372
Correspondence
Richard P. Wenzel, Vincent T. Andriole, John G. Bartlett, Murray D. Batt, Ward E. Bullock, C. Glen Cobbs, Bruce Light, Michael A. Martin, Jay Sanford, and Merle A. Sande
Oxygen Tensions and Mycobacterial Infections SIR-We read with interest the review by Park et al. [l] on oxygen tensions and infections. We think, however, that the special relationship between Mycobacterium tuberculosis and oxygen deserves to be mentioned in this context. Cavitary tuberculosis [2] and progressive primary tuberculosis [3] have long been noted to occur preferentially at the apex of the lung. Dock [4] originally suggested that the apical localization of'tuberculo.sis is related to the fact that, while a patient is in an upright position, the pulmonary artery's perfusion of desaturated blood is diminished at the lung apex so that the P0 2 in tissue is higher; Dock considered this a rationale for treating patients with tuberculosis with prolonged bed rest. A body of observations about animal experiments (for instance, those quoted in [5]) supports this hypothesis. In 1933 Adams et al. demonstrated that reducing alveolar oxygen through occlusion ofa bronchus resulted in almost complete healing of the lung tissue supplied by this bronchus. Such experimental observations represented the basis for various therapies for lung collapse that were used before the advent of antituberculous chemotherapy. Later, Olson et al. showed that increasing the alveolar oxygen pressure ("arterialization") either by formation of local left-to-right shunts or by pulmonary artery ligation resulted in increased tuberculosis in the arterialized pulmonary segment in monkeys.
Correspondence: Dr. Pascal R. A. Meylan, Departments of Pathology and Medicine, 0679, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0679. Clinical Infectious Diseases 1992;15:372-3 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1502-0023$02.00
Division ofGeneral Medicine, Clinical Epidemiology, and Health Services Research, Department of Internal Medicine. The University of Iowa College of Medicine, Iowa City, Iowa; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut; Division of Infectious Disease, Johns Hopkins Hospital, Baltimore, Maryland; Division of Hospital Epidemiology, Lutheran General Hospital, Park Ridge. lllinois; Division of Infectious Diseases, University of Cincinnati Medical Center, Cincinnati, Ohio; Department of Veterans Affairs Medical Center. Birmingham, Alabama; St. Bonaface Hospital. Winnipeg. Manitoba. Canada; Oregon Health Sciences University, Portland. Oregon; Uniformed Services. University ofthe Health Sciences. Dallas. Texas; and San Francisco General Hospital. San Francisco, California
References I. Wenzel RP, Andriole VT, Bartlett JG, et al. Antiendotoxin monoclonal antibodies for gram-negative sepsis: Guidelines from the IDSA. Clin Infect Dis 1992; 14:973-6. 2. Wenzel RP. Anti-endotoxin monoclonal antibodies-a second look. N Engl J Med 1992;326: 1151-3. 3. Warren HS, Danner RL. Munford RS. Anti-endotoxin monoclonal antibodies. N Engl J Med 1992;326: 1153-7. 4. Wenzel RP, Bone R, Fein A, et al. Results of a second double-blind, randomized. controlled trial of antiendotoxin E5 in gram negative sepsis. In: Program and abstracts of the 31 st Interscience Conference on Antimicrobial Agents and Chemotherapy [extended abstract). Washington. DC: American Society for Microbiology, 1991:294.
Rich and Follis reported in 1942 that housing tuberculous guinea pigs in an atmosphere containing only 10% oxygen diminished the extent oftuberculous lesions; conversely, exposing mice to an atmosphere enriched in oxygen resulted in increased mycobacterial counts in the lung and liver [5]. In addition, Vorwald reported that fetal guinea pigs were relatively resistant to M. tuberculosis infection compared with adults, a refractoriness that disappeared at the time of birth. Perhaps the most suggestive experimental results concerning a relationship between progressive tuberculosis at the apex and increased oxygen availability due to reduced venous blood perfusion at the lung apex were presented by Medlar and Sasano in 1935. By maintaining tuberculous rabbits in a vertical position (I), they shifted development of caseous lesions, typically in the posterior dorsal basal area of the lungs, to the apical region. While this explanation for the preferential apical localization of pulmonary tuberculosis is not uncontested [6], the bulk of the evidence mentioned here does suggest a relationship between P0 2 in tissue and progressive tuberculosis. This relationship between P0 2 in tissue and progressive tuberculosis has been classically explained by the fact that M. tuberculosis is a strict aerobe and that its growth is promoted by increased oxygen availability [5, 7]. However, it appears that the growth of M. tuberculosis is suboptimal only at a P0 2 of well below 40 mm Hg, the venous oxygen pressure that prevails in many tissues [5, 8, 9]. We recently examined the effect of oxygen concentration on the growth not only of free mycobacteria but also of mycobacteria inside human macrophages (9]. The amount of growth of M. tuberculosis and Mycobacterium avium as free organisms was not different when cultured at a P0 2 of 36 mm Hg (a pressure close to the venous P0 2 and to that prevailing in many tissues) compared with growth at the P0 2 regularly used
Downloaded from http://cid.oxfordjournals.org/ at University of Glasgow on June 25, 2015
Chmel and Emmanuel, the critical problem is that efficacyis not demonstrated in the overall group (i.e., all enrolled). We agree that retrospective analysis of subgroups-defined by data that are not available at the time that the monoclonal antibodies are administered-may show differences, to which both tables allude with semantic, but not substantive, differences. Our intent in preparing these guidelines [I], in the event that the U.S. Food and Drug Administration chooses to license one or the other of the monoclonal antibodies for the treatment of gram-negative sepsis, was to help clinicians minimize inappropriate clinical utilization of these expensive agents. It had been estimated that perhaps 10% of patients with sepsis would have improved survival if either monoclonal antibody was used wisely [2]. A recent reexamination of the HA-IA data [3] and preliminary data from the second E-5 study [4], however, has cast doubt on these estimations. We have no argument with Chmel and Emmanuel that a subset of patients with suspected gram-negative sepsis could benefit from these agents. The challenge in clinical practice is to prospectively identify that subset.
CID 1992; 15 (August)
CID 1992; 15 (August)
Correspondence
Pascal R. A. Meylan, Douglas D. Richman, and Richard S. Kornbluth Departments of Pathology and Medicine. University of California San Diego School of Medicine. and San Diego Veterans Affairs Medical Center. San Diego. California
Spotless Boutonneuse Fever SIR-We read with interest the article by Brouqui et al. [1] that reported the first case of spotless boutonneuse fever documented by blood culture. In the last few years, several cases of spotless boutonneuse fever have been reported [2-4], although not all of them were diagnosed by means of specific tests. It has been suggested that the absence of the characteristic rash could be due to early therapy for this disease [5). Recently, there were two patients who did not have a rash in a series of246 patients with Mediterranean spotted fever (MSF). At least in one case, the absence of rash could be attributed to early therapy. The patients, aged 8 and 9 years, presented with high fever, headache, and myalgia that lasted 1 and 4 days, respectively. A tache noire was observed in both cases. In accordance with our standard therapeutic regimen for MSF [6, 7], the patients received two doses of doxycycline. They recovered uneventfully and had no rash at any time. The results of serological tests for Rickettsiaconorii that were performed with use ofmicroimmunofluorescence revealed that both patients had seroconverted. According to our experience, the rash associated with MSF lasts for a variable period, and, when not purpuric, it may last
Correspondence: Dr. Elena Espejo. Department of Internal Medicine. Hospital de Terrassa, Ctra. de Torrebonica sin. 08227 Terrassa, Barcelona. Spain.
Clinical Infectious Diseases 1992;15:373-4 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1502-0024$02.00
References I. Park MK, Myers RAM. Marzella L. Oxygen tensions and infections: modulation of microbial growth. activity of antimicrobial agents. and immunologic responses. Clin Infect Dis 1992;14:720-40. 2. Sweany He. Cook CEo Kegerreis R. A study of the position of primary cavities in pulmonary tuberculosis. Am Rev Respir Dis 1931;24:558. 3. Medlar EM. The pathogenesis of minimal pulmonary tuberculosis. Am Rev Respir Dis 1948;58:583. 4. Dock W. Apical localization of phthisis. Am Rev Respir Dis 1946;53:297. 5. Sever JL. Youmans GP. The relation of oxygen tension to virulence of tubercle bacilli and to acquired resistance in tuberculosis. J Infect Dis 1957;101:193. 6. Des Prez RM. Heim CR. Mycobacterium tuberculosis. In: Mandell GL. Douglas RG Jr. Bennett JE. eds. Principles and practice of infectious diseases. New York: Churchill Livingstone. 1990: 1877-906. 7. Youmans GP. Virulence of mycobacteria. In: Youmans GP. ed. Tuberculosis. Philadelphia: WB Saunders. 1979: 194-200. 8. Heplar JQ. Clifton CEo Raffel S. Futrelle CM. Virulence of the tubercle bacillus. J Infect Dis 1954;94:90. 9. Meylan PRA, Richman DD. Kornbluth RS. Reduced intracellular growth of mycobacteria in human macrophages cultivated at physiologic oxygen pressure. Am Rev Respir Dis 1992; 145:947. 10. Simon LM. Axline SG. Horn BR. Robin ED. Adaptations of energy metabolism in the cultivated macrophage. J Exp Med 1990; 138:1413.
only a few days. Furthermore, when the maculopapules are sparse, patients frequently are not aware of them until admission. Therefore. when a patient with a paucisymptomatic form ofMSF is examined relatively late in the course of the disease, it is possible that an unnoticed rash had been present earlier. We agree with Brouqui et al. that MSF should be considered in the diagnosis for any individual who is in an area in which MSF is endemic during the summer and who develops fever. The patient may have a spotless form or, more probably, be in the pre- or posteruptive phase of MSF in this situation. On the other hand. we want to emphasize that tache noire, a clinical clue for the diagnosis of MSF. is observed in three-quarters of the cases when it is carefully searched for [4, 5].
Elena Espejo, Marta Rodriguez, Abel Martinez, Socorro Uriz, and Feliu Bella Departments of internal Medicine and Pediatrics. Hospital de Terrassa, Terrassa, Barcelona. Spain
References I. Brouqui P. Tissot Dupont HT, Drancourt M. Bourgeade A, Raoult D. Spotless bouton neuse fever. Clin Infect Dis 1992; 14:114-6. 2. Zechini F. Osservazioni epidemiologiche, c1iniche e terapeutiche su 50 casi di rickettsiosi conori. Minerva Med 1977;68:2387-92. 3. Raoult D. Jean-Pastor MJ. Xeridat B. et al. La fievre boutonneuse mediterraneenne. A propos de 154 cas recents. Ann Dermatol Venereol 1983; II 0:909-14.
Downloaded from http://cid.oxfordjournals.org/ at University of Glasgow on June 25, 2015
in incubators, i.e., 140 mm Hg (a pressure only approached by the P02 in tissue at the lung apex). In contrast, the growth of mycobacteria inside infected macrophages was significantly decreased at a P0 2 of 36 mm Hg compared with that at 140 mm Hg. The mechanism of this reduced growth of mycobacteria in macrophages at low oxygen concentration is unknown. On the one hand, it is possible that the intracellular oxygen pressure in macrophages cultured at a low oxygen concentration dropped to a level that affects mycobacteria, a hypothesis already put forth in 1942 by Rich and Follis. On the other hand, there is evidence that the oxygen pressure during culture of macrophages influences their morphological and physiological differentiation [9, 10]. It is thus possible that macrophages at low oxygen pressure had more efficacious antimycobacterial defense mechanisms. Our data suggest that the effect of P0 2 on the growth of mycobacteria inside macrophages rather than on mycobacteria themselves may explain the preferential localization of tuberculous lesions at the lung apex.
373
Correspondence
Richard P. Wenzel, Vincent T. Andriole, John G. Bartlett, Murray D. Batt, Ward E. Bullock, C. Glen Cobbs, Bruce Light, Michael A. Martin, Jay Sanford, and Merle A. Sande
Oxygen Tensions and Mycobacterial Infections SIR-We read with interest the review by Park et al. [l] on oxygen tensions and infections. We think, however, that the special relationship between Mycobacterium tuberculosis and oxygen deserves to be mentioned in this context. Cavitary tuberculosis [2] and progressive primary tuberculosis [3] have long been noted to occur preferentially at the apex of the lung. Dock [4] originally suggested that the apical localization of'tuberculo.sis is related to the fact that, while a patient is in an upright position, the pulmonary artery's perfusion of desaturated blood is diminished at the lung apex so that the P0 2 in tissue is higher; Dock considered this a rationale for treating patients with tuberculosis with prolonged bed rest. A body of observations about animal experiments (for instance, those quoted in [5]) supports this hypothesis. In 1933 Adams et al. demonstrated that reducing alveolar oxygen through occlusion ofa bronchus resulted in almost complete healing of the lung tissue supplied by this bronchus. Such experimental observations represented the basis for various therapies for lung collapse that were used before the advent of antituberculous chemotherapy. Later, Olson et al. showed that increasing the alveolar oxygen pressure ("arterialization") either by formation of local left-to-right shunts or by pulmonary artery ligation resulted in increased tuberculosis in the arterialized pulmonary segment in monkeys.
Correspondence: Dr. Pascal R. A. Meylan, Departments of Pathology and Medicine, 0679, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0679. Clinical Infectious Diseases 1992;15:372-3 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1502-0023$02.00
Division ofGeneral Medicine, Clinical Epidemiology, and Health Services Research, Department of Internal Medicine. The University of Iowa College of Medicine, Iowa City, Iowa; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut; Division of Infectious Disease, Johns Hopkins Hospital, Baltimore, Maryland; Division of Hospital Epidemiology, Lutheran General Hospital, Park Ridge. lllinois; Division of Infectious Diseases, University of Cincinnati Medical Center, Cincinnati, Ohio; Department of Veterans Affairs Medical Center. Birmingham, Alabama; St. Bonaface Hospital. Winnipeg. Manitoba. Canada; Oregon Health Sciences University, Portland. Oregon; Uniformed Services. University ofthe Health Sciences. Dallas. Texas; and San Francisco General Hospital. San Francisco, California
References I. Wenzel RP, Andriole VT, Bartlett JG, et al. Antiendotoxin monoclonal antibodies for gram-negative sepsis: Guidelines from the IDSA. Clin Infect Dis 1992; 14:973-6. 2. Wenzel RP. Anti-endotoxin monoclonal antibodies-a second look. N Engl J Med 1992;326: 1151-3. 3. Warren HS, Danner RL. Munford RS. Anti-endotoxin monoclonal antibodies. N Engl J Med 1992;326: 1153-7. 4. Wenzel RP, Bone R, Fein A, et al. Results of a second double-blind, randomized. controlled trial of antiendotoxin E5 in gram negative sepsis. In: Program and abstracts of the 31 st Interscience Conference on Antimicrobial Agents and Chemotherapy [extended abstract). Washington. DC: American Society for Microbiology, 1991:294.
Rich and Follis reported in 1942 that housing tuberculous guinea pigs in an atmosphere containing only 10% oxygen diminished the extent oftuberculous lesions; conversely, exposing mice to an atmosphere enriched in oxygen resulted in increased mycobacterial counts in the lung and liver [5]. In addition, Vorwald reported that fetal guinea pigs were relatively resistant to M. tuberculosis infection compared with adults, a refractoriness that disappeared at the time of birth. Perhaps the most suggestive experimental results concerning a relationship between progressive tuberculosis at the apex and increased oxygen availability due to reduced venous blood perfusion at the lung apex were presented by Medlar and Sasano in 1935. By maintaining tuberculous rabbits in a vertical position (I), they shifted development of caseous lesions, typically in the posterior dorsal basal area of the lungs, to the apical region. While this explanation for the preferential apical localization of pulmonary tuberculosis is not uncontested [6], the bulk of the evidence mentioned here does suggest a relationship between P0 2 in tissue and progressive tuberculosis. This relationship between P0 2 in tissue and progressive tuberculosis has been classically explained by the fact that M. tuberculosis is a strict aerobe and that its growth is promoted by increased oxygen availability [5, 7]. However, it appears that the growth of M. tuberculosis is suboptimal only at a P0 2 of well below 40 mm Hg, the venous oxygen pressure that prevails in many tissues [5, 8, 9]. We recently examined the effect of oxygen concentration on the growth not only of free mycobacteria but also of mycobacteria inside human macrophages (9]. The amount of growth of M. tuberculosis and Mycobacterium avium as free organisms was not different when cultured at a P0 2 of 36 mm Hg (a pressure close to the venous P0 2 and to that prevailing in many tissues) compared with growth at the P0 2 regularly used
Downloaded from http://cid.oxfordjournals.org/ at University of Glasgow on June 25, 2015
Chmel and Emmanuel, the critical problem is that efficacyis not demonstrated in the overall group (i.e., all enrolled). We agree that retrospective analysis of subgroups-defined by data that are not available at the time that the monoclonal antibodies are administered-may show differences, to which both tables allude with semantic, but not substantive, differences. Our intent in preparing these guidelines [I], in the event that the U.S. Food and Drug Administration chooses to license one or the other of the monoclonal antibodies for the treatment of gram-negative sepsis, was to help clinicians minimize inappropriate clinical utilization of these expensive agents. It had been estimated that perhaps 10% of patients with sepsis would have improved survival if either monoclonal antibody was used wisely [2]. A recent reexamination of the HA-IA data [3] and preliminary data from the second E-5 study [4], however, has cast doubt on these estimations. We have no argument with Chmel and Emmanuel that a subset of patients with suspected gram-negative sepsis could benefit from these agents. The challenge in clinical practice is to prospectively identify that subset.
CID 1992; 15 (August)
CID 1992; 15 (August)
Correspondence
Pascal R. A. Meylan, Douglas D. Richman, and Richard S. Kornbluth Departments of Pathology and Medicine. University of California San Diego School of Medicine. and San Diego Veterans Affairs Medical Center. San Diego. California
Spotless Boutonneuse Fever SIR-We read with interest the article by Brouqui et al. [1] that reported the first case of spotless boutonneuse fever documented by blood culture. In the last few years, several cases of spotless boutonneuse fever have been reported [2-4], although not all of them were diagnosed by means of specific tests. It has been suggested that the absence of the characteristic rash could be due to early therapy for this disease [5). Recently, there were two patients who did not have a rash in a series of246 patients with Mediterranean spotted fever (MSF). At least in one case, the absence of rash could be attributed to early therapy. The patients, aged 8 and 9 years, presented with high fever, headache, and myalgia that lasted 1 and 4 days, respectively. A tache noire was observed in both cases. In accordance with our standard therapeutic regimen for MSF [6, 7], the patients received two doses of doxycycline. They recovered uneventfully and had no rash at any time. The results of serological tests for Rickettsiaconorii that were performed with use ofmicroimmunofluorescence revealed that both patients had seroconverted. According to our experience, the rash associated with MSF lasts for a variable period, and, when not purpuric, it may last
Correspondence: Dr. Elena Espejo. Department of Internal Medicine. Hospital de Terrassa, Ctra. de Torrebonica sin. 08227 Terrassa, Barcelona. Spain.
Clinical Infectious Diseases 1992;15:373-4 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1502-0024$02.00
References I. Park MK, Myers RAM. Marzella L. Oxygen tensions and infections: modulation of microbial growth. activity of antimicrobial agents. and immunologic responses. Clin Infect Dis 1992;14:720-40. 2. Sweany He. Cook CEo Kegerreis R. A study of the position of primary cavities in pulmonary tuberculosis. Am Rev Respir Dis 1931;24:558. 3. Medlar EM. The pathogenesis of minimal pulmonary tuberculosis. Am Rev Respir Dis 1948;58:583. 4. Dock W. Apical localization of phthisis. Am Rev Respir Dis 1946;53:297. 5. Sever JL. Youmans GP. The relation of oxygen tension to virulence of tubercle bacilli and to acquired resistance in tuberculosis. J Infect Dis 1957;101:193. 6. Des Prez RM. Heim CR. Mycobacterium tuberculosis. In: Mandell GL. Douglas RG Jr. Bennett JE. eds. Principles and practice of infectious diseases. New York: Churchill Livingstone. 1990: 1877-906. 7. Youmans GP. Virulence of mycobacteria. In: Youmans GP. ed. Tuberculosis. Philadelphia: WB Saunders. 1979: 194-200. 8. Heplar JQ. Clifton CEo Raffel S. Futrelle CM. Virulence of the tubercle bacillus. J Infect Dis 1954;94:90. 9. Meylan PRA, Richman DD. Kornbluth RS. Reduced intracellular growth of mycobacteria in human macrophages cultivated at physiologic oxygen pressure. Am Rev Respir Dis 1992; 145:947. 10. Simon LM. Axline SG. Horn BR. Robin ED. Adaptations of energy metabolism in the cultivated macrophage. J Exp Med 1990; 138:1413.
only a few days. Furthermore, when the maculopapules are sparse, patients frequently are not aware of them until admission. Therefore. when a patient with a paucisymptomatic form ofMSF is examined relatively late in the course of the disease, it is possible that an unnoticed rash had been present earlier. We agree with Brouqui et al. that MSF should be considered in the diagnosis for any individual who is in an area in which MSF is endemic during the summer and who develops fever. The patient may have a spotless form or, more probably, be in the pre- or posteruptive phase of MSF in this situation. On the other hand. we want to emphasize that tache noire, a clinical clue for the diagnosis of MSF. is observed in three-quarters of the cases when it is carefully searched for [4, 5].
Elena Espejo, Marta Rodriguez, Abel Martinez, Socorro Uriz, and Feliu Bella Departments of internal Medicine and Pediatrics. Hospital de Terrassa, Terrassa, Barcelona. Spain
References I. Brouqui P. Tissot Dupont HT, Drancourt M. Bourgeade A, Raoult D. Spotless bouton neuse fever. Clin Infect Dis 1992; 14:114-6. 2. Zechini F. Osservazioni epidemiologiche, c1iniche e terapeutiche su 50 casi di rickettsiosi conori. Minerva Med 1977;68:2387-92. 3. Raoult D. Jean-Pastor MJ. Xeridat B. et al. La fievre boutonneuse mediterraneenne. A propos de 154 cas recents. Ann Dermatol Venereol 1983; II 0:909-14.
Downloaded from http://cid.oxfordjournals.org/ at University of Glasgow on June 25, 2015
in incubators, i.e., 140 mm Hg (a pressure only approached by the P02 in tissue at the lung apex). In contrast, the growth of mycobacteria inside infected macrophages was significantly decreased at a P0 2 of 36 mm Hg compared with that at 140 mm Hg. The mechanism of this reduced growth of mycobacteria in macrophages at low oxygen concentration is unknown. On the one hand, it is possible that the intracellular oxygen pressure in macrophages cultured at a low oxygen concentration dropped to a level that affects mycobacteria, a hypothesis already put forth in 1942 by Rich and Follis. On the other hand, there is evidence that the oxygen pressure during culture of macrophages influences their morphological and physiological differentiation [9, 10]. It is thus possible that macrophages at low oxygen pressure had more efficacious antimycobacterial defense mechanisms. Our data suggest that the effect of P0 2 on the growth of mycobacteria inside macrophages rather than on mycobacteria themselves may explain the preferential localization of tuberculous lesions at the lung apex.
373
