PyelonephritisSymposium This paper was presented at the Paul Ehrlich Society Symposium on Pyelonephritis, held aboard the MS "Illiria" in
the Mediterranean Sea, May 1974. For other papers presented at this symposium please refer to INFECTION Nr. 1 and 2 (1975).
G. G. Jackson
Diagnosis and Importance of Asymptomatic Bacteriuria in Adults Summary: There are now laboratory means of screening and identifying people who, although they are free from the signs of urinary tract infection, fit into abnormal groups owing to the high numbers of bacteria and leukocytes in their urine. Chronic bacteriuria and pathologic pyuria, with or without symptoms, have important physiologic and pathologic consequences. It is the physicians opportunity to recognize and treat these asymptomatic as well as symtomatic urinary tract infections. If untreated and uncorrected, the result, with progressive frequency over a period of 10--15 years, is increased morbidity, especially with pregnancies, structural damage to the kidneys, kidney stones, uremia, hypertension, and premature death.
Zusammenfassung: Diagnose und Bedeutung der asymptomatischen Bakteriurie bei Erwachsenen. Es stehen nunmehr Labormittel zur OberpriJfung und Identifizierung yon Patienten zur Verftigung, die sich, wenngleich frei yon den Symptomen einer Harnwegsinfektion, aufgrund der groBen Zahl yon Bakterien und Leukozyten in ihrem Harn in abnorme Gruppen einpassen. Chronische Bakteriurie und pathologische Pyurie, mit oder ohne Symptome, ziehen bedeutsame physiologische und pathologische Folgen nach sich. Dem Arzt ist die MSglichkeit gegeben, diese asymptomatischen wie auch symptomatischen Harnwegsinfektionen zu erkennen und zu behandetn. Werden sie nicht behandelt und korrigiert, so sind in zunehmender H~iufigkeit tiber einen Zeitraum von 10 bis 15 Jahren die Folgen erhShte Morbidit[it, vor allem bei Schwangerschaften, Schiidigung der Nierenstruktur, Nierensteine, Uriimie und vorzeitiger Tod.
Background
In additional studies, clinicians began to define the findings in the urine associated with chronic urinary tract infection, and differentiate other renal diseases some of which were associated with coincidental renal infection. Also, it became increasingly possible to characterize and differentiate other end stage kidney diseases that the early pathologists had called pyelonephritis. Both primary and secondary pyelonephritis occur in patients having terminal renal insufficiency. The initiation of the practice of quantitative urine cultures was the third historical event of importance. By that procedure, it was possible to distinguish normal and abnormal bacilluria on the basis of statistical frequency of occurrence. When measured in a random mid-stream specimen, one statistically separate population of persons had bacteria in their urine in larger numbers than most normal persons. In a coordinate plot, the results from many laboratories showed the point of separation between the normal and abnormally- infected populations to be at 105, or 100,000 organisms per ml of urine. People whose urine specimens have more organisms than that are said to have "significant bacteriuria". It is
Asymptomatic bacteriuria is a term used to identify people, mostly female, with laboratory evidence of significant infection of the urinary tract, but without the symptoms of pyelonephritis. Although symptomatic, pyelonephritis is familiar to physicians and patients, the importance of asymptomatic bacteriuria is less well known. Of medical interest, are those persons with too few symptoms or symptoms of too little severity to recommend hospital admission, or, in many cases, to motivate them to seek any medical care. Periodically, members of this group may develop bouts of symptomatic acute, or chronic pyelonephritis. More regularly, they will be seen in the clinic or office for minor complaints related to the urinary tract. Three historical events pertaining to the development of our knowledge about pyelonephritis are noteworthy. First, the occurence of asymptomatic pyelonephritis was learned from routine autopsies. In the period around 1925--35, reports from pathologists drew attention to the fact that most patients who at autopsy were discovered to have end-stage kidney disease characteristic of pyelonephritis had no appreciable history of severe or episodic acute urinary tract infections. Subsequently, it was confirmed from clinical investigations that histologic pyelonephritis and symptomatic pyelonephritis do not have a good correlation. Thus, from both pathological and clinical points of view, we began to gain an awareness of the importance of asymptomatic urinary tract infection.
Prof. G. G. Jackson, Section of Infections Diseases, Abraham Lincoln School of Medicine, University of Illinois, P. O. Box 6998, Chicago, Ill. 60680, USA. This study was supported in part by a research grant, AI 09 149, from the United States Public Health Service, National Institute of Allergy and Infectious Dieseases, Department of HEW, Bethesda, Maryland, USA.
Infection 3 (1975) Nr. 3
175
G. G. Jackson: Diagnosis and Importance of Asymptomatic Bacteriuria in Adults
on that basis that we have begun to observe persons with asymptomatic but significant bacilluria to see if they are the source of the patients who, at autopsy, have pyetonephritis without a history of antecedent urinary tract infection.
Pathophysiology As further measures of the importance of significant bacteriuria are its association with demonstrable alterations of renal function, structure, and clinical diseases. The functional changes involve both the glomerular and tubular components. Proof that the bacilluria is the cause of the impairment is provided by showing that its eradication results in a disappearance of the abnormal kidney function. Chronic bacilluria can lead to papillary necrosis, contribute to the formation of kidney stones, and cause scarring of the renal pelvis which is manifest in the pyelogram as blunting of the renal calyces. In pregnancyasymptomatic bacteriuria has potentially ill effects on both the mother and fetus. F o r the mother, its presence is associated with an increased frequency of perinatal acute pyelonephritis and suppurative complications in the puerperium. F o r the fetus, its presence is associated with premature delivery and excess neonatal mortality. The ultimate adverse end point of chronic bacteriuria is renal insufficiency. The diminished excretory function has the primary effect of increasing the retention of nitrogeneous substances, but it also influences blood pressure and hematopoiesis through the mechanism of a deficiency of endocrine substances produced in the kidney that cause vasodepressor responses and hematopoiesis.
Recognition of BaciUuria The various functional and clinical reasons are an adequate basis for considering asymptomatic bacteriuria to be of importance. On that premise, the problem for physicians is to detect and treat asymptomatic bacteriuria before the clinical and pathological manifestations are expressed. In a screening program in our hospital during one year in which approximately 100,000 patients visited the hospital, significant bacilluria was found in five per cent of them. F o r at least one-third, the infection was persistent for a period of two years or more. Among the patients, it can be observed that there are certain conditions in which asymptomatic bacteriuria is more likely to occur. Although the frequency of infection may not be the same in ever3' clinic, the general trend is the same. A disproportionately high frequency of bacteriuria is found among pregnant women, patients with hypertension, diabetes, women with cystocoele or rectocoele, and in association with congenital or acquired abnormalities of the urinary tract, or kidney stones. A suspicion about the presence of significant asymptomatic bacteriuria can be obtained by the patients clinical history and confirmed by laboratory examination of the
176
Infection 3 (1975) Nr. 3
urine. In screening all patients coming to the hospital, it was found that if a physician asked four questions, he could identify eighty per cent of the people who were found to have significant bacteriuria upon culture. The questions were: 1) H a d instrumentation of the urinary tract ever been performed previously; 2) H a d treatment ever been given for urinary tract infection; 3) Did the person have known diabetes or hypertension; and 4) If female, was she pregnant. The procedure for presumptive validation of the presence of significant bacteriuria is a stained smear of the urine sediment. If any organisms are seen in the stained sediment from an uncentrifuged urine specimen, the number per ml determined by culture will nearly always be 100,000 or more. Similarly, if large numbers of bacteria are seen in the sediment spun from several ml of urine, it also is significant. Quantitative urine culture and identification of the bacterial species are the final validation of significant bacteriuria. If one examines a single initial screening culture and it shows no bacteriuria, subsequent cultures over a period of six months were observed to give the same result in 9 5 - - 9 9 % of the patients. If intermediate bacteriuria or significant bacteriuria was found, repeated cultures during the next six months showed the result to be valid at least 85 % of the time.
Pathologic Pyuria One of the great contributions of Paul Ehrlich to the science of medicine was the differentiation of leukocyte types. The excretion of leukocytes in the urine is an important manifestation of inflammatory disease in patients with chronic bacteriuria, and some investigators have differentiated urinary leukocytes morphologically. When the urine sediment is stained with a supravital stain, one or more of four types of polymorphonuclear cells can be seen. The four types relate to pale or dark staining characteristics and to the size of the cell. In low specific gravity, the cells tend to be swollen, and with supravital stains, fresh viable cells are not stained or are pale. The so-called "glitter" cell is a large, pale staining cell in which the granules in the cytoplasm show Brownian motion. If a patient has renal insufficiency, or the urine is dilute, the granules in the cytoplasm will be active and the cell will appear to glitter. If the patient does not have renal insufficiency and the urine has a high specific gravity, that same cell will be pale staining, but will not have active cytoplasmic granules. The motion of the granules can also be altered by the potassium concentration in the urine. The important feature of the kind of leukocyte in the urine is the pale staining characteristic. This is an indication of its viability and thus recent exit from the blood stream, and, when present, is a sign of acute inflammation. The quality of pyuria can thus be of some diagnostic importance. The number of white cells in the urine is a more important corollary of bacteriuria. If a coordinate plot is made of urine specimens according to the per cent of
G. G. Jackson: Diagnosis and Importance of Asymptomatic Bacterit~ia in Adults specimens having specific numbers of leukocytes per ml of urine, the curve is strikingly bimodal. Thus, as with bacilluria, it is possible to identify a statistical population of people with significant pyuria. T h e upper limit of n o r m a l is 104.~ or 25,000 white cells per m l of urine. B e y o n d that n u m b e r is excressive and can be considered to be pathologic pyuria.
The Natural Course of Disease Answers to the question about the need for t r e a t m e n t of asymptomatic bacteriuria depends u p o n our knowledge
of the course of patients with chronic persistent pyuria and bacteriuria. A m o n g a group of patients we followed f o r 15 years, the adverse consequences of chronic bacteriuria were clearly shown. A l t h o u g h forty per cent of the patients had an a b n o r m a l p y e l o g r a m f r o m previous episodes of infection b e f o r e entry into the sudy, almost all of t h e m developed or increased the abnormalities during the next ten years. A f t e r ten years, the f r e q u e n c y of renal insufficiency, stones, hypertension, and death were all appreciably increased by persistent bacteriuria. D e a t h had o c c u r r e d in six per cent, or at a p p r o x i m a t e l y twice the expected rate.
Impressum Herausgeber: Walter Marget (Editor-in-chief), Miinchen . Rudolf Ackermann, K61n. Meta Alexander, Berlin - Ernst Holzer, Mtinchen . Werner Lang, Mtinchen . Gerhard Mtissner, Wiesbaden • Helmut Stickl, Mtinchen.
Beiriite: G. Beck, Miinchen • L. Binder, Budapest • L Bee, Bergen (Norwegen) - W. Brumfitt, London • G. R. Burgio, Pavia - J. Drews, Wien • M. Duniewicz, Prag - D. Frommel, Le Kremlin-Bic~tre • R. van Furth, Leiden • E. Haefliger, Wald (Schweiz) . M. von Hattingberg, GieBen • H. Hirsch, Basel. F. O. H6ring, Berlin. H. Huber, Innsbruck. M. Just, Basel . B. Kassur, Warschau- W. Knapp, Erlangen • H. Knothe, Frankfurt/M. • G. Linzenmeier, Essen • Th. Luthardt, Freiburg • G. Marinescu, Bukarest • P. Mollaret, Paris • H. von Otdershausen, Tiibingen • H. Pohle, Berlin • C. Regamey, G e n f . R. A. Shooter, London • W. Siegenthaler, Ztirich • R. Skalova, Zagreb • O. Thalhammer, Wien • D. Tyrell, Harrow • O. Vivell, Karlsruhe • T. Wegmann, St. Gallen • I. Winberg, Ume~t • E. Yourassowsky, Briissel.
Schriftleitung/Managing Editors: Prof. Dr. med. Walter Marget und Prof. Dr. reed. Werner Lang. Sekretariat/Editorial Secretary: Miss Daryl Eider, Universit~its-Kinderklinik, LindwurmstraBe 4, D-8000 Miinchen 2, Telefon 0 89/53 47 33. Die Zeitschrift I N F E C T I O N erscheint vorerst jiihrlich mit einem Band (4 Hefte) in der Vertagsgesellschaft Otto Spatz OHG, 8 Mfinchen 2, Posffach 20 23 40, Blumenstr. 48, Telefon: (0 89) 2 60 40 88. Verantwortlich fiir den InhaIt: Professor Dr. med. Walter Marget und Professor Dr. med. Werner Lang, beide Miinchen.
Inhaber und Beteiligungsverhiiltnisse: Pers/Snlich haftender Gesellschafter Dr. Ulrich Wechsler und Bertelsmann-Thomson Fachverlag GmbH.
Anzeigenverwaltung: Deutscher )~rzte-Verlag GmbH, 5023 L f venich, Posffach 1440, Dieselstr. 2, Tel. (0 22 34) 70 11--2 17, Telex: 889 168. Z. Z. gilt Anzeigenpreisliste Nr. 3a. Anzeigenschlug: 4 Wochen vor Erscheinen. Anzeigenleiter: Eugen Volkert. Verantwortlich ftir den Anzeigenteil: Olaf Borchert.
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Infection 3 (1975) Nr. 3
177
the Mediterranean Sea, May 1974. For other papers presented at this symposium please refer to INFECTION Nr. 1 and 2 (1975).
G. G. Jackson
Diagnosis and Importance of Asymptomatic Bacteriuria in Adults Summary: There are now laboratory means of screening and identifying people who, although they are free from the signs of urinary tract infection, fit into abnormal groups owing to the high numbers of bacteria and leukocytes in their urine. Chronic bacteriuria and pathologic pyuria, with or without symptoms, have important physiologic and pathologic consequences. It is the physicians opportunity to recognize and treat these asymptomatic as well as symtomatic urinary tract infections. If untreated and uncorrected, the result, with progressive frequency over a period of 10--15 years, is increased morbidity, especially with pregnancies, structural damage to the kidneys, kidney stones, uremia, hypertension, and premature death.
Zusammenfassung: Diagnose und Bedeutung der asymptomatischen Bakteriurie bei Erwachsenen. Es stehen nunmehr Labormittel zur OberpriJfung und Identifizierung yon Patienten zur Verftigung, die sich, wenngleich frei yon den Symptomen einer Harnwegsinfektion, aufgrund der groBen Zahl yon Bakterien und Leukozyten in ihrem Harn in abnorme Gruppen einpassen. Chronische Bakteriurie und pathologische Pyurie, mit oder ohne Symptome, ziehen bedeutsame physiologische und pathologische Folgen nach sich. Dem Arzt ist die MSglichkeit gegeben, diese asymptomatischen wie auch symptomatischen Harnwegsinfektionen zu erkennen und zu behandetn. Werden sie nicht behandelt und korrigiert, so sind in zunehmender H~iufigkeit tiber einen Zeitraum von 10 bis 15 Jahren die Folgen erhShte Morbidit[it, vor allem bei Schwangerschaften, Schiidigung der Nierenstruktur, Nierensteine, Uriimie und vorzeitiger Tod.
Background
In additional studies, clinicians began to define the findings in the urine associated with chronic urinary tract infection, and differentiate other renal diseases some of which were associated with coincidental renal infection. Also, it became increasingly possible to characterize and differentiate other end stage kidney diseases that the early pathologists had called pyelonephritis. Both primary and secondary pyelonephritis occur in patients having terminal renal insufficiency. The initiation of the practice of quantitative urine cultures was the third historical event of importance. By that procedure, it was possible to distinguish normal and abnormal bacilluria on the basis of statistical frequency of occurrence. When measured in a random mid-stream specimen, one statistically separate population of persons had bacteria in their urine in larger numbers than most normal persons. In a coordinate plot, the results from many laboratories showed the point of separation between the normal and abnormally- infected populations to be at 105, or 100,000 organisms per ml of urine. People whose urine specimens have more organisms than that are said to have "significant bacteriuria". It is
Asymptomatic bacteriuria is a term used to identify people, mostly female, with laboratory evidence of significant infection of the urinary tract, but without the symptoms of pyelonephritis. Although symptomatic, pyelonephritis is familiar to physicians and patients, the importance of asymptomatic bacteriuria is less well known. Of medical interest, are those persons with too few symptoms or symptoms of too little severity to recommend hospital admission, or, in many cases, to motivate them to seek any medical care. Periodically, members of this group may develop bouts of symptomatic acute, or chronic pyelonephritis. More regularly, they will be seen in the clinic or office for minor complaints related to the urinary tract. Three historical events pertaining to the development of our knowledge about pyelonephritis are noteworthy. First, the occurence of asymptomatic pyelonephritis was learned from routine autopsies. In the period around 1925--35, reports from pathologists drew attention to the fact that most patients who at autopsy were discovered to have end-stage kidney disease characteristic of pyelonephritis had no appreciable history of severe or episodic acute urinary tract infections. Subsequently, it was confirmed from clinical investigations that histologic pyelonephritis and symptomatic pyelonephritis do not have a good correlation. Thus, from both pathological and clinical points of view, we began to gain an awareness of the importance of asymptomatic urinary tract infection.
Prof. G. G. Jackson, Section of Infections Diseases, Abraham Lincoln School of Medicine, University of Illinois, P. O. Box 6998, Chicago, Ill. 60680, USA. This study was supported in part by a research grant, AI 09 149, from the United States Public Health Service, National Institute of Allergy and Infectious Dieseases, Department of HEW, Bethesda, Maryland, USA.
Infection 3 (1975) Nr. 3
175
G. G. Jackson: Diagnosis and Importance of Asymptomatic Bacteriuria in Adults
on that basis that we have begun to observe persons with asymptomatic but significant bacilluria to see if they are the source of the patients who, at autopsy, have pyetonephritis without a history of antecedent urinary tract infection.
Pathophysiology As further measures of the importance of significant bacteriuria are its association with demonstrable alterations of renal function, structure, and clinical diseases. The functional changes involve both the glomerular and tubular components. Proof that the bacilluria is the cause of the impairment is provided by showing that its eradication results in a disappearance of the abnormal kidney function. Chronic bacilluria can lead to papillary necrosis, contribute to the formation of kidney stones, and cause scarring of the renal pelvis which is manifest in the pyelogram as blunting of the renal calyces. In pregnancyasymptomatic bacteriuria has potentially ill effects on both the mother and fetus. F o r the mother, its presence is associated with an increased frequency of perinatal acute pyelonephritis and suppurative complications in the puerperium. F o r the fetus, its presence is associated with premature delivery and excess neonatal mortality. The ultimate adverse end point of chronic bacteriuria is renal insufficiency. The diminished excretory function has the primary effect of increasing the retention of nitrogeneous substances, but it also influences blood pressure and hematopoiesis through the mechanism of a deficiency of endocrine substances produced in the kidney that cause vasodepressor responses and hematopoiesis.
Recognition of BaciUuria The various functional and clinical reasons are an adequate basis for considering asymptomatic bacteriuria to be of importance. On that premise, the problem for physicians is to detect and treat asymptomatic bacteriuria before the clinical and pathological manifestations are expressed. In a screening program in our hospital during one year in which approximately 100,000 patients visited the hospital, significant bacilluria was found in five per cent of them. F o r at least one-third, the infection was persistent for a period of two years or more. Among the patients, it can be observed that there are certain conditions in which asymptomatic bacteriuria is more likely to occur. Although the frequency of infection may not be the same in ever3' clinic, the general trend is the same. A disproportionately high frequency of bacteriuria is found among pregnant women, patients with hypertension, diabetes, women with cystocoele or rectocoele, and in association with congenital or acquired abnormalities of the urinary tract, or kidney stones. A suspicion about the presence of significant asymptomatic bacteriuria can be obtained by the patients clinical history and confirmed by laboratory examination of the
176
Infection 3 (1975) Nr. 3
urine. In screening all patients coming to the hospital, it was found that if a physician asked four questions, he could identify eighty per cent of the people who were found to have significant bacteriuria upon culture. The questions were: 1) H a d instrumentation of the urinary tract ever been performed previously; 2) H a d treatment ever been given for urinary tract infection; 3) Did the person have known diabetes or hypertension; and 4) If female, was she pregnant. The procedure for presumptive validation of the presence of significant bacteriuria is a stained smear of the urine sediment. If any organisms are seen in the stained sediment from an uncentrifuged urine specimen, the number per ml determined by culture will nearly always be 100,000 or more. Similarly, if large numbers of bacteria are seen in the sediment spun from several ml of urine, it also is significant. Quantitative urine culture and identification of the bacterial species are the final validation of significant bacteriuria. If one examines a single initial screening culture and it shows no bacteriuria, subsequent cultures over a period of six months were observed to give the same result in 9 5 - - 9 9 % of the patients. If intermediate bacteriuria or significant bacteriuria was found, repeated cultures during the next six months showed the result to be valid at least 85 % of the time.
Pathologic Pyuria One of the great contributions of Paul Ehrlich to the science of medicine was the differentiation of leukocyte types. The excretion of leukocytes in the urine is an important manifestation of inflammatory disease in patients with chronic bacteriuria, and some investigators have differentiated urinary leukocytes morphologically. When the urine sediment is stained with a supravital stain, one or more of four types of polymorphonuclear cells can be seen. The four types relate to pale or dark staining characteristics and to the size of the cell. In low specific gravity, the cells tend to be swollen, and with supravital stains, fresh viable cells are not stained or are pale. The so-called "glitter" cell is a large, pale staining cell in which the granules in the cytoplasm show Brownian motion. If a patient has renal insufficiency, or the urine is dilute, the granules in the cytoplasm will be active and the cell will appear to glitter. If the patient does not have renal insufficiency and the urine has a high specific gravity, that same cell will be pale staining, but will not have active cytoplasmic granules. The motion of the granules can also be altered by the potassium concentration in the urine. The important feature of the kind of leukocyte in the urine is the pale staining characteristic. This is an indication of its viability and thus recent exit from the blood stream, and, when present, is a sign of acute inflammation. The quality of pyuria can thus be of some diagnostic importance. The number of white cells in the urine is a more important corollary of bacteriuria. If a coordinate plot is made of urine specimens according to the per cent of
G. G. Jackson: Diagnosis and Importance of Asymptomatic Bacterit~ia in Adults specimens having specific numbers of leukocytes per ml of urine, the curve is strikingly bimodal. Thus, as with bacilluria, it is possible to identify a statistical population of people with significant pyuria. T h e upper limit of n o r m a l is 104.~ or 25,000 white cells per m l of urine. B e y o n d that n u m b e r is excressive and can be considered to be pathologic pyuria.
The Natural Course of Disease Answers to the question about the need for t r e a t m e n t of asymptomatic bacteriuria depends u p o n our knowledge
of the course of patients with chronic persistent pyuria and bacteriuria. A m o n g a group of patients we followed f o r 15 years, the adverse consequences of chronic bacteriuria were clearly shown. A l t h o u g h forty per cent of the patients had an a b n o r m a l p y e l o g r a m f r o m previous episodes of infection b e f o r e entry into the sudy, almost all of t h e m developed or increased the abnormalities during the next ten years. A f t e r ten years, the f r e q u e n c y of renal insufficiency, stones, hypertension, and death were all appreciably increased by persistent bacteriuria. D e a t h had o c c u r r e d in six per cent, or at a p p r o x i m a t e l y twice the expected rate.
Impressum Herausgeber: Walter Marget (Editor-in-chief), Miinchen . Rudolf Ackermann, K61n. Meta Alexander, Berlin - Ernst Holzer, Mtinchen . Werner Lang, Mtinchen . Gerhard Mtissner, Wiesbaden • Helmut Stickl, Mtinchen.
Beiriite: G. Beck, Miinchen • L. Binder, Budapest • L Bee, Bergen (Norwegen) - W. Brumfitt, London • G. R. Burgio, Pavia - J. Drews, Wien • M. Duniewicz, Prag - D. Frommel, Le Kremlin-Bic~tre • R. van Furth, Leiden • E. Haefliger, Wald (Schweiz) . M. von Hattingberg, GieBen • H. Hirsch, Basel. F. O. H6ring, Berlin. H. Huber, Innsbruck. M. Just, Basel . B. Kassur, Warschau- W. Knapp, Erlangen • H. Knothe, Frankfurt/M. • G. Linzenmeier, Essen • Th. Luthardt, Freiburg • G. Marinescu, Bukarest • P. Mollaret, Paris • H. von Otdershausen, Tiibingen • H. Pohle, Berlin • C. Regamey, G e n f . R. A. Shooter, London • W. Siegenthaler, Ztirich • R. Skalova, Zagreb • O. Thalhammer, Wien • D. Tyrell, Harrow • O. Vivell, Karlsruhe • T. Wegmann, St. Gallen • I. Winberg, Ume~t • E. Yourassowsky, Briissel.
Schriftleitung/Managing Editors: Prof. Dr. med. Walter Marget und Prof. Dr. reed. Werner Lang. Sekretariat/Editorial Secretary: Miss Daryl Eider, Universit~its-Kinderklinik, LindwurmstraBe 4, D-8000 Miinchen 2, Telefon 0 89/53 47 33. Die Zeitschrift I N F E C T I O N erscheint vorerst jiihrlich mit einem Band (4 Hefte) in der Vertagsgesellschaft Otto Spatz OHG, 8 Mfinchen 2, Posffach 20 23 40, Blumenstr. 48, Telefon: (0 89) 2 60 40 88. Verantwortlich fiir den InhaIt: Professor Dr. med. Walter Marget und Professor Dr. med. Werner Lang, beide Miinchen.
Inhaber und Beteiligungsverhiiltnisse: Pers/Snlich haftender Gesellschafter Dr. Ulrich Wechsler und Bertelsmann-Thomson Fachverlag GmbH.
Anzeigenverwaltung: Deutscher )~rzte-Verlag GmbH, 5023 L f venich, Posffach 1440, Dieselstr. 2, Tel. (0 22 34) 70 11--2 17, Telex: 889 168. Z. Z. gilt Anzeigenpreisliste Nr. 3a. Anzeigenschlug: 4 Wochen vor Erscheinen. Anzeigenleiter: Eugen Volkert. Verantwortlich ftir den Anzeigenteil: Olaf Borchert.
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