TRANSPLANT OSTEONECROSIS

965

SMOKING, OCCUPATION, AND ALLERGIC LUNG

was

DISEASE

serum

INHALED tobacco smoke exerts an important influence on the response of the lungs to other inhaled materials. The interaction between asbestos and tobacco consumption in causing lung cancer is found consistently in asbestos workers. Cigarette smoking also seems to influence the immunological response in the lungs to the inhaled agents that cause extrinsic allergic alveolitis and occupational asthma. Extrinsic allergic alveolitis, an immunologically mediated granulomatous reaction to inhaled organic dusts, seems to be a rare example of a respiratory disease that occurs more frequently in non-smokers than in smokers. Warren! reported that 14 (78%) of 18 patients with allergic alveolitis (11with farmer’s lung and 7 with bird fancier’s lung) were non-smokers-twice the proportion found in patients with cryptogenic fibrosing alveolitis or sarcoidosis, or in farmer patients or the local population. Also, precipitating antibodies to Micropolyspora faeni, the most important cause of farmer’s lung in the United Kingdom, have been found to be twice as common in the sera of non-smoking than smoking members of farming communities.2,3 The apparent protection conferred by smoking may be explained by its effects on alveolar macrophage function. Smoking depresses phagocytosis by alveolar macrophages4 and in addition inhibits the expression of surface Ia antigens,5 hampering their ability to present antigen to lymphocytes. In contrast to the findings in extrinsic allergic alveolitis, smokers seem more susceptible to asthma caused by agents inhaled at work and more likely to switch on specific IgE antibody production. Of 60 pharmaceutical workers exposed to

ispaghula dust, specific IgE antibody

found in the

to

ispaghula

was

of 22% of smokers but only 4% of nonsmokers.6 A similar association with smoking was found in this study with skin prick test reactions to green coffee bean extract in coffee workers. Smoking also may predispose to asthma and production of specific IgE antibody to lowmolecular-weight chemicals. 7 individuals who were made asthmatic by the acid anhydride tetrachlorophthalic anhydride (TCPA) while working in one factory, were all current smokers; and, of another group of 5 patients with TCPA asthma, 3 were current smokers, 1 a recent ex-smoker, and the fifth a smoker whose smoking habit at diagnosis was unclear.8 The prevalence of specific IgE antibody to TCPA in 300 exposed employees of the factory where the first group of7asthmatics were employed was 13% in smokers and 3% in ex-smokers and non-smokers.9 This study also identified aninteraction between smoking and atopy (skin test reactions to common inhalant allergens). Although exposure to TCPA serum

1. Warren CPW. Extrinsic allergicalveolitis: adiseasecommonerinnon-smokers. Thorax

1977; 32: 567-69. 2 Morgan DC, Smyth JT, Lister RW, Pethybridge RJ. Chest symptoms and farmer’s lung: a community survey. Br J Ind Med 1973; 30: 259-65. 3. Morgan DC, Smyth JT, Lister RW, et al. Chest symptoms in farming communities with special reference to farmer’s lung. Dr J Ind Med 1975; 32: 228-34. 4 Hocking WG, Golde DW. The pulmonary-alveolar macrophage. N Engl J Med 1979; 301: 580-87, 639-45. 5 Lawrence EC, Fox TB, Hall BT, Martin RR. Deleterious effects of cigarette smoking on expression of Ia antigens by human pulmonary alveolar macrophages. Clin Res 1983, 31: 418A. 6. Zetterstrom O, Osterman K, Machado L, Johansson SGO. Another smoking hazard: raised serum IgE concentration and increased risk of 1981; 283: 1215-17 7 Howe

occupational allergy. Br Med J

W, Venables KM, Topping MD, et al. Tetrachlorophthahc anhydride asthma. specific IgE antibody. J Allergy Clin Immunol 1983; 71: 5-11. 8. Schlueter DP, Banaszak EF, Fink JN, Barboriak J. Occupational asthma due to tetrachlorophthalic anhydride. J Occup Med 1978; 20: 183-88. 9 Venables KM, Topping MD, Howe W, Luczynska CM, Hawkins R, Newman Taylor AJ. Interaction of smoking and atopy in producing specific IgE antibody against a hapten protein conjugate. Br Med J 1985; 290: 201-04. evidence for

similar, specific IgE antibody to TCPA was found in the of 16% of smoking atopics, 12% of smoking non-

atopics, 8% of ex-smokers and non-smoking atopics, but none of the 98 non-atopic ex-smokers and non-smokers. Few early reports of occupational asthma describe the smoking habits of exposed populations, but in an Australian study of 98 enzyme detergent workerslO lower-respiratory-tract symptoms typical of occupational asthma were found in 42% of current smokers but only 22% of ex-smokers and non-smokers. A British survey of 121 enzyme detergent workers undertaken at about the same time" had strikingly similar findings for skin prick test reactions to an enzyme extract-elicited in 43% of smokers and 25% of non-smokers. This association of asthma (or specific IgE) with smoking is unexplained. However, in laboratory animals cigarette smoking causes mucosal inflammation and increases airway permeability to a marker protein (horseradish peroxidase)12 and in man it increases lung permeability.13 If cigarette smoke increases airway permeability in man, this could increase antigen access to immunocompetent cells. Whatever the explanation, the association has important preventive potential for occupational asthma.

TRANSPLANT OSTEONECROSIS ASEPTIC osteonecrosis most commonly occurs when blood supply to bone is disrupted. Trauma is the usual cause of such vascular interruption, but it may arise as the result of arterial obstruction in disorders such as atherosclerosis, sickle-cell disease, neoplasia, and post-irradiation fibrosis. The association between avascular osteonecrosis and corticosteroids was first reported 28 years agol and has been confirmed in numerous patients, irrespective of the underlying reason for steroid treatment. Over the past 20 years, aseptic osteonecrosis has been increasingly recognised as a complication of transplant surgery, most commonly in renal transplant recipients but also in those who receive other organ grafts ;2 it may therefore become a problem of similar magnitude in other transplant programmes. Average prevalence of aseptic osteonecrosis after organ grafting is approximately 16%3 but reports have varied widely, from around 3%4 to over 40%.5When aseptic osteonecrosis develops in transplant recipients it usually presents within the first 2 years, with pain as the predominant symptom. The diagnosis may be confirmed radiologically; weight-bearing bones are usually affected, most commonly the femoral head. The cause of osteonecrosis in transplant recipients is not established but several aetiological factors have been

CA, Gandevia B. Respiratory symptoms and skin reactivity in workers exposed to proteolytic enzymes in the detergent industry. Am Rev Respir Dis 1971;

10. Mitchell

104: 1-12. 11

Greenberg M, Milne JF,

Watt A. A survey of workers exposed to dusts containing derivatives of Bacillus subtilis. Br Med J 1970; ii: 629-33. 12. Hulbert WC, Walker DC, Jackson A, Hogg JC. Airway permeability to horseradish peroxidase in guinea pigs: the repair phase after injury by cigarette smoke. Am Rev Respir Dis 1981; 123: 320-26. 13. Jones JG, Minty BD, Royston D, Royston JP Carboxyhaemoglobin and pulmonary epithelial permeability in man. Thorax 1983; 38: 129-33. I Pietrogrande V, Mastomarino R. Osteopatia de prolungato corticosico Ortop Traumatol 1957, 25: 791-810.

2. Bradford DS, Szalapski EW, Sutherland DER, Simmons RL, Najarian JS. Osteonecrosis in the transplant recipient. Surg Gynecol Obstet 1984; 159: 328-34. 3. Ibels LS, Alfrey AC, Huffer WE, Weil R Aseptic necrosis of bone following renal transplantation: experience in 194 transplant recipients and review ofthe literature Medicine 1978; 57: 25-45. 4. Bewick M, Stewart PH, Rudge C, et al. Avascular necrosis of bone in patients undergoing renal allotransplantation. Clin Nephrol 1976; 5: 66-72. 5. Hawking KM. Avascular necrosis of bone after renal transplantation. N Engl J Med 1976; 294: 397.

966

implicated.

There is little doubt about

a

relation with

corticosteroids, although there are conflicting reports. Some but not all,3-5,9,10 have shown that patients with osteonecrosis have taken the largest doses of corticosteroids.

studies,6-8

Reports of a drop in prevalence of osteonecrosis on reduction of

postoperative

steroid

dosagell-13

are

probably

most

did this not occur. 14 How do corticosteroids cause osteonecrosis? One hypothesis is that corticosteroids lead to fat embolism in the small subchondral arteries. Animal studies have shown that cortisone has a pronounced effect on lipids,l5 resulting in severe hyperlipidaemia, fatty infiltration of the liver, and systemic fat embolism. Embolism of subchondral arterioles with osteocytic necrosis also occurS.16 If lipid is injected into rabbit aorta, intraosseous fat emboli can be demonstrated, especially in the subchondral arteries and capillaries of the femoral head.17 In man, systemic fat embolism has been described after renal transplantation and corticosteroid therapy.18 Fatty infiltration of the liver is common in such patients and evidence of systemic fat embolism may be found in those with aseptic osteonecrosis. Nevertheless, some workers have not found fat emboli in osteonecrotic bones of transplant recipients and there may not be a consistent relation between hyperlipidaemia and avascular necrosis.19 An alternative explanation for corticosteroid-induced osteonecrosis implicates osteoporosis. Glucocorticosteroids have direct effects on bone, with depression of bone formation and possibly some increase in bone resorption.2o They impair intestinal calcium absorption, thereby causing serum calcium levels to fall, and may induce or aggravate secondary hyperparathyroidism. They also seem to suppress calcitonin secretion," which will tend to enhance bone resorption. All these changes result in loss of bone and development of osteoporosis, which is well recognised in these patients.3 It has been suggested that osteoporosis may lead to microfractures, especially in weight-bearing bones, which in turn could result in osteonecrosis.22 However, osteonecrosis is not prominent in patients with generalised osteoporosis from other causes, and it therefore seems unlikely that osteoporosis plays a major role in transplant osteonecrosis.

relevant; in only

one

published study

6. Fisher DW, Bickel WH Corticosteroid-induced avascular necrosis. J Bone Joint Surg 1971, 53A: 859-73 7 Briggs WA, Hampers CL, Merrill JP, et al. Aseptic necrosis in the femur after renal transplantation. Ann Surg 1972, 175: 282-89 8. Harris RR, Niemann KM, Diethelm AG. Skeletal complications after renal transplantation. South Med J 1974; 67: 1016-19 9. Cruess RL, Blennerhassett J, Macdonald FR, Maclean LD, Dossetor J. Aseptic necrosis following renal transplantation J Bone Joint Surg 1968, 50A: 1577-90. 10 Diethelm AG, Sterling WA, Hartley MW, Morgan JM. Alternate-day prednisone therapy in recipients of renal allografts. Arch Surg 1976; 111: 867-70. 11. Harrington KD, Murray WR, Kountz SL, Belzer FO. Avascular necrosis of bone after renal transplantation. J Bone Joint Surg 1971, 53A: 203-15 12. Nelson CL, Evarts CM, Popowniak K. Musculoskeletal complications of renal transplantation. Surg Clin North Am 1971; 51: 1205-09. 13. Woods JE, DeWeerd JH, Johnson WJ, Anderson CF, Shorter RG. Experience in human renal allotransplantation. Surg Gynecol Obstet 1972; 134: 394-98 14. Pierides AM, Simpson W, Stainsby D, Alvarez-Ude F, Uldall PR Avascular necrosis of bone following renal transplantation. Quart J Med 1975; 44: 459-80. 15. Moran TJ Cortisone-induced alterations in lipid metabolism. Arch Pathol 1962; 73: 300-12 16. Fisher DE, Bickel WH, Holley KE, Ellefson RD Corticosteroid-induced aseptic necrosis II Experimental study. Clin Orthop 1974; 84: 200-06 17 Jones PJ, Sakovich L Fat embolism of bone. J Bone Joint Surg 1966, 48A: 149-64 18 Jones PJ, Engleman EP, Najarian JS. Systemic fat embolism after renal homotransplantation and treatment with corticosteroids. N Engl J Med 1965, 273: 1453-58 19. Solomon L Drug-induced arthropathy and necrosis of the femoral head. J Bone Joint Surg 1973, 55B: 246-61 20 Jowsey J, Riggs BL. Bone formation in hypercortisolism Acta Endocrinol 1970, 63: 21-28. 21 Cascio VL, Adami S, Avioli L, et al Suppressive effect of chronic glucocorticoid treatment on circulating calcitonin in men. Calcif Tissue Int 1982; 34: 309-10. 22 Evarts CM, Phalen GS. Osseous avascular necrosis associated with renal transplantation Clin Orthop 1971; 78: 330-35.

Another suggestion is that corticosteroids may cause avascular osteonecrosis by means of arterial occlusion. Coagulation abnormalities have been reported in patients with aseptic necrosis23 and these might result in thrombosis or haemorrhage in an area of susceptible blood supply. Indeed, patients on corticosteroid treatment have an of incidence events.z4 increased thromboembolic Nevertheless, there is no evidence of arterial thrombosis or 3 haemorrhage in osteonecrotic bones of transplant patients.3 Thus, while other factors cannot be excluded, it appears that avascular osteonecrosis in transplant recipients is largely attributable to corticosteroids; the underlying mechanisms are still unclear but fat embolism remains a possibility. In terms of management, hopes lie with prevention; unfortunately, there are no suitable biochemical or hormonal markers for predicting which patients will develop aseptic osteonecrosis after transplant surgery. There is no doubt, however, that selection of the postoperative corticosteroid regimen is of paramount importance. Ibels and colleagues,3 in a literature review, found a weak but significant correlation between mean daily corticosteroid dose during the first post-transplant month and the prevalence of aseptic necrosis. They also suggested that the critical daily dose during this time was in the order of 100 mg/day of prednisone; osteonecrosis was uncommon in patients who received lower doses. Thus the corticosteroid dose should be as low as possible. At present, corticosteroids are widely used for immunosuppression and it would seem a good idea to substitute modified glucocorticoids such as deflazacort for standard preparations. These modified steroids retain the anti-inflammatory properties while reducing the unwanted effects on bone and carbohydrate metabolism.25-27 Studies with such agents appear warranted. Similarly, the metabolic effects of other new immunosuppressants such as cyclosporin28 should be assessed. In patients with established osteonecrosis, immediate management includes non weight-bearing and antiinflammatory agents. Some patients will respond to this but

treatment

perhaps

50%

or more

will have

symptoms and may benefit from surgery. In

continuing

a recent

study,2

Bradford and colleagues reported their experience of 83 joint replacements for post-transplant avascular necrosis, 70 of which were total hip replacements. Only one death was directly attributable to the operation. All the patients experienced dramatic relief of pain and function improved. The main complication was dislocation of the hip, perhaps due to unusually lax connective tissues in these patients. They suggest that this complication could be minimised by avoiding the posterolateral surgical approach and by meticulous capsular repair. It therefore seems reasonable to recommend joint surgery when possible in transplant patients with aseptic osteonecrosis. 23. Boettcher

WG, Bonfiglio M, Hamilton HH, Sheets RF, Smith K. Non-traumatic of the femoral head. J Bone Joint Surg 1970; 52A: 312-21.

necrosis

24.

25

Coagriff SW. Thromboembolic complications associated with ACTH and cortisone therapy. JAMA 1951, 147: 924-26. Scudeletti M, Pende D, Barabino B, Imbimbo B, Grifoni V, Indiveri F. Effect of single oral doses of prednisone and deflazacort on human lymphocyte distribution and function. Analysis with monoclonal antibodies. Adv Exp Med Biol 1984; 171: 335-44.

26.

Caniggia A, Marchetti M, Gennari C, Vattimo A, Nicolis FB. Effects of a new glucocorticoid, oxazacort, on some variables connected with bone metabolism in man A comparison with prednisone Int J Clin Pharmacol Biopharm 1977; 15:

27.

Pagano G, Cavallo-Perin P, Bruno A, et al. Deflazacort versus prednisone diabetogenic effect evaluated by glucose clamp and compartmental analysis. Adv Exp Med Biol

28.

European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: One-year follow-up of amulticentre trial. Lancet 1983; ii: 986-89.

126-34

1984; 171: 45-51.