IMPAIRED DEFENSE MECHANISMS ASSOCIATED WITH ACUTE ALCOHOLISM Warren D. Johnson, Jr. Cornell University Medical College New York, New York 10021 It has generally been assumed that alcohol increases host susceptibility t o infection. l-' This assumption is correct in the presence of profound intoxication with stupor or coma, where aspiration of oropharyngeal contents may lead t o the development of p n e ~ m o n i a . ~However, .~ there is little evidence t o suggest that nonpulmonary infections are more common in healthy subjects who are acutely intoxicated. In some experimental studies it is difficult t o distinguish between the effects of alcohol per se and those of chronic alcoholism and its associated problems. For this reason, the present report will be restricted t o acute alcohol intoxication and will rely o n studies that determined the effects of single doses of ethanol in healthy volunteers or animals. The effect of ethanol on numerous pulmonary and systemic defense mechanisms has been experimentally determined (TABLE 1 ). These include nonimmunologic mechanisms, such as glottis closure or tracheal ciliary activity, as well as immunologic mechanisms such as leukocyte mobilization, chemotaxis, and function, and serum bactericidal activity. The influence of ethanol o n these defense mechanisms will be reviewed.
PULMONARYDEFENSEMECHANISMS Glottis Closure Glottis closure is an important mechanism in preventing the entrance of foreign particles, including infectious agents, into the lung. It has been shown that rats are unable to effect glottis closure after receiving large doses of ethanoL5 The impairment of this mechanism by ethanol facilitated the aspiration of intranasal pneumococci and mucin and the subsequent development of pneumonia. However, there was n o specificity in the action of ethanol. Similar results were obtained in animals subjected t o either deep ether anesthesia, exposure t o cold, or local benzocaine anesthesia of the epiglottis region. An impairment of this mechanical barrier t o infection is undoubtedly the major reason for an increased incidence of pneumonia in the setting of profound alcohol intoxication and other conditions such as shock or coma. Ciliary Activity Ciliary activity was not inhibited by the amounts of ethanol that impaired glottis closure in the aforementioned studiess Serum ethanol levels of 600 t o 1000 mg% were required t o depress the ciliary activity of the cat trachea.' Since these concentrations of ethanol are potentially lethal in man, it is very unlikely that an impairment of ciliary activity predisposes to pulmonary infections.
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Annals New York Academy of Sciences Lung Bacterial Clearance
The pulmonary clearance of infectious agents has recently been reviewed.6 There has been considerable interest during the past decade o n the effects of ethanol on this mechanism. Green and Kass demonstrated that intoxication of mice with ethanol decreased the rate at which inhaled staphylococci were cleared from the l u n g g In their study, animals made ataxic or stuporous with ethanol and then exposed t o aerosolized staphylococci had twice as many bacteria recovered from their lungs 4 hours later than did control animals. This inhibitory effect of ethanol was dose-related. A similar depressant effect on bacterial clearance was also observed in animals subjected t o either severe hypoxia or acute starvation. Animals receiving large doses of ethanol had altered patterns of respiration; hypoxia produced by this respiratory depression seemed a plausible explanation for the ethanol effect. However, attempts t o reverse the effects of ethanol by placing the mice in increased concentrations of oxygen after the aerosolized pulmonary infections were unsuccessful. TABLE 1 Host Defense Mechanisms Experimentally Evaluated Following Acute Administration of Ethanol Pulmonary Defense Mechanisms Glottis Closure Ciliary Activity Lung Bacterial Clearance Alveolar Macrophage
Mobilization Function Systemic Defense Mechanisms Polymorphonuclear Leukocyte Mobilization Chemotaxis Function Peritoneal Macrophage Serum Bactericidal Activity
Alveolar Macrophage Mobilization: A possible mechanism for the observed ethanol-induced decrease in pulmonary clearance was offered by Guarneri and Laurenzi.lo They utilized a similar experimental model t o demonstrate that mice given ethanol had a decrease in the number of alveolar macrophages that could be recovered by lavage of the lungs after a pulmonary bacterial challenge. However, when these studies were repeated in the rabbit, they were unable t o demonstrate any adverse effect of ethanol o n alveolar macrophage mobilization. The variability in the response of different species t o ethanol indicates the potential danger in extrapolating from animal experiments t o man. Function: Gee e t al. have studied the effect of ethanol o n the phagocytic and antistaphylococcal activity of isolated rabbit alveolar macrophages." They were unable t o demonstrate any impairment in the phagocytosis and killing of S. aureus by macrophages exposed t o ethanol in vitro.
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SYSTEMICDEFENSE MECHANISMS Poly m orph on uclear Leukocyte Mobilization: The accumulation of polymorphonuclear leukocytes at sites of induced infection or trauma is decreased in animals and man following ethanol administration. Pickrell demonstrated that rabbits made stuporous with large amounts of ethanol (blood ethanol levels of 550-700 mg%) had fewer polymorphonuclear leukocytes in experimental pneumococcal infections of skin, lung, and pleural spaces than did control animals6 However, ether anesthesia had as marked an inhibitory effect o n the inflammatory response as did ethanol intoxication. Louria confirmed these observations in mice given a single injection of 0.5 ml of 30% ethanol subcutaneously and then challenged with l o 8 coagulase-negative staphylococci intraperitoneally. The number of polymorphonuclear leukocytes in peritoneal washouts 4 hours later was significantly lower than in saline-injected mice or animals rendered comatose with barbiturates and was inversely related t o the blood ethanol concentrations. Peripheral blood leukocyte counts did not differ in control and alcohol-treated mice. Moses e t al. reported that alcohol also diminished leukocyte mobilization into the suprapatellar bursa of rabbits following the local injection of a “stimulating substance” obtained from rabbit granulocyte^.'^ This was attributed t o a defect in vascular permeability and could be partially corrected by increasing the skin temperature. No abnormalities in leukocyte margination or stickiness were observed following ethanol administration in studies utilizing a rabbit ear chamber model. A leukocyte mobilization defect has also been documented in man with the Rebuck skin window technique.14 Human volunteers were given 50-75 ml of 95% ethanol intravenously over a 30-minute period. Immediately before injecting the alcohol a 1-cm2 area of the volunteers’ forearm was abraded t o the point of uniform redness and then covered with a siliconized glass cup, which was then filled with isotonic saline. The contents of the cup were evacuated at multiple time points and the numbers of polymorphonuclear leukocytes counted. A marked reduction in the leukocyte counts occurred during the first 4 hours after ethanol infusion. Similar findings were observed in volunteers given ethanol by mouth. However, a comparable degree of impaired leukocyte mobilization was observed in patients with profound terminal shock. Diabetic patients showed a less marked decrease in mobilization. No significant depression of mobilization was observed in patients with cirrhosis, uremia, or coma, or in patients undergoing prolonged general anesthesia for major surgery. The mechanisms responsible for these observations were not defined. There was n o clinical evidence of intoxication in the volunteers, nor was there hypotension, perceptible skin cooling, or changes in peripheral blood leukocyte counts. The investigators emphasized that “failure of emigration of leukocytes into the skin does not necessarily mean that alcohol will induce a similar abnormality in the lung parenchyma, the only site in which alcohol ingestion is clearly associated with increased proclivity t o and severity of infection.” Chemotaxis: The effect of ethanol on leukocyte chemotaxis was first studied in the 1930s by Klepser and N u n g e ~ t e r . ’They ~ measured the movement of human leukocytes toward pneumococci on glass slides after exposure of the leukocytes t o ethanol in vitro. The chemotactic response of the leukocytes was diminished by as little as 100 mg% of ethanol. Leukocytes from “deeply intoxicated” rats also had a diminished chemotactic response.
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Annals New York Academy of Sciences
A recent report has confirmed that exposure of human leukocytes to ethanol in vitro will impair their chemotactic response, but only at ethanol concentrations of 800-1600 mg%.16 Function: Animal studies initially suggested that polymorphonuclear leukocyte phagocytic capacity and ability to effect intracellular killing was impaired by ethanol.12 These observations have not been confirmed by more recent studies utilizing quantitative measures of leukocyte function. Brayton et al. l4 utilized a modification of the technique of Maaloe to gauge phagocytosis and intracellular killing of coagulase-negative staphylococci by human polymorphonuclear leukocytes. They were unable to demonstrate any impairment of these functions in leukocytes exposed to 200 to 400 mg% of ethanol in vitro or in leukocytes obtained from volunteers receiving infusions of ethanol.
Peritoneal Macrophages Louria reported a decrease in the clearance of staphylococci from the peritoneal cavity of mice rendered comatose or ataxic with ethanol.12 Seventy-seven percent of control animals reduced peritoneal bacterial populations at least 10-fold during a 1-hour period following intraperitoneal infection. In contrast, only 47% of ataxic mice and 21% of comatose animals effected similar reductions in bacterial counts. In vitro studies suggested that peritoneal macrophages from comatose animals had a reduction in their phagocytic ability and perhaps impaired intracellular killing. Macrophages from ataxic animals had variable and often normal phagocytic and intracellular killing activity.
Serum Bactericidal Activity Studies by Kaplan and Brande on 2 human volunteers suggested that the bactericidal activity of serum was decreased against a strain of Escherichia coli and a strain of Hemophilus influenzae following ingestion of ethanol." This observation was confirmed and extended in subsequent studies in which normal volunteers received intravenous infusions of 50-75 ml of absolute ethanol.18 Serum bactericidal activity against strains of E. coli and H. influenzae type B were transiently decreased but near normal 5 hours after the ethanol infusion. The decrease in bactericidal activity was demonstrated by testing diluted serum. The decrease in bactericidal activity was not related t o the presence of ethanol or acetaldehyde in the serum per se and could not be attributed to changes in serum lysozyme or electrolytes or to alterations of bactericidal antibody or complement levels. There was no correlation between the serum ethanol level of the degree to which bactericidal activity was decreased. A preliminary report on the bactericidal activity of dog serum following ethanol infusion suggests that the effect of ethanol might be to impair the in vivo production of ~ o m p l e m e n t . ' ~
SUMMARY Ethanol administered t o animals in large amounts sufficient to produce coma and occasionally death will impair glottis closure, ciliary activity, lung and peritoneal bacterial clearance, mobilization of macrophages, and polymorphonuclear leukocytes and leukocyte chemotaxis. There is little or no impairment of these pulmonary and systemic host defense mechanisms in experimental studies employing amounts of ethanol that produce serum concentrations likely to be
Johnson: Impaired Defense Mechanisms
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e n c o u n t e r e d in an intoxicated human. Modest amounts o f ethanol in man, sufficient to p r o d u c e minimal euphoria to mild intoxication, are associated with i m p a i r e d m o b i l i z a t i o n o f p o l y m o r p h o n u c l e a r l e u k o c y t e s into skin a n d decreased s e r u m bactericidal a c t i v i t y against certain gram-negative bacteria. The mechanism b y w h i c h e t h a n o l i m p a i r s these l a t t e r d e f e n s e mechanisms has not been clearly defined.
REFERENCES 1. RUSH, B. 1943. An inquiry into the effects of ardent spirits upon the human body and mind with an account of the means of preventing and of the remedies for curing them. (1785). Reprinted in Quart. J. Stud. Alcohol 4: 321-341. 2. PERLA, D. & J. MARMORSTON. 1941. Alcohol and resistance. In Natural Resistance and Clinical Medicine. 1153-1 161. Little, Brown and Co. Boston, Mass. 3. EICHNER, E. R. 1973. The hematologic disorders of alcoholism. Amer. I. Med. 54: 621-630. 4. LOURIA, D. B. 1973. The infectious complications of alcohol ingestion. Rev. Environ. Health 1: 175-184. 5. NUNGESTER, W. J. & R. G. KLEPSER. 1938. A possible mechanism of lowered re-
sistance to pneumonia. J. Infect. Dis. 63: 94-1 02. 6. PICKRELL, K. L. 1938. Effect of alcoholic intoxication and ether anesthesia on resistance to pneumococcic infection. Bull. Johns Hopkins Hosp. 63: 238-260. 7. LAURENZI, G. A. & J. J. GUARNERI. 1966. A study of the mechanisms of pulmonary resistance to infection: the relationship of bacterial clearance to ciliary activity and alveolar macrophage function. Amer. Rev. Resp. Dis. 93: 134-141. (Supplement) 8. GREEN, G. 1968. Pulmonary clearance of infectious agents. Ann. Rev. Med. 19: 315336. 9. GREEN, G. M. & E. H. KASS. 1964. Factors influencing the clearance of bacteria by the lung. 3. Clin. Invest. 43: 769-776. 10. GUARNERI, J. J. & G. A. LAURENZI. 1968. Effect of alcohol on the mobilization of alveolar macrophages. J. Lab. Clin. Med. 72: 40-51. 11. GEE, J. B. L., J. KASKIN, M. P. DUNCOMBE & C. L. VASSALLO. 1974. The effects of ethanol on some metabolic features of phagocytosis in the alveolar macrophage. J. Reticuloendothel. SOC. 15: 61-68. 12. LOURIA, D. B. 1963. Susceptibility t o infection during experimental alcohol intoxication. Trans. Ass. Amer. Physicians 76: 102-1 12. 13. MOSES, J. M., E. H. GESCHICKTER & R. H. EBERT. 1968. Pathogenesis of inflammation. The relationship of enhanced permeability t o leukocyte mobilization in delayed inflammation. Brit. J. Exp. Path. 49: 385-394. 14. BRAYTON, R. G., P. E. STOKES, M. S. SCHWARTZ & D. B. LOURIA. 1970. Effect of alcohol and various diseases on leukocyte mobilization, phagocytosis and intracellular bacterial killing. New Eng. J. Med. 282: 123-1 28. 15. KLEPSER, R. G. & W. J. NUNGESTER. 1939. The effect of alcohol upon the chemotactic response of leukocytes. J. Infect. Dis. 65: 196-199. 16. CROWLEY, J. P. & N. ABRAMSON. 1971. Effect of ethanol on complement-mediated chemotaxis. Clin. Res. 19: 415. 17. KAPLAN, N. M. & A. I. BRANDE. 1958. Hemophilus influenzae infection in adults: observations on the immune disturbance. Arch. Intern. Med. 101: 515-523. 18. JOHNSON, W. D. Jr., P. STOKES & D. KAYE. 1969. The effect of intravenous ethanol on the bactericidal activity of human serum. Yale J. Biol. Med. 42: 71-85. 19. MARR, J. J. & 1. SPILBERG. 1973. A mechanism for infection by gram-negative bacteria in acute alcohol intoxication. Clin. Res. 22: 449a.
PULMONARYDEFENSEMECHANISMS Glottis Closure Glottis closure is an important mechanism in preventing the entrance of foreign particles, including infectious agents, into the lung. It has been shown that rats are unable to effect glottis closure after receiving large doses of ethanoL5 The impairment of this mechanism by ethanol facilitated the aspiration of intranasal pneumococci and mucin and the subsequent development of pneumonia. However, there was n o specificity in the action of ethanol. Similar results were obtained in animals subjected t o either deep ether anesthesia, exposure t o cold, or local benzocaine anesthesia of the epiglottis region. An impairment of this mechanical barrier t o infection is undoubtedly the major reason for an increased incidence of pneumonia in the setting of profound alcohol intoxication and other conditions such as shock or coma. Ciliary Activity Ciliary activity was not inhibited by the amounts of ethanol that impaired glottis closure in the aforementioned studiess Serum ethanol levels of 600 t o 1000 mg% were required t o depress the ciliary activity of the cat trachea.' Since these concentrations of ethanol are potentially lethal in man, it is very unlikely that an impairment of ciliary activity predisposes to pulmonary infections.
343
344
Annals New York Academy of Sciences Lung Bacterial Clearance
The pulmonary clearance of infectious agents has recently been reviewed.6 There has been considerable interest during the past decade o n the effects of ethanol on this mechanism. Green and Kass demonstrated that intoxication of mice with ethanol decreased the rate at which inhaled staphylococci were cleared from the l u n g g In their study, animals made ataxic or stuporous with ethanol and then exposed t o aerosolized staphylococci had twice as many bacteria recovered from their lungs 4 hours later than did control animals. This inhibitory effect of ethanol was dose-related. A similar depressant effect on bacterial clearance was also observed in animals subjected t o either severe hypoxia or acute starvation. Animals receiving large doses of ethanol had altered patterns of respiration; hypoxia produced by this respiratory depression seemed a plausible explanation for the ethanol effect. However, attempts t o reverse the effects of ethanol by placing the mice in increased concentrations of oxygen after the aerosolized pulmonary infections were unsuccessful. TABLE 1 Host Defense Mechanisms Experimentally Evaluated Following Acute Administration of Ethanol Pulmonary Defense Mechanisms Glottis Closure Ciliary Activity Lung Bacterial Clearance Alveolar Macrophage
Mobilization Function Systemic Defense Mechanisms Polymorphonuclear Leukocyte Mobilization Chemotaxis Function Peritoneal Macrophage Serum Bactericidal Activity
Alveolar Macrophage Mobilization: A possible mechanism for the observed ethanol-induced decrease in pulmonary clearance was offered by Guarneri and Laurenzi.lo They utilized a similar experimental model t o demonstrate that mice given ethanol had a decrease in the number of alveolar macrophages that could be recovered by lavage of the lungs after a pulmonary bacterial challenge. However, when these studies were repeated in the rabbit, they were unable t o demonstrate any adverse effect of ethanol o n alveolar macrophage mobilization. The variability in the response of different species t o ethanol indicates the potential danger in extrapolating from animal experiments t o man. Function: Gee e t al. have studied the effect of ethanol o n the phagocytic and antistaphylococcal activity of isolated rabbit alveolar macrophages." They were unable t o demonstrate any impairment in the phagocytosis and killing of S. aureus by macrophages exposed t o ethanol in vitro.
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SYSTEMICDEFENSE MECHANISMS Poly m orph on uclear Leukocyte Mobilization: The accumulation of polymorphonuclear leukocytes at sites of induced infection or trauma is decreased in animals and man following ethanol administration. Pickrell demonstrated that rabbits made stuporous with large amounts of ethanol (blood ethanol levels of 550-700 mg%) had fewer polymorphonuclear leukocytes in experimental pneumococcal infections of skin, lung, and pleural spaces than did control animals6 However, ether anesthesia had as marked an inhibitory effect o n the inflammatory response as did ethanol intoxication. Louria confirmed these observations in mice given a single injection of 0.5 ml of 30% ethanol subcutaneously and then challenged with l o 8 coagulase-negative staphylococci intraperitoneally. The number of polymorphonuclear leukocytes in peritoneal washouts 4 hours later was significantly lower than in saline-injected mice or animals rendered comatose with barbiturates and was inversely related t o the blood ethanol concentrations. Peripheral blood leukocyte counts did not differ in control and alcohol-treated mice. Moses e t al. reported that alcohol also diminished leukocyte mobilization into the suprapatellar bursa of rabbits following the local injection of a “stimulating substance” obtained from rabbit granulocyte^.'^ This was attributed t o a defect in vascular permeability and could be partially corrected by increasing the skin temperature. No abnormalities in leukocyte margination or stickiness were observed following ethanol administration in studies utilizing a rabbit ear chamber model. A leukocyte mobilization defect has also been documented in man with the Rebuck skin window technique.14 Human volunteers were given 50-75 ml of 95% ethanol intravenously over a 30-minute period. Immediately before injecting the alcohol a 1-cm2 area of the volunteers’ forearm was abraded t o the point of uniform redness and then covered with a siliconized glass cup, which was then filled with isotonic saline. The contents of the cup were evacuated at multiple time points and the numbers of polymorphonuclear leukocytes counted. A marked reduction in the leukocyte counts occurred during the first 4 hours after ethanol infusion. Similar findings were observed in volunteers given ethanol by mouth. However, a comparable degree of impaired leukocyte mobilization was observed in patients with profound terminal shock. Diabetic patients showed a less marked decrease in mobilization. No significant depression of mobilization was observed in patients with cirrhosis, uremia, or coma, or in patients undergoing prolonged general anesthesia for major surgery. The mechanisms responsible for these observations were not defined. There was n o clinical evidence of intoxication in the volunteers, nor was there hypotension, perceptible skin cooling, or changes in peripheral blood leukocyte counts. The investigators emphasized that “failure of emigration of leukocytes into the skin does not necessarily mean that alcohol will induce a similar abnormality in the lung parenchyma, the only site in which alcohol ingestion is clearly associated with increased proclivity t o and severity of infection.” Chemotaxis: The effect of ethanol on leukocyte chemotaxis was first studied in the 1930s by Klepser and N u n g e ~ t e r . ’They ~ measured the movement of human leukocytes toward pneumococci on glass slides after exposure of the leukocytes t o ethanol in vitro. The chemotactic response of the leukocytes was diminished by as little as 100 mg% of ethanol. Leukocytes from “deeply intoxicated” rats also had a diminished chemotactic response.
346
Annals New York Academy of Sciences
A recent report has confirmed that exposure of human leukocytes to ethanol in vitro will impair their chemotactic response, but only at ethanol concentrations of 800-1600 mg%.16 Function: Animal studies initially suggested that polymorphonuclear leukocyte phagocytic capacity and ability to effect intracellular killing was impaired by ethanol.12 These observations have not been confirmed by more recent studies utilizing quantitative measures of leukocyte function. Brayton et al. l4 utilized a modification of the technique of Maaloe to gauge phagocytosis and intracellular killing of coagulase-negative staphylococci by human polymorphonuclear leukocytes. They were unable to demonstrate any impairment of these functions in leukocytes exposed to 200 to 400 mg% of ethanol in vitro or in leukocytes obtained from volunteers receiving infusions of ethanol.
Peritoneal Macrophages Louria reported a decrease in the clearance of staphylococci from the peritoneal cavity of mice rendered comatose or ataxic with ethanol.12 Seventy-seven percent of control animals reduced peritoneal bacterial populations at least 10-fold during a 1-hour period following intraperitoneal infection. In contrast, only 47% of ataxic mice and 21% of comatose animals effected similar reductions in bacterial counts. In vitro studies suggested that peritoneal macrophages from comatose animals had a reduction in their phagocytic ability and perhaps impaired intracellular killing. Macrophages from ataxic animals had variable and often normal phagocytic and intracellular killing activity.
Serum Bactericidal Activity Studies by Kaplan and Brande on 2 human volunteers suggested that the bactericidal activity of serum was decreased against a strain of Escherichia coli and a strain of Hemophilus influenzae following ingestion of ethanol." This observation was confirmed and extended in subsequent studies in which normal volunteers received intravenous infusions of 50-75 ml of absolute ethanol.18 Serum bactericidal activity against strains of E. coli and H. influenzae type B were transiently decreased but near normal 5 hours after the ethanol infusion. The decrease in bactericidal activity was demonstrated by testing diluted serum. The decrease in bactericidal activity was not related t o the presence of ethanol or acetaldehyde in the serum per se and could not be attributed to changes in serum lysozyme or electrolytes or to alterations of bactericidal antibody or complement levels. There was no correlation between the serum ethanol level of the degree to which bactericidal activity was decreased. A preliminary report on the bactericidal activity of dog serum following ethanol infusion suggests that the effect of ethanol might be to impair the in vivo production of ~ o m p l e m e n t . ' ~
SUMMARY Ethanol administered t o animals in large amounts sufficient to produce coma and occasionally death will impair glottis closure, ciliary activity, lung and peritoneal bacterial clearance, mobilization of macrophages, and polymorphonuclear leukocytes and leukocyte chemotaxis. There is little or no impairment of these pulmonary and systemic host defense mechanisms in experimental studies employing amounts of ethanol that produce serum concentrations likely to be
Johnson: Impaired Defense Mechanisms
347
e n c o u n t e r e d in an intoxicated human. Modest amounts o f ethanol in man, sufficient to p r o d u c e minimal euphoria to mild intoxication, are associated with i m p a i r e d m o b i l i z a t i o n o f p o l y m o r p h o n u c l e a r l e u k o c y t e s into skin a n d decreased s e r u m bactericidal a c t i v i t y against certain gram-negative bacteria. The mechanism b y w h i c h e t h a n o l i m p a i r s these l a t t e r d e f e n s e mechanisms has not been clearly defined.
REFERENCES 1. RUSH, B. 1943. An inquiry into the effects of ardent spirits upon the human body and mind with an account of the means of preventing and of the remedies for curing them. (1785). Reprinted in Quart. J. Stud. Alcohol 4: 321-341. 2. PERLA, D. & J. MARMORSTON. 1941. Alcohol and resistance. In Natural Resistance and Clinical Medicine. 1153-1 161. Little, Brown and Co. Boston, Mass. 3. EICHNER, E. R. 1973. The hematologic disorders of alcoholism. Amer. I. Med. 54: 621-630. 4. LOURIA, D. B. 1973. The infectious complications of alcohol ingestion. Rev. Environ. Health 1: 175-184. 5. NUNGESTER, W. J. & R. G. KLEPSER. 1938. A possible mechanism of lowered re-
sistance to pneumonia. J. Infect. Dis. 63: 94-1 02. 6. PICKRELL, K. L. 1938. Effect of alcoholic intoxication and ether anesthesia on resistance to pneumococcic infection. Bull. Johns Hopkins Hosp. 63: 238-260. 7. LAURENZI, G. A. & J. J. GUARNERI. 1966. A study of the mechanisms of pulmonary resistance to infection: the relationship of bacterial clearance to ciliary activity and alveolar macrophage function. Amer. Rev. Resp. Dis. 93: 134-141. (Supplement) 8. GREEN, G. 1968. Pulmonary clearance of infectious agents. Ann. Rev. Med. 19: 315336. 9. GREEN, G. M. & E. H. KASS. 1964. Factors influencing the clearance of bacteria by the lung. 3. Clin. Invest. 43: 769-776. 10. GUARNERI, J. J. & G. A. LAURENZI. 1968. Effect of alcohol on the mobilization of alveolar macrophages. J. Lab. Clin. Med. 72: 40-51. 11. GEE, J. B. L., J. KASKIN, M. P. DUNCOMBE & C. L. VASSALLO. 1974. The effects of ethanol on some metabolic features of phagocytosis in the alveolar macrophage. J. Reticuloendothel. SOC. 15: 61-68. 12. LOURIA, D. B. 1963. Susceptibility t o infection during experimental alcohol intoxication. Trans. Ass. Amer. Physicians 76: 102-1 12. 13. MOSES, J. M., E. H. GESCHICKTER & R. H. EBERT. 1968. Pathogenesis of inflammation. The relationship of enhanced permeability t o leukocyte mobilization in delayed inflammation. Brit. J. Exp. Path. 49: 385-394. 14. BRAYTON, R. G., P. E. STOKES, M. S. SCHWARTZ & D. B. LOURIA. 1970. Effect of alcohol and various diseases on leukocyte mobilization, phagocytosis and intracellular bacterial killing. New Eng. J. Med. 282: 123-1 28. 15. KLEPSER, R. G. & W. J. NUNGESTER. 1939. The effect of alcohol upon the chemotactic response of leukocytes. J. Infect. Dis. 65: 196-199. 16. CROWLEY, J. P. & N. ABRAMSON. 1971. Effect of ethanol on complement-mediated chemotaxis. Clin. Res. 19: 415. 17. KAPLAN, N. M. & A. I. BRANDE. 1958. Hemophilus influenzae infection in adults: observations on the immune disturbance. Arch. Intern. Med. 101: 515-523. 18. JOHNSON, W. D. Jr., P. STOKES & D. KAYE. 1969. The effect of intravenous ethanol on the bactericidal activity of human serum. Yale J. Biol. Med. 42: 71-85. 19. MARR, J. J. & 1. SPILBERG. 1973. A mechanism for infection by gram-negative bacteria in acute alcohol intoxication. Clin. Res. 22: 449a.
