Miliary diseases of the lungs

Miliary Diseases

of the Lungs D.. GERAINT JAMES L. S. CARSTAIRS

TABLE TERMINOLOGY

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INTERPRETATION OF T I I E ABNORMAL X - R A Y

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CLASSWICATION

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INFECTIONS

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Fungal Infections .

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Bacterial Infections . Metazoan Infestations

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Viral and Rickettsial Infections .

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O C C U P A T I O N A L DISEASES COLLAGEN DISORDERS .

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CmCULATORY DISORDERS

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Idiopathic Haemosiderosis

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H a e m o s i d e r o s i s D u e to O t h e r C a u s e s

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NeovLAssm . . . . . . . . . . . . . . . . Bronchial Carcinoma . . . . . . . . . . . . . Pulmonary Adenomatosis . . . . . . . . . . . Lymphangitlc Carclnomatosis . . . . . . . . . . I laematogenous Carcinomatosis . . . . . . . . . . Reticuloses and Leukaemia . . . . . . . . . . . Radiation Reaction . . . . . . . . . . . . .

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~[ISCELI~'~NEOUS C O N D I T I O N S

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Sarcoidosis . . . . . . . . . . . . . . . Tuberous Sclerosis . . . . . . . . . . . . .

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C h r o n i c Diffuse I u t e r s t i t i a l F i b r o s i s (Hanmmn-Rich

Syndrome)

Alveolar Microlithiasis

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Alveolar Protelnosis

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Mucoviscidosis

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Sj~gren's Syndrome

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The IIistiocytoses .

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Iodised Oil

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I'~[ANACEM E N T SU~r~IARY

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~-~_~..~_~-L _~ received his medical degree from the University of Cambridge and was intern and resident at the Middlesex IIosphal. He was a Research Fellow, College o! Physicians and Surgeons, New York City. He L~consultant ph~iclan, Royal Northern tIospital, London; Presldent-elect, Harveian Society of London; Secretary of the Section of Medicine, Royal Society of/,,fedidne; and Secretary of the Oder Club of London. Dr. James wrote the textbook The Diagno~ds and Treatment o] ln lecHons, and is author of various publlcations on sareoldosis.

is Director, Radiodiagnostie Department, Royal Northern Hospital, London, lion. See., Section of Radiology, Royal Society of Medicine, Late Consulting Radiologist, Royal Chest Hospital and Clinical Assistant, Royal National Orthopaedic Itospital. Qualif,]ing M.R.C.S., L.R.C.P. in 1941, he held house appointments in surgery, radlodiagnosls and radiotherapy at St. George's Hespltal. Six years' army servlce as a radiologist wa~ followed by appointment as First Assistant, Radlodiagnostle Department, St. George'n IIospital.

T H E DIFFERENTIAL DIAGNOSIS of widespread pulmonary shadows composed of small round opacities tests the clinical acumen of the radiologist and the interpretive judgment of the physician called upon to read the abnormal" chest radiograph. The combined experience and judgment of both clinician and radiologist are most likely to reduce the differential diagnosis or to reach the true solution in any given case. From a consideration of the history, symptoms or physical signs, the clinician may gather evidence, which is helpful for the diagnosis, prognosis and management of the problem. The radiologist, for his part, may likewise narrow the field by his assessment of the size and number of lesions, their appearance, distribution and density and-by serial radiography--the progression or retrogression of the changes. Finally, the clinician may invoke ancillary tests (blood, skin, pulmonary function, biopsy, and so on) for final definition

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of the problem. This combined clinicoradiologic a p p r o a c h is the essence of current practice, an a p p r o a c h which wiU be followed in this text. Nonetheless, it is well to recognise that this conventional concept does not even answer the simple question, " W h a t casts those several shadows?" (1). T h e radiographic picture of an excised lung m a y have little similarity to the picture obtained when the lung is enclosed within the thorax. I n order to penetrate the walls of the thorax, the quality and quantity of radiation is such that

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Fxo. l.--Plastle foam. A, 0.5 cm. thick; B, 5.5 cm. thick; 6', 18 cm. thick. m u c h of tile finer lung detail is obliterated. Part of the problem in routine chest radiography is to decide whether the shadows we see represent single structures or whether they are s u m m a t i o n effects produced by the superimposition of m a n y shadows. T h e r e is no difficulty in the case of large vessels, calcifications, fiat structures seen edge-on and large shadows surrounded by well-aerated lung. T h e i r shadows correctly represent their physical state. I t is with numerous fine shadows, often referred to as "miliary mottling," that difficulties of interpretation arise. This has been investigated in a series of experiments in which moistened plastic f o a m was used to simulate the background reticular pattern of normal lung. I n sections varying in depth from 0.5 cm. to 18 cm. (Fig. 1) the 4

radiographic pattern is essentially unchanged, but with increasing layers a summation effect gives the false impression that the components of the network are thicker. Similarly with a plastic lattice used to simulate linear opacities lying at right angles to the x-ray beam: the summation of 80 such layers (Fig. 2) pro-

Fzo. 2.--Linear plastic lattice. A, 1 layer; B, 7 layers; C, 40 layers; D, 80 layers. duces a radiographic appearance of irregular nodules interspersed by ill-defined translucent areas. The summation effect produced by 80 layers of a plastic lattice is somewhat similar to that provided by a 20 cm. thick collection of small solid spheres or marbles varying in size from 2 to 5 ram. (Fig. 3). Thus, 2 entirely different structures--a plastic latticework or a collection of

FIo. 3 . h A layer of discrete nodules 20 cm. thick and 2 - 5 ram. in width

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Fio. 4.--A, model lung, wax slabs, 18 cm. of plastic foam and plastlelne hilum. B, more than a hundred 2 ram. "nodules" have been placed in the triangle.

-solid spheres--may cast the same radiographic appearance of diffuse nodular shadowing. Moreover, on rescrutlny of the film, an observer could equally well describe it as well-defined nodular shadows or as numerous hollow structures. T h e difficulties of interpretation are heightened when the various substances are all brought together to create a model lung composed of an 18 cm. thickness of moistened plastic foam to provide a reticular background of "lung tissue," a plasticine vascular hilum, and

FIo. 5 (le[t).--Model lung. Thousands of 2 ram. "nodules" have been introduced at many levels throughout the model. Fro. 6 (rlght).--A plastlcine "hilum" placed against the 20 cm. thick layer of "nodules." The finer vessels cannot be seen. 2 mm. marbles to mimic pulmonary nodular infiltrates (Fig. 4). When the model is loaded with thousands of marbles, a nodular pattern is obtained (Fig. 5). T h e summation of nodules obscures the finer vascular shadows of the plasticine hilum and even tile larger hilar shadows become ill-defined (Fig. 6). F r o m these experiments it is realized that under varying circumstances nodular structures may look cystic, linear structures may look nodular and an increase in the quantity of background reticulation may give the false impression that the components of the network have become thicker. I n conditions of good contrast, that is, when the relative volume of air to solid structures

is high, small opacities of tissue density may be visible if their diameter in the line of the x-ray beam adds materially to the thickness of the solid background (the detail of which is largely .obliterated in normal radiography). When the background density is markedly increased, the interpretation of any shadows in terms of individual structures is difficult. It underlines the fallacy of radiologic classifications which subdivide nodular shadows according to pattern (netlike, reticular, honeycomb) or grade shadows in various millimetre sizes. TERMINOLOGY

In an attempt to provide a precise description of shadows in chest radiographs, physicians and radiologists over the years have developed a peculiar glossary. Snowstorm, fluffy, soft, hard, diffuse, nodular, patchy, mottled, miliary--these are terms which we understand pictorially, for they recall familiar appearances, shapes and consistencies. Nevertheless, although we know what these words mean, we do not always agree on their visual interpretations. The use of the word "mottling," particularly of the lung apices, has become synonymous with tuberculosis. In fact, however, mottling means nonuniform or variegated and as such could equally well apply to the various densities and translucencies produced by ribs, blood and air in the normal chest radiograph. Nonetheless, the term mottling is confined to abnormal shadows. Since it has been applied indiscriminately to all heterogeneous shadows, it is now quite nonspecific and is seldom used by itself. It could well be replaced by the words shadows, shadowing or opacity. "Miliary" derives from millet seed and was originally introduced to evoke the physical peculiarities of a grain; namely, a small, round and compact structure or shadow. ("Nodular" suggests the same except that it implies bigger size.) If the discussion to follow were restricted to the original and exclusive sense of the term "miliary," then the diseases producing such shadows can probably be counted on the fingers of one hand. Miliary tuberculosis is the notable prototype, and there are very few others which can truly be said to produce x-ray shadows of the size and shape of millet seed. But the term has been broadened

to encompass shadows which are neither small nor even well"defined. The conjoined term "miliary mottling" or "miliary shadowing" has gradually evolved into a description of numerous fairly small shadows conveying some pattern of regularity and symmetry. Although the term is somewhat unsatisfactory and nonspecific, the continued universal usage of the term "miliary mottling of the lungs" in the medical literature indicates that it will be retained, certainly until the responsible causes of the syndrome are sufficiently well-delineated to provide an alternative nomenclature. INTERPRETATION OF THE ABNORMAL X-RAY

The heavy metals, including calcium, iodine, tin, barium and iron, as well as fat give rise to fine and distinctive shadows. Microlithlasis alveolaris is associated with a characteristic and diagnostic radiologic picture. Apart from these examples it is probably true to say that all nonaerated solid and fluid structures encountered in the thorax are of much the same density and hence unlikely to be distinguished one from the other. Variation in the kilovoltage used in exposure time and the introduction of ultrafine grids and lead foil filters may be helpful. Tomography is disappointingly of little assistance except perhaps in confirming cystic lung disease, when the fine curvilinear shadows may be diagnostic. Suggestive information may be obtained from the relation of the opacities to the small vascular shadows. If there is loss of definition of these fine vascular markings, then it is likely that they are being obscured by adjacent perivascular solid or fluid, which accounts for the pulmonary shadowing. On the other hand, if the small vascular markings remain well-delineated, then any adjacent pulmonary shadows or opacities are distinct from the vasculature and probably represent independent solitary miliary aggregations. The lungs have a conical shape and small evenly disseminated lesions will appear more numerous at the base where the depth of lung is greater than at the apex. Sclerodermatous and rheumatoid lung lesions are predominantly basal, and this may be useful in diagnosis.

T h e radiologic picture of coarse; ill-defined linear shadows against a background of irregular discrete and confluent opacities is not diagnostic of any single disorder, for it is encountered in 9 several conditions ranging from simple pneumonia to carcinomatous lymphangitis (Fig. 7). Although the pathology is so dissimilar and the clinical pictures are distinctive, it may be difficult on radlologic grounds to

Fro. 7.--Coarse nodular shadowing with discrete and confluent elements on a background of ill-defined linear shadows (some of which are vascular markings) is commonplace and nonspecifie. A, a simple bronchopneumonic lesion occurring in an emphysematous chest and associated with pulmonary congestion and cardiac enlargement. B, carcinomatous lymphangitis. distinguish miliary tuberculosis from honeycomb lung. Portions of the lung fields are strikingly similar (Fig. 8). Different areas of the same film may show variegated appearances as will be seen in a series (Fig. 9) from the same chest radiograph of a patient with pulmonary sarcoidosls. It is as well that clinicians are cognisant of these radiologic pitfalls. They serve to emphasise the importance of a combined clinicomdiologic approach to tile assessment and management of miliary diseases of the lungs. 10

Fxo. 8 . - - T w o examples of similar radiographic appearances produced by different diseases. Note that in each instance the shadowing is "miliary" in type but there are also small ring shadows which appear to be derived from cylindrical structures. (Compare these with the experimentally produced films, illustrated in Figs. 2D and 3.) A, miliary tuberculosis. B, as the disease responds to treatment, the miliary character of the shadow regresses and the finer vascular markings become visible. C, honeycomb lung, in which a thick-walled reticular and linear pattern surrounds air spaces. D, shadowgraph from a thin section of the same lung. 11

FIo. 9.--The variegated appearances in this series are from different parts of one chest film of a patient with pulmonary sarcoidosis. A, coarse ill-defined nodular shadowing with loss"of definition of vascular markings, probably indicating an increase in thickness of the finer components of the lung. B, linear shadows predominant. C, ill-defined heterogenous opacity in which separation of indi~qdual elements is difficult.

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CLASSIFICATION

This classification is based on the one that was developed independently by an American radiologist (2) and by a British clinician (3), but has now brought up to date, for the succeeding decade or so has changed the emphasis of pulmonary infections, brought to the fore other diseases and introduced new technics in the investigation and treatment of practically all these conditions whether they be pulmonary or generalised disorders. Infections Fungi Bacteria Metazoa Rickettsiae and viruses Occupational diseases Collagen disorders Circulatorydisorders Neoplasms Miscellaneousconditions INFECTIONS

FUNGAL INFECTIONS Very few of the thousands of known fungi have been found pathogenic to man. They can be subdivided into those causing superficial lesions and those producing deep-seated infections. Whereas the former are relatively innocuous, the deep mycoses may be highly fatal or cause prolonged morbidity. The superficial dermatophyte infections do not invade the lungs, but the systemic or deep mycoses commonly do so, producing various nonspecific radiographic appearances. There are some pointers (Table 1), radiographic and clinical, which may distinguish one fungus infection from another, but the most satisfactory proof depends upon isolation of the organism and serologic evidence of specific antibodies. BACTERIAL INFECTIONS Widespread public health measures, vaccination and effective antituberculous chemotherapy have relegated tuberculosis from its former position of prototype to a less comon cause of miliary ]3

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shadowing. Miliary tuberculosis should not be forgotten in the older age group, when it may present as obscure fever, possibly associated with hypersplenism and pancytopenia. During the 1950's it was evident that there was a world-wide endemic of penicillin-resistant staphylococcal infections. Since this bacterial infection often followed indwelling intravascular catheterisation (and as such was iatrogenic), staphylococcal septicaemia became increasingly frequent. The earliest radiologic signs of staphylococcal pyaemic pulmonary disease consist of oval or round, lowdensity shadows situated peripherally, usually in the middle zone of the lungs. The diameter of the opacities may range from 0.5 to 1.5 cm. and only 1 may be visible in the first radiograph (4) (Table 2). Within a few days, further films reveal fresh lesions or a slight increase in the size of the shadows. Associated radiographic changes include oval, thin-walled air-containing cysts or cavities peripherally and small pleural effusions. FriedlS.nder's pneumonia may present with numerous small abscesses and diffuse fine mottling, but its more usual presentation is that of a penicillin-resistant abscess in the right upper lobe in men over 40 years of age who cough up tenacious redcurrant jelly sputum. Tularaemia and plague, when septicaemic, involve the lungs, causing widespread pulmonary changes. METAZOAN INFESTATIONS The helminths which infest man are classified into trematodes (flukes), cestodes (tapeworms) and nematodes (roundworms). Some of these are capable of transpulmonary migration, giving rise to pleomorphic pulmonary shadowing including a coarse reticular pattern. It is sometimes responsible for the syndrome tropical eosinophilia. The diagnosis is rarely overlooked in endemic zones of the tropics (Table 3), but pulmonary ascariasis can quite easily escape detection in temperate zones. The swallowed ova of Ascarfs lurnbricoides hatch in the intestine into larvae which penetrate the intestinal wall, invade the blood, reach the lungs, and then pass directly from the trachea to the oesophagus and back to the intestine. Invasion of the viscera by the larvae of the dog or cat ascarid, Toxocara, may cause transient radiologic changes in the lungs resembling miliary tuber16

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culosis in children below 3 years of age (5). A history of pica is almost constant and ingestion of the ova of Toxocara in the dirt is the source of infection. This unusual means of infection may also account for the age incidence, for pica becomes less common with advancing childhood. Apart from the disseminated pulmonary infiltration with wheezy bronchitis, the syndrome comprises hepatomegaly, eosinophilia and a raised serum gamma globulin level; anaemia and convulsions are common findings. Examination of material obtained by aspiration liver biopsy reveals miliary granulomata resembling sarcoid tissue but also including a heavy concentration of eosinophils. Toxocara cati measures 350 /~ in length and 17 /~ in diameter, and Toxocara canls is a little larger. VIRAL AND RIOKETTSIAL INFECTIONS

Infection of the lungs by a virus may occur in measles, chickenpox and influenza, but the pneumonia in these diseases usually is a secondary bacterial bronchopneumonia and the accompanying clinical picture usually is distinctive. There remains a group of nonbacterial pneumonias which are often buried in the meaningless term "primary atypical pneumonia." This refers to an acute pulmonary infection that does not conform clinically, radiologlcally or therapeutically to the accepted pattern of bacterial pneumonia. It is suspected of being viral in view of its epidemic explosiveness, fairly long incubation period for a respiratory tract infection, and by its lack of response to sulphonamides or penicillin. Confusion arises when the term "primary atypical pneumonia" is regarded as synonymous with penicillin-resistant pneumonia, for it is apt to encompass such totally dissimilar conditions as aspiration br0nchopneumonia or pneumonia associated with a neoplasm. Symptoms of a constitutional upset overshadow those of a respiratory disorder. Headache, chilliness, malaise, muscular pains and anorexia are associated with a slight dry cough, retrosternal discomfort and pyrexla, and a paucity of abnormal signs in the lung fields. There is no pathognomonie radiologie appearance, which is occasionally that of diffuse miliary shadowing. The extent of the opacities may be, surprisingly, out of proportion to the few abnormal signs; they may be ill-defined, ground19

glass in density and, most important, need bear no precise relation to the bronchopulmonary segments, such as occurs with aspiration bronchopneumonia. The leukocyte count is not raised but there may be a relative lymphocytosis (Table 4). This is a point of differentiation from bacterial pneumonia, although it is quite nonspecific and holds for all virus infections. This clinicoradiologic picture is common to psittacosis, Q fever

T A B L E 4.--DIFFERENTIAL DIAONOSIS OF VIRUS PNEUMONIA AND ASPIRATION PNEU~tONIA VIRUS P/~'EUMONIA

ASPIRATION P~,'EUSt0N~.

Onset

Nonspecific constitutional Upper respiratory disorder tract infection Chest radiograph Surprisingly widespread Bronchopulmonary changes in view of segmental lesion paucity of physical signs. Opacities not segmental Bacterial flora of sputum No significant pathogen Mixed flora Complement fixation test for psittacosis, Q fever, influenza Negative Cold haemagglutinlns, }May be positive streptococcus ~I"G agglutinins Poor Variable Response to sulphonamides and penicillin Variable Response to tetracyclines Good None Very good Response to correct postural drainage and cold-haemagglutinin pneumonia. They may only be dlstlnguished by laboratory means (Table 5). The term psittacosis is derived from the Greek word "psittakos," meaning parrot, and was applied to this disease because infection was considered to have been transmitted by birds of the order Psittaciformes. In its widest sense the name parrot includes in this group the macaws, cockatoos, lories and parra20

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keets. The domestic fowl, duck and pigeon may also harbour the virus and so they are also potential reservoirs of human air-borne infection. The alternative term, ornithosis, is more comprehensive. The causative organism may be isolated from blood, nasopharyngeal washings or from lung at necropsy, but it is more convenient to demonstrate a significant increase in serum antibody titre during convalescence. Cows and sheep are reservoirs for Rickettsia (or Coxiella) burneti, which is transmitted by tick faeces or contaminated milk and causes Q fever. The rickettsiae may be isolated from blood or nasopharyngeal washings, or recent infection is demonstrated by a convalescent rise in serum antibodies. Whereas the aetiology of psittacosis and Q fever are wellrecognised, that of disseminated pneumonia associated with raised cold haemagglutinins has been the subject of controversy for the past 20 years. There has been recent strong evidence (6, 7) in favour of the filterable agent transmitted to cotton rats, hamsters and chick embryos by Eaton and his coworkers (8). Still, the most practicable means of segregating patients with diffuse pulmonary shadowing due to this group is by serologic evidence of cold haemagglutinins (9) and/or streptococcus M.G. agglutinins (10). The viral and rickettsial]nfcctions undcr discussion are responsible for transient pulmonary shadows. Mackay and Cairncy (11) have rcccntly claimcd that varicclla in adults may lead to permanent chest radiographic changes consisting of evenly distrlbutcd calcificd nodules of I-3 ram. size widely scattered throughout both lung fields. They have observed the same scqucncc in 7 adults all of w h o m had sustained chickcnpox, usually scvcrc, during adult life. It is suggestcd that thcsc calcificd nodules are the end result of caseatlon occurring as a result of varicclIa pncumonla. The differential diagnosis bascd on thcsc radiologic findings included miliary tuberculosis, histoplasmosis and occupational lung disease due to tin, iron and barium; but on a combination of evidencc all of these altcrnativcs scemcd less likely in their cases. Further epidemlologic studics are awaitcd to assess whether pulmonary varlcclla should bc included alongside histoplasmosls and tuberculosis as a c o m m o n cause of diffuse coarse widcspread calcification in the lungs. 22

OCCUPATIONAL DISEASES

The clinical, radiologic and functional changes produced by exposure to various known inhaled irritants do not usually give rise to'diagnostic difficulty if an accurate history, including a list of all occupations from the time of leaving school, is obtained (Table 6). If the inhaled particles are of high atomic weight and high radiopacity, then the shadows are very radiopaque. Barium, calcium, tin and iron are capable of producing such miliary shadows throughout both lung fields. Silica, on the other hand, provokes a fibrotic reaction and the resulting chest x-ray may represent a combination of massive fibrosis, accompanying tuberculosis, cavitation, bullae and bronchiectasis. The clinical and radiologic changes observed in beryllium disease and in farmer's hmg may closely mlmie sarcoidosis. Beryllium, the fourth element in the periodic table, has a low density, high modulus of elasticity, good thermal conductivity, and high melting point, and it resists atmospheric corrosion; but these attractive metallurgic properties are offset by its brittleness. VChen 2% of beryllium is added to copper, however, the alloy is hard, resists high temperatures and corrosion, is nonmagnetic and it does not spark--a big advantage in tools used at oil refineries, and in aircraft engines and electrical circuits. Its low atomic number makes beryllium useful as a moderator in slowing down and reflecting neutrons, particularly since it does so without wastefully absorbing them, thus ensuring for itself a special place in atomic reactors. These uses have replaced its former role as a beryllium phosphor, which gave fluorescent tubes their glow but also contributed to severe poisoning among workers engaged in coating these tubes or preparing the fluorescent powders. Respiratory diseases due to inhalation of beryllium have been arbitrarily divided into acute and chronic forms, depending on the abruptness of onset and progression of the disease. Identical findings in chronic beryllium disease and sarcoidosis include not only clinical, radiologic and hlstologlc features but also the results of respiratory flmction tests (12), serum protein changes, and abnormalities in calcium metabolism (i3). These similarities throw even greater emphasis on the results of skin tests, which have proved helpfl,1 in distinguishing the two conditions. Curtis has demonstrated that the Kveim test is negative in beryllium 23

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disease (14) and James (15) has shown that the beryllium patch test is negative in sarcoidosis; so these two skin tests, involving different antigens, are mutually helpful in distinguishing beryllium disease from sarcoidosis. Israel and Sones (16) emphasise massive hilar l)a'nphadenopathy as a differential radiologic point, for it is common in sarcoidosis but absent in berylliosis. Similar diffuse miliary shadowing and the identical granulomatous response may also be observed in the acute or progressive 24

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phase of farmer's lung, but the history of exposure to m o u l d y hay or to threshing is present and the K v e i m test is negative. COLLAGEN DISORDERS

Polyarteritis nodosa is a disease or more likely a group of diseases of u n k n o w n aetiology, in w h i c h the characteristic hlstologle 25

appearance is that of a segmental arteritis of varying severity affecting blood vessels of medium and small calibre. There is fibrinoid necrosis, particularly of the media, and destruction of the intlrnal elastic tissue. All coats become oedematous and infiltrated with leukocytes, eosinophils being conspicuous. Mononuclear cell infiltration is followed by granuloma formation, fibroblastic proliferation and healing with fibrous tissue scarring. Thrombosis of the vessel, recanalisation and aneurysms at points of bifurcation are common accompaniments. The severity and diversity of the clinlcoradiologic pictures depend upon the magnitude and particular distribution of this necrotising panarteriffs. Rose and Spencer (17) distinguished pulmonary polyarteritis nodosa by its respiratory onset which sometimes precedes evidence of extrathoracic involvement by several years. In their series, asthmatic bronchitis and recurrent pneumonias were associated with blood and tissue eosinophilia, and also occasionally with mucosal ulceration of the trachea and alimentary tract. Radiographic abnormalities include changes due to heart failure, diffuse fine shadowing, cavitation and pleural effusion. Dyspnoea may be out of proportion to the apparent degree of lung involvement due to difficulty in gaseous alveolocapillary diffusion. Rose (18) preferred to distinguish the natural history of the disease, depending upon whether there was lung involvement. In his group of 32 patients (16 males) with lung involvement all but. 1 died, commonly from pulmonary disease (nearly 50%) or renal disease (25~b). If the antecedent history of vague respiratory illnesses is excluded, the duration from the appparent onset of pulmonary polyarteritis to death is less than 6 months. Corticosteroid therapy provides symptomatic relief and suppresses the constitutional upset, but it is not yet certain whether it alters the natural history of the disease. IVegener's granulomatosis is characterlsed by necrotic ulcerative lesions of the respiratory tract. It should be considered when widespread pulmonary shadowing is associated with necrotlslng lesions of the sinuses, nares and trachea. Rarely, diffuse nodular shadowing of the lungs may be associated with disseminated lupus erythematosus, scleroderma and rheumatoid arthritis. Wet or dry pleurisy is a common accompaniment. Ellman (19) reviewed the pulmonary and pleural 96

manifestations of what he preferred to term the connective tissue disorders. CIRCULATORY DISORDERS

~DIOPATHIG HAEMOSIDEROSIS The pathogenesls of this poorly understood disorder appears to be recurrent leakage of blood from pulmonary capillaries into alveoli, associated with pulmonary artery hypertension. This sequence of events causes recurring episodes of dyspnoea, cyanosis, tachycardia, cough and haemoptysis. As a result of the deposition of haemoslderin, the chest radiograph reveals widespread millary shadows. Although encountered mainly in infancy and childhood, it is now being increasingly recognised in adults. In young men it may be associated with a rapidly progressive form of diffuse glomerulonephritis, characterised histologically by numerous necroses in the glomerular tufts. Severe nephritis may be sufficiently dramatic that it overshadows mild pulmonary haemoslderosls, which thereby remains unrecognised (20). There may be a common lesion in the capillaries of lungs and kidneys. There is no evidence that the syndrome is a manifestation of polyarteritis, but a hypersensitivity reaction may be basically responsible. HAEMOSIDEROSIS ]~UE TO O T H E R CAUSES A similar radiologic and pathologic appearance may be associated with mltral stenoslsand pulmonary hypertension, or following repeated blood transfusions. The history and physical signs are sumcient to suggest the nature of the lung changes in such cases. M a n y other cardlovascular disorders give rise to widespread pulmonary changes, but they rarely cause diagnostic confusion either c]inlcallyor radlologically.This would apply to cardiac failure and pulmonary oedema; renal failure or hexamethonium lung; diffuse millary haemorrhages due to blast injuries or following troublesome haemoptyses. In polycythaemla vera, changes 27

of cardiac failure may be superimposed on pre-existing vascular plethora of both lungs, producing a summation effect of widespread mottling. NEOPLASMS

Intrathoracic neoplasms are so frequently encountered that their presence is constantly suspected. The forms which should be consldered in the differential diagnosis of diffuse millary shadowing are: Bronchial carcinoma Pulmonary adenomatosis (multiple nodular carcinoma, bronchlolar carcinoma or alveolar cell carcinoma) Lymphangltlc carclnomatosls Haematogenous carcinomatosls Retlculoses and leukaemia Radiation reaction

BRONCHIAL CARCINOMA Bronchial carcinoma is commonplace and its radiographic guises are protean. If the shadows are bilateral and symmetrical, with no evidence of involvement of one bronchopulmonary segment, it is often tempting to interpret the chest radiograph as that of haematogenous metatases from a primary tumour elsewhere in the body. Necropsy eventually reveals the primary bronchial carcinoma which, despite the production of numerous intrapulmonary metatases, has remained too small to cause telltale bronchopulmonary segmental atelectasls. P U L M O N A R Y ADENOMATOSIS Pulmonary adenomatosis tends to cast a coarser appearance and more irregular distribution than true millary mottling, but this may in part be due to associated diffuse chronic inflammatory disease of the lungs. Both benign and malignant pulmonary adenomatosis originate as a bronchiolar reaction to lung damage in its broadest sense, with fibrosis and hyperplastic epithelial changes. The diffuse mulficentric neoplastic changes may be associated not only with fibrous scars, diffuse fibrosis and bronchiectasls, but also with such collagen disorders as scleroderma (21). 28

LYMPHANGITIC

CARCINOI~IATOSIS

Lymphangitic carcinomatosls may have various radiographic appearances. In a group of 24 cases reviewed by Harold (22), 5 showed fine miliary mottling; 9 revealed secondary changes including pleural effusion, consolidation or collapse; whereas 9 patients displayed a most characteristic string-network appearance radiating from hila to periphery. In one instance normal lung fields-persisted in all chest radiographs. The sites of the primary tumours were the bronchus in 10 patients; stomach and pancreas each in 4 instances; breast in 2 patients; and 1 each involving the prostate, rectum, kidney, or a mediastinal teratoma. HAEI~IATOGENOUS

CARCINOI~IATOSIS

Haematogenous carcinomatosis appeared as fine miliary shadowing in about 10~b of a series investigated at the Middlesex Hospital, London, by an enterprising group of medical students (93). The investigation was undertaken to correlate radiologic and pathologic findings in patients with pulmonary metastases. In an unselected series in which there was necropsy evidence of pulmonary metastases, chest radiographs had been made in the week or so before death in 79 patients. Pulmonary metastases were radiologically apparent in only 49 (629b) of these, the remaining 30 cases being associated with normal chest radiographs (Table 7). Even when these negative films were reviewed T A B L E 7 . - - C O R R E L A T I O N OF C H E S T I{ADIOGRAPHIfi ABNORMALITIES W I T H SIZE AND DISTRIBUTION OF PULMONARY ~ E T A S T A S E S NECROPSY GROUP~

*Group 1 = Group 2 = Group 3 = Group 4 = Group 5 =

CIIEST RADIOC~H POSITIVE ~EOATIVE

1 2 5

3

4

14

24

10

4

14

5

8

2 0 0

Total = 79

49

30

Diffuse miHary nodules up to 2.5 ram. in d;3meter. Few scattered nodules up to 25 ram. in diameter. Diffuse metastases up to 25 ram. in diameter. Metastases over 25 ram. in diameter. Massive invasion replacing one lobe or greater.

29

TABLE

8 . - - C O R R E L A T I O N OF PRIMARY SITE OF NEOPLAS~t ~VITII C I t E S T RADIOGRAPtIIG ABNORMALITY PRIMARY SITZ OF NEOPLASM

Breast Bronchus Osteosarcoma Kidney Pharynx; larynx Ovary Thyroid Cervix Colon Bladder Lymphosarcoma Oesophagus Rectum Adrenal cortex Fibrosareoma Bile duct Testis Thymoma Prostate Caecum Parotld Trachea Synovloma

CIIEST I~LDIOGRAPII PO$1TIVI~ NEC,ATIVE

6 6 5 6 4 3 2 1 1 3 1 I 0 2 0 1 2 1 1 1 1 0 1

4 2 3 0 2 1 1 2 2 0 2 2 3 1 2 1 0 1 0 0 0 1 0

49

30

in retrospect, knowing that metastases were f o u n d at necropsy, no radlologlc evidence of metatases was discernible. Miliary carclnomatosis was radlologlcally visible in 3, b u t was not apparent in another 4 instances. Scattered small nodules were only revealed radlologieaUy in one third of the cases. But if nodules of this same size were diffuse, they almost always cast abnormal shadows in the chest radiograph, suggesting radlopacity due to a summation effect. As would be expected, when the nodules were cannonball in character, or when there was massive infiltration, there was no difficulty in detecting them radlologlcally. T h e sites of the primary tumours were c o m m o n l y breast and bronchus (Table 8). Metastases from tumours of the kldncy and bladder gave rise to large p u l m o n a r y metastases, all of which 30

showed radiologic opacities. Pulmonary metastases from alimentary tract carcinomata were frequently associated with clear chest radiographs; none of those from the rectum and only 1 from the co.lon showed up in the chest film. Bronchial carcinoma in particular gave rise to miliary carcinomatosis, which was radiographically evident in only half the cases. RETICULOSES AND LEUKAEMIA Hodgkin's disease has no pathognomonic x-ray pattern; it may be miliary, nodular or infiltrative, or solitary lesions may be present. Mediastinal adenopathy commonly accompanies the lung changes. Thc prcsencc of lymphadenopathy and diffuse pulmonary shadowing may pro, rlde superficial confusion with sarcoidosis. An increase in the size of the mediastlnal lymph nodes in serial chest films is in favour of Hodgkin's diseasc and argues against sarcoldosls. Likewise, the presence of pleural involvement is commonplace in Hodgkin's discase and rare in sarcoidosls. PIeural cffusion may be bloody due to direct pleuropulmonary invasion or associated with compression of the large vessels in the upper medlastlnum. Occasionally, compression of the thoracic duct gives rise to chylous effusion in Hodgkin's disease. Lcukaemla is rarely associated with diffuse fine pulmonary shadowing. When leukaemlc infiltration of the lungs Icads to such a radiologic picture, there is little difficulty in dlag'nosls, for other clinical and hacmatologic features place it beyond doubt. Mycosis fungoldes may be associated with numerous circular shadows in both lungs. The cutaneous findings are diagnostic. RADIATION REACTION Irradiation may itself cause widespread damage. Tile differentiation of irradiation pneumonitis from involvement of the lungs by growth is of crucial importance for the correct management of the patient. Whitfield, Bond and Arnott (24) have pointed out that it may be impossible to be certain whether changes in the lung are the result of irradiation or due to infiltration with growth. They llst 8 useful differential points. Evidence in favour of radiation pneumonitis includes a clear chest radiograph immediately prior to radiotherapy, the development of 31

radiographic changes coinciding with such treatment, and the presence of radiation skin changes conforming precisely to the same area as the pulmonary abnormality. A therapeutic trial with systemic corticosteroids usually provides a clear-cut distinctlon, for this will bring about resolution of irradiation pneumonitis but not, of course, metastatic infiltration. MISCELLANEOUS CONDITIONS

S~comosm There are three stages in the natural history of intrathoraclc sarcoidosis. The initial presentation is that of bilateral hilar lymphadenopathy, which may be accompanied in one quarter of instances by right paratracheal lymphadenopathy. The second stage reveals, in addition, widespread pulmonary shadows. The final or latest stage comprises these pulmonary shadows but without hilar adenopathy. Resolution of these chest x-ray abnormalities may be anticipated in 80~b of patients with hilar adenopathy (Stage 1); in 6 0 ~ of those with hilar adenopathy and pulmonary involvement (Stage 2); but in only 3 0 ~ of patients with the late stage of pulmonary shadowing (Stage 3) which may be due to irreverslble and irremediable pulmonary fibrosis. It has long been recoguised and it remains true that as the hilar lymph nodes are seen to shrink, so does pulmonary infiltration develop or become more marked. This is most clearly witnessed in the group of patients presenting with erythema nodosum (25). This characteristic sequence in the evolution of pulmonary sarcoidosls helps to distinguish it from retlculoses, in which the reverse occurs; namely, pulmonary involvement is often followed by progressive increase in the size of the mediastinal lymph nodes. Evidence of extrathoracic sarcoidosis should be sought in the eyes, (26), skin (15), lymph nodes, spleen or bone. Histologlc confirmation is secured by biopsy of a skin lesion or involved lymph node; or by a blind biopsy technic, such as biopsy of liver, scalene lymph node, gastrocnemius muscle or even lung. As an alternative to these blind biopsy technics, the Kveim test is a reliable and specific means of obtaining histologlc proof of sarcoidosls. It consists of the intradermal injection of a saline suspension of sarcold tissue obtained from a sarcold lymph node or 32

spleen. In patients with active sarcoidosis, a dusky red nodule develops insidiously at the injection site during the ensuing weeks. Histologic examination of the nodule reveals sarcoid tissue (27). Miliary shadowing of the lungs due to sarcoidosis may be segregated from other causes in almost all instances by a combination of clinical and histologic features; and in this respect the Kveim test is invaluable. Corticosteroid therapy should only be considered if there is no radiologic evidence of spontaneous resolution at the end of 6 months' observation. TUBEROUS SCLEROSIS This inherited disorder may involve lungs, skin, viscera, bone, brain and eye. The underlying pathology is that of overgrowth of connective tissue in various tissues including smooth muscle and blood vessels. When this occurs in the lungs, the alveolar pattern is almost completely replaced by thick-walled cysts, surrounded by a new tissue comprising fibrous tissue, smooth muscle and blood vessels. The corresponding radiologic changes are widespread and symmetrical, consisting of a meshwork of lines variously described as reticulation when the pattern is close-knlt,. honeycombing when it is more open, or even cystlike when it is still coarser. When the intersections of the lines or shadows are sufficiently prominent, the appearance merits the term millary. It is a useful radlologlc point in differential diagnosis that the hilar glands are never large enough to show up in the chest radiograph (98). When the lungs are involved, patients come under medical care because of increasing breathlessness an.d recurrent spontaneous pneumothoraces. Clinical associations are adenoma sebaceum, subungual fibromas and peau chagrin6 readily seen in the skin, and polycystlc disease which may be found in kidneys, liver and pancreas. Other stigTnata include epilepsy, mental defect, intracranial calcification, retinal tumours and characteristic bone changes comprising periosteal thickening and bone cysts in hands or long bones. There is no known treatment for what is fundamentally a problem in genetics and eugenics. 33

CIIRONIG DIFFUSE INTERSTITIAL FIBROSIS (HAI~IMAN-RICH SYNDROME) The essential lesion in chronic diffuse interstitial fibrosis is "diffuse thickening of most or all alveolar walls throughout the lungs, making the lung less distensible and giving rise to the nonspccific clinical picture of alveolocapillary block. Because of the difficulty of oxygen transfer across the alveolar membrane incapacitating dyspnoea, cyanosis and finger clubbing are present. The corresponding radiographic picture is that of widespread symmetrical changes, which may include fine shadowing of the lungs. The cause is unknown but it may be the nondescript endresult of many diseases. The diagnosis is established by hmg biopsy, and symptomatic palliative treatment with corticosteroids is tim only worthwhile management at present. ALVEOLAR ~ICROLITHIASIS Intra-alveolar calcified laminated concretions occur throughout both lungs in tile absence of any known disturbance of calcium metabolism. Symptoms may be minimal or absent whereas radlologic changes are extensive and unique. No other pulmonary disease produces miliary calcification of such density and once recognised it can be diagnosed with confidence from a single radiograph (29). It seems likely that inflammatory exudate passes from alveolar capillaries into the alveoli where it becomes organised and for some reason calcified. Thickened alveolar membrane causes reduction in diffusing capacity, which may be noted by clinical evidence of alveolocapillary block and also confirmed by pulmonary function studies. Symptomatic treatment with corticosteroids is the only rational management at present. Familial cases have been recogniscd; therefore, chest radiographs of siblings may be worthwhile. ALVEOLAR PROTEINOSIS This rare condition was first described as recently as 1958 (30) and at present about 60 or so instances have been reported, a third of whom have died in less than 4 years. It predominates in adult men, who present with clinical evidence of alveolo34

capillary block and radiographic changes of widespread shadowing. The changes are most dense in the perihilar region, producing an appearance not unlike pulmonary oedema. These changes are produced by deposition in the alveoli of a finely granular, amorphous, lightly eosinophilic proteinaceous material, which stains with periodic acid Schiff stain. It also stains with Sudan and oll red O fat stains, Schultz method for cholesterol, and luxol-blue stain indicating the presence of phospholipid (31). The antemortem diagnosis is established by lung biopsy. Death may be due to anoxia, cor pulmonale or to secondary infections to which patients with the condition seem peculiarly prone. If corticosteroids are to be used for the alleviation of symptoms, broad-spectrum antibiotics should be administered concurrentl),. ~/~UCOVIS CIDOSIS

Mucoviscidosis, a constitutional disorder of secretion of mucous glands throughout the body, principally affects the function of the lungs and pancreas. Formerly considered a disease of infancy and early childhood, it is now increasingly recognised in later childhood and even in early adult life. The viscid secretion of the mucous glands in the bronchi leads to areas of segmental collapse and bronchiectasis, compensatory emphysema, recurrent bronchopneumonia and eventually to respiratory failure. The chest radiographic changes are therefore varied, but may include widespread fine shadows at some stage. There is similar obstruction of pancreatic ducts by eosinophilic concretions which distend the ducts and acini, causing cyst formation and eventually leading to pancreatic fibrosis and atrophy. Clinical evidence of pancreatic insufficiency in the presence of pulmonary shadowing is strongly suggestive of the disease. The diagnosis is confirmed by determining the tryptic activity of the duodenal juice or, more conveniently, by demonstrating the abnormal concentration of electrolytes in sweat A silver chloride finger print reaction, resuiting from excess chloride in the skin, is the basis of a test using filter paper impregnated with silver chromate (32). The prognosis depends upon the degree of respiratory insufficiency. Vigorous treatment with postural drainage, breathing exercises and ringing the changes with antibiotics is worthwhile. 35

SJ~JOREN'S SYNDROI~IE A generalised inadequacy of the secretion of the lacrimal and salivary glands, bronchial glands and the synovial membrane of joints may give rise to dry eyes (keratoconjunctlvitis sicca), dry mouth, dry bronchial mucosa and arthritis resembling the rhcumatoid type. Because of the dry bronchial mucosa, insplssated mucus tends to collect in thc smaller bronchi and bronchioles, casting widespread shadows in the chest radiograph. Thcsc changes mimic sarcoidosls and in the prcsence of keratoconjunctivitis sicca and pcrhaps parotid gland enlargement confusion may be heightened. The diagnostic difficulty, however, is only superficial and is dispelled by careful analysis of history, symptoms and signs. Sarcoid tissue is not found in the various tissues in SjSgren's syndrome and the Kveim test is negative. SjSgren's syndrome is cu~ently classified as an autoimmunopathy, and circulating antibodies against parotid tissue have been demonstrated. It is a distressing condition for which symptomatic relief is best afforded by an adequate combination of topical and oral cortlcosteroids.

THE HISTIOOYTOSES Millary or nodular infiltration of the lungs may be seen in Letterer-Siwe disease, Hand-Schtiller-Christian disease and in eosinophilic granuloma and the group constitutes one variety of honeycomb lung. The changes seen in the x-ray are probably due to hlstiocytic permeation, granulomatous and fibrotic changes at the alveolobronchiolar junction, and valvular obstruction leadlng to cyst formation. The accompanying extrathoracic changes in this group of diseases help to dispel any diagnostic difficulty based on the chest x-ray changes alone.

IODISED OIL When this radiopaque dye is retained in bronchioles and alveoli, the radiographic appearance is that of widespread miliary shadows. It may be forced into the alveoli by a bout of coughing after bronchography and its occurrence is transitory. In the presence of chronic bronchopulmonary disease, iodised oil may 36

persist indefinitely in bronchioles and emphysematous spaces. During salpingography, venous intravasation of the opaque material may occur. The dye passes from uterine veins into the pulmon.ary circulation, giving rise to discrete miliary shadows in well-penetrated films. Its occurrence in this manner is transient. MANAGEMENT

In most instances, the history, symptoms, physical signs and radiographic changes are sufficiently clear-cut to point to the correct diagnosis. Indeed, on the basis of the clinicoradiologie findings the differential diagnosis rarely involves more than 4 or 5 disorders, and the problem of differentiation may ultimately resolve itself if changes in these physical and radiologic slg'ns become apparent in the course of serial examinations. In the minority, further investigation may include lung function studies; bacteriolo~; examination of the formed elements of the peripheral blood and sternal marrow, serologic tests using acute-phase and convalescent-phase sera (Tables 1-5) ; and skin tests (Table 9). In still more obscure conditions, histologlc evidence of tile diagnosis is the most informative and satisfying investigation. It provides evidence upon which a confident diagnosis can be made and a prognosis based. Serial histology, llke serial radiography, can also supply invaluable information of the patient's response to treatment. Skin and lymph node, being the most ~tccessible tissues, are fruitful sources of biopsy material if they are clinically involved. Other sites which should not be overlooked include bronchus, conjunctiva, nasal mucosa, tonsil, palate and scar tissue. In the absence of obvious clinical involvement, it may be necessary to resort to a blind biopsy technic, such as scalene or mediastinal lymph node biopsy, aspiration liver biopsy, or gastrocnemins muscle biopsy. It may be considered sufficiently important and worthwhile to undertake lung biopsy intercostally or by open thoracotomy. This is undoubtedly the most fruitful source of biopsy material but the magnitude of the undertaking makes it a less conventional investigation than some others. Finally, blind biopsy of the pleura should be done if there is an accompanying pleural effusion, and exfoliative cytology of pleural fluid, sputum and bronchial aspirate is accomplished whenever indicated. It is important with all blind biopsy technics 37

T A B L E 9 . - - S K i n TESTS ~VIIICH I~IAY PROVE HELPFUL IN THE DIFFERENTIAL DIAONOSIS OF WIDESPREAD FXNE PULMONARY SIIADO~,VINO DIs~.s~

Test

Arcrxo~,'r

Rr.MXr~KS

Delayed-type or tuberculin-type hypersensitivity. The interpretation of all these skin tests is the same as for the prototype, the Mantoux reaction. The antigen is injected intradermally and the reaction read at 48 hours. A positive reaction comprises induration greater than 5 ram. diameter, with possible surrounding eryth. ema

Tuberculosis

Mantoux

Old tubercu- " lin or P.P.D.

Histoplasmosis

Histoplasmin

Extract from Histoplasma capsulatum

Coccidioldomycosis

Coccidioidin

Extract from coccidioides immhis

Tularemia

Detoxified suspension of Pasteurella tularense

Sarcoldosis

Kveim

Ifuman sarcoid tissue from lymph node or spleen

In the course of a month, an insidious development of dusky red nodule composed of sarcold tissue

Beryllium disease

Patch

1% beryllium sulphate or nitrate

Delayed-type hypersensitivity at 48 hours; at the end ot 1 month a Kveimlike nodule of sarcold tissue

to cut n u m e r o u s serial sections of the submitted specimen, for this will u n d o u b t e d l y increase the yield of miliary g r a n u l o m a t a .

SUMMARY O n l y very few conditions produce strictly miliary l u n g shadows, that is, of the small size a n d compactness of a grain of

38

millet.. But by universal usage the term miliary diseases or mottling of the lungs has broadened to embrace m a n y different conditions which produce widespread fine shadows conveying some regularity of form and pattern. These conditions include infections due to fungi, bacteria, metazoa, rickettsiae and viruses; occupational diseases; collagen disorders; neoplasma; circulatory upsets; and a miscellany of apparently unrelated and largely idiopathic diseases. I n the foregoing discussion an attempt has been made to present these conditions as clinicoradlologic syndromes, the interpretation of which are the joint responsibility of clinician and radiologist. Thus, the emphasis has been placed on the clinical and radiologic differential diagnosis. I n most instances, the history, symptoms, physical signs and radiographic changes are sufficiently clear-cut to narrow the differential diagnosis to very few conditions, or indeed point to the correct diagnosis. Where the diagnosis remains obscure, the most helpful and relevant ancillary aids to diagnosis are discussed. T h e management of patients with miliary lung shadowing is that of the many different individual diseases producing this appearance. For this reason early and accurate diagnosis provides the most secure framework upon which are based the prognosis and treatment. REFERENCES 1. Carstalrs, L. S.: The interpretation of shadows in a restricted area of a lung field on the chest radiograph, Proc. Roy. Soc. Med. 54:42, 1961. 2. Felson, H., and Heublein, C. W.: Some observations on diffuse pulmonary lesions, Am. J. Roentgenol. 59:59, 1948. 3. Scadding, J. G.: Chronic lung diseases with diffuse nodular or reticular radiographic shadows, Tubercle 33 : $52, 1952. 4. Hay, D. R.: Pulmonary manifestations of staphylococcal pyaemia, Thorax 15:82, 1960. 5. Dickson, W., and Woodcock, R. S.: Visceral larva migrans, Arch. Dis. Childl~ood 34:63, 1959. 6. Liu, C.: Studies on primary atypical pneumonia. I. Localisatlon, isolation and cultivation of a virus in chick embryos, J. Exper. Med. 106: 455, 1957. 7. Cook, M. K., et al.: Role of Eaton agent in disease of lower respiratory tract, Brit. M. J. 1:905, 1960. 8. Eaton, M. D., Meiklejohn, G., and Van Herick, W.: Studies on the etiology of primary atypical pneumonia: A filterable agent transmissible to cotton rats, hamsters and chick embryos, J. Exper. Med. 79:649, 1944. 39

9. Peterson, O. L., Ham, T. H., and Finland, M.: Cold agglutinlns (autohaemagglutinins) in primary atypical pneumonias, Science 97 : 167, 194-3. 10. James, D. G.: I'fimary atypical pneumonia, J.A.M.A. 151:810, 1953. .11. Mackay, J. B., and Caimey, P.: Pulmonary calcification following varicella, New Zealand M. J. 59:453, 1960. 12. Gaensler, E. A., et al.: Respiratory pathophyslology in chronic berylllum disease, A.M.A. Arch. Indust. Health 19:132, 1959. 13. Hardy, H. L.: Differential diagnosis between beryllium poisoning and sarcoidosis, Am. Rev. Tuberc. 74:885, 1956. 14. Curtis, G. H.: The diagnosis of beryllium disease, with special reference to the patch test, A.M.A. Arch. Indust. Health 19:150, 1959. 15. James, D. G.: Dermatological aspects of sarcoidosis, Quart. J. Med. 28:109, 1959. 16. Israel, H. L., and Sones, M.: The differentiation of sarcoldosis and beryllium disease, A.M.A. Arch. Indust. Health 19:160, 1959. 17. Rose, G. A., and Spencer, H.: Polyarteritis nodosa, Quart. J. Mcd. 26:43, 1957. 18. Rose, G. A.: Natural history of polyarterltis, Brit. M. J. 2:1148, 1957. 19. Ellman, P.: The lungs as an index of systemic disease, Proc. Roy, Soc. Med. 51:654, 1958. 20. MacGregor, C. S., Johnson, R. S., and Turk, K. A. D.: Fatal nephritis complicating idiopathic pulmonary haemosiderosis in young adults, Thorax 15:198, 1960. 21. Caplan, H.: Honeycomb lungs and malignant pulmonary adenomatosis in scleroderma, Thorax 14: 89, 1959. 22. Harold, J. T.: Lymphangltis carcinomatosa of the lungs, Quart. J. Med. 21:353, 1952. 23. Lee, I. N.: Pulmonary metastases: A radlologlcal and pathological correlation, Middlesex Hosp. J. 53 : 107, 1953. 24. Whltfield, A. G. W., Bond, W. H., and Arnott, W. M.: Radiation reactions in the lung, Quart. J. Med. 25:67, 1956. 25. James, D. G.: Erythema nodosum, Brit. M. J. 1:853, 1961. 26. James, D. G.: Ocular sarcoidosls, Am. J. Med. 26:331, 1959. 27. Siltzbach, L. E.: The Kvelm test in sarcoidosls, J.A.M.A. 178:476, 1961. 28. Dawson, J.: Pulmonary tuberous sclerosis, Quart. J. Med. 23:113, 1954. 29. Thomson, W. B.: Pulmonary alveolar mlcrolithiasls, Thorax 14:76, 1959. 30. Rosen, S. H., Castleman, B., and Liebow, A. A.: Pulmonary alveolar proteinosis, New England J. Med. 258:1123, 1958. 31. Wolman, L.: The cerebral complications of pulmonary alveolar protelnosls, Lancet 2 : 733, 1961. 32. Knights, E. M., Jr., Brush, J. S., and Schrveder, J.: Simplified screening test for cystic fibrosis of the pancreas, J.A.M.A. 169:1279, 1959.

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