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Hypogammaglobulinemia: Fifty Years Later
Clinical Immunology Vol. 104, No. 3, September, pp. 201–203, 2002 doi:10.1006/clim.2002.5252
EDITORIAL Hypogammaglobulinemia: Fifty Years Later In 1952, Colonel Ogden Bruton described an 8-year-old boy with recurrent pneumococcal sepsis and a selective loss of the fraction of serum protein containing gammaglobulins (1). Despite several immunizations, the patient failed to make antibody to pneumococcus, diphtheria toxoid, or a typhoid vaccine. He was treated with approximately 100 mg/kg of gammaglobulins, given subcutaneously, and he showed remarkable improvement. Sequential serum studies showed that the half-life of the gammaglobulin was about 30 days. Bruton wondered whether the defect was congenital or acquired because the patient was relatively well until 4 21 years of age, but one might expect an acquired disorder to be transient and, in this patient, the defect was persistent. This insightful paper opened a new era in the recognition and treatment of immunodeficiency. We have made enormous progress in the past 50 years but we have not yet determined the ideal way to identify and manage patients with hypogammaglobulinemia. We would like to facilitate early recognition of patients, monitor patients for potential complications in a cost-effective manner, and provide therapy that is effective, nonintrusive, inexpensive, and without side effects (short term or long term). This issue of Clinical Immunology includes three papers that touch on practical aspects of the diagnosis and care of patients with antibody deficiencies. Plebani et al. describe clinical findings in 73 patients with a definitive diagnosis of X-linked agammaglobulinemia (XLA); that is, all of the patients had proven mutations in Btk (Bruton’s tyrosine kinase). This is the first paper delineating the natural history of XLA, based on primary data, since the identification of Btk in 1993 (2, 3). We realize now that some of the earlier papers may have included patients that were clinically similar to those with XLA but genetically different. Some patients with mutations in Btk may have been excluded in previous papers because they were considered atypical. Plebani’s paper confirms some of our biases. For example, it provides clear evidence that delayed diagnosis is associated with a higher incidence of chronic lung disease. We know that physicians often fail to test the siblings, nephews, and cousins of patients with XLA. In the study from Plebani et al., only 1 of the 29 patients with a family history of XLA was evaluated for immunodeficiency before the onset of infections. But there are some surprises in the paper as well. A significant proportion of the patients (42/73) had serum concentrations of IgG, IgM, and/or IgA that were higher than expected at the time of diagnosis. Serum concentrations of IgM and IgA usually fell into the undetectable range after the initiation of gammaglobulin treatment. We have occasionally seen similar patients who had serum IgM concentrations that were greater than 40 mg/dl at the time of diagnosis that fell to less than 20 mg/dl after intravenous gammaglobulin was started. We have never been sure whether this represents a lab error at the first evaluation or a feedback mechanism by which the therapeutic gammaglobulin decreases the stimulus for endogenous production. The paper from Plebani et al. also brings up the question of the genotype/ phenotype relation in XLA. Several groups have shown that the same mutation in Btk may be associated with a variable clinical phenotype (4 – 6). As a result, we generally say that there is not a strong genotype/phenotype correlation in XLA. But the possibility remains that some mutations in Btk are 201
1521-6616/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
202
EDITORIAL
more likely to result in a mild phenotype, as defined by higher concentrations of serum immunoglobulins or a delayed onset of symptoms. This paper describes three patients with amino acid substitutions in Btk and serum concentrations of IgG that were in the normal range at the time of diagnosis. Splice defects that occur at sites that are conserved, but not invariant, in the splice consensus sequence may also be associated with a milder phenotype. Quinti et al. address the issue of appropriate monitoring for patients with hypogammaglobulinemia. They collected information about 1327 patients with antibody deficiencies and focused on the incidence and the outcome of hepatitis C infection in these patients. Hepatitis C infection was documented in 71 patients by RT–PCR; in 33 cases, the patients were known to have received intravenous gammaglobulin preparations contaminated with hepatitis C. The majority of the remaining patients had received other blood products or had undergone major surgery. As has been previously reported, the outcome of infection was worse in patients with common variable immunodeficiency than in patients with XLA (7). Based on these findings, the authors recommend that the lot of intravenous gammaglobulin be recorded for every treatment. This is a widely accepted standard that should be rigorously maintained. The authors also recommend that patients have liver function tests, specifically ALT, measured every 3 months and an RT–PCR for hepatitis C once a year. I am less comfortable with these recommendations. Modifications in the preparation of intravenous gammaglobulin have markedly reduced the risk of contamination with hepatitis C. Thus, infectious agents that we do not know and cannot test for are likely to pose a greater risk than infectious agents that have caused problems in the past. There is no clear agreement about whether asymptomatic individuals with normal liver function tests who are found to be positive for hepatitis C during the screening of blood donors should be treated (8, 9). Therefore, we do not routinely screen for hepatitis C in our immunodeficient patients. There are no published guidelines that indicate which tests should be used to monitor patients with antibody deficiencies for complications of their disease and the side effects of their therapy. In our clinic, if our patients are asymptomatic, we obtain a yearly complete blood count with differential, a chemistry panel that includes liver and renal function tests, quantitative serum immunoglobulins, lymphocyte cell surface markers, and chest and sinus X rays. Patients with problems, or abnormal test results in the past, are evaluated more frequently. Other centers may choose a slightly different group of tests. Pulmonary function tests or a CT of the chest may be more sensitive indicators of changes in lung disease but, depending on the specific testing format, they may be more expensive. A urine analysis is cheap but the yield is low. Giardia is common; should we obtain a yearly stool evaluation? There are no easy answers to these questions. Hansen et al. evaluated the safety and feasibility of giving patients subcutaneous gammaglobulin at a rapid rate. Patients used a pump to self-administer a high-concentration, intramuscular preparation of gammaglobulin at weekly intervals at home. Very few problems were encountered. This approach has several potential advantages. First, the use of weekly therapy rather than monthly therapy results in less fluctuation in serum IgG concentrations. Second, intramuscular preparations of gammaglobulin are less expensive to manufacture than intravenous preparations. Thus, significant cost savings could be associated with the use of subcutaneous gammaglobulin. However, currently, very little intramuscular gammaglobulin is available in the United States. Should we lobby for more? Third, self-administration of gammaglobulin at home is more convenient for patients and therefore less likely to intrude on their normal daily activities. Home therapy is not limited to subcutaneous gammaglobulin treatment. Although Quinti et al. found that the majority of
EDITORIAL
patients in Europe on intravenous gammaglobulin received their therapy at a clinic or hospital, home therapy for patients on intravenous gammaglobulin is common in the United States and England (10 –13). Most patients prefer home therapy and it can be cost effective (14). Primary immunodeficiencies are uncommon, making it difficult to address questions about optimal monitoring and therapy. Two of the three studies reported in this issue, the Plebani et al. and the Quniti et al. papers, are large multicenter studies that required the participation of many physicians. These types of studies clearly benefit our patients and should be encouraged. As the European Society for Immunodeficiency (ESID) and the Pan-American Group for Immunodeficiency (PAGID) develop and flex their muscles, we hope to see more collaborative studies. REFERENCES 1. Bruton, O. C., Agammaglobulinemia. Pediatrics 9, 722–728, 1952. 2. Tsukada, S., Saffran, D. C., Rawlings, D. J., Parolini, O., Allen, R. C., Klisak, I., Sparkes, R. S., Kubagawa, H., Mohandas, T., Quan, S., Belmont, J. W., Cooper, M. D., Conley, M. E., and Witte, O. N., Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72, 279 –290, 1993. 3. Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., and Bentley, D. R., The gene involved in X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases. Nature 361, 226 –233, 1993. 4. Saffran, D. C., Parolini, O., Fitch-Hilgenberg, M. E., Rawlings, D. J., Afar, D. E. H., Witte, O. N., and Conley, M. E., A point mutation in the SH2 domain of Bruton’s tyrosine kinase in atypical X-linked agammaglobulinemia. N. Engl. J. Med. 330, 1488 –1491, 1994. 5. Bykowsky, M. J., Haire, R. N., Ohta, Y., Tang, H., Sung, S. S., Veksler, E. S., Greene, J. M., Fu, S. M., Litman, G. W., and Sullivan, K. E., Discordant phenotype in siblings with X-linked agammaglobulinemia. Am. J. Hum. Genet. 58, 477– 483, 1996. 6. Kornfeld, S. J., Haire, R. N., Strong, S. J., Tang, H., Sung, S.-S. J., Fu, S. M., and Litman, G. W., A novel mutation (Cys 145-stop) in Bruton’s tyrosine kinase is associated with newly diagnosed X-linked agammglobulinemia in a 51-year-old male. Mol. Med. 2, 619 – 623, 1996. 7. Razvi, S., Schneider, L., Jonas, M. M., and Cunningham-Rundles, C., Outcome of intravenous immunoglobulin-transmitted hepatitis C virus infection in primary immunodeficiency. Clin. Immunol. 101, 284 –288, 2001. 8. Marcellin, P., Martinot, M., Boyer, N., and Levy, S., Treatment of hepatitis C patients with normal aminotransferases levels. Clin. Liver Dis. 3, 843– 853, 1999. 9. Tassopoulos, N. C., Treatment of patients with chronic hepatitis C and normal ALT levels. J. Hepatol. 31(Suppl 1), 193–196, 1999. 10. Ashida, E. R., and Saxon, A., Home intravenous immunoglobulin therapy by self-administration. J. Clin. Immunol. 6, 306 –309, 1986. 11. Daly, P. B., Evans, J. H., Kobayashi, R. H., Kobayashi, A. L., Ochs, H. D., Fischer, S. H., Pirofsky, B., and Sprouse, C., Home-based immunoglobulin infusion therapy: Quality of life and patient health perceptions. Ann. Allergy 67, 504 –510, 1991. 12. Haeney, M., Intravenous immune globulin in primary immunodeficiency. Clin. Exp. Immunol. 97(Suppl 1), 11–15, 1994. 13. Brennan, V. M., Cochrane, S., Fletcher, C., Hendy, D., and Powell, P., Surveillance of adverse reactions in patients self-infusing intravenous immunoglobulin at home. J. Clin. Immunol. 15, 116 –119, 1995. 14. Bielory, L., and Long, G. C., Home health care costs: Intravenous immunoglobulin home infusion therapy. Ann. Allergy Asthma Immunol. 74, 265–268, 1995.
Mary Ellen Conley Department of Pediatrics University of Tennessee College of Medicine Memphis, Tennessee Department of Immunology St. Jude Children’s Research Hospital Memphis, Tennessee
203
EDITORIAL Hypogammaglobulinemia: Fifty Years Later In 1952, Colonel Ogden Bruton described an 8-year-old boy with recurrent pneumococcal sepsis and a selective loss of the fraction of serum protein containing gammaglobulins (1). Despite several immunizations, the patient failed to make antibody to pneumococcus, diphtheria toxoid, or a typhoid vaccine. He was treated with approximately 100 mg/kg of gammaglobulins, given subcutaneously, and he showed remarkable improvement. Sequential serum studies showed that the half-life of the gammaglobulin was about 30 days. Bruton wondered whether the defect was congenital or acquired because the patient was relatively well until 4 21 years of age, but one might expect an acquired disorder to be transient and, in this patient, the defect was persistent. This insightful paper opened a new era in the recognition and treatment of immunodeficiency. We have made enormous progress in the past 50 years but we have not yet determined the ideal way to identify and manage patients with hypogammaglobulinemia. We would like to facilitate early recognition of patients, monitor patients for potential complications in a cost-effective manner, and provide therapy that is effective, nonintrusive, inexpensive, and without side effects (short term or long term). This issue of Clinical Immunology includes three papers that touch on practical aspects of the diagnosis and care of patients with antibody deficiencies. Plebani et al. describe clinical findings in 73 patients with a definitive diagnosis of X-linked agammaglobulinemia (XLA); that is, all of the patients had proven mutations in Btk (Bruton’s tyrosine kinase). This is the first paper delineating the natural history of XLA, based on primary data, since the identification of Btk in 1993 (2, 3). We realize now that some of the earlier papers may have included patients that were clinically similar to those with XLA but genetically different. Some patients with mutations in Btk may have been excluded in previous papers because they were considered atypical. Plebani’s paper confirms some of our biases. For example, it provides clear evidence that delayed diagnosis is associated with a higher incidence of chronic lung disease. We know that physicians often fail to test the siblings, nephews, and cousins of patients with XLA. In the study from Plebani et al., only 1 of the 29 patients with a family history of XLA was evaluated for immunodeficiency before the onset of infections. But there are some surprises in the paper as well. A significant proportion of the patients (42/73) had serum concentrations of IgG, IgM, and/or IgA that were higher than expected at the time of diagnosis. Serum concentrations of IgM and IgA usually fell into the undetectable range after the initiation of gammaglobulin treatment. We have occasionally seen similar patients who had serum IgM concentrations that were greater than 40 mg/dl at the time of diagnosis that fell to less than 20 mg/dl after intravenous gammaglobulin was started. We have never been sure whether this represents a lab error at the first evaluation or a feedback mechanism by which the therapeutic gammaglobulin decreases the stimulus for endogenous production. The paper from Plebani et al. also brings up the question of the genotype/ phenotype relation in XLA. Several groups have shown that the same mutation in Btk may be associated with a variable clinical phenotype (4 – 6). As a result, we generally say that there is not a strong genotype/phenotype correlation in XLA. But the possibility remains that some mutations in Btk are 201
1521-6616/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
202
EDITORIAL
more likely to result in a mild phenotype, as defined by higher concentrations of serum immunoglobulins or a delayed onset of symptoms. This paper describes three patients with amino acid substitutions in Btk and serum concentrations of IgG that were in the normal range at the time of diagnosis. Splice defects that occur at sites that are conserved, but not invariant, in the splice consensus sequence may also be associated with a milder phenotype. Quinti et al. address the issue of appropriate monitoring for patients with hypogammaglobulinemia. They collected information about 1327 patients with antibody deficiencies and focused on the incidence and the outcome of hepatitis C infection in these patients. Hepatitis C infection was documented in 71 patients by RT–PCR; in 33 cases, the patients were known to have received intravenous gammaglobulin preparations contaminated with hepatitis C. The majority of the remaining patients had received other blood products or had undergone major surgery. As has been previously reported, the outcome of infection was worse in patients with common variable immunodeficiency than in patients with XLA (7). Based on these findings, the authors recommend that the lot of intravenous gammaglobulin be recorded for every treatment. This is a widely accepted standard that should be rigorously maintained. The authors also recommend that patients have liver function tests, specifically ALT, measured every 3 months and an RT–PCR for hepatitis C once a year. I am less comfortable with these recommendations. Modifications in the preparation of intravenous gammaglobulin have markedly reduced the risk of contamination with hepatitis C. Thus, infectious agents that we do not know and cannot test for are likely to pose a greater risk than infectious agents that have caused problems in the past. There is no clear agreement about whether asymptomatic individuals with normal liver function tests who are found to be positive for hepatitis C during the screening of blood donors should be treated (8, 9). Therefore, we do not routinely screen for hepatitis C in our immunodeficient patients. There are no published guidelines that indicate which tests should be used to monitor patients with antibody deficiencies for complications of their disease and the side effects of their therapy. In our clinic, if our patients are asymptomatic, we obtain a yearly complete blood count with differential, a chemistry panel that includes liver and renal function tests, quantitative serum immunoglobulins, lymphocyte cell surface markers, and chest and sinus X rays. Patients with problems, or abnormal test results in the past, are evaluated more frequently. Other centers may choose a slightly different group of tests. Pulmonary function tests or a CT of the chest may be more sensitive indicators of changes in lung disease but, depending on the specific testing format, they may be more expensive. A urine analysis is cheap but the yield is low. Giardia is common; should we obtain a yearly stool evaluation? There are no easy answers to these questions. Hansen et al. evaluated the safety and feasibility of giving patients subcutaneous gammaglobulin at a rapid rate. Patients used a pump to self-administer a high-concentration, intramuscular preparation of gammaglobulin at weekly intervals at home. Very few problems were encountered. This approach has several potential advantages. First, the use of weekly therapy rather than monthly therapy results in less fluctuation in serum IgG concentrations. Second, intramuscular preparations of gammaglobulin are less expensive to manufacture than intravenous preparations. Thus, significant cost savings could be associated with the use of subcutaneous gammaglobulin. However, currently, very little intramuscular gammaglobulin is available in the United States. Should we lobby for more? Third, self-administration of gammaglobulin at home is more convenient for patients and therefore less likely to intrude on their normal daily activities. Home therapy is not limited to subcutaneous gammaglobulin treatment. Although Quinti et al. found that the majority of
EDITORIAL
patients in Europe on intravenous gammaglobulin received their therapy at a clinic or hospital, home therapy for patients on intravenous gammaglobulin is common in the United States and England (10 –13). Most patients prefer home therapy and it can be cost effective (14). Primary immunodeficiencies are uncommon, making it difficult to address questions about optimal monitoring and therapy. Two of the three studies reported in this issue, the Plebani et al. and the Quniti et al. papers, are large multicenter studies that required the participation of many physicians. These types of studies clearly benefit our patients and should be encouraged. As the European Society for Immunodeficiency (ESID) and the Pan-American Group for Immunodeficiency (PAGID) develop and flex their muscles, we hope to see more collaborative studies. REFERENCES 1. Bruton, O. C., Agammaglobulinemia. Pediatrics 9, 722–728, 1952. 2. Tsukada, S., Saffran, D. C., Rawlings, D. J., Parolini, O., Allen, R. C., Klisak, I., Sparkes, R. S., Kubagawa, H., Mohandas, T., Quan, S., Belmont, J. W., Cooper, M. D., Conley, M. E., and Witte, O. N., Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72, 279 –290, 1993. 3. Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., and Bentley, D. R., The gene involved in X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases. Nature 361, 226 –233, 1993. 4. Saffran, D. C., Parolini, O., Fitch-Hilgenberg, M. E., Rawlings, D. J., Afar, D. E. H., Witte, O. N., and Conley, M. E., A point mutation in the SH2 domain of Bruton’s tyrosine kinase in atypical X-linked agammaglobulinemia. N. Engl. J. Med. 330, 1488 –1491, 1994. 5. Bykowsky, M. J., Haire, R. N., Ohta, Y., Tang, H., Sung, S. S., Veksler, E. S., Greene, J. M., Fu, S. M., Litman, G. W., and Sullivan, K. E., Discordant phenotype in siblings with X-linked agammaglobulinemia. Am. J. Hum. Genet. 58, 477– 483, 1996. 6. Kornfeld, S. J., Haire, R. N., Strong, S. J., Tang, H., Sung, S.-S. J., Fu, S. M., and Litman, G. W., A novel mutation (Cys 145-stop) in Bruton’s tyrosine kinase is associated with newly diagnosed X-linked agammglobulinemia in a 51-year-old male. Mol. Med. 2, 619 – 623, 1996. 7. Razvi, S., Schneider, L., Jonas, M. M., and Cunningham-Rundles, C., Outcome of intravenous immunoglobulin-transmitted hepatitis C virus infection in primary immunodeficiency. Clin. Immunol. 101, 284 –288, 2001. 8. Marcellin, P., Martinot, M., Boyer, N., and Levy, S., Treatment of hepatitis C patients with normal aminotransferases levels. Clin. Liver Dis. 3, 843– 853, 1999. 9. Tassopoulos, N. C., Treatment of patients with chronic hepatitis C and normal ALT levels. J. Hepatol. 31(Suppl 1), 193–196, 1999. 10. Ashida, E. R., and Saxon, A., Home intravenous immunoglobulin therapy by self-administration. J. Clin. Immunol. 6, 306 –309, 1986. 11. Daly, P. B., Evans, J. H., Kobayashi, R. H., Kobayashi, A. L., Ochs, H. D., Fischer, S. H., Pirofsky, B., and Sprouse, C., Home-based immunoglobulin infusion therapy: Quality of life and patient health perceptions. Ann. Allergy 67, 504 –510, 1991. 12. Haeney, M., Intravenous immune globulin in primary immunodeficiency. Clin. Exp. Immunol. 97(Suppl 1), 11–15, 1994. 13. Brennan, V. M., Cochrane, S., Fletcher, C., Hendy, D., and Powell, P., Surveillance of adverse reactions in patients self-infusing intravenous immunoglobulin at home. J. Clin. Immunol. 15, 116 –119, 1995. 14. Bielory, L., and Long, G. C., Home health care costs: Intravenous immunoglobulin home infusion therapy. Ann. Allergy Asthma Immunol. 74, 265–268, 1995.
Mary Ellen Conley Department of Pediatrics University of Tennessee College of Medicine Memphis, Tennessee Department of Immunology St. Jude Children’s Research Hospital Memphis, Tennessee
203