inflammatory reaction. As a rule, the whole lung is uniformly affected. The changes cannot be differentiated from those found in the acute respiratory distress syndrome (ARDS). In the organisation phase, there is abundant type II cell hyperplasia and loose, fibrotic thickening of the alveolar septa. The disease is thought to be preceded clinically by a viral episode with myalgia, arthralgia, fever and malaise. The respiratory insufficiency develops relatively quickly. On initial contact, the picture of bilateral alveolar consolidation is often already present. Intubation with ventilation is more the rule and for many patients the ARDS criteria also apply. Recovery is possible but may also progress towards the terminal picture of honeycomb lung.
Lymphoid interstitial pneumonia (LIP)
LIP was also described as early as 1969 by Liebow. For many years, the significance was low in view of the inability to differentiate it from pulmonary lymphomas (mucosa-associated lymphoid tissue [MALT] lymphomas). It was only with the newer molecular biology and immunohistochemical methods that it was possible to reliably differentiate malignant from reactive changes. Pure idiopathic LIP is certainly a very rare disease, occasionally it occurs in conjunction with underlying systemic diseases such as rheumatoid arthritis, Sjögren’s syndrome, pernicious anaemia, chronic active hepatitis, SLE, primary biliary cirrhosis, myasthenia gravis, severe immune deficiency syndromes (AIDS) and others. The disease more frequently affects women in the fifth decade of life and has a slow progressive course with dry cough and exertional dyspnoea. There is rarely a marked fibrosing reaction, but instead extensive, diffusely distributed infiltration of the alveolar septa with lymphocytes, plasma cells and histiocytes, often also with the hyperplasia of MALT. However, a distribution along the lymphatics (bronchovascular bundle, pleura, interlobular septa) should suggest lymphoma. The pneumocytes are hyperplastic and intra-alveolar organisation tissue is also occasionally present. The HRCT is marked by a ground glass appearance and reticular markings, and occasionally perivascular cysts or honeycombing.