Brit. ff. Dis. Chest (I965) 59, i.

CYSTIC FIBROSIS: A REVIEW

BY JOHN BATTEN Physician, St. George's Hospital.

Assistant Physician, Brompton Hospital.

Introduct ion CYSTIC fibrosis is a hereditary disorder of children and young adults due to a widespread dysfunction of exocrine glands. The cause of this defect is obscure but it is probably inherited as a simple Mendelian recessive trait (Carter, 1952 ). The incidence of cystic fibrosis in the homozygous state is of the order of I : I,OOO births, and this implies that about I : 20 of the population carry the trait (i.e. are heterozygotes).

The syndrome comprises pancreatic insufficiency, chronic lung disease, high concentration of salt in sweat, and, less commonly, cirrhosis of the liver. It was first recognized by Dorothy Anderson in 1938. She included meconium ileus in the syndrome and reported that "bi l iary" cirrhosis might also be found very occasionally. She considered maternal vitamin A deficiency as the probable cause of the pancreatic changes. Steatorrhea might cause further deficiency of the vitamin in the child and lead to the severe and often fatal staphylococcal infection in the lung. She called the disease "fibrocystic disease of the pan- creas" and concluded that the diagnosis could be established only by demon- stration of enzyme deficiency in the duodenal contents and by microscopy of the pancreas. Farber in 1944 described inspissated material in the mucus glands of the trachea, bronchi, oesophagus, duodenum, gall bladder, and salivary tissue, in addition to the inspissafion of secretion in the pancreatic ducts. He realized that the pancreas was only one of many organs involved by a widespread physical change in mucus. This led to the disease being called mucoviscidosis. Following Kessler and Anderson's observation of heat prostration in children with the disease during a severe heat wave in 195 I, Darling and his associates in 1953 found this to be due to a defect in sweat secretion and demonstrated high concentrations of chloride in the sweat.

Thus most exocrine glands are involved and until the cause is found no comprehensive name can be given to the disease. For the time being it is best known as cystic fibrosis. Cystic fibrosis is now one of the commoner chronic pulmonary diseases of childhood, and earlier diagnosis and improving treatment allow many more children to survive into adolescence and adult life. The severity and rate of progression of each of the manifestations varies greatly, so that some cases are now discovered for the first time in later childhood and even in adult life.

PATHOLOGY Dorothy Anderson (i 962) in summarizing the pathological changes divided

the exocrine glands in cystic fibrosis into 3 types: (Received for publication, November 1964)

V O L . L I E . I I

2 BATTEN

(I) those in which there is eosinophilic concretion of precipitated secretion in glands and ducts with obstruction toflow. Apart from the pancreas they are found in the intestine, intrahepatic bile ducts, gall bladder, prostate, and sub-lingual salivary glands. In the pancreas the intralobular ducts become cystic and the acini atrophic. Diffuse fibrosis develops in and around the lobules but the islets remain intact; a variable degree of fatty replacement occurs. All these changes slowly evolve, so that after ten years little remains of acini or ducts at all. The mucus secreting salivary glands show cystic dilation of ducts and interstitial fibrosis. Changes in the liver vary from small focal areas in which the pro- liferating bile ducts are distended with eosinophilic concretions to gross multi- lobular cirrhosis, which may cause portal hypertension. Fatty changes are common but amyloid degeneration is rare even with prolonged suppurative disease in the lung.

(~) those serous glands producing sweat, saliva, and tears. These glands remain normal morphologically while they produce abnormal secretions with high electrolyte concentration.

(3) those in which the glands are hypersecreting. The ducts are distended but not blocked by secretion. The mucus glands of the whole respiratory tract secrete a tenacious viscid mucus which impedes ciliary clearance.

The lungs may be normal at birth and in these cases no increase in the mucus gland activity can be demonstrated (de Hal le r& Reid, I964). Early in life, however, infection occurs usually with eoagulase positive staphylococci, and the smaller airways become blocked by mucus and pus. Hypertrophy of the tracheo-bronchial mucus glands develops very rapidly, and goblet cells are found in large numbers in peripheral airways, where normally none are found. This great increase in activity of cells secreting mucus is probably a response to infection though the remarkable incidence and persistence ofinfectlon, not only with Staph. pyogenes but also with Ps. pyocyanea and B. proteus remains un- explained. No intrinsic physiochemical change has been conclusively demon- strated in bronchial mucus but such alteration in the mucus might provide a favourable environment for staphylococcal growth.

The walls of the smaller bronchi and bronchioles become thickened by chronic inflammation and infection spreads to adjacent alveoli where abscesses may develop. Alveolar enlargement either by distension or by ulceration of their wails may indicate the presence of emphysema, though this is by no means always present even in advanced cases of respiratory failure (Reid, x964). Occlusion of larger bronchi by mucous plugs may cause collapse of lobes or segments and if unrelieved this may result in gross inflammatory change and bronchiectasis in the affected segment or lobe. Otherwise gross bronchiectasis is unusual. Hilar and tracheo-bronchial lymph node enlargement may occur early in the course of the infection. Dunnil (1959) has described metaplasia in the mesothelial layer of the pleura in which the cells assume a cuboidal, colum- nar or even squamous form quite unrelated to underlying infection. If this were a manifestation of the basic defect in cystic fibrosis it would be exceptional, for it would be occurring in cells not of ectodermal origin.

Progressive impairment of structure and function of the lung leads to res-

CYSTIC FIBROSIS: A REVIEW

piratory failure, a rise in pulmonary vascular resistance and right ventricular hypertrophy. Failure of the right ventricle may be a terminal event and its development resembles that reported in suffocative bronchitis rather than emphysema (Fletcher, r963).

Cardiac enlargement and heart failure may be due to myocardial fibrosis which has been reported in cystic fibrosis (Powell et al., I957). This complica- tion was reviewed by McGiven (1962). Dilation and hypertrophy of both ventricles was reported at autopsy in all the 8 cases under review--the left ventricle was more affected than the right. Degenerate muscle fibres were replaced by dense scar tissue of variable extent. In 2 cases endocardial fibro- elastosis was found in the left atrium. Acute inflammatory changes were notably absent. The cause of the cardiac lesion is unknown but nutritional deficiency has to be considered.

CLINICAL PICTURE

Digestive Tract Pancreatic insufficiency is probably responsible for meconium ileus in the

neonatal period. This causes i o per cent. of deaths in cystic fibrosis. Absence of pancreatic enzymes and malabsorbtion however usually result in failure to regain birth weight and malnutrition, failure to thrive and wasting, in spite of a good appetite. There is usually gross steatorrhea, abdominal distension, and sometimes rectal prolapse. Cirrhosis and portal hypertension with h~ematemesis are a rare presenting feature in later childhood. Liver failure is uncommon.

Sweat Glands Excessive loss of salt in sweat in high temperatures may precipitate collapse.

Lungs The clinical picture is usually dominated by the changes in the lungs. These

are frequently severe and progressive and cause death in more than half the patients before the age of io, and 80 per cent. of all deaths. Their onset is some- times rapid and early, and sometimes delayed, but usually follows the first respiratory infection. Cough is distressing and persistent, and increasingly severe: sputum is extremely viscid and is expectorated with difficulty. The child may wheeze, and asthmatic bronchitis may be the presenting feature. Com- plaint of breathlessness on exertion usually develops much later than would be expected from the extent of the disease. Hmmoptysis and spontaneous pneumo- thorax occasionally occur later. On examination there may be central cyanosis and tachypn~ea, and the chest is hyperinflated with retraction of the lower intercostal spaces and lower sternum. Clubbing of the fingers is common. Inspiratory~and expiratory wheezes may be heard. There may be signs of lobar collapse or pneumonia. Persistence of physical signs, particularly rales, indi- cates permanent lung damage. Respiratory failure and cyanosis may occur in acute exacerbations and may persist late in the disease with carbon dioxide retention and signs of right heart failure.

4 BATTE N

INVESTIGATIONS

Chest Radiographs While no single abnormality is diagnostic of cystic fibrosis the radiological

appearances are often very characteristic (Hodson and France, i962 ). In the first months of life with acute infection there is hypertranslucency due to hyper- inflation. Segmental or lobar shadows, due to collapse or consolidation, may be seen. If this period is survived then parallel line shadows appear in relation to the larger bronchi, and these may persist in the absence of symptoms or signs of disease (Fig. i). Coarse mottled shadows, up to 2 cm. in size, frequently arise in the lung periphery. These may be transient, permanent or recurrent and may cavitate. They represent either focal pneumonia or abscess formation in relation to smaller bronchi. Occasionally cystic spaces develop like those found after staphylococcal pneumonia. Hilar and mediastinal lymph node enlargement is sometimes prominent. The characteristic changes widely dis- seminated throughout both lungs are shown in Fig. 2. Bronchograms reveal more commonly the changes of bronchitis than gross bronchiectasis, though minor degrees of bronchial dilatation are common.

Duodenal intubation Examination of the duodenal fluid for pancreatic enzymes, especially tryp-

sin, is important in diagnosis. Estimation of fzecal fat will establish the presence of steatorrhea.

Sweat A high concentration of sweat electrolytes has been a constant finding in

nearly all cases of cystic fibrosis, and is therefore of great value in diagnosis. Various methods have been used to stimulate and collect sweat for analysis (Lancet, i96i), either by heat or pharmacologically using mecholyl or pilo- carpine. The latter is applied to the forearm and sweating stimulated by pilo- carpine iontophoresis (Gibson and Cooke, I959). The sweat is collected on gauze pad or filter paper, the amount collected measured by weighing, and the sodium and chloride eluted and measured by chemical analysis. Alternatively the sweat can be collected in a capillary tube and the volume measured with a micropipette before chemical analysis by flame photometry (de Haller, 1964). The electrical conductivity of sweat varies with its salt content and a new method of analysis using this property may be of value (Shwachman, I963). A rough screening test for excessive chloride in sweat can be carried out by obtaining a finger print on filter paper impregnated with silver nitrate (MacFarlane, I957) - - a positive result requires confirmation by accurate quantitative analysis. The results have varied according to method, but there is little disagreement about the significance of electrolyte concentrations in the sweat of children. Anderson and Freeman (i 960) found that 95 per cent. of children with cystic fibrosis had more than 60 mEq./litre of sodium in mecholyl induced sweat--6o per cent. of these children had more than 9 ° mEq./litre. Control children under the age of 14 years all had less than 6o mEq./litre sodium and the majority less than 4 ° mEq./litre. McKendrick (I962) found that the sodium concentration was

GYSTIG FIBROSIS: A REVIEW

greater than 7 ° mEq./litre in 95 per cent. of children with cystic fibrosis in pilocarpine induced sweating--and he found similar low concentrations in con- trols (less than 4o mEq./litre). With increasing age the concentration of sweat electrolytes increases and becomes more variable. Higher levels are obtained in cold weather. Results obtained in adults must, therefore, be assessed with care. Claims that siblings and parents of children with cystic fibrosis have higher levels of sweat electrolytes than controls and therefore that the hetero- zygous state can be revealed by sweat analysis must be critically reviewed with these facts in mind (see later). Siegenthaler et aL (i964) have reviewed the effects of salt deprivation and aldosterone on sweat secretion and have shown that sodium concentration in patients with cystic fibrosis is little affected by salt deprivation or aldosterone load. The urinary sodium is reduced and aldo- sterone increased during the experiment. These findings should therefore be of diagnostic value in doubtful cases of cystic fibrosis especially in adolescents and adults where high concentrations of sweat electrolytes may be found and which may be of no significance.

Pulmonary function As a result of the pathological changes in the lung impairment of lung func-

tion may develop. On the one hand there is increased resistance to airflow due to airway obstruction; on the other, restriction and diminished compliance of the lung due to collapse and fibrosis. These defects combine to produce uneven distribution of inspired gas and blood flow, so that in the advanced case or with episodes of acute infection there is reduction of arterial oxygen saturation and central cyanosis. Inadequate total alveolar ventilation will result in a rise in arterial carbon dioxide.

The earliest physiological change which may be detected in asymptomatic patients with cystic fibrosis is uneven distribution of gas in the lung (de Muth et al. I962 ). A large residual volume is consistently found with increasing severity of disease. This is due mainly to airway obstruction and consequent hyperinflation. Reduction of vital capacity is a direct consequence of the in- creased residual volume though diminished compliance may be a contributory factor (Cook et al. 1959). Because of the considerable individual variation in vital capacity a significant reduction in the individual case can be anticipated only late in the disease. Simple measurements of airflow e.g. the peak expira- tory flow rate (P.E.F.) or the forced expiratory volume in I second (F.E.V.1) are useful in assessing both the severity of the disease and the response to treat- ment. Children of 5 years and over are quite able to co-operate in these tests. In the majority of cases a significant increase in airflow can be achieved with bronchodilators, e.g. isoprenaline I per cent. by aerosol.

T R E A T M E N T

While the provision of a high calorie, high protein diet, restricted in fat and starch, with vitamin supplements and pancreatic extract has been important, control of pulmonary infection has been the chief factor which has allowed

6 BATTEN

greater numbers of children to reach adolescence and beyond. The aim of treatment of the lung component of cystic fibrosis is to keep the large and small airways clear both by physical and by chemical measures:

Physiotherapy The proper use of postural drainage, percussion and, effective coughing is of

major importance and with skill and patience these physical methods can be applied to infants and small children as well. Treatment should be given several times a day and continue as long as any secretion can be expectorated. It can be performed at school and at home, if the nurse or mother has been trained by the physiotherapist.

Mueolytic agents Aerosols containing a number of agents have been advocated to reduce the

viscosity of sputum in cystic fibrosis, and an effective harmless agent would be of great value. No agent, enzymatic or otherwise, while safe has yet been con- elusively shown to be better than a simple water mist. Preliminary reports of N-acetyl cysteine (Raes, I963) while promising have yet to be confirmed. I f simple tests of airflow (F.E.V. 1 and P.E.F.) show at least a I o per cent. increase with isoprenaline or orciprenaline then the bronchodilator can be given by aerosol before and after physiotherapy.

Chemotherapy With episodes of acute infection sensitivity tests should be carried out on

organisms cultivated from the sputum. Staphylococcus pyogenes is usually found, less commonly B. proteus, Ps. pyocyanea etc. Appropriate drugs can be given in an attempt to eradicate infection, and bactericidal drugs (e.g. peni- cillin, streptomycin, eolistin, bacitracin, neomycin) are preferable for the pur- pose. Tetracyclines, erythromycin, novobiocin have however been of great value, while chloramphenlcol is best avoided because of its toxic effects. Oral or parenteral routes must be employed and adequate doses given. Failure of the new synthetic penicillins has often been due to inadequate dose. Chemo- therapy by aerosol is used as well by experienced paediatricians, and they claim it to be of particular benefit in infants and small children; neomycin, bacitracin, and other antibiotics, which may be toxic by other routes, can be used. Chemo- therapy by this route is given four to six hourly through a Wright's nebuliser. Metal and plastic parts are best avoided and rubber tubing and face masks should be used. Severe uncontrolled infection with Staph. pyogenes which is resistant to the above named drugs may be treated with fucidin, pristinamycin or vancomycin, depending on sensitivities.

Chemotherapy should be continued until the organism is eradicated, or at least cannot be grown on culture from the sputum.

Chemoprop hylaxis In most older children and adolescents it is sufficient to treat the acute

C Y S T I G F I B R O S I S : A R E V I E W

episode only. In infants and younger children particularly it may be necessary to give chemotherapy continuously either because it is impossible to eradicate infection or because of very frequent re-infection. A careful watch must be kept for evidence of drug toxicity.

Prevention of infection Cases of cystic fibrosis should be shielded from infection. Their visits to

hospital should be as infrequent as possible, and they should be isolated from other cases. Pertussis vaccine should be given in infancy, influenza vaccine should be given if epidemics threaten, and gamma globulin should be given to young children in contact with measles.

Other measures In certain selected cases where structural changes in bronchi are localized

to a lobe or segment benefit has occurred from resection (Young, W. F., I964). The main aim has been t o prevent continual re-infection from "spill over". Smoking at any age should be prohibited.

Prognosis There are few reports concerned with the prognosis of cystic fibrosis, but

there has been a progressive improvement since 1938 when Anderson found that 8o per cent. of her cases died in the first year of life.

Shwachman (I958) reviewed io 5 cases which he had followed for at least 5 years. Ten had died, 47 were better than at the time of diagnosis, and 48 were the same or worse. He attributed the recent improvement in prognosis at that time to the newer chemotherapeutic drugs such as chlortetracycline. In a pilot survey in 3 New England states (Kramm, i962) which included Boston, a centre where there is a considerable interest in cystic fibrosis, 169 deaths from cystic fibrosis were reported from i952-i959. From i952-i955 62 per cent. of deaths were in children under 4 years of age and only 7 per cent. were over Io years old. There was a striking difference in the period I956-I959 when only 41 per cent. of deaths occurred under 4 years, while 28 per cent. were over Io.

In this country Jackson and Young (I964) have recently reviewed Iox eases diagnosed between 195 ° and 1963 and revealed a similar improvement in prog- nosis. They divide their cases into 2 groups--one in which treatment has been adequate and the other in which treatment has been inadequate. Adequate treatment required early and proper treatment of the first respiratory infection with removal of Staph. pyogenes from the respiratory tract, chemoprophylaxis for 3 months thereafter and prompt and proper treatment of subsequent infection. Of the 45 cases diagnosed during 195o-I 958 and followed until 1964 29 received inadequate treatment and 15 died, whereas 16 received adequate treatment and only I died. The period of follow-up in the remaining 56 cases is too short to be of immediate value but the same trend is reported--not only have those children properly treated survived longer, but, equally important, very few have deteriorated clinically or radiologically.

8 BATTEN

Information on prognosis has been reported from only a few centres where cystic fibrosis has been intensively studied and expertly treated. I t is impossible therefore to assess the overall prognosis or mortality. Many more patients are approaching adolescence but often with considerable respiratory disability. I f this is to be diminished early diagnosis and proper treatment are necessary. I f adolescence is reached growth may procede normally, but the spurt before puberty is usually delayed. Sexual maturation is usually normal (di Sant Agnese P.A., 1959). The prognosis in cystic fibrosis is largely determined by the extent of the pulmonary disease.

HETEROZYGOUS STATE

The syndrome of cystic fibrosis is considered to be a homozygous form of the disease which is due to a recessive gene. One in twenty of the population are probably heterozygous for this gene. I t has been claimed that these hetero- zygotes, discovered by analysis of sweat electrolytes, have a high incidence of chronic chest disease (Karlish and Tarnoky, i96o ). Variations in electrolyte concentration of sweat with season and age render this method of selection of heterozygotes unreliable. Ninety-five parents of children with cystic fibrosis (heterozygotes) and 94 parents of children with other disease were compared with respect to chest symptoms, smoking habits, chest radiographs and ventila- tory capacity (Batten et al., I963). No significant difference could be found. I t was considered that the heterozygous state was not associated with chronic chest disease, and confirmed the earlier work of Anderson et al. (i 962).

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mann, London, p. 50. CooK, E. D., HELLIESBN, P. J., KULCZYCKI, L., BAINE, H., FRIF-DLANDER, L., AGATHON, S.,

HAms, O. B. G., & SnWACHMAN, H. (1959). Paediatrics, 24, 18i. DARLmO, R. C., DI SANT AGNFSE, P. A., P~.R~RO, G. A., & ANDERSON, D. H. (I953). Amer07.

reed. Sd., 225, 67. DE HALL~.R, J., D~ HALL~R, R., & Smo~rrHAL~R, P. (I964). To be published. DE HALLBR, R. & REID, L. (I964). To be published. DE MtrrH, G. R., HOWAT, W. F., & TALN1ZR, N. S. (I962). Amer07. Dis. Child., xo3, I~9. DI SANT AONBS% P. A. & ANDERSON, D. H. (I959). Ann. intern. Med., 50, I321. DtrNNILL, M. (1959). 07. Path. Bact., 77, 299. FARBER, S. (1944). Arch. Path., 37, 238. FLETCHER, G. M., HUOHJoNES, P., MCNICHOL, M. W., & PRID% N. B. (1963). Quart.07. Med.,

3% 33. GIBSON, L. E. & COOK, R. E. (1959). Paediatrics, 23, 545. HODSON, C.J. & FRANCS, N. E. (1962). Clin. Radiol., 13, 54- JACKSON, A. D. IV[. & YOUNO, W. F. (I964). Cystic Fibrosis--A Symposium. The Chest and

Heart Association, London, p. 77. KARLISH, A.J. & TAgNOCKY, A. L. (I96o). Lancet, xx, 514. KSSSL~R, W. R. & ANDERSON, D. H. (I95I). Pediatrics, 8, 648. K ~ M , E. R., CRANE, M. M., Sura~N, M. G., & BROWN, M. L. (I962). Amer. o7. Pub. Hlth,

52, 2o4 I. Lancet (i96i). x, IO35.

PLATE I

FIG. i.---Left upper zone, showing the charac- teristic parallel line shadow.

FIc. 2.--Chest radiograph, showing widespread mottling.

To face p.

CYSTIC FIBROSIS: A R E V I E W 9

McFAR~NE, J. C. W., NORMAN, A. P., & STROUD, C. E. (1957). Brit. med.aT., s, 274. McGXVEN, A. R. (x96~). Arch. Dis. Childh., 37, 656" MGKENDRICK, T. (I962). Lancet, z, i83. POWELL, L. W., NSWMAN, S., & Hooza~R, J. W. (x957). Virginia Med., 84, x78. RAGS, H. W. (x963). 3- Paediat., 62, 3 I. RSID, L. (I964). Personal communication. SnWACHMAN, H. & JAH~, N. (I956). New Engl. J . Med., 255, 999- SnWACHMA_~, H., DUNHAM, R., & PHILUPS, W. R. (1963). Pediatrics, 32, 85. SHWACHMAN, H. & KULCZYCKI, L. (2958). Amer. 3. Dis. Child., 96, 6. SmOENTHALER, P., DE HALLSR, J., DE HAL~a~R, R., HAMPAI, A., & MULLER, A. F. (I964).

Arch. Dis. Childh., 39, 6I. YOUN% W. F. (I964). Personal communication