REVIEW IN COLLAGEN
W. N. THOMSON, M.B., CH.B., D.M.R.D., F.F.R.
Eastern General Hospital, Edinburgh IF Bichat had been able to complete his text-book In scurvy it does not stain with the normal dyes. of Pathology before his death in 1802, the idea that Its permeability to water is altered by the enzyme certain diseases were due to disorders of the con- hyaluronidase which removes hyaluronic acid. In nective tissue system might have gained acceptance certain diseases of the endocrine glands, such as at an earlier date. As it is, the great advances which hypopituitarism and severe myxoedema, the colwere made in cellular histology attracted so much lagen bundles and elastic fibres are degenerate. In interest that the role of the connective tissue in some conditions it is thought that the connective disease was forgotten until Klemperer, Pollock and tissue may possess antigen-like properties. The basic pathology in this group of diseases is Baehr published their now classic article 'Diffuse Collagen Disease, Acute Disseminated Lupus a fibrinoid necrosis of the connective tissue which is Erythematosis and Diffuse Scleroderma' in May, manifested histologically by swelling, necrosis and 1942. Since then, by common consent, a number disorganisation, followed by inflammatory cell of diseases including rheumatoid arthritis, peri- proliferation and repair. The aetiology of these conditions is by no means arteritis nodosa, scleroderma, dermatomyositis, rheumatic fever and serum sickness have been decided. There is considerable evidence that tissue grouped together and termed the collagen diseases. hypersensitivity is an important factor and that Although the basic pathology is similar in these the changes are in the nature of an allergic response. conditions, the connective tissue is not uniformly The relationship of streptococcal sore throats to involved throughout the body and it is possible to rheumatic fever and periarteritis nodosa seems separate these diseases on clinical grounds. Since well established. There is also evidence that the connective tissue occurs in the lung, it would be changes are of an auto-immune nature (i.e., the surprising if the lungs did not show changes in these body is unable to recognise proteins of its own origin from those outside itself). It seems likely conditions. Connective tissue consists of three elements-- that connective tissue can respond in only a few cellular, fibrillary and ground substance. The ways to injury or disease and that several factors predominant cell is the fibroblast which is probably will therefore evoke the same type of response. Since connective tissue in the lung appears in the responsible for the formation of the fibrillary elements, elastic, reticular and collagenous within bronchi, in the pulmonary vessels, and in the the ground substance. The other type of cell which interstitial tissues, as well as in the alveoli, any of is found in connective tissue is known as the mast these structures can be involved in the collagen cell. It is thought that the mast cell liberates a diseases. In the first three, the histological changes mucopolysaccharide into the ground substance are those of the collagen group as a whole, but in which forms a complex with the collagen fibres. the alveoli the changes are rather more specific. The mast cells are also connected with sulphate Fibrinoid necrosis of the alveolar walls results in metabolism and the formation of chondroitin leakage into the alveoli. Proliferation of the alveolar sulphate which gives cartilage its hard character. lining cells occurs and organisation of the fibrinous The mast cells may store heparin and secrete exudate in the alveolar spaces gives rise to a hyaluronic acid which is responsible for the gel-like carnified type of lung. In the course of time, weeks, consistency of connective tissue and synovial fluid. months, or even years, a form of resolution may They are also connected with histamine release. occur leaving thickened alveolar walls and irregular The composition of the ground substance is not air spaces. constant and depends on the site in which it is found, be it in cartilage, synovia or in the soft RHEUMATOID LUNG tissues. With the recognition of visceral lesions associIt is changes in this ground substance which are responsible for diseases of the collagen group. ated with rheumatoid arthritis (Cruickshank 1954, Little is known about ground substance in general. Sinclair and Cruickshank 1956), it became clear 451
FIG. 1 F1G. 2 F1G. I - - A fifty-year-old male with a long history of rheumatoid arthritis. No history of' dust exposure. There are numerous rounded nodules in both lungs. One of the nodules in the right upper lobe shows central cavitation. The pleural effusion was chyliform. Nodules on both elbows. Strongly positive sheep cell test. There has been little change in the x-ray appearances for four years. FIG. 2--Rheumatoid nodules. Several rounded nodules in both lungs. Note marked central calcification in nodule in the lingular area. Tomograms confirmed that the nodules were peripherally situated. Patient was a fifty-three-year-old postman with no history of dust inhalation. No change in x-ray appearances for four years.
that this condition is really a systemic one with arthritis as only one of its manifestations. Although the changes found in rheumatoid lungs are in many cases similar to the changes of the collagen group as a whole, there is one type of lesion which is specific for this group. Before a lesion can be accepted as being specific it must either have characteristic pathological features or occur with a greater frequency in the rheumatoid patient than in the general population. In 1953 Caplan showed that progressive massive fibrosis was much more common in miners with rheumatoid arthritis and that in 25 per cent of these there were peculiar rounded lesions which proved histologically to be rheumatoid nodules. Caplan also demonstrated that these nodules may precede the development of rheumatoid arthritis by several years. Although the nodular lesions in the lung usually occur in the presence of an industrial dust disease they can occur without it. The rheumatoid nodules vary in size from 1 to 4 cm. and they have sharply defined, slightly irregular borders (Fig. 1). Characteristically they occur below the pleural surface of the lung but they may also occur in the pleura itself and the presence of an effusion is one sign of pleural involvement. The nodules may remain static for
years but some show central cavitation and others central calcification. Rheumatic nodules in the soft tissues around the elbows are often present in association with nodules in the lung (Fig. 2). Rounded secondary deposits in the lung can be very similar in appearance to rheumatic nodules. The distribution of the nodules in the lung, the presence of cavitation and calcification are the main guides to the true diagnosis. Only secondary deposits from tumours arising in squamous or transitional epithelium and occasionally deposits in Hodgkin's Disease show any tendency to cavitate. Often the true diagnosis is overlooked until the static nature of the nodules is appreciated. The other common lesion, which is not specific for rheumatoid arthritis but is more characteristic of the collagen group as a whole, is a fine diffuse fibrosis of the interstitial tissues. The fibrosis is usually first detected in the lung bases. In the early stages it is manifested only by fine, diffuse reticulation, which later proceeds to more definite small coarse nodular opacities and streaky shadows (Fig. 3). In the course of time the fibrosis gives rise to honeycombing and the formation of cystic areas (Fig. 4). These do not proceed to gross bullous formation. Many conditions are simulated by the
CHANGES IN COLLAGEN DISEASES
FIG. 3 FIG. 4 Fro. 3--Pulmonary fibrosis. A moderate degree of pulmonary fibrosis in a patient with long standing rheumatoid arthritis. Note early honeycombing, diffuse nodulation. FIG. 4--Pulmonary fibrosis. More advanced degree of pulmonary fibrosis--generalised honeycombing and the formation of one or two larger cysts. The formation of gross bullae is unusual. This is the type of lesion found in the slowly progressive collagen lesion and is most marked in rheumatoid arthritis, scleroderma and dermatomyositis.
FIG. 5 FIG. 6 FIG. 5--Pleural nodules. Pleural nodules demonstrated after aspiration ofpleural fluid. Fro. 6--Pleural nodulation from bronchial carcinoma.
various stages. Sarcoidosis and tuberose sclerosis are the difficult, differential diagnostic problems. Despite the fibrosis the bronchi are not crowded and thickened as in bronchiectasis. Areas of fibrinous pneumonia occur in this condition. These are segmental and characteristically remain unchanged for long periods of time. In one of our patients with long standing rheuma-
told arthritis on whom a bronchogram was performed dense opacities formed around residual traces of Lipiodol. These opacities cleared slowly over the course of two years. It was felt at the time that this might have been an abnormal response in a rheumatoid subject. Persisting and recurring pleural effusions are found. After aspiration and air replacement,
B FIG. 7
A and B--Disseminated lupus erythematosis. Note large pericardial effusion clearing with steroids in three weeks. Patient was a middle-aged housewife who was gravely ill on admission. Pericardial and Neural effusions are the common lesions in D.L.E.
nodular lesions may be demonstrated in the pleura (Fig. 5) and in some of our cases the pleural effusion has been chyliform in type. This is thought to be due to lymphatic obstruction. DISSEMINATED LUPUS E R Y T H E M A T O S I S The disseminated form of lupus erythematosis is an acute, sub-acute or chronic degeneration of the collagen tissues throughout the body. It occurs more commonly in females than in males and the maximum incidence lies between the ages of ten and forty. The lesion is again a granular eosinophilic change of the collagen tissues giving rise to complete disruption with a slight leucocytic response. The blood vessels are similarly involved showing fibrinoid degeneration of the media and the interna. The characteristic clinical feature of this disease is the presence of the L.E. cell. This is a neutrophil with a large, round inclusion body which stains with the basic dyes. These inclusion bodies contain nuclear material in the form of dipolymerous desoxyribonucleic acid. Libman and Sachs described atypical verrucal endocarditis in 1924. This is the endocardial lesion of D.L.E. In the myocardium areas of degeneration similar to rheumatic nodules are found. As can be seen from the table (Table 1), the disease is a widespread one affecting many bodily systems and patients with D.L.E. may turn up in the rheumatic
CEI~CAE SIGNS D.L.E.
100 per cent
Remittent clinical course Low grade fever Lympbadenopathy Rash on face Renal damage Arthritis and joint pains Enlarged liver
50 per cent
Pleural effusion Pericardial effusion Abdominal pain
20 per cent
units, in the medical or surgical wards and in the chest units or even the psychiatric clinics. Pericardial and pleural effusions are the most common lesions found in the chest (Figs. 7A and 7B). The effusions are usually small and persistent. Actual pulmonary involvement is less frequently seen although Ellman and Cudkowicz (1954) reported five out of a series of twelve cases. The lung lesions may be indistinguishable from areas of bronchopneumonia and segmental consolidation or collapse (Figs. 8A and 8B). More dense segmental opacities suggesting infarction occur. The lesions are usually basal. Many of these patients are subject to intercurrent infection including tuberculosis and it is usually impossible to
B FIG. 8 A and B--Disseminated lupus erythematosis, Lung lesions are not common in D.L,E, and when present they are usually basal and segmental. There are areas of consolidation at the R. apex and in the anterior segment of the right upper lobe, The presence of a cavity was suspected on the plain films, The lesions cleared quickly with steroids, ]No acid fast bacilli detected, L,E, cells present in blood.
assess the true nature of the lung lesions without observation over a period. PERIARTERITIS N O D O S A This is a disease characterised by local areas of necrosis in the walls of the blood vessels. The blood vessels are not uniformly affected throughout the body and the symptoms, whether they be renal, neurological, abdominal or pulmonary, depend on the group of blood vessels involved. Lung changes can be first evidence of this disease. Rose and Spencer (1957) report that pulmonary lesions were the first manifestation in thirty-two out of one hundred and eleven cases. Clinically these cases were interesting. Eosinophilia of more than one and a half thousand per cubic millimetre occurred in half of them and was highest in the twelve who were regarded as having asthma. It is important, therefore, to consider periarteritis nodosa in the
differential diagnosis of asthma occurring for the first time over the age of thirty and without a family history of asthma or other allergy, especially if a significant degree of eosinophilia is present. In 16 per cent of the patients with periarteritis nodosa, granuloma were also present in the nose, pharynx or trachea (Wegener's Disease). The lung lesions tend to fall into three types:-l. The transient opacities of eosinophilia (Fig. 9). These may occur as isolated segmental opacities which appear and disappear in various areas of the lung but may be manifest by fine nodular or streaky lobar opacities. 2. Miliary nodulation may be found occurring along the lines of the blood vessels. 3. Segmental areas of apparent consolidation may also be found in the lung. These are persistent and sometimes cavitate and they may be brought about by infarction.
aspiration pneumonia from oesophageal spill now seems unlikely. The differential diagnosis resolves around the other conditions causing honeycomb lung:--sarcoid, eosinophilic granuloma and tuberose sclerosis. DERMATOMYOSITIS This relatively rare condition is characterised by swellings usually in voluntary muscle. In general it is the elderly male who is affected and death is often due to recurrent ~espiratory infection. The lung changes are typical of the collagen group as a whole, and are usually those of pulmonary fibrosis. R H E U M A T I C PNEUMONITIS
FIG. 9 Periarteritis nodosa. An example of an eosinophilic lesion. Note fading nodular lesion in left lung.
Zeek (1952) split necrotising angiitis into two groups, a primary and secondary type which was the sequel of pulmonary hypertension. There is some evidence that the bronchial arteries are more involved than the pulmonary arteries leading to the appearance of infarction. In the terminal phases central pulmonary oedema can occur. The differential diagnosis is from tuberculosis and also possibly pulmonary aspergilliosis. The miliary type may simulate haemosiderosis. SCLERODERMA Scleroderma as well as being a localised lesion can be diffuse and there is a tendency now to call it progressive systemic sclerosis. It is interesting that Raynaud's phenomenon frequently precedes sclerodactyly by many years and can be a presenting symptom. Pulmonary involvement is a well recognised feature of this disease and is important because,the lung changes can antidate the onset of skin lesions. Pulmonary involvement is heralded by a progressive dyspnoea and later by pulmonary hypertension. Radiologically the picture is usually one of diffuse fibrosis with honeycomb lung. In some regions one may find more solid areas of fibrosis. Enlargement of the pulmonary artery indicates pulmonary hypertension. The belief that the lung changes in this disease were due to an
The pathology is a fibrinous necrosis and oedema with inflammatory swelling of the smaller blood vessels. Small vascular thrombi occur. Fibrinous pulmonary exudates form and give rise to hyalinisation. The picture suggests central pulmonary oedema--it may clear, it may fibrose. The pulmonary fibrosis gives rise to a reduced vascular bed. Right heart failure can occur in the absence of mitral stenosis. It has been suggested that pulmonary oedema-like opacities can also be caused by the use of salicylates in rheumatic fever. ALLIED CONDITIONS There are a considerable number of other conditions in which widespread pulmonary fibrosis occurs, some of which are of importance. It may follow the use of drugs such as hydrallazine hydrochloride for the relief of hypertension (Morrow, Schroedei: and Pervey 1953), or it may follow inhalation of certain gases and metallic poisons which do not prove fatal. Hamman and Rich in 1944 described a rapidly progressive pulmonary fibrosis leading to dyspnoea, oxygen deficiency but not carbon dioxide retention (because of the greater diffusability of this gas). Their cases all ended fatally. Subsequent authors have reported cases of an apparently similar disease which appeared to run a remittent course or which were much more slowly progressive. In some of these cases the disease can be halted at least temporarily by cortisone. In the original description by Hamman and Rich there was no mention of vascular involvement but cases have been reported with periarteritis nodosa and in a series of fifty-four cases reported, six were in siblings (Ruben and Lubliner 1957). Many of these patients have had
P U L M O N A R Y CHANGES IN C O L L A G E N DISEASES a h i s t o r y o f allergy a n d s o m e h a v e h a d r h e u m a t o i d symptoms. It is difficult t o k n o w at this stage w h e t h e r t h e H a m m a n - R i c h S y n d r o m e is in fact the n a r r o w l y defined entity w h i c h t h e s e a u t h o r s d e s c r i b e d o r w h e t h e r it f o r m s p a r t o f a l a r g e r g r o u p o f f i b r o t i c lesions w h i c h m e r g e i n t o the c o l l a g e n diseases.
Acknowledgements.--I would like to thank Dr J. J. R. Duthie of the Rheumatic Diseases Unit, Northern General Hospital, for the willing help which he has given me. I am also grateful to Dr I. W. B. Grant, Dr N. W. Home and Dr J. K. Sclater who have allowed me to use films of patients under their care to illustrate this review and I am particularly grateful to Dr J. MacNamara for reading the proofs and for offering much helpful criticism.
SUMMARY T h e c o m m o n l u n g l e s i o n in t h e c o l l a g e n diseases is p u l m o n a r y fibrosis. I t is f o u n d m o s t f r e q u e n t l y a n d is g r e a t e s t in d e g r e e in t h e s l o w l y p r o g r e s s i v e f o r m s o f this disease p a r t i c u l a r l y s c l e r o d e r m a , d e r m a t o m y o s i t i s a n d r h e u m a t o i d arthritis. The m o r e a c u t e diseases o f this g r o u p s h o w l u n g c h a n g e s w h i c h are n o t specific. Pleural and pericardial effusions are c o m m o n in D . L . E . a n d e o s i n o p h i l i c lesions o c c u r in p e r i a r t e r i t i s n o d o s a . I n b o t h o f these dense infarct-like o p a c i t i e s m a y b e f o u n d a n d these m a y c a v i t a t e . T h e o n l y specific l e s i o n is the r h e u m a t i c n o d u l e w h i c h c a n o c c u r in t h e a b s e n c e o f p n e u m o c o n i o s i s a n d is t h e n difficult to dist i n g u i s h f r o m s e c o n d a r y deposits.
REFERENCES CAPLAN, A. (1953). Thorax, 8, 29. CRUICKSHANK,B. (1954). Ann. rheum. Dis. 13, 136. ELLMAN, P. & CUDKOWlCZ, L. (1954). Thorax, 9, 46. HA~MAN, A. L. & RIc*q, A. R. (1944). Bull. Johns Hopk. Hosp. 74, 177. KLEMPERER, P., POLLOCK, A. D. & BAEHR, G. (1942). J. Amer. reed. Ass. 119, 331. MORROW, J. (3., SCHROEDER,H. R. & PERVEY,H. M. (1953). Circulation, 8, 828. RosE, (3. A. & SPENCER, H. (1957). Quart. J. Med. 26, 43. RUBEN, E. H. & LunLrt~R, R. (1957). Medicine, 36, 397. SCAD~IN~, J. (3. (1958). Proc. R. Soc. Med. 51, 649. S~NCLAIR, R. J. (3. & CRUICKSHANK,B. (1956). Quart. J. Med. 25, 313. Z~EK, P. M. (1953). New Engl. J. Med. 248, 764.
BOOK REVIEW Cardiac Arrest and Resuscitation. By B. B. MILSTEIN. Pp. 219, 37 illustrations. 1963. London: Lloyd Luke. Price, 35s. As the title suggests this book deals solely with the aetiology, pathology, diagnosis and treatment of cardiac arrest. It was not designed to meet solely the needs of diagnostic radiologists, and does not cover the wide variety of allergic reactions that arise from the use of contrast media. Cardiac arrest is an emergency with which any doctor may have to deal. However, in modern radiological practice it may be encountered more frequently than in the past, owing to the great increase in the number of diagnostic techniques employing contrast media. The first one hundred pages are devoted to the pathology, prevention and diagnosis of cardiac arrest. The author points out that there may be premonitory symptoms and signs, which if noted, may give an opportunity to prevent either cardiac asystole or ventricular fibrillation. Cardiac arrest in the radiodiagnostic department certainly occurs with greater frequency after the use of excessive doses of contrast material. The writer emphasises the large part played by anoxia in inducing arrest in a large number of cases.
It is emphasised that the diagnosis of cardiac arrest should be made by noting the absence of pulsation in a large artery, e.g., the carotid or femoral--and not by listening to the chest with a stethoscope. However it is not pointed out that even in normal patients it may be at times difficult for the inexperienced to palpate carotid pulsation.
It is stated that fatalities are usually due to delay in starting treatment--often as a result of multiple diagnostic tests being applied. It should be appreciated that the immediate objective is not to restart the heart, but to restore the supply of oxygenated blood to the brain. If this is not done within three minutes, serious cerebral damage or death is inevitable. External cardiac massage will supply an adequate artificial circulation. The method of applying this i s described and the need for maintaining adequate respiration at the same time is discussed. The indications for performing internal cardiac massage are considered and the present position regarding both internal and external defibrillators is stated. The value of the electrocardiogram is considered to differentiate asystole and ventricular fibrillation. Attention is given to the various steps necessary to treat cardiac arrest as it occurs in different situations such as the theatre, the x-ray department, the consulting rooms and even in the home. It is the duty of those doctors not already familiar with the present position regarding cardiac arrest, to read this book. At least some of the fear of encountering this emergency will disappear, and the case examples quoted will justify the adoption of a more optimistic outlook. The need for some authoritative direction in this subject has been apparent for some time, and the author has admirably dealt with this need, in this excellent publication. J. O. C.