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Infectious hazards of immune globulin
EDITORIAL CORRESPONDENCE
Usefulness of cerebrospinal fluid bacterial antigen tests To the Editor." We found the recent article 1 attempting to quantify the clinical utility of the cerebrospinal fluid (CSF) Directigen test (Becton Dickinson Microbiology Systems, Cockeysville, Md.) very interesting. This study addresses issues of cost containment that are vital to providing quality care in a managed care environment. If a diagnostic study or therapeutic intervention is without utility, it should be abandoned. We applaud the authors for having the intellectual courage to examine the usefulness of CSF bacterial studies in that light. Of the 901 reviewed circumstances in which a CSF Directigen test was obtained, 29 antigen test results were positive and 872 resuits were negative. The authors describe in detail the negligible impact that the positive test result had on the management of the 29 patients with positive results, but are curiously silent about the 872 patients with negative results, except to say that results for 6 patients were deemed falsely negative. Is it possible that the real benefit of the Directigen test is in the true-negative results? How many of these patients would have been hospitalized and given intravenously administered antibiotics (with all of the costs involved) had it not been for the negative Directigen test result? Preventing only a few needless admissions each year could more than offset the cost savings of not performing the test. Given that the purpose of the study was to try to find ways to cut costs without decreasing the quality of care rendered, have the authors considered eliminating the routine ordering of determinations of CSF protein and glucose levels? On the basis of our understanding of their protocol, the results of these determinations apparently never affected the clinical decisions made for patients in whom a diagnosis of meningitis was suspected. At a cost of $54 per test, not obtaining these studies in the 901 subjects would have saved nearly $49,000 during t h e study period. Perhaps the utility of those tests should be the focus of a future clinical review. In this era of changes in health care delivery, all health care professionals are obligated to seek opportunities to cut costs. Provided our efforts serve to eliminate the "dead wood" and preserve the "good wood," we can be assured that we are making progress; however, it is incumbent on us to consider the value of a negative test result when we make those determinations. This article serves an admirable purpose in focusing our attention toward the goal of practicing quality, cost-conscious medicine, but until all of the potential cost benefits of a negative test result are included in the equation, the author's conclusion that the Directigen test not be used is premature. C. R. Warren, DO IV. R. Kiser, MD, M A Department o f Family Practice Naval Hospital 2080 Child St. Jacksonville, FL 32214-5227 9/35/61127 The Journal of Pediatrics
REFERENCE 1. Maxson S, Lewno M J, Schultze GE. Clinical usefulness of cerebrospinal fluid bacterial antigen studies. J PEDIATR 1994; 125:235-8.
Reply To the Editor: In our institution, a decision to admit a patient from the clinic or emergency department has never been based on the results of a cerebrospinal fluid bacterial antigen test. Therefore we cannot comment on its role in keeping patients out of the hospital. As for determinations of cerebrospinal fluid protein and glucose levels, we believe that their role is very useful. The first part of our suggested protocol states that % . . two groups of patients with bacterial meningitis could benefit from having CSF antigens tested." Patients with bacterial meningitis are implied to have abnormal protein and glucose values. We understand that bacterial antigen testing has a different role at different institutions. We believe, however, that the routine use of these tests for every patient who has a lumbar puncture is not cost effective. 111. Suzanne Maxson, MD Fellow, Pediatric Infectious Diseases Mary Jo Lewno, BS Chief Technical Director Microbiology Laboratory Gordon E. Schutze, MD Assistant Professor o f Pediatrics and Pathology Pediatric Infectious Diseases/Immunology Arkansas Children's Hospital 800 Marshall St. Little Rock, A R 72202-3591 9/35/61126
Infectious hazards of immune globulin To the Editor." I read with interest the article by Karna et al., "Passive Transfer of Hepatitis Antibodies During Intravenous Administration of Immune Globulin. ''1 The authors found no clinical or laboratory evidence of transmission of hepatitis B or C, despite passive transfer of hepatitis B and C an6bodies in the majority of the 10 premature neonates studied. However, the small number of infants studied does not preclude a type II error. Lest complacency develop regarding the safety of U.S. preparations of intravenously administered immune globulin, a recent outbreak of acute hepatitis C infections in 112 recipients of licensed intravenous immune globulin February 1995
321
322
Editorial correspondence
The Journal of Pediatrics February 1995
preparations serves as a reminder of the infectious hazards of all biologic preparations. 2
Leslie L. Barton, MD Department of Pediatrics Section of Infectious Diseases University of Arizona Health Sciences Center Steele Memorial Children's Research Center Tucson, A Z 85724 9/35/61305
REFERENCES
1. Karna P, Murray DL, Valduss D, Mattarella N, Dyke JW, Maier GA. Passive transfer of hepatitis antibodies during intravenous administration of immune globulin. J PEDIATR 1994; 125:463-5. 2. CDC. Outbreak of hepatitis C associated with intravenous immunoglobulin administration--United States, October t993-June 1994. M M W R Morb Mortal Wkly Rep 1994;43: 505-9.
Reply Intravenous immune globulin preparations have enjoyed a very successful track record in this country for safety from infectious diseases. As mentioned in our article, initial preparations of intravenously administered immune globulin in Europe were associated with non-A, non:B hepatitis.~ Testing for hepatitis C (non-A, non-B hepatitis) is not 100% sensitive at this time. We agree with Dr. Barton that the recent problem with intravenously administered immune globulin is disturbing and should cause physicians to use such preparations cautiously.
Padmani Karna, AID Dennis L, Murray, MD John W. Dyke, PhD Michigan State University and Sparrow Hospital Lansing, MI 48909-7980 9/35/61304
REFERENCES
1. Ochs MD, Fischer SH, Virant FS, et al. Non-A, non-B hepatitis after intravenous immunoglobulin. Lancet 1986; 1:322-3.
Differences in clinical significance of maternal-infant blood group incompatibility in mothers with blood type O, A, or B To the Editor," I read with interest the article by Ozolek et at.,1 which is an elegant study of a very large population base. I was disappointed, however, to find that there was no mention of the physiologic basis of their findings. I was atso surprised to find that a standard pediatric hematology textbook also does not mention the physiologic basis for their results.
On the other hand. a standard adult hematology textbook states 'Antibodies of the ABO system are 'naturally occurring,' suggesting immunization against cross-reactive antigens that are widespread on cell types of other organisms such as bacteria. Anti-A and anti-B are predominantly IgM in group B or A individuals, whereas the serum of group O subjects contains significant amounts of anti-A and anti-B that is also of the IgG class. This difference m immune response remains unexplained," 2 Although the cause for these differences remains unexplained, the fact that they do occur provides a simple and logical explanation for the findings of OzoIek et al. Mothers with blood type A or B whose anti-B or anti-A antibodies are predominantly of the IgM class, which do not cross the placenta, would be far less iikely ~o encounter complications of incompatibility than mothers with blood type O, in whom a significant amoum of anti-A and anti-B antibody is of the IgG class. which readily crosses the placenta. This is consistent with the findings of Ozolek et al. that "type A or B mothers were 5.5 times less likely to have a positive Coombs test result than type O mothers "" Although individuals with blood type O have a significant amount of IgG isoantibodies, the exact amount or percentage probably varies in each person with blood type O. This is probably a major reason for the observed clinical variability, even in O-A and O-B incompatibilities. One might hope that this knowledge of the antibodies of the ABO system wilt become as common in the pediatric literature as it is in the adult literature.
Harold Pert, MD Division of Neonatology Hackensack Medical Center Hackensack, NJ 0760) 9/35/61299
REFERENCES
1. Ozolek JA, Watchko JF, Mimouni F. Prevalence and lack of clinical significance of blood group incompatibility in mothers with blood type A or B. J PEDIATR 1994;125:87-9I. 2. Silberstein LE, Spitalnick SL. Human blood group antigens and antibodies. In: Hoffman R, Benz EJ Jr, Shattel S J; Furie B, Cohen H J, eds. Hematology: basic principlesand practice: New York: Churchill Livingstone, 1991:1548-56.
Reply To the Editor." Contrary to Dr. Perl's impression, the pediatric hematology literature does address the pathophysiology of ABO incompatibility in the newborn infant and specifically the role of different antibody classes in this phenomenon, In Hematologic Problems in the Newborn, by Oski and Naiman,1 the explanation cited for cases of hemolytic disease of the newborn as a result of ABO incompatibility is that natural anti-A and anti-B of mothers with blood group O are of the IgG class and can cross the placenta, whereas those of mothers with blood type A or B are predominantly IgM and cannot cross the placenta. The original work describing the predominance of 19S (IgM) globulin in B anti-A and A anti-B donors was reported by Abelson and Rawson in 19611z We did not discuss the possible path0physiology of our findings because that was beyond the scope
Usefulness of cerebrospinal fluid bacterial antigen tests To the Editor." We found the recent article 1 attempting to quantify the clinical utility of the cerebrospinal fluid (CSF) Directigen test (Becton Dickinson Microbiology Systems, Cockeysville, Md.) very interesting. This study addresses issues of cost containment that are vital to providing quality care in a managed care environment. If a diagnostic study or therapeutic intervention is without utility, it should be abandoned. We applaud the authors for having the intellectual courage to examine the usefulness of CSF bacterial studies in that light. Of the 901 reviewed circumstances in which a CSF Directigen test was obtained, 29 antigen test results were positive and 872 resuits were negative. The authors describe in detail the negligible impact that the positive test result had on the management of the 29 patients with positive results, but are curiously silent about the 872 patients with negative results, except to say that results for 6 patients were deemed falsely negative. Is it possible that the real benefit of the Directigen test is in the true-negative results? How many of these patients would have been hospitalized and given intravenously administered antibiotics (with all of the costs involved) had it not been for the negative Directigen test result? Preventing only a few needless admissions each year could more than offset the cost savings of not performing the test. Given that the purpose of the study was to try to find ways to cut costs without decreasing the quality of care rendered, have the authors considered eliminating the routine ordering of determinations of CSF protein and glucose levels? On the basis of our understanding of their protocol, the results of these determinations apparently never affected the clinical decisions made for patients in whom a diagnosis of meningitis was suspected. At a cost of $54 per test, not obtaining these studies in the 901 subjects would have saved nearly $49,000 during t h e study period. Perhaps the utility of those tests should be the focus of a future clinical review. In this era of changes in health care delivery, all health care professionals are obligated to seek opportunities to cut costs. Provided our efforts serve to eliminate the "dead wood" and preserve the "good wood," we can be assured that we are making progress; however, it is incumbent on us to consider the value of a negative test result when we make those determinations. This article serves an admirable purpose in focusing our attention toward the goal of practicing quality, cost-conscious medicine, but until all of the potential cost benefits of a negative test result are included in the equation, the author's conclusion that the Directigen test not be used is premature. C. R. Warren, DO IV. R. Kiser, MD, M A Department o f Family Practice Naval Hospital 2080 Child St. Jacksonville, FL 32214-5227 9/35/61127 The Journal of Pediatrics
REFERENCE 1. Maxson S, Lewno M J, Schultze GE. Clinical usefulness of cerebrospinal fluid bacterial antigen studies. J PEDIATR 1994; 125:235-8.
Reply To the Editor: In our institution, a decision to admit a patient from the clinic or emergency department has never been based on the results of a cerebrospinal fluid bacterial antigen test. Therefore we cannot comment on its role in keeping patients out of the hospital. As for determinations of cerebrospinal fluid protein and glucose levels, we believe that their role is very useful. The first part of our suggested protocol states that % . . two groups of patients with bacterial meningitis could benefit from having CSF antigens tested." Patients with bacterial meningitis are implied to have abnormal protein and glucose values. We understand that bacterial antigen testing has a different role at different institutions. We believe, however, that the routine use of these tests for every patient who has a lumbar puncture is not cost effective. 111. Suzanne Maxson, MD Fellow, Pediatric Infectious Diseases Mary Jo Lewno, BS Chief Technical Director Microbiology Laboratory Gordon E. Schutze, MD Assistant Professor o f Pediatrics and Pathology Pediatric Infectious Diseases/Immunology Arkansas Children's Hospital 800 Marshall St. Little Rock, A R 72202-3591 9/35/61126
Infectious hazards of immune globulin To the Editor." I read with interest the article by Karna et al., "Passive Transfer of Hepatitis Antibodies During Intravenous Administration of Immune Globulin. ''1 The authors found no clinical or laboratory evidence of transmission of hepatitis B or C, despite passive transfer of hepatitis B and C an6bodies in the majority of the 10 premature neonates studied. However, the small number of infants studied does not preclude a type II error. Lest complacency develop regarding the safety of U.S. preparations of intravenously administered immune globulin, a recent outbreak of acute hepatitis C infections in 112 recipients of licensed intravenous immune globulin February 1995
321
322
Editorial correspondence
The Journal of Pediatrics February 1995
preparations serves as a reminder of the infectious hazards of all biologic preparations. 2
Leslie L. Barton, MD Department of Pediatrics Section of Infectious Diseases University of Arizona Health Sciences Center Steele Memorial Children's Research Center Tucson, A Z 85724 9/35/61305
REFERENCES
1. Karna P, Murray DL, Valduss D, Mattarella N, Dyke JW, Maier GA. Passive transfer of hepatitis antibodies during intravenous administration of immune globulin. J PEDIATR 1994; 125:463-5. 2. CDC. Outbreak of hepatitis C associated with intravenous immunoglobulin administration--United States, October t993-June 1994. M M W R Morb Mortal Wkly Rep 1994;43: 505-9.
Reply Intravenous immune globulin preparations have enjoyed a very successful track record in this country for safety from infectious diseases. As mentioned in our article, initial preparations of intravenously administered immune globulin in Europe were associated with non-A, non:B hepatitis.~ Testing for hepatitis C (non-A, non-B hepatitis) is not 100% sensitive at this time. We agree with Dr. Barton that the recent problem with intravenously administered immune globulin is disturbing and should cause physicians to use such preparations cautiously.
Padmani Karna, AID Dennis L, Murray, MD John W. Dyke, PhD Michigan State University and Sparrow Hospital Lansing, MI 48909-7980 9/35/61304
REFERENCES
1. Ochs MD, Fischer SH, Virant FS, et al. Non-A, non-B hepatitis after intravenous immunoglobulin. Lancet 1986; 1:322-3.
Differences in clinical significance of maternal-infant blood group incompatibility in mothers with blood type O, A, or B To the Editor," I read with interest the article by Ozolek et at.,1 which is an elegant study of a very large population base. I was disappointed, however, to find that there was no mention of the physiologic basis of their findings. I was atso surprised to find that a standard pediatric hematology textbook also does not mention the physiologic basis for their results.
On the other hand. a standard adult hematology textbook states 'Antibodies of the ABO system are 'naturally occurring,' suggesting immunization against cross-reactive antigens that are widespread on cell types of other organisms such as bacteria. Anti-A and anti-B are predominantly IgM in group B or A individuals, whereas the serum of group O subjects contains significant amounts of anti-A and anti-B that is also of the IgG class. This difference m immune response remains unexplained," 2 Although the cause for these differences remains unexplained, the fact that they do occur provides a simple and logical explanation for the findings of OzoIek et al. Mothers with blood type A or B whose anti-B or anti-A antibodies are predominantly of the IgM class, which do not cross the placenta, would be far less iikely ~o encounter complications of incompatibility than mothers with blood type O, in whom a significant amoum of anti-A and anti-B antibody is of the IgG class. which readily crosses the placenta. This is consistent with the findings of Ozolek et al. that "type A or B mothers were 5.5 times less likely to have a positive Coombs test result than type O mothers "" Although individuals with blood type O have a significant amount of IgG isoantibodies, the exact amount or percentage probably varies in each person with blood type O. This is probably a major reason for the observed clinical variability, even in O-A and O-B incompatibilities. One might hope that this knowledge of the antibodies of the ABO system wilt become as common in the pediatric literature as it is in the adult literature.
Harold Pert, MD Division of Neonatology Hackensack Medical Center Hackensack, NJ 0760) 9/35/61299
REFERENCES
1. Ozolek JA, Watchko JF, Mimouni F. Prevalence and lack of clinical significance of blood group incompatibility in mothers with blood type A or B. J PEDIATR 1994;125:87-9I. 2. Silberstein LE, Spitalnick SL. Human blood group antigens and antibodies. In: Hoffman R, Benz EJ Jr, Shattel S J; Furie B, Cohen H J, eds. Hematology: basic principlesand practice: New York: Churchill Livingstone, 1991:1548-56.
Reply To the Editor." Contrary to Dr. Perl's impression, the pediatric hematology literature does address the pathophysiology of ABO incompatibility in the newborn infant and specifically the role of different antibody classes in this phenomenon, In Hematologic Problems in the Newborn, by Oski and Naiman,1 the explanation cited for cases of hemolytic disease of the newborn as a result of ABO incompatibility is that natural anti-A and anti-B of mothers with blood group O are of the IgG class and can cross the placenta, whereas those of mothers with blood type A or B are predominantly IgM and cannot cross the placenta. The original work describing the predominance of 19S (IgM) globulin in B anti-A and A anti-B donors was reported by Abelson and Rawson in 19611z We did not discuss the possible path0physiology of our findings because that was beyond the scope