- Email: [email protected]
CHOLECYSTOGRAPHY OR ULTRASOUND?
684 increased risk (1-6) for lung cancer of children of smoking mothers. I note that Heller is an assistant to Prof M. Rutsch, who is a member of the Forschungsrat Rauchen und Gesundheit (Research Council Smoking and Health) of the German cigarette industry. This body was given, for distribution for research projects on smoking and health in the past eight years, more than DM20 million by the cigarette industry. Rutsch’s name, together with those of other members of this council, has appeared on full-page newspaper advertisements from the German cigarette industry denying the health-damaging effects of passive smoking, despite the cumulative effects of more than forty cancerogenic substances in sidestream tobacco smoke, the part that the non-smoker inhales. Research Department for Preventive Oncology,
University of Heidelberg, D-6800 Mannheim, West Germany
counts of L pneumophila previously exposed to ugin-d erythromycin in broth for 6 h (0 0), 24 h (*———————*),and48h(W————*). Colonies on legionella blood agar were counted daily and increasing viable counts indicate organism recovery, provided incubation was prolonged.
Fig
2-Viable
10
The fact that erythromycin accumulates in macrophages points to erythromycin as the drug of choice in the treatment oflegionellosis; however, it probably acts by bacteriostatic rather than bactericidal activity, allowing the cell-mediated immune system time to eradicate the bacterium.
FERDINAND SCHMIDT
SIR,-Dr Heller notes that our crude relative risk estimates for lung cancer among passive smokers (Sept 17, p 677) do not correspond to the crude odds ratios. He is right, and we apologise for our typing error (which was pointed out by others including Dr Gosta Axelson of Goteborg, Sweden). On the other hand, all our statements in the letter-including results of statistical testing-are correct and the adjusted relative risk figures are higher than the crude ones (although the adjusted Mantel-extensionx2 statistic is similar to the crude Xfor the trend statistic, there being insufficient cross-matching in the detailed age strata). Our newer data do add independent (although non-significant) weight to the evidence implicating passive smoking as a factor in lung cancer, and so does the smoothness of the overall trend and the accumulating evidence. Laboratory of Hygiene and Epidemiology, Medical
Department of Microbiology and PHLS Laboratory, Queen’s Medical Centre, Nottingham NG7 2UH
School, University of Athens,
FRANK G. RODGERS TOM S. J. ELLIOTT
PASSIVE SMOKING AND LUNG CANCER
_
SlR,—Dr Heller (Dec 3, p 1309) dismisses our paperl with a sweep of the hand ("... contains only tentative conclusions based on poor data analysed by unacceptable methods"). Our original aim was not to examine the connection between passive smoking and lung cancer. In 792 lung-cancer patients of both sexes we found that 97’ 3% of the men were smokers while 39 (66%) of the 59 female patients with bronchial carcinoma were non-smokers. Because we could not ’find any indication of hereditary factors or special professional risks-more than 47% of our female lung-cancer patients were housewives, the rest were in unskilled work or office workers-we turned our attention towards the smoking habits of their husbands and other people in the home. We found that 61 -5% had lived with smokers. This is nearly three times the frequency expected on the basis of figures on the smoking habits of men in the age-group concerned, from a "microcensus" in more than two million people conducted by the Federal Office of Statistics. We felt that passive smoking was the most likely explanation for the increased percentage of non-smokers in our female lung cancer patients. This interpretation is supported by the proportion of squamous cell and oat cell cancers which, at 67%, was not significantly lower than the proportion in our smoking female patients with bronchial carcinoma (80%). Does Heller have a more convincing explanation of our findings? We will discuss it with pleasure. Heller does not mention the arguments, set out in our paper, which in sum, leave no doubt about the damaging effect of passive 2 smoking on health. Nor does he refer to Correa et al’s paper,2 the customs of the of 1338 relatives comparing smoking patients with bronchial carcinoma with those of 1393 controls. For female non-smokers with heavy-smoking husbands they calculated a and there was an 3’5-fold risk for bronchial carcinoma (p<0’05),
CHOLECYSTOGRAPHY OR ULTRASOUND?
SIR,—Dr Sowerbutts (March 10, p 566) suggests that the only of cholecystography in the investigation of symptoms which suggest gallbladder disease is to pick up a calculous
advantage
adenomyomatosis. Surely it is important to establish whether gallstones, if present, are likely to be causing the type of symptom of which the patient complains-and, with this in mind, demonstration of whether the gallbladder is functioning or not must be important. Countless numbers of patients have their gallbladders removed because of the finding of gallstones, and yet in the long run they do not
benefit: their symptoms, due
to
irritable gut
or
other
causes,
persist after a short period of relief which may be attributed to the placebo effect of the operation. Exactly the same considerations must apply to the protracted and tedious treatment necessary to ensure the dissolution of gallstones, which may in the first instance not have been responsible for the patient’s symptoms. Vast numbers of patients with functioning gallbladders containing stones have no symptoms whatsoever. It must surely be foolish to attribute vague right subcostal symptoms to gallstones in a functioning gallbladder without a thorough assessment, and I would have thought that most clinicians would accept that an obstructed gallbladder was more likely to produce symptoms on the whole than an unobstructed gallbladder containing stones, unless of course in the latter case clearly definable biliary colic was occurring. 149 Harley Street, LondonWIN2DH
JOHN SQUIRE KIRKHAM
SIR,-In the light of Dr de Lacey and colleagues’ paper (Jan 28, p 205) on the primary investigation in gallbladder disease, we would like to report a retrospective study of 117 cases of cholecystectomy done in the fourteen months October, 1982, to January, 1983. Three years ago, at Ashford Hospital, ultrasound was adopted in to cholecystography, as the primary method of investigation in gallbladder disease. All but 5 (emergency laparotomies) of the 117 cases reported, were investigated in this
preference 1. Knoth A, Bohn H, Schmidt F. Passivrauchen als Lungenkrebssursache bei Nichtraucherinnen. Med Klin Prax 1983; 78: 54-59. 2. Correa P, Pickle LW, Fontham E, Lin Y, Haenszel W. Passive smoking and lung cancer Lancet 1983; ii: 595-97.
DIMITRIOS TRICHOPOULOS
11527 Athens, Greece
way.
685
gallstones were confirmed preoperatively in 109. negative results and there was 1 case of acalculous gangrenous cholecystitis, these cases being diagnosed at laparotomy. Of the 109 cases of gallstones confirmed preoperatively, 93 were diagnosed by ultrasound alone, 12 cases had ultrasound scans suggestive of stones but cholecystography was required for confirmation, and in 4 cases ultrasound was unhelpful, requiring cholecystography for a definite diagnosis. Thus ultrasound was 96’3% (105/109) accurate in the diagnosis of gallstones. In 17 cases with preoperative confirmation of gallstones in the gallbladder, the common bileduct was explored. 6 cases had stones in the duct and these had been detected preoperatively by ultrasound; in 2 cases stones were seen in the duct by cholecystography but not by ultrasound; in 7 cases ultrasound failed Of the 112
2
cases
cases
gave false
demonstrate either a stone or dilated ducts, but a stone was confirmed at operation; and in 2 cases ultrasound showed no stone in the duct but the duct was explored because of dilatation, and no stones were found. The above results give a 35% (6/17) accuracy for ultrasound in the diagnosis of stones in the common bileduct. In addition, there were 4 false-positive cases, in which ultrasound suggested the presence of a stone in the common bileduct, but no stones were found. These figures support the use of ultrasound as the primary investigation in gallbladder disease, but highlight the difficulty of diagnosing stones in the common bileduct. M. J. HERSHMAN Ashford Hospital, Ashford, Middlesex K. M. CAMPION to
PLASMA &bgr;2-MICROGLOBULIN LEVELS IN BONE MARROW TRANSPLANT PATIENTS WITH CYTOMEGALOVIRUS INFECTION
SiR,-Cytomegalovirus (CMV) infection, particularly interstitial pneumonitis, is an important cause of death in bone marrow transplant (BMT) recipients.’ There is no effective treatment for established CMV infection, and.the mortality from biopsy-proven CMV pneumonia remains above 85%.2 The success of acyclovir in treating other herpesvirus diseases3leads to the hope that newer agents may be of value in CMV infection, and early diagnosis may well be important for any effective treatment. For this reason, we wish to draw attention to our observations of plasma (32-microglobulin (2) allogeneic BMT recipients. In two patients with CMV pneumonitis plasma (32M levels rose sharply before clinical evidence of disease (figure). Neither patient had renal glomerular dysfunction during the period illustrated (serum creatinine <120 pmol/1). The upper panel relates to a 28-year-old woman with acute myeloid leukaemia in first remission. Intravenous acyclovir was given from day 0 to day 21 as prophylaxis against herpes simplex virus (HSV) reactivation. Engraftment was successful and early bacterial infection and mild acute graft-versushost disease (GVHD) of the skin responded to standard treatment. An episode of buccal HSV infection on day 29 responded to intravenous acyclovir. Fever, dyspnoea, and jaundice developed from day 47 and CMV pneumonitis was confirmed by open biopsy on day 55. Renal failure developed in the terminal stages of her illness (132M levels not shown) and she died on day 66. Plasma fl2M had risen progressively from day 25. The second case (middle panel) was a 30-year-old man with T-cell acute lymphoblastic leukaemia in first remission. Engraftment was again successful and he survived early problems with bacterial infection and acute GVHD of skin. Progressive dyspnoea began on day 42 and CMV pneumonitis was proven by open biopsy on day 48. He died in respiratory failure on day 53 despite acyclovir and ventilation. Plasma (32M increased progressively from day 20. Both patients had antibodies to CMV before BMT and, since only CMV-negative blood products were used, their infection was presumably due to reactivation of latent virus. Both patients had marked lymphopenia throughout the period of j32M levels. 1. O’Reilly RJ. Allogeneic
bone marrow transplantation. current status and future directions. Blood 1983; 62: 941-64. 2. Meyers JD, Atkinson K. Infection in bone marrow transplantation. Clin Haematol
1983; 12: 791-811.
(32M levels after BMT in two patients with cytomegalovirus pneumonitis and in one uninfected patient.
Plasma
NR= normal range.
This marked rise in plasma 02M in BMT patients has, in our been confined to those with CMV infection. We have monitored nine other patients and seen no increase in response to bacterial infection (eight episodes), generalised aspergillosis (one episode), or acute GVHD (twelve episodes). The lower panel shows, for comparison, a patient grafted for acute lymphoblastic leukaemia who had an uneventful course. (32M forms the light chain of HLA A, B, and C antigens, and plasma levels are derived from cell surface membrane shedding.4 Stimulation of lymphoid cells increases 02M production and release and there is evidence that T-lymphocytes are more potent 92M producers than B-lymphocytes.5 Type-1 (leucocyte) interferon increases /32M expression by lymphocytes6 and, in this respect, it is interesting that murine CMV induces production of type-1 interferon in the mouse model.Human CMV causes the emergence of a specific subset of suppressor T-lymphocytes which has been implicated in the characteristic depression of cellular immune functionRaised levels of plasma (32M in infectious mononucleosis, another herpesvirus infection, have- also been linked to T-cell activation.9 Our preliminary evidence shows that monitoring of plasma (32M levels may provide early evidence of CMV infection in BMT
experience,
3. Saral
R, Burns WH, Laskin OL, et al. Acyclovir prophylaxis of herpes-simplex-virus infections; a randomised, double-blind, controlled trial in bone-marrow transplant recipients. N Engl J Med 1981; 305: 63-67. 4. Cresswell P, Springer T, Strominger JL, et al. Immunological identity of the small subunit of HLA-antigens and beta-2-microglobulin and its turnover on the cell membrane. Proc Natl Acad Sci USA 1974; 71: 2123-27. 5. Kin K, Kasahara T, Itoh Y, et al. Beta-2-microglobulin production by highly purified human T and B lymphocytes in cell cultures stimulated with various mitogens. Immunol 1979, 36: 47-54. 6. Fellous M, Kamoun M, Gresser I, Bono R. Enhanced expression of HLA antigens and beta -microglobulin on interferon treated human lymphoid cells. Eur J Immunol 1979; 9: 446-49. 7. Grundy (Chalmer) JE, Trapman J, Allan JE, et al. Evidence for a protective role of interferon
resistance to murine cytomegalovirus and its control by non-H-2Infect Immun 1982; 37: 143-50. 8. Rinaldo CR Jr, Ho M, Hamouidi WH, et al. Lymphocyte subsets and natural killer cell responses during cytomegalovirus mononucleosis. Infect Immun 1983; 40: 472-77. 9. Lamelin J-P, Vincent C, Fontaine-Legrand C, Revillard J-P. Elevation of serum B2microglobulin during infectious mononucleosis. Clin Immunol Immunopathol 1982; in
linked genes.
24: 55-62
University of Heidelberg, D-6800 Mannheim, West Germany
counts of L pneumophila previously exposed to ugin-d erythromycin in broth for 6 h (0 0), 24 h (*———————*),and48h(W————*). Colonies on legionella blood agar were counted daily and increasing viable counts indicate organism recovery, provided incubation was prolonged.
Fig
2-Viable
10
The fact that erythromycin accumulates in macrophages points to erythromycin as the drug of choice in the treatment oflegionellosis; however, it probably acts by bacteriostatic rather than bactericidal activity, allowing the cell-mediated immune system time to eradicate the bacterium.
FERDINAND SCHMIDT
SIR,-Dr Heller notes that our crude relative risk estimates for lung cancer among passive smokers (Sept 17, p 677) do not correspond to the crude odds ratios. He is right, and we apologise for our typing error (which was pointed out by others including Dr Gosta Axelson of Goteborg, Sweden). On the other hand, all our statements in the letter-including results of statistical testing-are correct and the adjusted relative risk figures are higher than the crude ones (although the adjusted Mantel-extensionx2 statistic is similar to the crude Xfor the trend statistic, there being insufficient cross-matching in the detailed age strata). Our newer data do add independent (although non-significant) weight to the evidence implicating passive smoking as a factor in lung cancer, and so does the smoothness of the overall trend and the accumulating evidence. Laboratory of Hygiene and Epidemiology, Medical
Department of Microbiology and PHLS Laboratory, Queen’s Medical Centre, Nottingham NG7 2UH
School, University of Athens,
FRANK G. RODGERS TOM S. J. ELLIOTT
PASSIVE SMOKING AND LUNG CANCER
_
SlR,—Dr Heller (Dec 3, p 1309) dismisses our paperl with a sweep of the hand ("... contains only tentative conclusions based on poor data analysed by unacceptable methods"). Our original aim was not to examine the connection between passive smoking and lung cancer. In 792 lung-cancer patients of both sexes we found that 97’ 3% of the men were smokers while 39 (66%) of the 59 female patients with bronchial carcinoma were non-smokers. Because we could not ’find any indication of hereditary factors or special professional risks-more than 47% of our female lung-cancer patients were housewives, the rest were in unskilled work or office workers-we turned our attention towards the smoking habits of their husbands and other people in the home. We found that 61 -5% had lived with smokers. This is nearly three times the frequency expected on the basis of figures on the smoking habits of men in the age-group concerned, from a "microcensus" in more than two million people conducted by the Federal Office of Statistics. We felt that passive smoking was the most likely explanation for the increased percentage of non-smokers in our female lung cancer patients. This interpretation is supported by the proportion of squamous cell and oat cell cancers which, at 67%, was not significantly lower than the proportion in our smoking female patients with bronchial carcinoma (80%). Does Heller have a more convincing explanation of our findings? We will discuss it with pleasure. Heller does not mention the arguments, set out in our paper, which in sum, leave no doubt about the damaging effect of passive 2 smoking on health. Nor does he refer to Correa et al’s paper,2 the customs of the of 1338 relatives comparing smoking patients with bronchial carcinoma with those of 1393 controls. For female non-smokers with heavy-smoking husbands they calculated a and there was an 3’5-fold risk for bronchial carcinoma (p<0’05),
CHOLECYSTOGRAPHY OR ULTRASOUND?
SIR,—Dr Sowerbutts (March 10, p 566) suggests that the only of cholecystography in the investigation of symptoms which suggest gallbladder disease is to pick up a calculous
advantage
adenomyomatosis. Surely it is important to establish whether gallstones, if present, are likely to be causing the type of symptom of which the patient complains-and, with this in mind, demonstration of whether the gallbladder is functioning or not must be important. Countless numbers of patients have their gallbladders removed because of the finding of gallstones, and yet in the long run they do not
benefit: their symptoms, due
to
irritable gut
or
other
causes,
persist after a short period of relief which may be attributed to the placebo effect of the operation. Exactly the same considerations must apply to the protracted and tedious treatment necessary to ensure the dissolution of gallstones, which may in the first instance not have been responsible for the patient’s symptoms. Vast numbers of patients with functioning gallbladders containing stones have no symptoms whatsoever. It must surely be foolish to attribute vague right subcostal symptoms to gallstones in a functioning gallbladder without a thorough assessment, and I would have thought that most clinicians would accept that an obstructed gallbladder was more likely to produce symptoms on the whole than an unobstructed gallbladder containing stones, unless of course in the latter case clearly definable biliary colic was occurring. 149 Harley Street, LondonWIN2DH
JOHN SQUIRE KIRKHAM
SIR,-In the light of Dr de Lacey and colleagues’ paper (Jan 28, p 205) on the primary investigation in gallbladder disease, we would like to report a retrospective study of 117 cases of cholecystectomy done in the fourteen months October, 1982, to January, 1983. Three years ago, at Ashford Hospital, ultrasound was adopted in to cholecystography, as the primary method of investigation in gallbladder disease. All but 5 (emergency laparotomies) of the 117 cases reported, were investigated in this
preference 1. Knoth A, Bohn H, Schmidt F. Passivrauchen als Lungenkrebssursache bei Nichtraucherinnen. Med Klin Prax 1983; 78: 54-59. 2. Correa P, Pickle LW, Fontham E, Lin Y, Haenszel W. Passive smoking and lung cancer Lancet 1983; ii: 595-97.
DIMITRIOS TRICHOPOULOS
11527 Athens, Greece
way.
685
gallstones were confirmed preoperatively in 109. negative results and there was 1 case of acalculous gangrenous cholecystitis, these cases being diagnosed at laparotomy. Of the 109 cases of gallstones confirmed preoperatively, 93 were diagnosed by ultrasound alone, 12 cases had ultrasound scans suggestive of stones but cholecystography was required for confirmation, and in 4 cases ultrasound was unhelpful, requiring cholecystography for a definite diagnosis. Thus ultrasound was 96’3% (105/109) accurate in the diagnosis of gallstones. In 17 cases with preoperative confirmation of gallstones in the gallbladder, the common bileduct was explored. 6 cases had stones in the duct and these had been detected preoperatively by ultrasound; in 2 cases stones were seen in the duct by cholecystography but not by ultrasound; in 7 cases ultrasound failed Of the 112
2
cases
cases
gave false
demonstrate either a stone or dilated ducts, but a stone was confirmed at operation; and in 2 cases ultrasound showed no stone in the duct but the duct was explored because of dilatation, and no stones were found. The above results give a 35% (6/17) accuracy for ultrasound in the diagnosis of stones in the common bileduct. In addition, there were 4 false-positive cases, in which ultrasound suggested the presence of a stone in the common bileduct, but no stones were found. These figures support the use of ultrasound as the primary investigation in gallbladder disease, but highlight the difficulty of diagnosing stones in the common bileduct. M. J. HERSHMAN Ashford Hospital, Ashford, Middlesex K. M. CAMPION to
PLASMA &bgr;2-MICROGLOBULIN LEVELS IN BONE MARROW TRANSPLANT PATIENTS WITH CYTOMEGALOVIRUS INFECTION
SiR,-Cytomegalovirus (CMV) infection, particularly interstitial pneumonitis, is an important cause of death in bone marrow transplant (BMT) recipients.’ There is no effective treatment for established CMV infection, and.the mortality from biopsy-proven CMV pneumonia remains above 85%.2 The success of acyclovir in treating other herpesvirus diseases3leads to the hope that newer agents may be of value in CMV infection, and early diagnosis may well be important for any effective treatment. For this reason, we wish to draw attention to our observations of plasma (32-microglobulin (2) allogeneic BMT recipients. In two patients with CMV pneumonitis plasma (32M levels rose sharply before clinical evidence of disease (figure). Neither patient had renal glomerular dysfunction during the period illustrated (serum creatinine <120 pmol/1). The upper panel relates to a 28-year-old woman with acute myeloid leukaemia in first remission. Intravenous acyclovir was given from day 0 to day 21 as prophylaxis against herpes simplex virus (HSV) reactivation. Engraftment was successful and early bacterial infection and mild acute graft-versushost disease (GVHD) of the skin responded to standard treatment. An episode of buccal HSV infection on day 29 responded to intravenous acyclovir. Fever, dyspnoea, and jaundice developed from day 47 and CMV pneumonitis was confirmed by open biopsy on day 55. Renal failure developed in the terminal stages of her illness (132M levels not shown) and she died on day 66. Plasma fl2M had risen progressively from day 25. The second case (middle panel) was a 30-year-old man with T-cell acute lymphoblastic leukaemia in first remission. Engraftment was again successful and he survived early problems with bacterial infection and acute GVHD of skin. Progressive dyspnoea began on day 42 and CMV pneumonitis was proven by open biopsy on day 48. He died in respiratory failure on day 53 despite acyclovir and ventilation. Plasma (32M increased progressively from day 20. Both patients had antibodies to CMV before BMT and, since only CMV-negative blood products were used, their infection was presumably due to reactivation of latent virus. Both patients had marked lymphopenia throughout the period of j32M levels. 1. O’Reilly RJ. Allogeneic
bone marrow transplantation. current status and future directions. Blood 1983; 62: 941-64. 2. Meyers JD, Atkinson K. Infection in bone marrow transplantation. Clin Haematol
1983; 12: 791-811.
(32M levels after BMT in two patients with cytomegalovirus pneumonitis and in one uninfected patient.
Plasma
NR= normal range.
This marked rise in plasma 02M in BMT patients has, in our been confined to those with CMV infection. We have monitored nine other patients and seen no increase in response to bacterial infection (eight episodes), generalised aspergillosis (one episode), or acute GVHD (twelve episodes). The lower panel shows, for comparison, a patient grafted for acute lymphoblastic leukaemia who had an uneventful course. (32M forms the light chain of HLA A, B, and C antigens, and plasma levels are derived from cell surface membrane shedding.4 Stimulation of lymphoid cells increases 02M production and release and there is evidence that T-lymphocytes are more potent 92M producers than B-lymphocytes.5 Type-1 (leucocyte) interferon increases /32M expression by lymphocytes6 and, in this respect, it is interesting that murine CMV induces production of type-1 interferon in the mouse model.Human CMV causes the emergence of a specific subset of suppressor T-lymphocytes which has been implicated in the characteristic depression of cellular immune functionRaised levels of plasma (32M in infectious mononucleosis, another herpesvirus infection, have- also been linked to T-cell activation.9 Our preliminary evidence shows that monitoring of plasma (32M levels may provide early evidence of CMV infection in BMT
experience,
3. Saral
R, Burns WH, Laskin OL, et al. Acyclovir prophylaxis of herpes-simplex-virus infections; a randomised, double-blind, controlled trial in bone-marrow transplant recipients. N Engl J Med 1981; 305: 63-67. 4. Cresswell P, Springer T, Strominger JL, et al. Immunological identity of the small subunit of HLA-antigens and beta-2-microglobulin and its turnover on the cell membrane. Proc Natl Acad Sci USA 1974; 71: 2123-27. 5. Kin K, Kasahara T, Itoh Y, et al. Beta-2-microglobulin production by highly purified human T and B lymphocytes in cell cultures stimulated with various mitogens. Immunol 1979, 36: 47-54. 6. Fellous M, Kamoun M, Gresser I, Bono R. Enhanced expression of HLA antigens and beta -microglobulin on interferon treated human lymphoid cells. Eur J Immunol 1979; 9: 446-49. 7. Grundy (Chalmer) JE, Trapman J, Allan JE, et al. Evidence for a protective role of interferon
resistance to murine cytomegalovirus and its control by non-H-2Infect Immun 1982; 37: 143-50. 8. Rinaldo CR Jr, Ho M, Hamouidi WH, et al. Lymphocyte subsets and natural killer cell responses during cytomegalovirus mononucleosis. Infect Immun 1983; 40: 472-77. 9. Lamelin J-P, Vincent C, Fontaine-Legrand C, Revillard J-P. Elevation of serum B2microglobulin during infectious mononucleosis. Clin Immunol Immunopathol 1982; in
linked genes.
24: 55-62