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Intravenous gammaglobulin comes of age
68 I n f e c t i o u s Diseases N e w s l e t t e r
include: congenital heart disease, otitic and sinus infections, head injuries, immunosuppressed states, and cystic fibrosis. 5 Cerebral abscesses may be seen in children following esophageal dilatation. 6 Presenting symptoms and physical findings vary, but include headache, other neurological symptoms or deficit, and evidence of sepsis (fever and/or leukocytosis). The clinical picture is not specific, and the diagnosis may still -be a "surprise" to the unsuspecting clinician. CSF findings include variable pleocytosis and elevated protein level, b u t the spinal fluid may be entirely normal, and cultures may be negative. The most common organisms involved in brain abscesses:include streptococci (25% anaerobic) and Staphylococcus aureus. Uncommon organisms such as Citrobacter diversus and Listeria monocytogenes have been reported recently. Medical therapy of brain abscesses usually includes initial intravenous penicillin and chloramphenicol in "meningitis" doses which can be altered if a specific etiology is identified, if sensitivities dictate or if the clinical course is unsatisfactory. The first nonsurgical cure of a brain abscess in an infant was reported recently, with early diagnosis by CT scan and treatment with antibiotic therapy. 7 As clinicians keep in mind the clinical substrates in which brain abscess may occur, and use the CT scan to aid in early diagnosis, and to follow patient serially, antibiotic therapy alone may become more usual. Peggy C. Ferry, M.D. Professor Departments of Pediatrics and Neurology Arizona Health Sciences Center References i.
2.
3. 4. 5. 6.
Weisberg, LA, Cerebral computerized tomography in intracranial inflammatory disorders. Arch Neurol 37:137, 1980. Weisberg, LA, Nonsurgical management of focal intracranial infection. Neurol 31:575, 1981. Kamin, M, and Bittle, D, Conservative management of focal intracerebral infection. Neurol 31:103, 1981. Editorial: Chemotherapy of brain abscess. Lancet ii:1081, 1978. Fisher, EG, Cerebral abscess in children. Am J Dis Child 135:746, 1981. Leahey, WR, Cerebral abscess in children secondary to esophageal dilatation. Pediatr 59:300, 1977.
9
7.
Levy, RL, and Saunders, RL, Citrobacter meningitis and cerebral abscess in early infancy: Cure by moxalactam. Neurol 31:1575, 1981.
INTRAVENOUS GAMMAGLOBULIN COMES OF AGE Passive replacement of antibodies using gammaglobulin preparations is currently the only effective treatment for B-lymphocyte dysfunction syndromes and known or possible exposure to selected infectious diseases. 1 The mainstay of such antibody preparations is immune serum globulin (ISG), a product prepared by precipitation of human serum (Cohn fraction II). This product consists primarily of IgG and has a wide spectrum of antibody specificities. Trace amounts of other immunoglobulins and serum proteins are present. The second most frequently used source of antibodies is fresh frozen plasma. Each preparation has advantages and disadvantages which have been discussed in detail by Stiehm, et al. 2 Three practical drawbacks to the use of these products are: (i) the pain engendered by repeated ISG administration; (2) the limited ability of ISG and plasma infusions to provide truly adequate levels of antibody protection; and (3) the hazard of local bleeding in patients with concomitant decrease coagulability (e.g., thrombocytopenia). One potential solution is use of gammaglobulin preparations intravenously. However, because of the aggregates formed during its preparation, a variety of adverse reactions mediated by complement activation may occur, including anaphylaxis. A variety of attempts have been made to eliminate this adverse effect. Until recently, these efforts have not been successful. In September 1981, the FDA licensed for use a modified Cohn fraction II preparation which is stabilized in maltose (Gamimmune, Cutter Biologicals). It is a 5% protein solution in 10% maltose and provides an average of 50 mg of IgG per ml of solution. When a dose of i00 mg/kg was given once a month, it was shown to be safe and acceptable by a series of patients with immunoglobulin deficiency syndromes. 3 The dose and frequency of infusions m a y vary from patient to patient and in different clinical situations. Disease entities amenable to routine I.V. treatment include X-linked agammaglobulinemia, common variable immunodeficiency, X-linked immunodeficiency with hyper-IgM, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and deficient specific antibody production syndromes. 4 Current dosing
by Elsevier Science Publ!s.hing Co., Inc.
69 Infectious Diseases N e w s l e t t e r
recommendations include the monthly infusion of i00 mg/kg at an initial rate of 0.01-0.02 ml/kg/minute for 30 minutes with careful monitoring of the patient. If no adverse effects are seen, the infusion rate is increased to a maximum of 0.04 ml/kg/minute with persistent monitoring of the patient. Alternative schedules using a loading dose followed by monthly fixed-dose infusions are being tested as another method to provide maximum protection. The use of I.V. gammaglobulin may also be of benefit in a variety of specific infectious diseases. It has been used to treat a chronic echovirus infection in a patient with hypogammaglobulinemia. 5 We have treated a patient with X-linked aggammaglobulinemfa with acute hepatitis A who demonstrated prompt and persistent resolution of his infection. In vitro studies 6 have shown that this preparation retains its opsonic capabilities and, therefore, may be useful in the treatment of bacterial infections where this capability is important (e.g., streptococcal infections). Thus, the time has come for the judicious use of this and other intravenous gammaglobulin preparations currently under trial in Europe. Long-term studies with immunodeficient patients are required to determine if this mode of administration will alter the natural history of these diseases. Our optimism must also be tempered with two notes of caution. The material is not recommended for patients w~th only IgA deficiency; it would be dangerous and of no obvious benefit to these individuals. Likewise, the establishment of a diagnosis of an immunoglobulin deficiency state should be firmly made, using specific immunoglobulin quantitation and after a thorough immune evaluation prior to the regular use of an intravenous preparation.
References
2.
3.
5.
6.
Fulginiti, VA, Immunization in Clinical Practice. Philadelphia: J.B. Lipincott, 1982, pp 221-244. Stiehm, ER, Standard and -special human immune serum immunoglobulins as therapeutic agents. Pediatr 63:301, 1979. Ochs, HD, et al., Safety and patient acceptability of intravenous immune globulin in 10% maltose. Lancet ii:i158, 1980.
9
Buckley, RH, Immunoglobulin replacement therapy: Indications and contraindications for use and variable IgG levels achieved. In Alving, BM, Finlayson, JS (Eds.), Immunoglobulins: Characteristics and Uses of Intravenous Preparations. Washington, D.C.: U.S. Government Printing Office, HEW Publication No. (FDA)-80-9005, 1980. Mease, P, et al., Successful treatment of echovirus meningoencephalitis and myositisfasciatis with intravenous immunoglobulin therapy in a patient with X-linked agammaglobulinemia. New Engl J Med 304:1278, 1981. Fischer, G, et al., Modified immune serum globulin (Letter). Lancet i:271, 1981.
PERTUSSIS VACCINE: AN UNNECESSARY RENEWAL OF ANTI-VACCINE SENTIMENT On April 19th, the local NBC affiliate in Washington, D.C. , WRC-TV, aired a one-hour documentary "examining" the benefits and risks from pertussis vaccine. On April 20th, a 20-minute edited excerpt from that hour-long show was aired nationally on the Today Show. As a result, tens of thousands of parents queried their physicians across the country in the belief that 1:700 children who received DPT might be "brain-damaged." This is not the place to criticize the shows except to say that the 20-minute Today segment presented an entirely negative view which gave incorrect statistics and a totally incorrect impression of the vaccine's side effects. To correct errors in the benefit-risk evaluation of pertussis and pertussis vaccine, I offer the following: I.
James F. Jones, M.D. Associate Professor Department of Pediatrics Arizona Health Sciences Center
I.
4.
Pertussis is not a benign disease, even today with antibiotics and expert respiratory care. We still experience 1000-3000 reported cases annually with 5-20 deaths. It has been estimated that approximately 1:8000 children with pertussis will suffer brain damage (New Engl J Med 301:906, 1979) and any physician or parent who has encountered the disease recognizes its severity in infancy and the complications that can ensue. Thus, despite claims of Gordon Stewart in England and Ehrengut in Germany, pertussis is not a benign, trivial infection. In fact, in England when public display of several cases of encephalopathy attributed to pertussis vaccine
by ElsevierSciencePublishing Co., Inc.
include: congenital heart disease, otitic and sinus infections, head injuries, immunosuppressed states, and cystic fibrosis. 5 Cerebral abscesses may be seen in children following esophageal dilatation. 6 Presenting symptoms and physical findings vary, but include headache, other neurological symptoms or deficit, and evidence of sepsis (fever and/or leukocytosis). The clinical picture is not specific, and the diagnosis may still -be a "surprise" to the unsuspecting clinician. CSF findings include variable pleocytosis and elevated protein level, b u t the spinal fluid may be entirely normal, and cultures may be negative. The most common organisms involved in brain abscesses:include streptococci (25% anaerobic) and Staphylococcus aureus. Uncommon organisms such as Citrobacter diversus and Listeria monocytogenes have been reported recently. Medical therapy of brain abscesses usually includes initial intravenous penicillin and chloramphenicol in "meningitis" doses which can be altered if a specific etiology is identified, if sensitivities dictate or if the clinical course is unsatisfactory. The first nonsurgical cure of a brain abscess in an infant was reported recently, with early diagnosis by CT scan and treatment with antibiotic therapy. 7 As clinicians keep in mind the clinical substrates in which brain abscess may occur, and use the CT scan to aid in early diagnosis, and to follow patient serially, antibiotic therapy alone may become more usual. Peggy C. Ferry, M.D. Professor Departments of Pediatrics and Neurology Arizona Health Sciences Center References i.
2.
3. 4. 5. 6.
Weisberg, LA, Cerebral computerized tomography in intracranial inflammatory disorders. Arch Neurol 37:137, 1980. Weisberg, LA, Nonsurgical management of focal intracranial infection. Neurol 31:575, 1981. Kamin, M, and Bittle, D, Conservative management of focal intracerebral infection. Neurol 31:103, 1981. Editorial: Chemotherapy of brain abscess. Lancet ii:1081, 1978. Fisher, EG, Cerebral abscess in children. Am J Dis Child 135:746, 1981. Leahey, WR, Cerebral abscess in children secondary to esophageal dilatation. Pediatr 59:300, 1977.
9
7.
Levy, RL, and Saunders, RL, Citrobacter meningitis and cerebral abscess in early infancy: Cure by moxalactam. Neurol 31:1575, 1981.
INTRAVENOUS GAMMAGLOBULIN COMES OF AGE Passive replacement of antibodies using gammaglobulin preparations is currently the only effective treatment for B-lymphocyte dysfunction syndromes and known or possible exposure to selected infectious diseases. 1 The mainstay of such antibody preparations is immune serum globulin (ISG), a product prepared by precipitation of human serum (Cohn fraction II). This product consists primarily of IgG and has a wide spectrum of antibody specificities. Trace amounts of other immunoglobulins and serum proteins are present. The second most frequently used source of antibodies is fresh frozen plasma. Each preparation has advantages and disadvantages which have been discussed in detail by Stiehm, et al. 2 Three practical drawbacks to the use of these products are: (i) the pain engendered by repeated ISG administration; (2) the limited ability of ISG and plasma infusions to provide truly adequate levels of antibody protection; and (3) the hazard of local bleeding in patients with concomitant decrease coagulability (e.g., thrombocytopenia). One potential solution is use of gammaglobulin preparations intravenously. However, because of the aggregates formed during its preparation, a variety of adverse reactions mediated by complement activation may occur, including anaphylaxis. A variety of attempts have been made to eliminate this adverse effect. Until recently, these efforts have not been successful. In September 1981, the FDA licensed for use a modified Cohn fraction II preparation which is stabilized in maltose (Gamimmune, Cutter Biologicals). It is a 5% protein solution in 10% maltose and provides an average of 50 mg of IgG per ml of solution. When a dose of i00 mg/kg was given once a month, it was shown to be safe and acceptable by a series of patients with immunoglobulin deficiency syndromes. 3 The dose and frequency of infusions m a y vary from patient to patient and in different clinical situations. Disease entities amenable to routine I.V. treatment include X-linked agammaglobulinemia, common variable immunodeficiency, X-linked immunodeficiency with hyper-IgM, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and deficient specific antibody production syndromes. 4 Current dosing
by Elsevier Science Publ!s.hing Co., Inc.
69 Infectious Diseases N e w s l e t t e r
recommendations include the monthly infusion of i00 mg/kg at an initial rate of 0.01-0.02 ml/kg/minute for 30 minutes with careful monitoring of the patient. If no adverse effects are seen, the infusion rate is increased to a maximum of 0.04 ml/kg/minute with persistent monitoring of the patient. Alternative schedules using a loading dose followed by monthly fixed-dose infusions are being tested as another method to provide maximum protection. The use of I.V. gammaglobulin may also be of benefit in a variety of specific infectious diseases. It has been used to treat a chronic echovirus infection in a patient with hypogammaglobulinemia. 5 We have treated a patient with X-linked aggammaglobulinemfa with acute hepatitis A who demonstrated prompt and persistent resolution of his infection. In vitro studies 6 have shown that this preparation retains its opsonic capabilities and, therefore, may be useful in the treatment of bacterial infections where this capability is important (e.g., streptococcal infections). Thus, the time has come for the judicious use of this and other intravenous gammaglobulin preparations currently under trial in Europe. Long-term studies with immunodeficient patients are required to determine if this mode of administration will alter the natural history of these diseases. Our optimism must also be tempered with two notes of caution. The material is not recommended for patients w~th only IgA deficiency; it would be dangerous and of no obvious benefit to these individuals. Likewise, the establishment of a diagnosis of an immunoglobulin deficiency state should be firmly made, using specific immunoglobulin quantitation and after a thorough immune evaluation prior to the regular use of an intravenous preparation.
References
2.
3.
5.
6.
Fulginiti, VA, Immunization in Clinical Practice. Philadelphia: J.B. Lipincott, 1982, pp 221-244. Stiehm, ER, Standard and -special human immune serum immunoglobulins as therapeutic agents. Pediatr 63:301, 1979. Ochs, HD, et al., Safety and patient acceptability of intravenous immune globulin in 10% maltose. Lancet ii:i158, 1980.
9
Buckley, RH, Immunoglobulin replacement therapy: Indications and contraindications for use and variable IgG levels achieved. In Alving, BM, Finlayson, JS (Eds.), Immunoglobulins: Characteristics and Uses of Intravenous Preparations. Washington, D.C.: U.S. Government Printing Office, HEW Publication No. (FDA)-80-9005, 1980. Mease, P, et al., Successful treatment of echovirus meningoencephalitis and myositisfasciatis with intravenous immunoglobulin therapy in a patient with X-linked agammaglobulinemia. New Engl J Med 304:1278, 1981. Fischer, G, et al., Modified immune serum globulin (Letter). Lancet i:271, 1981.
PERTUSSIS VACCINE: AN UNNECESSARY RENEWAL OF ANTI-VACCINE SENTIMENT On April 19th, the local NBC affiliate in Washington, D.C. , WRC-TV, aired a one-hour documentary "examining" the benefits and risks from pertussis vaccine. On April 20th, a 20-minute edited excerpt from that hour-long show was aired nationally on the Today Show. As a result, tens of thousands of parents queried their physicians across the country in the belief that 1:700 children who received DPT might be "brain-damaged." This is not the place to criticize the shows except to say that the 20-minute Today segment presented an entirely negative view which gave incorrect statistics and a totally incorrect impression of the vaccine's side effects. To correct errors in the benefit-risk evaluation of pertussis and pertussis vaccine, I offer the following: I.
James F. Jones, M.D. Associate Professor Department of Pediatrics Arizona Health Sciences Center
I.
4.
Pertussis is not a benign disease, even today with antibiotics and expert respiratory care. We still experience 1000-3000 reported cases annually with 5-20 deaths. It has been estimated that approximately 1:8000 children with pertussis will suffer brain damage (New Engl J Med 301:906, 1979) and any physician or parent who has encountered the disease recognizes its severity in infancy and the complications that can ensue. Thus, despite claims of Gordon Stewart in England and Ehrengut in Germany, pertussis is not a benign, trivial infection. In fact, in England when public display of several cases of encephalopathy attributed to pertussis vaccine
by ElsevierSciencePublishing Co., Inc.