82
"art of the soluble"14) and the more or less hypothesisgenerating studies of nutritional epidemiologists, who are at best looking for very weak associations,l5 could not have been stated more succinctly. The outcome of the debate will determine whether we will stick to the cautious general admonition to vary our food intake so that we regularly eat vegetables of all colours, or whether the 21 st century will see us all swallowing preventive pills containing the winning competitor from industry. 1. Kraemer
KH, DiGiovanna JJ, Moshell AN, et al. Prevention of skin in xeroderma pigmentosum and the use of oral isotretinoin. N Engl J Med 1988; 318: 1633-37. 2. Hennekens Ch H, Mayrent SL, Willet W. Vitamin A, carotenoids and retinoids. Cancer 1986; 58: 1837-41. 3. Meyskens FL Jr. Coming of age—the chemoprevention of cancer. N Engl J Med 1990; 323: 825-26. 4. Editorial. Retinoids and control of cutaneous malignancy. Lancet 1988; ii: 545-46. 5. Peck GL, Yoder FW, Olsen TG, et al. Treatment of Darrier’s disease, lammelar ichthyosis, pityriasis rubra piloris, cystic acne and basal cell carcinoma with oral 13-cis-retinoic add. Dermatologica 1978; 157 cancer
(suppl 11): 1-12. 6. Hartvelt AM, Bouwes Bavinck JN, Kootte AMM, et al. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation
1990; 49: 506-09. 7. Shuttleworth D, Marks R, Griffin PJA, et al. Treatment of cutaneous neoplasia with etretinate in renal transplant patients. Q J Med 1988; 68: 717-24. 8. Greenberg RE, Baron JA, Stukel Th, et al. Clinical trial of beta carotene to prevent basal-cell and squamous-cell cancer of the skin. N Engl J Med 1990; 323: 789-95. 9. Doll R, Peto R. The causes of cancer. Oxford: Oxford University Press, 1981. 10. Peto R, Doll R, Buckley JD, et al. Can dietary beta carotene materially reduce human cancer rates? Nature 1981; 290: 201-08. 11. Wald N. Retinol, beta-carotene and cancer. Cancer Surv 1987; 6: 635-51. 12. Knekt P, Aromaa AA, Maatela J, et al. Serum vitamin A and subsequent risk of cancer: cancer incidence and follow-up of the Finnish mobile clinic health examination survey. Am J Epidemiol 1990; 132: 857-70. 13. de Vet HCW, Knipschild PG, Willebrand D, et al. The effect of beta-carotene on the regression and progression of cervical dysplasia: a clinical experiment. J Clin Epidemiol (in press). 14. Medawar P. Advice to a young scientist. London: Harper and Row, 1979. 15. Rothman KJ, Poole CH. A strengthening program for weak associations. Int J Epidemiol 1988; 17 (suppl): 955-59.
Bronchial inflammation and asthma treatment The realisation that fibreoptic bronchoscopy can be carried out safely in patients with asthma has encouraged researchers to look for inflammatory cells in bronchoalveolar lavage fluid (BAL) and, more recently, in mucosal biopsy specimens from such subjects. The salient findings to emerge from these studies are that the eosinophil-rich bronchial inflammation and epithelial desquamation, features previously documented in material obtained at necropsy from patients who had died in status asthmaticus, occur during life in some individuals with asthma.3,4 The emphasis on cellular appearances of the bronchial mucosa partly reflects the difficulties of interpreting findings in BAL, since the anatomical source of the cells and the denominator for the expression of concentrations in BAL have not been
clearly defined. In an early study, Laitinen and colleagues3 found damaged bronchial epithelial cells in asthmatic subjects but did not detect eosinophilic infiltration of the epithelium. Mast cell degranulation and pronounced mucosal infiltration by eosinophils were subsequently reported by other investigators in some subjects whose disease severity ranged from almost subclinical to mild, but there was no correlation between inflammatory cell numbers and bronchial hyperreactivity or severity of asthma. More detailed immunohistochemical studies have similarly failed to yield significant correlations with symptom 5 scores or bronchial responsiveness. Studies of peripheral blood lymphocytes have provided evidence of an immunological basis for some severe asthmatic attacks, but not in every case; surprisingly, patients with atopic asthma had the least indication of T-cell activation.66 Immunohistochemical analysis of bronchial mucosal T cells in stable asthma has not consistently shown features of inflammation in all
patients.7 Although measurements of inflammatory cell population have become increasingly complex, all studies that attempt to relate inflammation to asthma are hampered by the difficulties of quantifying the disease. The clinical significance of bronchial provocation tests is a separate issue, but both these and spirometry are measurements of the state of the airway, changes in which may differ in time course from those of inflammatory cell infiltration. Moreover, a biopsy done at one point in time may not reflect the patterns of disease found in patients. To relate disease severity to inflammation, Bousquet et al8 have used a cumulative clinical scoring system and eosinophil enumeration in BAL and biopsy specimens. Although they report significant correlations between BAL and intraepithelial eosinophil counts, many of their subjects with more severe disease did not have any bronchial eosinophils. Another cautionary note comes from studies that have shown similar sputum or biopsy features in patients with cough9 and in atopic subjects,lO,l1 none of whom had bronchial asthma. The demonstration of inflammatory cells in BAL and bronchial biopsy specimens from at least some subjects with asthma has led both physicians 12,13 and the pharmaceutical industry to identify suppression of inflammation as a therapeutic aim in the management of patients with asthma. Treatment of bronchial inflammation is based on the premise that such inflammation affects the clinical condition of most patients with asthma. However, a preliminary study has indicated that hyperreactivity and symptoms can persist in steroid-treated patients with intrinsic asthma despite biopsy evidence of suppression of inflammation. 14 Moreover, in an editorial last month (Dec 8, p 1411), we highlighted the controversy surrounding the anti-inflammatory actions of longacting inhaled (3Z agonists.
83
Many pathways end with the expression of increased airways resistance, and their relative contributions in individual patients are likely to differ considerably. Bronchial inflammation occurs in many patients with asthma, in whom it probably contributes to both acute and chronic disease, but the threshold level of inflammation necessary and the overall role of inflammation in the generation of symptoms have not been established. Consequently, whether suppression of inflammation should be a therapeutic goal in asthma remains to be determined. To address this issue the relative importance of bronchial inflammation needs to be defmed for the various clinical events and subgroups of patients that form the clinical spectrum of asthma. Clarification of the contribution of inflammation to acute severe asthma, chronic progressive disease, and atopic and intrinsic asthma may lead to more specific and effective use of existing and new treatments for this disease. 1. Nakhosteen JA. Bronchofiberscopy in asthmatics: a method for minimizing risk of complications. Respiration 1978; 36: 112-16. 2. Summary and recommendations of a workshop on the investigative use of fiberoptic bronchoscopy and bronchoalveolar lavage in asthmatics. Am Rev Respir Dis 1985; 132: 180-82. 3. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985; 131: 599-606. 4. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989; 139: 806-17. 5. Djukanovic R, Wilson JW, Britten KM, et al. Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry. Am Rev Respir Dis 1990; 142: 863-71. 6. Corrigan CJ, Kay AB. CD4 T lymphocyte activation in acute severe asthma. Relationship to disease severity and atopic status. Am Rev Respir Dis 1990; 141: 970-77. 7. Poulter LW, Power C, Burke C. The relationship between bronchial immunopathology and hyperresponsiveness in asthma. Eur RespirJ 1990; 3: 792-99. 8. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990; 323: 1033-39. 9. Gibson PG, Dolovich J, Denburg J, Ramsdale EH, Hargreave FE. Chronic cough: eosinophilic bronchitis without asthma. Lancet 1989; i: 1346-48. 10. Jeffrey PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989; 140: 1745-53. 11. Howarth P, Djukanovic R, Wilson J, Wilson S, Roche WR, Holgate ST. The influence of atopy on the endobronchial appearance in atopic asthma: a comparison between atopic asthma, atopic non-asthma and non-atopic non-asthma. Am Rev Respir Dis 1990; 141: A500. 12. Bames PJ. A new approach to the treatment of asthma. N Engl J Med
1989; 321: 1517-27. 13. Anon. Corticosteroids in asthma. Drug Ther Bull 1990; 28: 45-46. 14. Lundgren R, Soderberg M, Horstedt P, Stenling R. Morphological studies of bronchial mucosal biopsies from asthmatics before and after ten years treatment with inhaled steroids. Eur Respir J 1988; 1: 883-89.
Retiriopathy of prematurity of prematurity (ROP), formerly known as retrolental fibroplasia, dropped out of the headlines in the 1950s; many doctors, especially those who do not look after children, seem to believe that the disorder has all but disappeared. In the original description of the lesion in 1942, Terry1 suggested various possible causes, including
Retinopathy
It was not until the next decade that a link with oxygen therapy in newborn babies was discovered and publicised.2,3 Thereafter, the use of oxygen in nurseries was drastically curtailed, with the result that some babies, who might previously have survived, died of hypoxia. However, the epidemic of ROP, which had caused perhaps 10 000 cases world wade,4seemed to have been stopped in its tracks. The matter looked straightforward: ROP was an iatrogenic complication of the oxygenation of premature babies, now thankfully recognised and prevented.
hyperoxia.
Unfortunately, that complacency was misplaced, and the 1970s witnessed an unexpected resurgence, which nevertheless failed to make much impact on the medical profession. Phelps5 suggested that the annual incidence of ROP-induced blindness in 1979 in the USA almost equalled that of the epidemic years of 1943-53. The most vulnerable infants were those who weighed less than 1 kg at birth, of whom, Phelps estimated, 8% were blind. By contrast, among infants with a birthweight of 1-1-5 kg, only 0-5% were calculated to be blind. In a retrospective populationbased study from Canada,6the frequency of blindness was 7% in infants of birthweight 1 kg and less born between and A 1977 1980. prospective epidemiological study carried out in New Zealand’ showed total blindness in 2 % of very-low-birthweight ( < 1.5 kg) infants bom in that country over a year, and in 7% of those under 1 kg. In the only modem prospective epidemiological survey in the UK, Ng and colleagues8 reported that ROP developed in 50% of 505 infants born during 1985-87 who weighed 1-7 kg or less. In most cases acute ROP resolved completely, and cicatricial sequelae developed in only 5 infants, none of whom was blind. So are we in the midst of a second epidemic of ROP-associated blindness? According to Gibson and colleagues9 we are, at least among liveborn infants who weighed less than 1 kg at birth. However, their population-based data from British Columbia challenge the more pessimistic estimates of Phelps, in that the accrual of ROP-blind infants in the 1980s was lower than that during the original epidemic of the 1950s. A follow-up study of the same population1O attempted to test the hypothesis that the new epidemic could be attributed to increasing birthweight-specific survival, especially in infants weighing 750 to 999 g at birth. The frequency of blindness in first-year-of-life survivors of this weight remained constant at about 4-5% from 1965 to 1986 whereas the frequency in livebirths has increased steadily (from 0-6% to 3%). By contrast, in infants weighing 1-15 kg, the incidence of ROP-induced blindness has decreased, both in first-year survivors (from 1 % to 0-4%) and in livebirths (from 0-5% to 0-3%), since 1965. The static or declining rates of blindness in survivors may well reflect improvements in neonatal care; the Canadian researchers attribute the increasing rates in livebirths to the increasing birthweight-specific survival.
"art of the soluble"14) and the more or less hypothesisgenerating studies of nutritional epidemiologists, who are at best looking for very weak associations,l5 could not have been stated more succinctly. The outcome of the debate will determine whether we will stick to the cautious general admonition to vary our food intake so that we regularly eat vegetables of all colours, or whether the 21 st century will see us all swallowing preventive pills containing the winning competitor from industry. 1. Kraemer
KH, DiGiovanna JJ, Moshell AN, et al. Prevention of skin in xeroderma pigmentosum and the use of oral isotretinoin. N Engl J Med 1988; 318: 1633-37. 2. Hennekens Ch H, Mayrent SL, Willet W. Vitamin A, carotenoids and retinoids. Cancer 1986; 58: 1837-41. 3. Meyskens FL Jr. Coming of age—the chemoprevention of cancer. N Engl J Med 1990; 323: 825-26. 4. Editorial. Retinoids and control of cutaneous malignancy. Lancet 1988; ii: 545-46. 5. Peck GL, Yoder FW, Olsen TG, et al. Treatment of Darrier’s disease, lammelar ichthyosis, pityriasis rubra piloris, cystic acne and basal cell carcinoma with oral 13-cis-retinoic add. Dermatologica 1978; 157 cancer
(suppl 11): 1-12. 6. Hartvelt AM, Bouwes Bavinck JN, Kootte AMM, et al. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation
1990; 49: 506-09. 7. Shuttleworth D, Marks R, Griffin PJA, et al. Treatment of cutaneous neoplasia with etretinate in renal transplant patients. Q J Med 1988; 68: 717-24. 8. Greenberg RE, Baron JA, Stukel Th, et al. Clinical trial of beta carotene to prevent basal-cell and squamous-cell cancer of the skin. N Engl J Med 1990; 323: 789-95. 9. Doll R, Peto R. The causes of cancer. Oxford: Oxford University Press, 1981. 10. Peto R, Doll R, Buckley JD, et al. Can dietary beta carotene materially reduce human cancer rates? Nature 1981; 290: 201-08. 11. Wald N. Retinol, beta-carotene and cancer. Cancer Surv 1987; 6: 635-51. 12. Knekt P, Aromaa AA, Maatela J, et al. Serum vitamin A and subsequent risk of cancer: cancer incidence and follow-up of the Finnish mobile clinic health examination survey. Am J Epidemiol 1990; 132: 857-70. 13. de Vet HCW, Knipschild PG, Willebrand D, et al. The effect of beta-carotene on the regression and progression of cervical dysplasia: a clinical experiment. J Clin Epidemiol (in press). 14. Medawar P. Advice to a young scientist. London: Harper and Row, 1979. 15. Rothman KJ, Poole CH. A strengthening program for weak associations. Int J Epidemiol 1988; 17 (suppl): 955-59.
Bronchial inflammation and asthma treatment The realisation that fibreoptic bronchoscopy can be carried out safely in patients with asthma has encouraged researchers to look for inflammatory cells in bronchoalveolar lavage fluid (BAL) and, more recently, in mucosal biopsy specimens from such subjects. The salient findings to emerge from these studies are that the eosinophil-rich bronchial inflammation and epithelial desquamation, features previously documented in material obtained at necropsy from patients who had died in status asthmaticus, occur during life in some individuals with asthma.3,4 The emphasis on cellular appearances of the bronchial mucosa partly reflects the difficulties of interpreting findings in BAL, since the anatomical source of the cells and the denominator for the expression of concentrations in BAL have not been
clearly defined. In an early study, Laitinen and colleagues3 found damaged bronchial epithelial cells in asthmatic subjects but did not detect eosinophilic infiltration of the epithelium. Mast cell degranulation and pronounced mucosal infiltration by eosinophils were subsequently reported by other investigators in some subjects whose disease severity ranged from almost subclinical to mild, but there was no correlation between inflammatory cell numbers and bronchial hyperreactivity or severity of asthma. More detailed immunohistochemical studies have similarly failed to yield significant correlations with symptom 5 scores or bronchial responsiveness. Studies of peripheral blood lymphocytes have provided evidence of an immunological basis for some severe asthmatic attacks, but not in every case; surprisingly, patients with atopic asthma had the least indication of T-cell activation.66 Immunohistochemical analysis of bronchial mucosal T cells in stable asthma has not consistently shown features of inflammation in all
patients.7 Although measurements of inflammatory cell population have become increasingly complex, all studies that attempt to relate inflammation to asthma are hampered by the difficulties of quantifying the disease. The clinical significance of bronchial provocation tests is a separate issue, but both these and spirometry are measurements of the state of the airway, changes in which may differ in time course from those of inflammatory cell infiltration. Moreover, a biopsy done at one point in time may not reflect the patterns of disease found in patients. To relate disease severity to inflammation, Bousquet et al8 have used a cumulative clinical scoring system and eosinophil enumeration in BAL and biopsy specimens. Although they report significant correlations between BAL and intraepithelial eosinophil counts, many of their subjects with more severe disease did not have any bronchial eosinophils. Another cautionary note comes from studies that have shown similar sputum or biopsy features in patients with cough9 and in atopic subjects,lO,l1 none of whom had bronchial asthma. The demonstration of inflammatory cells in BAL and bronchial biopsy specimens from at least some subjects with asthma has led both physicians 12,13 and the pharmaceutical industry to identify suppression of inflammation as a therapeutic aim in the management of patients with asthma. Treatment of bronchial inflammation is based on the premise that such inflammation affects the clinical condition of most patients with asthma. However, a preliminary study has indicated that hyperreactivity and symptoms can persist in steroid-treated patients with intrinsic asthma despite biopsy evidence of suppression of inflammation. 14 Moreover, in an editorial last month (Dec 8, p 1411), we highlighted the controversy surrounding the anti-inflammatory actions of longacting inhaled (3Z agonists.
83
Many pathways end with the expression of increased airways resistance, and their relative contributions in individual patients are likely to differ considerably. Bronchial inflammation occurs in many patients with asthma, in whom it probably contributes to both acute and chronic disease, but the threshold level of inflammation necessary and the overall role of inflammation in the generation of symptoms have not been established. Consequently, whether suppression of inflammation should be a therapeutic goal in asthma remains to be determined. To address this issue the relative importance of bronchial inflammation needs to be defmed for the various clinical events and subgroups of patients that form the clinical spectrum of asthma. Clarification of the contribution of inflammation to acute severe asthma, chronic progressive disease, and atopic and intrinsic asthma may lead to more specific and effective use of existing and new treatments for this disease. 1. Nakhosteen JA. Bronchofiberscopy in asthmatics: a method for minimizing risk of complications. Respiration 1978; 36: 112-16. 2. Summary and recommendations of a workshop on the investigative use of fiberoptic bronchoscopy and bronchoalveolar lavage in asthmatics. Am Rev Respir Dis 1985; 132: 180-82. 3. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985; 131: 599-606. 4. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989; 139: 806-17. 5. Djukanovic R, Wilson JW, Britten KM, et al. Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry. Am Rev Respir Dis 1990; 142: 863-71. 6. Corrigan CJ, Kay AB. CD4 T lymphocyte activation in acute severe asthma. Relationship to disease severity and atopic status. Am Rev Respir Dis 1990; 141: 970-77. 7. Poulter LW, Power C, Burke C. The relationship between bronchial immunopathology and hyperresponsiveness in asthma. Eur RespirJ 1990; 3: 792-99. 8. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990; 323: 1033-39. 9. Gibson PG, Dolovich J, Denburg J, Ramsdale EH, Hargreave FE. Chronic cough: eosinophilic bronchitis without asthma. Lancet 1989; i: 1346-48. 10. Jeffrey PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989; 140: 1745-53. 11. Howarth P, Djukanovic R, Wilson J, Wilson S, Roche WR, Holgate ST. The influence of atopy on the endobronchial appearance in atopic asthma: a comparison between atopic asthma, atopic non-asthma and non-atopic non-asthma. Am Rev Respir Dis 1990; 141: A500. 12. Bames PJ. A new approach to the treatment of asthma. N Engl J Med
1989; 321: 1517-27. 13. Anon. Corticosteroids in asthma. Drug Ther Bull 1990; 28: 45-46. 14. Lundgren R, Soderberg M, Horstedt P, Stenling R. Morphological studies of bronchial mucosal biopsies from asthmatics before and after ten years treatment with inhaled steroids. Eur Respir J 1988; 1: 883-89.
Retiriopathy of prematurity of prematurity (ROP), formerly known as retrolental fibroplasia, dropped out of the headlines in the 1950s; many doctors, especially those who do not look after children, seem to believe that the disorder has all but disappeared. In the original description of the lesion in 1942, Terry1 suggested various possible causes, including
Retinopathy
It was not until the next decade that a link with oxygen therapy in newborn babies was discovered and publicised.2,3 Thereafter, the use of oxygen in nurseries was drastically curtailed, with the result that some babies, who might previously have survived, died of hypoxia. However, the epidemic of ROP, which had caused perhaps 10 000 cases world wade,4seemed to have been stopped in its tracks. The matter looked straightforward: ROP was an iatrogenic complication of the oxygenation of premature babies, now thankfully recognised and prevented.
hyperoxia.
Unfortunately, that complacency was misplaced, and the 1970s witnessed an unexpected resurgence, which nevertheless failed to make much impact on the medical profession. Phelps5 suggested that the annual incidence of ROP-induced blindness in 1979 in the USA almost equalled that of the epidemic years of 1943-53. The most vulnerable infants were those who weighed less than 1 kg at birth, of whom, Phelps estimated, 8% were blind. By contrast, among infants with a birthweight of 1-1-5 kg, only 0-5% were calculated to be blind. In a retrospective populationbased study from Canada,6the frequency of blindness was 7% in infants of birthweight 1 kg and less born between and A 1977 1980. prospective epidemiological study carried out in New Zealand’ showed total blindness in 2 % of very-low-birthweight ( < 1.5 kg) infants bom in that country over a year, and in 7% of those under 1 kg. In the only modem prospective epidemiological survey in the UK, Ng and colleagues8 reported that ROP developed in 50% of 505 infants born during 1985-87 who weighed 1-7 kg or less. In most cases acute ROP resolved completely, and cicatricial sequelae developed in only 5 infants, none of whom was blind. So are we in the midst of a second epidemic of ROP-associated blindness? According to Gibson and colleagues9 we are, at least among liveborn infants who weighed less than 1 kg at birth. However, their population-based data from British Columbia challenge the more pessimistic estimates of Phelps, in that the accrual of ROP-blind infants in the 1980s was lower than that during the original epidemic of the 1950s. A follow-up study of the same population1O attempted to test the hypothesis that the new epidemic could be attributed to increasing birthweight-specific survival, especially in infants weighing 750 to 999 g at birth. The frequency of blindness in first-year-of-life survivors of this weight remained constant at about 4-5% from 1965 to 1986 whereas the frequency in livebirths has increased steadily (from 0-6% to 3%). By contrast, in infants weighing 1-15 kg, the incidence of ROP-induced blindness has decreased, both in first-year survivors (from 1 % to 0-4%) and in livebirths (from 0-5% to 0-3%), since 1965. The static or declining rates of blindness in survivors may well reflect improvements in neonatal care; the Canadian researchers attribute the increasing rates in livebirths to the increasing birthweight-specific survival.
