BRITISH MEDICAL JOURNAL
27 MARCH 1976
In defence of the lungs The respiratory tract is in the front line of our defences against a continuous bombardment by allergens, atmospheric pollutants, infectious organisms, and other potentially harmful agents. Unique mechanisms have evolved for combating these hazards.' Particles more than 10 microns in diameter are mostly deposited in the nasopharynx. Smaller particles may penetrate to the airways or alveoli, but laryngeal and airway reflexes can initiate cough and bronchoconstriction to limit their entry and mucociliary action and lymphatic drainage remove those which are deposited. Infectious agents present special problems. Virus infections are resisted by the production of interferon, and the survival of many bacteria is limited by lysozyme and lactoferrin. Phagocytes act as scavengers in the airways, and alveolar macrophages perform this function within the alveoli. Specific immunity within the respiratory tract depends on humoral and cellular factors. Both IgG and IgM are present in the respiratery secretions and may neutralise exotoxins directly or kill bacteria via the activation of complement. IgE is concerned in hypersensitivity reactions, while cell-mediated immunity is responsible for protection against tuberculosis and some fungus infections. There is specialisation within the immune system in the respiratory tract, most clearly shown by the predominant immunoglobulin, IgA, which is produced by plasma cells within the respiratory tract and, unlike serum IgA, consists of two IgA molecules linked by a polypeptide "secretory piece" and a smaller "joining chain." This configuration confers a resistance to proteolytic enzymes which might come from pus cells in infected sputum. The finding that there is selective concentration of IgA in the respiratory tract secretions has naturally led to the suggestion that IgA is of prime importance in the defence of the lung. It may form complexes with harmful antigens, preventing their entry to the circulation, and there is some evidence that deficienLcy or late maturation of the IgA system is associated with development of the atopic trait.2 3 IgA does not fix complement by the classical pathway, but in the presence of lysozyme and complement secretory IgA can kill bacteria. Viruses are neutralised without involving complement, and resistance to virus infections is closely correlated with high levels of secretory IgA.4 An early report indicated5 that the 0.2% of the population who have low serum concentrations of IgA might be unusually susceptible to respiratory infections, but later studies6 7 have not confirmed this. It may be that IgA is not, after all, so important in resisting infection, or that in these cases IgM or IgG can substitute for IgA, or even that secretory Ig.A is still present in sufficient quantity even though serum IgA is deficient. Such dissociation between serum and secretory IgA levels has been described,8 and the opposite possibility of low secretory and normal serum IgA concentrations is of particular relevance to patients with chronic bronchitis. No consistent deficiency of serum IgA or secretory IgA in the saliva has been shown in these patients but some studies have suggested that concentrations of sputum IgA are lower than normal.910 Measurements in sputum are difficult to interpret because of wide variations, but some corroboration may be drawn from the observation that plasma cells (which produce IgA within the respiratory tract) are also deficient in patients with severe bronchitis." This may simply reflect the degree of airway damage in such cases, but an alternative hypothesis has recently been outlined by Turner-
733
Warwick.'2 She suggests that smoking and atmospheric pollutants may produce an initial deficiency in local IgA production'3; this could result in the failure of elimination of bacteria and viruses, and the subsequent inflammatory response might lead to further airway damage and a secondary deficiency of local IgA. Fortunately the other defences of the lung are very effective, but this mechanism may be a contributory factor in the evolution of chronic bronchitis. 1 2
Cohen, A B, and Gold, W M, Annual Review of Physiology, 1975, 37, 325Kaufman, H S, and Hobbs, J R, Lancet, 1970, 2, 1061. 3Taylor, B, et al, Lancet, 1973, 2, 111. 4 Rossen, R D, et al,j'ournal of the American Medical Association, 1970, 211, 1157. 5Hobbs, J R, Lancet, 1968, 1, 110. 6 Bachmann, R, Scandinavian Journal of Clinical and Laboratory Investigation, 1968, 17, 316. 7Koistinen, J, Vox Sanguinis, 1975, 29, 192. 8 Swanson, V, et al, Clinical Research, 1968, 16, 119. 9 Medici, T C, and Buergi, H, American Review of Respiratory Disease, 1971, 103, 784. 10 Deuschl, H, and Johansson, S G 0, Clinical and Experimental Immunology, 1973, 16, 401. 11 Soutar, C A, Thorax, 1975, 30, 239. 12 Turner-Warwick, M, Thorax, 1975, 30, 601. 13 Roszman, T L, and Rogers, A S, American Review of Respiratory Disease, 1973, 108, 1158.
Pregnancy after renal replacement Women with chronic renal failure are subfertile and remain so despite maintenance haemodialysis. Nevertheless, 53 pregnancies in patients having dialysis have been reported to the European Dialysis and Transplant Association Registry,' about one for every 200 women of childbearing age on dialysis in Europe. Half of these pregnancies ended in miscarriage, and most of the rest were terminated. Three living infants have been born, one of whom had congenital abnormalities. Successful kidney transplantation improves fertility: indeed, the desire for parenthood is sometimes the clinching factor in the decision to opt for a transplant. Sixty-six pregnancies in transplant recipients have been reported to the registry,' about one for every 50 women of childbearing age with a functioning transplant. Miscarriage has been less common in this group, occurring in 15 patients. Thirty-two pregnancies were terminated and 19 live infants, none with congenital abnormalities, have been born. Early diagnosis of pregnancy is difficult in patients having dialysis. Irregular menstruation is common,2 and a missed period will usually be ignored. Pregnancy tests on urine may be unreliable-even if any urine is obtainable. Pregnancy presents real hazards. The most common problem is hypertension, though it may be possible to control this by ultrafiltration. Patients remain anaemic during pregnancy, and transfusion shortly before delivery may be essential for safe obstetric management. An impression exists that smaller women and those with some residual renal function (in whom biochemical control is easier) are more likely to become pregnant and that more frequent dialysis during pregnancy may improve the outcome.3 Anaemia and uraemia are potential causes of impaired fetal growth, which can be assessed by ultrasonic cephalometry. Hypertension during pregnancy is common in transplant recipients, too, and demands appropriate drug treatment or
734
BRITISH MEDICAL JOURNAL
termination. Significant reduction of renal function has been reported by some4-6 but not all7 8 authors. Again, termination may be necessary. There is no evidence that pregnancy increases the likelihood of graft rejection. Viral and bacterial infections, which are common in transplant recipients, present a potential hazard, though anaemia is not usually a problem. The ideal outcome is a full-term vaginal delivery, but obstruction of the pelvis by the transplanted kidney may necessitate caesarean section,9 and premature labour is common.10 There is no evidence of an increased risk of fetal abnormality despite the fact that steroid and immunosuppressive treatment must be continued during pregnancy. The paediatrician must be aware of the potential problem of adrenocortical insufficiency in the infant, and paediatric intensive care should be available at delivery. The number of terminations that have been carried out in these women suggests a medical failure to advise patients having dialysis or after transplantation of their potential fertility. Patients of childbearing age who do not want to become pregnant need advice about contraception and sterilisation. Should all these patients be advised against pregnancy altogether ? The risks to the patient, the reduced likelihood of a successful outcome, and the possibility that the patient may not survive to bring up the child provide substantial arguments against pregnancy and valid indications for termination. Once informed, however, the patient must make the final decision. A successful outcome depends upon painstaking follow-up and co-operation among patient, husband, renal physician, obstetrician, and paediatrician. In an over-populated world Ivan Illich might regard this as a misuse of scarce resources and manpower. But Illich does not have to deal with the individual woman who wants a baby. Computer files of the European Dialysis and Transplant Association Registry containing data on questionnaires returned to 31 December 1974. Pregnancies quoted are those in which the outcome is known. 2 Goodwin, N J, et al, American Journal of Obstetrics and Gynecology, 1968,
I
100, 528.
3Ackrill, P, et al, British Medical3'ournal, 1975, 2, 172. 4Board, J A, et al, Obstetrics and Gynecology, 1967, 29, 318. 5 Caplan, R M, Dossetor, J B, and Maughan, G B, American Jrournal of Obstetrics and Gynecology, 1970, 106, 644. 6 Moore, T C, and Hume, D M, Annals of Surgery, 1699, 170, 12. 7Merkatz, I R, et al, Journal of the American Medical Association, 1971, 216, 1749. 8 Penn, I, et al,Journal of the American Medical Association, 1971, 216, 1755.
9 Nolan, G H, et al, Obstetrics and Gynecology, 1974, 43, 732. Sciarra, J J, et al, American J'ournal of Obstetrics and Gynecology, 1975, 123, 411.
10
Consultation or action? The re-examination of health priorities forced upon us by economic circumstances' has stimulated interest in preventive medicine, and last week the Departments of Health issued a consultative document titled Prevention and health: everybody's business.2 Welcome though the initiative may be, the report is a disappointment. Most of its pages are concerned with a review of historical and epidemiological data on the effects of environment and life-style on health, but it lacks any positive proposals. Indeed it "deliberately poses more questions than answers." Health authorities should, says the report, develop the preventive aspects of their work and it recognises the force
27 MARCH 1976
of the argument that, in the long term, money diverted from the expensive curative services to preventive medicine is likely to effect savings. In practice, of course, it is much more difficult for a health authority to cut hospital beds or reduce the number of nurses than to cancel health education campaigns and close screening clinics. Patients in need of treatment are individuals -identifiable and newsworthy-but illnesses prevented are necessarily anonymous. Two years ago the Canadian Federal Government published a broadly similar document,3 which covered the same historical ground but put forward detailed plans for dealing with the problems. Five strategies were proposed: health promotion by informing and influencing individuals and organisations; regulations to control hazards to health from environmental pollution, food and drugs, and the effects of alcohol on driving; research to identify risk factors and to analyse accident and disease statistics and evaluate screening programmes; a health care audit to assess the cost-effectiveness and overall efficiency of the medical services in current use; and a goal-setting strategy through which a rational set of objectives would be agreed with the health professions, including specific reductions in mortality and morbidity to be accomplished by specific dates. This programme has been widely accepted in Canada, and, more important, the proportion of its health expenditure (already at 7%0 of the GNP or $300 a year per head, well ahead of Britain) spent on preventive measures is to be raised progressively over the coming years. In the last year the experts interviewed in our series Medicine in the 'Seventies4-7 have agreed on the need for action on prevention. A private member's Bill seems likely to achieve the much-needed legal requirement on drivers and front seat passengers to wear seat belts, but many other aspects of road safety such as the lack of legal control over jay-walking have been ignored by the Government despite advice from its experts. It seems unwilling to act firmly on fluoridation; it has rejected the use of financial pressures to discourage smoking; and there is a real possibility that it will accede to pressures to extend licensing hours and lower the age at which alcohol can be bought. Yet these are the four really clear-cut issues where Government action-with the authority of Government and the force of law-could have immediate and substantial effects on mortality and morbidity. The consultative document asks why Britain's health statistics are so far behind countries such as Sweden. Without doubt the gap could be narrowed by application of the knowledge we already have. Furthermore, a determined effort by the Government on these aspects of health (where the arguments are so familiar that most people accept them) could spearhead a campaign in schools, factories, on television and radio, on the other, less well known aspects of health education such as the hazards of a diet high in animal fat. What is needed is not consultation but action. British Medical3Journal, 1975, 3, 64. Prevention and health: everybody's business. A reassessment of public and personal health. London, HMSO, 1976. Price 50p. 3 Lalonde, M, A new perspective on the health of Canadians. Ottawa, Government of Canada, 1974. 4 An interview with Mr Robert Maxwell, British Medical journal, 1975, 3, 424. 5 An interview with Professor C T Dollery, British Medical3Journal, 1975, 4, 750. 6 An interview with Dr David Owen, British Medical3Journal, 1976, 1, 513. 7 An interview with Sir George Godber, British Medical JIournal, 1976, 1, 638.
1
2
27 MARCH 1976
In defence of the lungs The respiratory tract is in the front line of our defences against a continuous bombardment by allergens, atmospheric pollutants, infectious organisms, and other potentially harmful agents. Unique mechanisms have evolved for combating these hazards.' Particles more than 10 microns in diameter are mostly deposited in the nasopharynx. Smaller particles may penetrate to the airways or alveoli, but laryngeal and airway reflexes can initiate cough and bronchoconstriction to limit their entry and mucociliary action and lymphatic drainage remove those which are deposited. Infectious agents present special problems. Virus infections are resisted by the production of interferon, and the survival of many bacteria is limited by lysozyme and lactoferrin. Phagocytes act as scavengers in the airways, and alveolar macrophages perform this function within the alveoli. Specific immunity within the respiratory tract depends on humoral and cellular factors. Both IgG and IgM are present in the respiratery secretions and may neutralise exotoxins directly or kill bacteria via the activation of complement. IgE is concerned in hypersensitivity reactions, while cell-mediated immunity is responsible for protection against tuberculosis and some fungus infections. There is specialisation within the immune system in the respiratory tract, most clearly shown by the predominant immunoglobulin, IgA, which is produced by plasma cells within the respiratory tract and, unlike serum IgA, consists of two IgA molecules linked by a polypeptide "secretory piece" and a smaller "joining chain." This configuration confers a resistance to proteolytic enzymes which might come from pus cells in infected sputum. The finding that there is selective concentration of IgA in the respiratory tract secretions has naturally led to the suggestion that IgA is of prime importance in the defence of the lung. It may form complexes with harmful antigens, preventing their entry to the circulation, and there is some evidence that deficienLcy or late maturation of the IgA system is associated with development of the atopic trait.2 3 IgA does not fix complement by the classical pathway, but in the presence of lysozyme and complement secretory IgA can kill bacteria. Viruses are neutralised without involving complement, and resistance to virus infections is closely correlated with high levels of secretory IgA.4 An early report indicated5 that the 0.2% of the population who have low serum concentrations of IgA might be unusually susceptible to respiratory infections, but later studies6 7 have not confirmed this. It may be that IgA is not, after all, so important in resisting infection, or that in these cases IgM or IgG can substitute for IgA, or even that secretory Ig.A is still present in sufficient quantity even though serum IgA is deficient. Such dissociation between serum and secretory IgA levels has been described,8 and the opposite possibility of low secretory and normal serum IgA concentrations is of particular relevance to patients with chronic bronchitis. No consistent deficiency of serum IgA or secretory IgA in the saliva has been shown in these patients but some studies have suggested that concentrations of sputum IgA are lower than normal.910 Measurements in sputum are difficult to interpret because of wide variations, but some corroboration may be drawn from the observation that plasma cells (which produce IgA within the respiratory tract) are also deficient in patients with severe bronchitis." This may simply reflect the degree of airway damage in such cases, but an alternative hypothesis has recently been outlined by Turner-
733
Warwick.'2 She suggests that smoking and atmospheric pollutants may produce an initial deficiency in local IgA production'3; this could result in the failure of elimination of bacteria and viruses, and the subsequent inflammatory response might lead to further airway damage and a secondary deficiency of local IgA. Fortunately the other defences of the lung are very effective, but this mechanism may be a contributory factor in the evolution of chronic bronchitis. 1 2
Cohen, A B, and Gold, W M, Annual Review of Physiology, 1975, 37, 325Kaufman, H S, and Hobbs, J R, Lancet, 1970, 2, 1061. 3Taylor, B, et al, Lancet, 1973, 2, 111. 4 Rossen, R D, et al,j'ournal of the American Medical Association, 1970, 211, 1157. 5Hobbs, J R, Lancet, 1968, 1, 110. 6 Bachmann, R, Scandinavian Journal of Clinical and Laboratory Investigation, 1968, 17, 316. 7Koistinen, J, Vox Sanguinis, 1975, 29, 192. 8 Swanson, V, et al, Clinical Research, 1968, 16, 119. 9 Medici, T C, and Buergi, H, American Review of Respiratory Disease, 1971, 103, 784. 10 Deuschl, H, and Johansson, S G 0, Clinical and Experimental Immunology, 1973, 16, 401. 11 Soutar, C A, Thorax, 1975, 30, 239. 12 Turner-Warwick, M, Thorax, 1975, 30, 601. 13 Roszman, T L, and Rogers, A S, American Review of Respiratory Disease, 1973, 108, 1158.
Pregnancy after renal replacement Women with chronic renal failure are subfertile and remain so despite maintenance haemodialysis. Nevertheless, 53 pregnancies in patients having dialysis have been reported to the European Dialysis and Transplant Association Registry,' about one for every 200 women of childbearing age on dialysis in Europe. Half of these pregnancies ended in miscarriage, and most of the rest were terminated. Three living infants have been born, one of whom had congenital abnormalities. Successful kidney transplantation improves fertility: indeed, the desire for parenthood is sometimes the clinching factor in the decision to opt for a transplant. Sixty-six pregnancies in transplant recipients have been reported to the registry,' about one for every 50 women of childbearing age with a functioning transplant. Miscarriage has been less common in this group, occurring in 15 patients. Thirty-two pregnancies were terminated and 19 live infants, none with congenital abnormalities, have been born. Early diagnosis of pregnancy is difficult in patients having dialysis. Irregular menstruation is common,2 and a missed period will usually be ignored. Pregnancy tests on urine may be unreliable-even if any urine is obtainable. Pregnancy presents real hazards. The most common problem is hypertension, though it may be possible to control this by ultrafiltration. Patients remain anaemic during pregnancy, and transfusion shortly before delivery may be essential for safe obstetric management. An impression exists that smaller women and those with some residual renal function (in whom biochemical control is easier) are more likely to become pregnant and that more frequent dialysis during pregnancy may improve the outcome.3 Anaemia and uraemia are potential causes of impaired fetal growth, which can be assessed by ultrasonic cephalometry. Hypertension during pregnancy is common in transplant recipients, too, and demands appropriate drug treatment or
734
BRITISH MEDICAL JOURNAL
termination. Significant reduction of renal function has been reported by some4-6 but not all7 8 authors. Again, termination may be necessary. There is no evidence that pregnancy increases the likelihood of graft rejection. Viral and bacterial infections, which are common in transplant recipients, present a potential hazard, though anaemia is not usually a problem. The ideal outcome is a full-term vaginal delivery, but obstruction of the pelvis by the transplanted kidney may necessitate caesarean section,9 and premature labour is common.10 There is no evidence of an increased risk of fetal abnormality despite the fact that steroid and immunosuppressive treatment must be continued during pregnancy. The paediatrician must be aware of the potential problem of adrenocortical insufficiency in the infant, and paediatric intensive care should be available at delivery. The number of terminations that have been carried out in these women suggests a medical failure to advise patients having dialysis or after transplantation of their potential fertility. Patients of childbearing age who do not want to become pregnant need advice about contraception and sterilisation. Should all these patients be advised against pregnancy altogether ? The risks to the patient, the reduced likelihood of a successful outcome, and the possibility that the patient may not survive to bring up the child provide substantial arguments against pregnancy and valid indications for termination. Once informed, however, the patient must make the final decision. A successful outcome depends upon painstaking follow-up and co-operation among patient, husband, renal physician, obstetrician, and paediatrician. In an over-populated world Ivan Illich might regard this as a misuse of scarce resources and manpower. But Illich does not have to deal with the individual woman who wants a baby. Computer files of the European Dialysis and Transplant Association Registry containing data on questionnaires returned to 31 December 1974. Pregnancies quoted are those in which the outcome is known. 2 Goodwin, N J, et al, American Journal of Obstetrics and Gynecology, 1968,
I
100, 528.
3Ackrill, P, et al, British Medical3'ournal, 1975, 2, 172. 4Board, J A, et al, Obstetrics and Gynecology, 1967, 29, 318. 5 Caplan, R M, Dossetor, J B, and Maughan, G B, American Jrournal of Obstetrics and Gynecology, 1970, 106, 644. 6 Moore, T C, and Hume, D M, Annals of Surgery, 1699, 170, 12. 7Merkatz, I R, et al, Journal of the American Medical Association, 1971, 216, 1749. 8 Penn, I, et al,Journal of the American Medical Association, 1971, 216, 1755.
9 Nolan, G H, et al, Obstetrics and Gynecology, 1974, 43, 732. Sciarra, J J, et al, American J'ournal of Obstetrics and Gynecology, 1975, 123, 411.
10
Consultation or action? The re-examination of health priorities forced upon us by economic circumstances' has stimulated interest in preventive medicine, and last week the Departments of Health issued a consultative document titled Prevention and health: everybody's business.2 Welcome though the initiative may be, the report is a disappointment. Most of its pages are concerned with a review of historical and epidemiological data on the effects of environment and life-style on health, but it lacks any positive proposals. Indeed it "deliberately poses more questions than answers." Health authorities should, says the report, develop the preventive aspects of their work and it recognises the force
27 MARCH 1976
of the argument that, in the long term, money diverted from the expensive curative services to preventive medicine is likely to effect savings. In practice, of course, it is much more difficult for a health authority to cut hospital beds or reduce the number of nurses than to cancel health education campaigns and close screening clinics. Patients in need of treatment are individuals -identifiable and newsworthy-but illnesses prevented are necessarily anonymous. Two years ago the Canadian Federal Government published a broadly similar document,3 which covered the same historical ground but put forward detailed plans for dealing with the problems. Five strategies were proposed: health promotion by informing and influencing individuals and organisations; regulations to control hazards to health from environmental pollution, food and drugs, and the effects of alcohol on driving; research to identify risk factors and to analyse accident and disease statistics and evaluate screening programmes; a health care audit to assess the cost-effectiveness and overall efficiency of the medical services in current use; and a goal-setting strategy through which a rational set of objectives would be agreed with the health professions, including specific reductions in mortality and morbidity to be accomplished by specific dates. This programme has been widely accepted in Canada, and, more important, the proportion of its health expenditure (already at 7%0 of the GNP or $300 a year per head, well ahead of Britain) spent on preventive measures is to be raised progressively over the coming years. In the last year the experts interviewed in our series Medicine in the 'Seventies4-7 have agreed on the need for action on prevention. A private member's Bill seems likely to achieve the much-needed legal requirement on drivers and front seat passengers to wear seat belts, but many other aspects of road safety such as the lack of legal control over jay-walking have been ignored by the Government despite advice from its experts. It seems unwilling to act firmly on fluoridation; it has rejected the use of financial pressures to discourage smoking; and there is a real possibility that it will accede to pressures to extend licensing hours and lower the age at which alcohol can be bought. Yet these are the four really clear-cut issues where Government action-with the authority of Government and the force of law-could have immediate and substantial effects on mortality and morbidity. The consultative document asks why Britain's health statistics are so far behind countries such as Sweden. Without doubt the gap could be narrowed by application of the knowledge we already have. Furthermore, a determined effort by the Government on these aspects of health (where the arguments are so familiar that most people accept them) could spearhead a campaign in schools, factories, on television and radio, on the other, less well known aspects of health education such as the hazards of a diet high in animal fat. What is needed is not consultation but action. British Medical3Journal, 1975, 3, 64. Prevention and health: everybody's business. A reassessment of public and personal health. London, HMSO, 1976. Price 50p. 3 Lalonde, M, A new perspective on the health of Canadians. Ottawa, Government of Canada, 1974. 4 An interview with Mr Robert Maxwell, British Medical journal, 1975, 3, 424. 5 An interview with Professor C T Dollery, British Medical3Journal, 1975, 4, 750. 6 An interview with Dr David Owen, British Medical3Journal, 1976, 1, 513. 7 An interview with Sir George Godber, British Medical JIournal, 1976, 1, 638.
1
2
