MEDICAL INFORMATION
H2, CH4 and CO2, and by these actions allow for the diffusion of N2 from blood into the colonic lumen. * Although attention to excessive air swallowing and change in diet may help some patients with "too much gas," alteration of abnormal gut motility may be of greater therapeutic benefit. REFERENCES 1. Levitt MD, Bond JH: Volume, composition, and source of intestinal gas. Gastroenterology 59:921-928, Dec 1970 2. Levitt MD: Volume and composition of human intestinal gas determined by means of an intestinal washout technique. N Engl J Med 284:1394-1398, Jun 1971 3. Levitt MD, Lasser RB, Schwartz JE, et al: Studies of a flatulent patient. N Engl J Med 295: 260-262, Jul 1976 4. Lasser RB, Bond JH, Levitt MD: The role of intestinal gas in functional abdominal pain. N Engl J Med 293:523-526 Sept 1975 5. Levitt MD, Berggren T, Hastings J, et al: Hydrogen (H.2) catabolism in the colon of the rat. J Lab Clin Med 84:163-167, Aug 1974 6. Levitt MD, Duane WC: Floating stools-flatus versus fat. N Engl J Med 286:973-975, May 1972
antibody, with or without the participation of complement. The basis for detecting the presence of such a reaction is the antiglobulin test, otherwise known as the Coombs' test.' Antiserum is produced by injecting rabbits with human immunoprotein, either antibody or complement. The animal makes antibody to whatever is injected. That antibody can be purified and then reacted in vitro with a patient's washed red blood cells (RBC). If the cells agglutinate, the test is positive. By serial dilutions the degree of positivity can be quantitated. In a recent review,2 Wendell Rosse has classified the Coombs' test results according to whether antibody alone is detected on the red cell, antibody plus complement, complement alone, or neither antibody nor complement. This classification is useful in understanding the pathophysiology of immune red cell destruction.
Antibody Alone on RBC Refer to: Cohen JR: Pathogenesis of hemolysis in immune hemolytic anemia (Medical Information). West J Med 127: 363-365, Oct 1977
Pathogenesis of Hemolysis in Immune Hemolytic Anemia JAMES R. COHEN, MD Stanford AUTOIMMUNE HEMOLYTIC ANEMIA is not an uncommon problem in clinical medicine, and when it occurs it can be quite perplexing to the practitioner. In recent years our understanding of the mechanisms involved in immune red cell destruction has advanced considerably. This discussion will attempt to summarize some of these mechanisms and relate them to clinical decisions concerning course and treatment. Hemolysis due to immunologic mechanisms is caused by a reaction between antigenic sites on the surface of the red blood cell and circulating From the Division of Hematology, Department of Medicine, Stanford University School of Medicine. Supported in part by: Public Health Service Grant CA-08122-10 and Hematology Small Gifts Fund. Reprint requests to: James R. Cohen, MD, Division of Hematology, Dept. of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
In 1967, LoBuglio and co-workers showed that red blood cells coated with IgG would bind to monocytes.3 That this binding was inhibited by excess IgG, and more specifically by excess Fc fragments, suggested that there was a binding site on monocytes for the Fc fragment of IgG. Electronmicrography showed that the monocytes caused membrane injury to the red cells coated with IgG, causing them to become spherocytes. Spherocytes were subsequently sequestered in the spleen. In the absence of monocytes, IgG caused no membrane injury. Cells coated with IgM did not bind to monocytes.4 Subsequent workers have shown that there are subclasses of IgG: IgG1, IgG2, IgG3 and IgG4. Monocyte receptors have been found only for subclasses IgG1, and IgG,.5 IgG2 and IgG, will not inhibit monocyte binding of cells coated with IgG1 and IgG2 but these two subtypes will inhibit each other, suggesting that there is only one binding site. Radiolabeling studies have showed in vivo that cells coated by IgG are sequestered in the spleen.7 The characteristic of autoimmune hemolytic anemia with a Coombs' test positive for antibody alone (the "gamma Coombs'"), therefore, is an IgG antibody, spherocytes and splenic sequestration.
Antibody Plus Complement on RBC In 1968 Huber and co-workers8 showed that there was a second monocyte receptor; this one for the third component of complement. That this receptor was separate from the above described THE WESTERN JOURNAL OF MEDICINE
363
MEDICAL INFORMATION
IgG receptor was concluded from the inability of free IgG to inhibit the binding. Cells coated with Cl, C1,4 and C1,4,2 did not bind, and the addition of C5,6,7 did not enhance the binding. It has been long known that IgM binds complement more readily than IgG.9 This is felt to be- due to the fact that complement fixation requires two Fc fragments a specific distance apart. A single molecule of IgM, which has five Fc fragments, can accomplish this, whereas two molecules of IgG must be adherent to the red blood cell at the correct distance apart to allow for the binding of C3.1'0'1 Chromium51 studies have shown that red cells coated with IgM and complement, unlike those coated with only IgG, tend to be sequestered in the liver preferentially, rather than the spleen. It has been shown both in experimental animals12 and in man,13 that some of these cells are subsequently released from the liver. This can be explained by looking at the fixation of C3 in somewhat greater detail. When adherent to a red cell, C1,4,2 is able to cleave C3 into subfragments. The fragment known as C3b adheres to the red blood cell, and the monocyte receptor is specific for C3b.11 A serum enzyme,' C3b inactivator, can cleave C3b leaving a second subfragment, C3d, adherent to the red cell. There is no monocyte receptor for C3d, hence the red cell is protected from sequestration and destruction.14 5 This explains the seemingly paradoxical finding that autologous red cells from some patients with cold agglutinin disease survive longer when reinjected in vivo than infused matched donor cells.'6
Complement Alone on RBC Whereas IgM has been shown to readily fix complement, the IgM itself does not adhere well to the red cells at room temperature. The IgM may come off the red cell in vivo, as when it is fixed in a cool extremity and removed at core temperature, or it may be removed in vitro when the red cells are washed at 37°C. Therefore, most cases of "cold" hemolytic anemia are IgM mediated, but only complement is detected when the Coombs' test is done. Such Coombs' tests are reported as "nongamma." Whereas, as discussed above, these cells are subsequently sequestered in the liver, complement can itself cause intravascular hemolysis. This requires the completion of the complement sequence through C9, at which point the red cell lyses.17"19 364
OCTOBER 1977 * 127 * 4
No Antibody or Complement Detected There are some patients who appear to have all the signs and, symptoms of classic immune hemolysis but in whom results of a Coombs' test are negative. It has recently been shown by Gilliland and associates,1'12'1 using a sensitive complement-fixing antibody consumption test, that such red blood cells do indeed have a small increase in the number of IgG molecules adherent to their red blood cells. Whereas normal red cells have approximately 35 molecules per red blood cell and commercial Coombs' antisera cannot detect less than 200 molecules, Gilliland has found hemolysis with as few as 70 molecules of IgG per red blood cell. The treatment of immune hemolytic anemia depends both on the underlying cause and upon which of the above types of immunologic reactions is involved. Most drug or viral related hemolyses are self-limited once the offending agent is removed or infection over. Hemolysis related to lymphoma or connective tissue disease may improve with treatment of the disease. From the above discussion, it is evident that the treatment of an IgG idiopathic hemolytic anemia should include serious consideration of a splenectomy. This gives up to 68 percent response in some series, although some of these patients subsequently may require continuous steroid treatment.22 Splenectomy clearly is not indicated in the hemolyses involving complement, since most sequestration and red blood cell destruction is here occurring in the liver. Steroids are often of benefit. The mechanism of action of steroids in hemolysis is not known, although they have been shown to decrease cell bound IgG,23 and increase free IgG, implying a decrease in red cell-antibody affinity. More important, steroids have been shown to decrease monocyte binding of IgGcoated red blood cells.24 Steroids also are lympholytic and may work partly by decreasing antibody production. This should be a slow action, however, and the response to steroids is often fairly dramatic.25 Although up to 80 to 90 percent of patients with autoimmune idiopathic hemolytic anemia may respond to therapy with steroids, in a number of these patients steroid administration will have to be maintained indefinitely. Although cytotoxic agents have been used with some success in patients refractory to steroids, these should not be employed unless hemolysis cannot be controlled by steroids and splenectomy.26
MEDICAL INFORMATION
This has been a brief attempt to present one way to approach the evaluation of a patient with an immune hemolytic anemia. Although sorting out the finer details of IgG subclass or quantification of IgG molecules requires a sophisticated laboratory, an initial understanding of the pathophysiology and initial treatment decisions can be made based on the type of Coombs' reaction described above. This information is available in any hospital blood bank laboratory. REFERENCES 1. Coombs RA, Mourant AE, Race RR: A new test for the detection of weak and "incomplete" Rh agglutinins. Brit J Exp Path 36:255, 1945 2. Rosse WF: The antiglobulin test in autoimmune hemolytic anemia. Ann Rev Med 26:331, 1975 3. LoBuglio AF, Cotran RS, Jandl JH: Red cells coated with immunoglobulin G: Binding and sphering by mononuclear cells in man. Science 158:1582, 1967 4. Abramson N, LoBuglio AF, Jandl JH, et al: The interaction between human monocytes and red cells. J Exp Med 132:1191, 1970 5. Abramson N, Gelfand EW, Jandl JH, et al: The interaction between human monocytes and red cells: Specificity for IgG subclasses and IgG fragments. J Exp Med 132:1207, 1970 6. Abramson N, Schur PH: The IgG subclasses of red cell antibodies and relationship to monocyte binding. Blood 40: 500, 1972 7. Schreiber AD, Frank MM: Role of antibody and complement in the immune clearance and destruction of erythrocytes. I. In vivo effect of IgG and IgM complement-fixing sites. J Clin Invest 51:575, 1972 8. Huber H, Polley MJ, Linscott WD, et al: Distinct receptor sites for third component of complement and for immunoglobulin G. Science 162:1281, 1968 9. Borsos T, Rapp HG: Complement fixation on cell surfaces by 19S and 7S antibodies. Science 150:505, 1965
10. Rosse WE: Fixation of the first component of complement la by human antibodies. J Clin Invest 47:2430, 1968
11. Rosse WF: Correlation of in vivo and in vitro measure-
ments of hemolysis in hemolytic anemia due to immune reactions. Prog Hemat VIII:51, 1973 12. Schreiber AD, Frank MM: Role of antibody and complement in the immune clearance and destruction of RBC's-II: Molecular nature of IgG and IgM complement-fixing sites and effects of their interaction with serum. J Clin Invest 51:583, 1972 13. Atkinson JP, Schreiber FD, Frank MM: Effects of corticosteroids and splenectomy on the immune clearance and destruction of erythrocytes. J Clin Invest 54:1509, 1973 14. Jaffe CJ, Atkinson JF, Frank MM: Role of complement in the clearance of cold agglutinin-sensitized erythrocytes in man. J Clin Invest 58:942, 1976 15. Ruddy S, Austen KF: C3b inactivator of man. J Immunol 107:742, 1971 16. Frank M, Atkinson JP, Gadek J: Cold agglutinins and cold-agglutinin disease. Ann Rev Med 28:291, 1977 17. Mollison PL: The role of complement in antibody mediated red cell destruction. Brit J Haemat 18:249, 1970 18. Mayer MM: Mechanism of cytolysis by complement. Proc Nat Acad Sci 69:2954, 1972 19. Gilliland BC, Leddy JP, Vaughan JH: The detection of cell-bound antibody on complement-coated human red ceUs. J Clin Invest 49:898, 1970 20. Gilliland BC, Baxter E, Evans RS: Red cell antibodies in acquired hemolytic anemia with negative antiglobulin serum tests. N Engl J Med 285:252, 1971 21. Gilliland BC: Coombs-negative immune hemolytic anemia. Sem Hemat 13:267, 1976 22. Allgood JW, Chaplin H Jr: Idiopathic acquired autoimmune hemolytic anemia. Amer J Med 43:254, 1967 23. Rosse WF: Quantitative immunology of immune hemolytic anemia-II. The relationship of cell-bound antibody to hemolysis and the effect of treatment. J Clin Invest 50:734, 1971 24. Schreiber AD, Parsons J, McDermott P, et al: Effect of corticosteroids on the human monocyte IgG and complement receptors. J Clin Invest 56:1189, 1975 25. Fauci AJ, Dale DC, Balow JE; Glucocorticosteroid therapy: Mechanism of action and clinical considerations. Ann Int Med
84:304, 1976 26. Murphy S, LoBuglio AF: Drug therapy of autoimmune hemolytic anemia. Sem Hemat 13:323, 1976
Combating Insulin Overtreatment in Children DR. ROSENBLOOM: "The problem that we see as the most common error in the management of diabetes in children . . . is overtreatment with insulin. We recommend reducing the insulin dose to the pre-overtreatment dose or to the usual dose of 0.6 to 0.7 units per kg of body weight per day. We try all-NPH (neutral protamine Hagedorn) or all-Lenteg if a mix has been used for unclear reasons. There may be a several weeks' period of increased glucosuria and ketonuria following reduction. And hypoglycemic symptoms may actually increase or emerge for the first time, indicating the need for further and faster reduction in decrements of 10 to 20 percent at four- to ten-day intervals." -ARLAN L. ROSENBLOOM, MD, Gainesville, FL
Extracted from Audio-Digest Pediatrics, Vol. 22, No. 23, in the Audio-Digest Foundation's subscription series of tape-recorded programs. For subscription information: 1577 East Chevy Chase Drive, Glendale, CA 91206.
THE WESTERN JOURNAL OF MEDICINE
365
H2, CH4 and CO2, and by these actions allow for the diffusion of N2 from blood into the colonic lumen. * Although attention to excessive air swallowing and change in diet may help some patients with "too much gas," alteration of abnormal gut motility may be of greater therapeutic benefit. REFERENCES 1. Levitt MD, Bond JH: Volume, composition, and source of intestinal gas. Gastroenterology 59:921-928, Dec 1970 2. Levitt MD: Volume and composition of human intestinal gas determined by means of an intestinal washout technique. N Engl J Med 284:1394-1398, Jun 1971 3. Levitt MD, Lasser RB, Schwartz JE, et al: Studies of a flatulent patient. N Engl J Med 295: 260-262, Jul 1976 4. Lasser RB, Bond JH, Levitt MD: The role of intestinal gas in functional abdominal pain. N Engl J Med 293:523-526 Sept 1975 5. Levitt MD, Berggren T, Hastings J, et al: Hydrogen (H.2) catabolism in the colon of the rat. J Lab Clin Med 84:163-167, Aug 1974 6. Levitt MD, Duane WC: Floating stools-flatus versus fat. N Engl J Med 286:973-975, May 1972
antibody, with or without the participation of complement. The basis for detecting the presence of such a reaction is the antiglobulin test, otherwise known as the Coombs' test.' Antiserum is produced by injecting rabbits with human immunoprotein, either antibody or complement. The animal makes antibody to whatever is injected. That antibody can be purified and then reacted in vitro with a patient's washed red blood cells (RBC). If the cells agglutinate, the test is positive. By serial dilutions the degree of positivity can be quantitated. In a recent review,2 Wendell Rosse has classified the Coombs' test results according to whether antibody alone is detected on the red cell, antibody plus complement, complement alone, or neither antibody nor complement. This classification is useful in understanding the pathophysiology of immune red cell destruction.
Antibody Alone on RBC Refer to: Cohen JR: Pathogenesis of hemolysis in immune hemolytic anemia (Medical Information). West J Med 127: 363-365, Oct 1977
Pathogenesis of Hemolysis in Immune Hemolytic Anemia JAMES R. COHEN, MD Stanford AUTOIMMUNE HEMOLYTIC ANEMIA is not an uncommon problem in clinical medicine, and when it occurs it can be quite perplexing to the practitioner. In recent years our understanding of the mechanisms involved in immune red cell destruction has advanced considerably. This discussion will attempt to summarize some of these mechanisms and relate them to clinical decisions concerning course and treatment. Hemolysis due to immunologic mechanisms is caused by a reaction between antigenic sites on the surface of the red blood cell and circulating From the Division of Hematology, Department of Medicine, Stanford University School of Medicine. Supported in part by: Public Health Service Grant CA-08122-10 and Hematology Small Gifts Fund. Reprint requests to: James R. Cohen, MD, Division of Hematology, Dept. of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
In 1967, LoBuglio and co-workers showed that red blood cells coated with IgG would bind to monocytes.3 That this binding was inhibited by excess IgG, and more specifically by excess Fc fragments, suggested that there was a binding site on monocytes for the Fc fragment of IgG. Electronmicrography showed that the monocytes caused membrane injury to the red cells coated with IgG, causing them to become spherocytes. Spherocytes were subsequently sequestered in the spleen. In the absence of monocytes, IgG caused no membrane injury. Cells coated with IgM did not bind to monocytes.4 Subsequent workers have shown that there are subclasses of IgG: IgG1, IgG2, IgG3 and IgG4. Monocyte receptors have been found only for subclasses IgG1, and IgG,.5 IgG2 and IgG, will not inhibit monocyte binding of cells coated with IgG1 and IgG2 but these two subtypes will inhibit each other, suggesting that there is only one binding site. Radiolabeling studies have showed in vivo that cells coated by IgG are sequestered in the spleen.7 The characteristic of autoimmune hemolytic anemia with a Coombs' test positive for antibody alone (the "gamma Coombs'"), therefore, is an IgG antibody, spherocytes and splenic sequestration.
Antibody Plus Complement on RBC In 1968 Huber and co-workers8 showed that there was a second monocyte receptor; this one for the third component of complement. That this receptor was separate from the above described THE WESTERN JOURNAL OF MEDICINE
363
MEDICAL INFORMATION
IgG receptor was concluded from the inability of free IgG to inhibit the binding. Cells coated with Cl, C1,4 and C1,4,2 did not bind, and the addition of C5,6,7 did not enhance the binding. It has been long known that IgM binds complement more readily than IgG.9 This is felt to be- due to the fact that complement fixation requires two Fc fragments a specific distance apart. A single molecule of IgM, which has five Fc fragments, can accomplish this, whereas two molecules of IgG must be adherent to the red blood cell at the correct distance apart to allow for the binding of C3.1'0'1 Chromium51 studies have shown that red cells coated with IgM and complement, unlike those coated with only IgG, tend to be sequestered in the liver preferentially, rather than the spleen. It has been shown both in experimental animals12 and in man,13 that some of these cells are subsequently released from the liver. This can be explained by looking at the fixation of C3 in somewhat greater detail. When adherent to a red cell, C1,4,2 is able to cleave C3 into subfragments. The fragment known as C3b adheres to the red blood cell, and the monocyte receptor is specific for C3b.11 A serum enzyme,' C3b inactivator, can cleave C3b leaving a second subfragment, C3d, adherent to the red cell. There is no monocyte receptor for C3d, hence the red cell is protected from sequestration and destruction.14 5 This explains the seemingly paradoxical finding that autologous red cells from some patients with cold agglutinin disease survive longer when reinjected in vivo than infused matched donor cells.'6
Complement Alone on RBC Whereas IgM has been shown to readily fix complement, the IgM itself does not adhere well to the red cells at room temperature. The IgM may come off the red cell in vivo, as when it is fixed in a cool extremity and removed at core temperature, or it may be removed in vitro when the red cells are washed at 37°C. Therefore, most cases of "cold" hemolytic anemia are IgM mediated, but only complement is detected when the Coombs' test is done. Such Coombs' tests are reported as "nongamma." Whereas, as discussed above, these cells are subsequently sequestered in the liver, complement can itself cause intravascular hemolysis. This requires the completion of the complement sequence through C9, at which point the red cell lyses.17"19 364
OCTOBER 1977 * 127 * 4
No Antibody or Complement Detected There are some patients who appear to have all the signs and, symptoms of classic immune hemolysis but in whom results of a Coombs' test are negative. It has recently been shown by Gilliland and associates,1'12'1 using a sensitive complement-fixing antibody consumption test, that such red blood cells do indeed have a small increase in the number of IgG molecules adherent to their red blood cells. Whereas normal red cells have approximately 35 molecules per red blood cell and commercial Coombs' antisera cannot detect less than 200 molecules, Gilliland has found hemolysis with as few as 70 molecules of IgG per red blood cell. The treatment of immune hemolytic anemia depends both on the underlying cause and upon which of the above types of immunologic reactions is involved. Most drug or viral related hemolyses are self-limited once the offending agent is removed or infection over. Hemolysis related to lymphoma or connective tissue disease may improve with treatment of the disease. From the above discussion, it is evident that the treatment of an IgG idiopathic hemolytic anemia should include serious consideration of a splenectomy. This gives up to 68 percent response in some series, although some of these patients subsequently may require continuous steroid treatment.22 Splenectomy clearly is not indicated in the hemolyses involving complement, since most sequestration and red blood cell destruction is here occurring in the liver. Steroids are often of benefit. The mechanism of action of steroids in hemolysis is not known, although they have been shown to decrease cell bound IgG,23 and increase free IgG, implying a decrease in red cell-antibody affinity. More important, steroids have been shown to decrease monocyte binding of IgGcoated red blood cells.24 Steroids also are lympholytic and may work partly by decreasing antibody production. This should be a slow action, however, and the response to steroids is often fairly dramatic.25 Although up to 80 to 90 percent of patients with autoimmune idiopathic hemolytic anemia may respond to therapy with steroids, in a number of these patients steroid administration will have to be maintained indefinitely. Although cytotoxic agents have been used with some success in patients refractory to steroids, these should not be employed unless hemolysis cannot be controlled by steroids and splenectomy.26
MEDICAL INFORMATION
This has been a brief attempt to present one way to approach the evaluation of a patient with an immune hemolytic anemia. Although sorting out the finer details of IgG subclass or quantification of IgG molecules requires a sophisticated laboratory, an initial understanding of the pathophysiology and initial treatment decisions can be made based on the type of Coombs' reaction described above. This information is available in any hospital blood bank laboratory. REFERENCES 1. Coombs RA, Mourant AE, Race RR: A new test for the detection of weak and "incomplete" Rh agglutinins. Brit J Exp Path 36:255, 1945 2. Rosse WF: The antiglobulin test in autoimmune hemolytic anemia. Ann Rev Med 26:331, 1975 3. LoBuglio AF, Cotran RS, Jandl JH: Red cells coated with immunoglobulin G: Binding and sphering by mononuclear cells in man. Science 158:1582, 1967 4. Abramson N, LoBuglio AF, Jandl JH, et al: The interaction between human monocytes and red cells. J Exp Med 132:1191, 1970 5. Abramson N, Gelfand EW, Jandl JH, et al: The interaction between human monocytes and red cells: Specificity for IgG subclasses and IgG fragments. J Exp Med 132:1207, 1970 6. Abramson N, Schur PH: The IgG subclasses of red cell antibodies and relationship to monocyte binding. Blood 40: 500, 1972 7. Schreiber AD, Frank MM: Role of antibody and complement in the immune clearance and destruction of erythrocytes. I. In vivo effect of IgG and IgM complement-fixing sites. J Clin Invest 51:575, 1972 8. Huber H, Polley MJ, Linscott WD, et al: Distinct receptor sites for third component of complement and for immunoglobulin G. Science 162:1281, 1968 9. Borsos T, Rapp HG: Complement fixation on cell surfaces by 19S and 7S antibodies. Science 150:505, 1965
10. Rosse WE: Fixation of the first component of complement la by human antibodies. J Clin Invest 47:2430, 1968
11. Rosse WF: Correlation of in vivo and in vitro measure-
ments of hemolysis in hemolytic anemia due to immune reactions. Prog Hemat VIII:51, 1973 12. Schreiber AD, Frank MM: Role of antibody and complement in the immune clearance and destruction of RBC's-II: Molecular nature of IgG and IgM complement-fixing sites and effects of their interaction with serum. J Clin Invest 51:583, 1972 13. Atkinson JP, Schreiber FD, Frank MM: Effects of corticosteroids and splenectomy on the immune clearance and destruction of erythrocytes. J Clin Invest 54:1509, 1973 14. Jaffe CJ, Atkinson JF, Frank MM: Role of complement in the clearance of cold agglutinin-sensitized erythrocytes in man. J Clin Invest 58:942, 1976 15. Ruddy S, Austen KF: C3b inactivator of man. J Immunol 107:742, 1971 16. Frank M, Atkinson JP, Gadek J: Cold agglutinins and cold-agglutinin disease. Ann Rev Med 28:291, 1977 17. Mollison PL: The role of complement in antibody mediated red cell destruction. Brit J Haemat 18:249, 1970 18. Mayer MM: Mechanism of cytolysis by complement. Proc Nat Acad Sci 69:2954, 1972 19. Gilliland BC, Leddy JP, Vaughan JH: The detection of cell-bound antibody on complement-coated human red ceUs. J Clin Invest 49:898, 1970 20. Gilliland BC, Baxter E, Evans RS: Red cell antibodies in acquired hemolytic anemia with negative antiglobulin serum tests. N Engl J Med 285:252, 1971 21. Gilliland BC: Coombs-negative immune hemolytic anemia. Sem Hemat 13:267, 1976 22. Allgood JW, Chaplin H Jr: Idiopathic acquired autoimmune hemolytic anemia. Amer J Med 43:254, 1967 23. Rosse WF: Quantitative immunology of immune hemolytic anemia-II. The relationship of cell-bound antibody to hemolysis and the effect of treatment. J Clin Invest 50:734, 1971 24. Schreiber AD, Parsons J, McDermott P, et al: Effect of corticosteroids on the human monocyte IgG and complement receptors. J Clin Invest 56:1189, 1975 25. Fauci AJ, Dale DC, Balow JE; Glucocorticosteroid therapy: Mechanism of action and clinical considerations. Ann Int Med
84:304, 1976 26. Murphy S, LoBuglio AF: Drug therapy of autoimmune hemolytic anemia. Sem Hemat 13:323, 1976
Combating Insulin Overtreatment in Children DR. ROSENBLOOM: "The problem that we see as the most common error in the management of diabetes in children . . . is overtreatment with insulin. We recommend reducing the insulin dose to the pre-overtreatment dose or to the usual dose of 0.6 to 0.7 units per kg of body weight per day. We try all-NPH (neutral protamine Hagedorn) or all-Lenteg if a mix has been used for unclear reasons. There may be a several weeks' period of increased glucosuria and ketonuria following reduction. And hypoglycemic symptoms may actually increase or emerge for the first time, indicating the need for further and faster reduction in decrements of 10 to 20 percent at four- to ten-day intervals." -ARLAN L. ROSENBLOOM, MD, Gainesville, FL
Extracted from Audio-Digest Pediatrics, Vol. 22, No. 23, in the Audio-Digest Foundation's subscription series of tape-recorded programs. For subscription information: 1577 East Chevy Chase Drive, Glendale, CA 91206.
THE WESTERN JOURNAL OF MEDICINE
365
