Int. J. Rodiotion
Oncology
Biol.
Phys..
1976, Vol.
I. pp. 309-311.
Pcrgamon
Press.
Printed
in the U.S.A.
DEFENSES AGAINST CANDIDA INFECTIONS DONALD
B. LOURIA,
M.D.
Department of Preventive Medicine and Community Health, College of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey. Candida fungemias, Lymphocytes, Leukemia, Antibiotics.
We have been particularly interested in matching underlying disease to type of superinfection. It has been stated that leukopenia is associated with Candida superinfection; however, this author does not believe there is evidence that people who have disease induced neutropenia acquire systemic candidiasis. Those acquiring candidiasis generally have had a variety of treatments and neutropenia may be one of the resulting effects; but I know of no epidemiologic data showing that untreated people with any disease which is associated with profound neutropenia have an increased incidence of disseminated infection from Candida or from species of Aspergillus or Mucor. The only two infections that are known to occur with increased frequency in untreated Hodgkin’s disease are tuberculosis and cryptococcosis. For these infections, the evidence seems reasonably good, but the data are less secure for listeriosis, toxoplasmosis, salmonellosis and nocardiosis, since these infections have all been described primarily after the patients with Hodgkin’s disease were under anti tumor therapy. We talk about the susceptibility of patients with, for example, Hodgkin’s disease to acquire superinfections; but often it is not the underlying disease, but their disease, plus what we’ve done to them that makes them susceptible to certain superinfections. Dr. Donald Armstrong (an earlier author in this series) and I examined his experience at Memorial Hospital in New York City; we found that ‘about one half the people acquiring listeria infections in that hospital had low lymphocyte counts before they developed listeriosis.’ This is of interest since Tripathy
and Mackanessz6”’ indicate that if the host wishes to handle listeria most effectively a committed lymphocyte and a macrophage that understands the information that it gets from the lymphocytes are necessary. Consequently, the half of the patients at Memorial Hospital who lack the normal number of lymphocytes may have had increased susceptibility to listeriosis because of this. In addition, the patients at Memorial Hospital generally manifested immunoglobulin G deficiency. A study by Njoku-obi and Osebold” indicates that optimal host defense against listeric infections requires not only committed lymphocytes and informed macrophages but also circulating immunoglobulins; in some way that is not clear, these immunoglobulins help in phagocytosis and also in intracellular destruction of the opsonized organisms. Here again, susceptibility to the listeric infection appears to be predicated upon underlying lymphocytic malignancy plus host modification by therapy. In the leukemic patient, the organisms causing most of the trouble among the fungi are species of Candida. Why are such patients inordinately susceptible to these particular yeasts? The data suggest that antibiotics, steroids, anti leukemia agents, neutropenia and direct access for the organism to the blood stream all act in concert to promote Candida. In this regard, the evidence is beginning to accumulate that the scalp vein needle is less dangerous than the intravenous catheter by about ten-fold in terms of the proclivity for superinfections.’ A prospective study by Curry and Quie’ on the use of hyperalimentation by intravenous catheter showed that 27% of individuals so treated developed bacteremia or fungemia, 309
310
Radiation Oncology 0 Biology 0 Physics
over half of the blood stream infections being due to yeasts. Clearly, we must look very carefully epidemiologically at the different types of catheters and needles and their superinfection potential. Our own data suggest that in 50% of the Candida fungemias, the infection appears to arise from direct invasion from vascular needles or catheters into the blood stream; even at autopsy there is no evidence of gastrointestinal tract Candida invasion in such cases.’ In regard to antibiotics, we have assumed heretofore that if one administers antibiotics, superinfection relates solely to suppression of the endogenous flora. This may be too simplistic and monolithic an explanation since some data suggest that certain of the antibiotics interfere with phagocytosis,” and recent in vitro studies suggest that tetracyclines may be associated with reduced chemotaxis? We must examine antibiotics in an attempt to determine why people receiving them become superinfected; in doing so, we must not assume that it is merely suppression of the existing endogenous flora. We do not yet know enough about naturally occurring host defenses against Candida invasion. We thought on the basis of our mouse experiments that th& polymorphonuclear leukocyte was the paramount defense cell; but in chronic infections, granulomas appear and it may be necessary to intensify our focus on the mononuclear cell in regard to control of candidiasis. This possibility is buttressed by the realization that in certain patients mucocutaneous candidiasis appears to represent a lymphocyte-macrophage defect modifiable by transfer factor. An additional question in regard to Candida relates to whether we should develop better Candida antigens in order to attempt to immunize certain people against this particular organism. At present, protection may be achieved in experimental animals by immunizing with whole Candida cells or cell ex-
Vol. 1, No. 3-4
tracts “~~“~‘4~‘6~17but
no vehicles
are being
devedped for use in man. One problem is that we do not have a good method of diagnosing Candida invasion very quickly except by culture. The precipitin test, using cell wall or cytoplasmic antigens, is good; however, both false positives and false negatives occur, and it usually is not available quickly enough to be preferable to the culture. Furthermore, .the precipitin test will not distinguish reliably between superficial and invasive candidal infection, although a strongly positive test using sonically treated Candida cells should suggest the possibility of deep-seated disease.” Similarly, a rise in agglutinating antibody titers should suggest systemic candidiasis even though such a rising titer can be misleading.‘* It has been suggested that the presence of mycelia in smear suggests invasive disease, but this does not appear to be true in urine. In urine the Candida count numerically; the presence or absence of pyuria and the predominance of yeast or mycelial forms do not help in distinguishing localized bladder infection from pyelonephritis.” In diEcult cases in which there is putative blood stream or meningeal involvement we may be able to establish the diagnosis more quickly by using hypertonic media that are highly enriched. Such media ordinarily are not needed since Candida grow well on a variety of standard media; occasionally, routine cultures are unrevealing, and placing specimens in hypertonic media may be rewarding in such cases. Finally, this author feels that all patients susceptible to Candida should have blood drawn for a precipitin or agglutinin test when they enter the hospital so that another blood can be obtained and tested if they develop an unexplained disease process that might be Candida. A striking increase in antibody titers suggests strongly the presence of Candida superinfection even if cultures are negative at the time.
REFERENCES 1. Crossley, K., Matsen, J.M.: The scalp vein needle. J.A.M.A. 22Q: 985-987, 1972. 2. Curry, C.R., Quie, P.G.: Fun8al septicemia in patients receiving parenteral hyperalimentation. N. Engl. J. Med. 285: 1221-1224, 1971.
3. Dobias, B.: Specific and non specific immunity in candida infections; Acta Med. Stand. 176: (suppl 421): l-79, 1964. 4. Kirkpatrick, C.H., Smith, T.K.: Chronic mucocutaneous candidiasis: Immunologic and
Defenses against Candida infections 0 D. B.
5.
6.
7.
8.
9.
10.
11.
antibiotic therapy. Ann. Inrem Med. 80: 310320, 1974. Louria, D.B.. Blevins, A., Armstrong, D.: Listeria infections. Ann. NY Acad. Sci. 174: 545-55 1, 1970. Louria, D.B., Fallon, N., Browne, H.G.: The influence of cortisone on experimental fungus infections in mice. J. Clin. Invest. 39: 14351449,196O. Louria, D.B., Stiff, D.P., Bermet, B.: Disseminated moniliasis in the adult. Medicine 41: 307-337, 1962. Martin, R.C., Warr, H., Yeager, H., Couch, R., Knight, V.: Effects of tetracycline on leukotaxis: Presented at 12th Interscience Conference on Antimicrobial Agents and Chemotherapy, 26-29 September, Atlantic City, New Jersey, 1972. Mourad, S., Friedman, L.: Active immunization of mice against Candida albicans. Proc. Sot. Exp. Biol. Med. 106: 570-572, 1%1. Munoz, J., Geister, R.: Inhibition of phagocytosis by aureomycin. Proc. Sot. Exp. Biol. Med. 75: 367-370, 1950. Njoku-obi, A.N., Osebold, J.W.: Studies on mechanisms of immunity in listeriosis-I.
12.
13.
14. 15.
16.
17.
LOUFUA
311
Interaction of peritoneal exudate cells from sheep with Listeria monocytogenes in vitro. J. Immunol. 89: 187-194, 1%2. Preisler, H.D., Hasenclever, H.F., Levitan, A.A., Henderson, ES.: Serologic diagnosis of disseminated candidiasis in patients with acute leukemia. Ann. Intern Med. 70: 19-30, 1%9. Schonebeck, J.: Studies on candida infection of the urinary tract and on the antimycotic drug 5-Fluorocytosine. Scan. J. Ural. Nephrol. (suppl 11) Vol. 6, Stockholm, 1972, pp. l-48. Soles, P., Lim, L.Y., Louria, D.B.: Active immunity in experimental candidiasis in mice. Sabouraudia 5: 315-322, 1%7. Taschdjian, C.L., Kozinn, P.J., Okas, A., Caroline, L., Halle, M.A.: Serodiagnosis of systemic candidiasis. J. Infect. Dis. 117: 180187, 1%7. Tripathy, S.P., Mackaness, G.B.: The effect of cytotoxic agents on the passive transfer of cell-mediated immunity. J. Exp. Med. 130: 17-30, 1%9. Tripathy, S.P., Mackaness, G.B.: The effect of cytotoxic agents on the primary response to Listeria monocytogenes. J. Exp. Med. 130: 1-16, 1%9.
Oncology
Biol.
Phys..
1976, Vol.
I. pp. 309-311.
Pcrgamon
Press.
Printed
in the U.S.A.
DEFENSES AGAINST CANDIDA INFECTIONS DONALD
B. LOURIA,
M.D.
Department of Preventive Medicine and Community Health, College of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey. Candida fungemias, Lymphocytes, Leukemia, Antibiotics.
We have been particularly interested in matching underlying disease to type of superinfection. It has been stated that leukopenia is associated with Candida superinfection; however, this author does not believe there is evidence that people who have disease induced neutropenia acquire systemic candidiasis. Those acquiring candidiasis generally have had a variety of treatments and neutropenia may be one of the resulting effects; but I know of no epidemiologic data showing that untreated people with any disease which is associated with profound neutropenia have an increased incidence of disseminated infection from Candida or from species of Aspergillus or Mucor. The only two infections that are known to occur with increased frequency in untreated Hodgkin’s disease are tuberculosis and cryptococcosis. For these infections, the evidence seems reasonably good, but the data are less secure for listeriosis, toxoplasmosis, salmonellosis and nocardiosis, since these infections have all been described primarily after the patients with Hodgkin’s disease were under anti tumor therapy. We talk about the susceptibility of patients with, for example, Hodgkin’s disease to acquire superinfections; but often it is not the underlying disease, but their disease, plus what we’ve done to them that makes them susceptible to certain superinfections. Dr. Donald Armstrong (an earlier author in this series) and I examined his experience at Memorial Hospital in New York City; we found that ‘about one half the people acquiring listeria infections in that hospital had low lymphocyte counts before they developed listeriosis.’ This is of interest since Tripathy
and Mackanessz6”’ indicate that if the host wishes to handle listeria most effectively a committed lymphocyte and a macrophage that understands the information that it gets from the lymphocytes are necessary. Consequently, the half of the patients at Memorial Hospital who lack the normal number of lymphocytes may have had increased susceptibility to listeriosis because of this. In addition, the patients at Memorial Hospital generally manifested immunoglobulin G deficiency. A study by Njoku-obi and Osebold” indicates that optimal host defense against listeric infections requires not only committed lymphocytes and informed macrophages but also circulating immunoglobulins; in some way that is not clear, these immunoglobulins help in phagocytosis and also in intracellular destruction of the opsonized organisms. Here again, susceptibility to the listeric infection appears to be predicated upon underlying lymphocytic malignancy plus host modification by therapy. In the leukemic patient, the organisms causing most of the trouble among the fungi are species of Candida. Why are such patients inordinately susceptible to these particular yeasts? The data suggest that antibiotics, steroids, anti leukemia agents, neutropenia and direct access for the organism to the blood stream all act in concert to promote Candida. In this regard, the evidence is beginning to accumulate that the scalp vein needle is less dangerous than the intravenous catheter by about ten-fold in terms of the proclivity for superinfections.’ A prospective study by Curry and Quie’ on the use of hyperalimentation by intravenous catheter showed that 27% of individuals so treated developed bacteremia or fungemia, 309
310
Radiation Oncology 0 Biology 0 Physics
over half of the blood stream infections being due to yeasts. Clearly, we must look very carefully epidemiologically at the different types of catheters and needles and their superinfection potential. Our own data suggest that in 50% of the Candida fungemias, the infection appears to arise from direct invasion from vascular needles or catheters into the blood stream; even at autopsy there is no evidence of gastrointestinal tract Candida invasion in such cases.’ In regard to antibiotics, we have assumed heretofore that if one administers antibiotics, superinfection relates solely to suppression of the endogenous flora. This may be too simplistic and monolithic an explanation since some data suggest that certain of the antibiotics interfere with phagocytosis,” and recent in vitro studies suggest that tetracyclines may be associated with reduced chemotaxis? We must examine antibiotics in an attempt to determine why people receiving them become superinfected; in doing so, we must not assume that it is merely suppression of the existing endogenous flora. We do not yet know enough about naturally occurring host defenses against Candida invasion. We thought on the basis of our mouse experiments that th& polymorphonuclear leukocyte was the paramount defense cell; but in chronic infections, granulomas appear and it may be necessary to intensify our focus on the mononuclear cell in regard to control of candidiasis. This possibility is buttressed by the realization that in certain patients mucocutaneous candidiasis appears to represent a lymphocyte-macrophage defect modifiable by transfer factor. An additional question in regard to Candida relates to whether we should develop better Candida antigens in order to attempt to immunize certain people against this particular organism. At present, protection may be achieved in experimental animals by immunizing with whole Candida cells or cell ex-
Vol. 1, No. 3-4
tracts “~~“~‘4~‘6~17but
no vehicles
are being
devedped for use in man. One problem is that we do not have a good method of diagnosing Candida invasion very quickly except by culture. The precipitin test, using cell wall or cytoplasmic antigens, is good; however, both false positives and false negatives occur, and it usually is not available quickly enough to be preferable to the culture. Furthermore, .the precipitin test will not distinguish reliably between superficial and invasive candidal infection, although a strongly positive test using sonically treated Candida cells should suggest the possibility of deep-seated disease.” Similarly, a rise in agglutinating antibody titers should suggest systemic candidiasis even though such a rising titer can be misleading.‘* It has been suggested that the presence of mycelia in smear suggests invasive disease, but this does not appear to be true in urine. In urine the Candida count numerically; the presence or absence of pyuria and the predominance of yeast or mycelial forms do not help in distinguishing localized bladder infection from pyelonephritis.” In diEcult cases in which there is putative blood stream or meningeal involvement we may be able to establish the diagnosis more quickly by using hypertonic media that are highly enriched. Such media ordinarily are not needed since Candida grow well on a variety of standard media; occasionally, routine cultures are unrevealing, and placing specimens in hypertonic media may be rewarding in such cases. Finally, this author feels that all patients susceptible to Candida should have blood drawn for a precipitin or agglutinin test when they enter the hospital so that another blood can be obtained and tested if they develop an unexplained disease process that might be Candida. A striking increase in antibody titers suggests strongly the presence of Candida superinfection even if cultures are negative at the time.
REFERENCES 1. Crossley, K., Matsen, J.M.: The scalp vein needle. J.A.M.A. 22Q: 985-987, 1972. 2. Curry, C.R., Quie, P.G.: Fun8al septicemia in patients receiving parenteral hyperalimentation. N. Engl. J. Med. 285: 1221-1224, 1971.
3. Dobias, B.: Specific and non specific immunity in candida infections; Acta Med. Stand. 176: (suppl 421): l-79, 1964. 4. Kirkpatrick, C.H., Smith, T.K.: Chronic mucocutaneous candidiasis: Immunologic and
Defenses against Candida infections 0 D. B.
5.
6.
7.
8.
9.
10.
11.
antibiotic therapy. Ann. Inrem Med. 80: 310320, 1974. Louria, D.B.. Blevins, A., Armstrong, D.: Listeria infections. Ann. NY Acad. Sci. 174: 545-55 1, 1970. Louria, D.B., Fallon, N., Browne, H.G.: The influence of cortisone on experimental fungus infections in mice. J. Clin. Invest. 39: 14351449,196O. Louria, D.B., Stiff, D.P., Bermet, B.: Disseminated moniliasis in the adult. Medicine 41: 307-337, 1962. Martin, R.C., Warr, H., Yeager, H., Couch, R., Knight, V.: Effects of tetracycline on leukotaxis: Presented at 12th Interscience Conference on Antimicrobial Agents and Chemotherapy, 26-29 September, Atlantic City, New Jersey, 1972. Mourad, S., Friedman, L.: Active immunization of mice against Candida albicans. Proc. Sot. Exp. Biol. Med. 106: 570-572, 1%1. Munoz, J., Geister, R.: Inhibition of phagocytosis by aureomycin. Proc. Sot. Exp. Biol. Med. 75: 367-370, 1950. Njoku-obi, A.N., Osebold, J.W.: Studies on mechanisms of immunity in listeriosis-I.
12.
13.
14. 15.
16.
17.
LOUFUA
311
Interaction of peritoneal exudate cells from sheep with Listeria monocytogenes in vitro. J. Immunol. 89: 187-194, 1%2. Preisler, H.D., Hasenclever, H.F., Levitan, A.A., Henderson, ES.: Serologic diagnosis of disseminated candidiasis in patients with acute leukemia. Ann. Intern Med. 70: 19-30, 1%9. Schonebeck, J.: Studies on candida infection of the urinary tract and on the antimycotic drug 5-Fluorocytosine. Scan. J. Ural. Nephrol. (suppl 11) Vol. 6, Stockholm, 1972, pp. l-48. Soles, P., Lim, L.Y., Louria, D.B.: Active immunity in experimental candidiasis in mice. Sabouraudia 5: 315-322, 1%7. Taschdjian, C.L., Kozinn, P.J., Okas, A., Caroline, L., Halle, M.A.: Serodiagnosis of systemic candidiasis. J. Infect. Dis. 117: 180187, 1%7. Tripathy, S.P., Mackaness, G.B.: The effect of cytotoxic agents on the passive transfer of cell-mediated immunity. J. Exp. Med. 130: 17-30, 1%9. Tripathy, S.P., Mackaness, G.B.: The effect of cytotoxic agents on the primary response to Listeria monocytogenes. J. Exp. Med. 130: 1-16, 1%9.
