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IgA deficiency and susceptibility to infection
642
Letters to the editor
withdrawal of the drug after production of a definite leukopenia. Etteldorf, on the other hand, has used maintenance doses after leukopenia appears, keeping the patient mildly leukopenic over extended periods of time. It is possible that a regimen such as that of Etteldorf would be of benefit to a greater number of patients than that which we employ. With our regimen, nearly all children with nephrosis benefit from a course of cyclophosphamide, but approximately 35 per cent have a recurrence of the disease at a later date and many of these have required 2 or more courses of the drug. If fewer recurrences follow a regimen such as that used by Etteldorf, this advantage would have to be weighed against the possible hazards of complications such as that which Dr. Grunberg describes. Studies to determine the relative efficacy of various regimens should be carried out; such studies would also give information as to the incidence of hazards. Dr. Grunberg's letter adds another dimension to the varicella hazard in the sick child. There are now a number of situations in which varicella is atypical or lethal. In the agammaglobulinemic o{ the Bruton type, varicella, of all the viral diseases, may linger for many weeks with recurrent crops of vesicles. The danger of varicella in the leukemic patient and in the patient who has received prednisone over long periods of time is well known, and now by Dr. Grunberg's observations we find varicella to be a potential hazard in patients receiving cyclophosphamide therapy. In his case, cyclophosphamide alone appeared to be the offender; a corticosteroid was not being given. Our defense against the varicella virus as compared with that of others seems to be especially delicately balanced. CLARK D. WEST~ M.D. T H E CHILDREN'S HOSPITAL RESEARCH FOUNDATION
CINCINNATI, 0 H I 0
The Journal o/ Pediatrics October 1968
IgA deficiency and susceptibility to infection. Dr. West writes: "Although a number of workers in this country have been investigating the serum levels of the immunoglobulin in childhood and their relation to disease states, a relationship such as that described by the Swiss workers has not been reported." I tried to form a personal opinion on this matter and I did not find a statistical relationship between the levels of IgA or IgM (measured by a quantitative method) and the susceptibility of infants to infection. On this point I quite agree with Dr. West and I think that a low level of IgA is not a sufficient reason for the therapeutic use of gammaglobulin. This therapy must be reserved to cases of agammaglobulinemia, transient hypogammaglobulinemia, or dysgammaglobulinemia in which an antibody deficiency syndrome has been biologically proved. However, the isolated absence of IgA, which has been reported in a small proportion of the healthy population, may be associated in some rare cases with undue susceptibility to infection. We have reported the case of a girl 8 years old, followed up by us since early childhood for repeated infections. She presented a failure of antibody formation and IgA was always absent on her immunoelectrophoretic pattern (specific antihuman IgA antiserum was also used). In 1966, traces of IgA appeared for the first time and a quantitative determination (method of Mancini) gave a level of 10 mg. per 100 ml? -2 Some other cases were published.3 Fulginitti and associates 4 bore such a witness not only in this country but even in this JOURNAL. IgA isolated deficiency has been reported in ataxiatelangiectasia. An isolated decrease of IgM was found in cases of Wiskott-Aldrich syndrome. Evidence is therefore presented that the lack of a single immunoglobulin may in some cases be responsible for an antibody deficiency syndrome. DOCTEUR DANIEL ROSENBERG
C H E F DE CLINIQUE CLINIQUE MEDICALE I N F A N T I L E B
IgA deficiency and susceptibility to infection To the Editor: In THE JOURNAL OF PEDIATRICS, January, 1968, Dr. C. D. West commented on an article by Buser and associates, which appeared in the same issue and established a connection between
HOPITAL E. HERRIOT LYON, FRANCE
REFERENCES 1. Francois, R., Rosenberg, D., Creyssel, R., and Manuel, Y.: Syndrome d'infections k r6p6tition par carence en beta2A-globulines, Arch. fran~. p6diat. 22: 913, 1965. 2. Francois, R., Rosenberg, D., Bertrand, J., Manuel, Y., Racle, P., and Guibaud, P.: D6ficit dissoci6 en immunoglobulines et insuffisence
Volume 73 Number 4
surr~nalienne. Association possible d'une carence immunitaire et d'une affection autoimmune, Semaine des Hopitaux, Ann. P~diat. 14: 2778, 1967. 3. Williams, R. T.: Acquired dysgammaglobulinaemia in a young man, Clin. & Exper. Immunol. 1: 223, 1966. 4. Fulginitti, V. A., Sieber, O. F., Jr., Claman, H. N., and Merill, D.: Serum immunoglobulin measurement during the first year of life and in immunoglobulin deficiency states, J. PEmAT. 68: 729, 1966.
Reply To the Editor: I wish to comment on the points raised by Dr. Rosenberg concerning our study on "Susceptibility to infection and IgA deficiency" reported in this JOURNAL.x With regard to the argument about the statistical relationship between IgA deficiency and susceptibility to infection, it should be emphasized that immunity is determined by many factors, each of which may vary considerably from one individual to another. Thus, a simple relationship between deficiency of an immunoglobulin class such as IgA and susceptibility to infection cannot be expected. Although the immunoglobulin levels (which were obtained by routine immunoelectrophoretic analyses) were not quantitatively determined by us and are not therefore suitable for statistical evaluation, a difference in IgA values was nevertheless found between a group of very susceptible infants (IgA not detected in 52 percent of cases) and a resistant control group (IgA present in all cases) (see Table I in our paper). It cannot be said whether the low level of IgA per se determines susceptibility to infection, or whether the level of IgA reflects only the degree of maturity of the immune mechanism. As to methods, we fully agree about the necessity for using more quantitative procedures such as the Mancini technique. There is increasing evidence that IgA plays an important role in the immune defense mechanisms, especially of the mucous membranes.2-4 The fact that a lack of IgA is occasionally found in healthy individuals is not necessarily counterevidence, as this deficiency may be made up in other ways. 5 Besides the well-known IgA deficiency in ataxia-telangiectasia, in which there is high susceptibility to respiratory infections, there are supporting case reports, such as the careful study relating IgA deficiency with high suseep-
Letters to the editor
64 3
tibility to infection in a child, by Dr. Rosenberg himsel] and his associatesl G We do not agree with Dr. Rosenberg's proposal to limit the use of gamma globulin to antibody deficiency syndromes only. Gamma globulin applied in adequate dosage has been proved to be beneficial and to have even a lifesaving effect in severe infections regardless of the immunoglobulin pattern as revealed by immunoelectrophoresis. It is therefore an indispensable therapeutic tool for a number of indications besides the classical antibody deficiency syndrome.~ Although the illnesses of our gamma globulintreated patients did not involve danger to life, they were nevertheless troublesome and lasted for months, and only treatment with gamma globulin was effective in bringing about decisive improvement. As such therapy is easy to apply, involves no danger, and is furthermore not very costly (moderate amounts only are needed), we advocate its use in cases such as those described by us. On the other hand, a promiscuous use of gamma globulin without careful indication should be avoided, as it would lead only to apparent failures. We hope that our study will be a stimulus to further investigations in tiffs important field of pediatrics. DR. Iq'. B U S E R H I R S C H E N G R A B E N Q~ BERN~ S W I T Z E R L A N D
REFERENCES i. Buser, F., Btitler, R., and Martin Du Pan, R.: Susceptibility to infection and IgA deficiency in the infant, J. PEDmT. 72: 29, 1968. Preliminary presentation--Buser, F., and Bfitler, R.: Transactions of the Swiss Pediatric Society, Annual Meeting Winterthur, June, 1964, Basel, S. Karger AG. 2. Janeway, C. A., Rosen, F. S., Merler, E., and Alper, C. A.: The gamma globulins, New England J. Med. Progress Series, p. 86, 1967. 3. South, M. A.: Secretory IgA and the immunologic deficiency diseases, Third Developmental Immunology Workshop on the Immunologic Deficiency Diseases in Man, Fort Meyers, Fla., 1967. 4. Tomasi, T. B.: Secretory IgA system, Third Developmental Immunology Workshop on the Immunologic Deficiency Diseases in Man, Fort Meyers, Fla., 1967. 5. Hansom, L. A.: Aspects of the absence of the IgA system, Third Developmental Immunology Workshop on the Immunologic Deficiency Diseases in Man, Fort Meyers, Fla., 1967. 6. Francois, R., Rosenberg, D., Creyssel, R., and Manuel, Y.: Syndrome d'infections ?~r6p6titions
Letters to the editor
withdrawal of the drug after production of a definite leukopenia. Etteldorf, on the other hand, has used maintenance doses after leukopenia appears, keeping the patient mildly leukopenic over extended periods of time. It is possible that a regimen such as that of Etteldorf would be of benefit to a greater number of patients than that which we employ. With our regimen, nearly all children with nephrosis benefit from a course of cyclophosphamide, but approximately 35 per cent have a recurrence of the disease at a later date and many of these have required 2 or more courses of the drug. If fewer recurrences follow a regimen such as that used by Etteldorf, this advantage would have to be weighed against the possible hazards of complications such as that which Dr. Grunberg describes. Studies to determine the relative efficacy of various regimens should be carried out; such studies would also give information as to the incidence of hazards. Dr. Grunberg's letter adds another dimension to the varicella hazard in the sick child. There are now a number of situations in which varicella is atypical or lethal. In the agammaglobulinemic o{ the Bruton type, varicella, of all the viral diseases, may linger for many weeks with recurrent crops of vesicles. The danger of varicella in the leukemic patient and in the patient who has received prednisone over long periods of time is well known, and now by Dr. Grunberg's observations we find varicella to be a potential hazard in patients receiving cyclophosphamide therapy. In his case, cyclophosphamide alone appeared to be the offender; a corticosteroid was not being given. Our defense against the varicella virus as compared with that of others seems to be especially delicately balanced. CLARK D. WEST~ M.D. T H E CHILDREN'S HOSPITAL RESEARCH FOUNDATION
CINCINNATI, 0 H I 0
The Journal o/ Pediatrics October 1968
IgA deficiency and susceptibility to infection. Dr. West writes: "Although a number of workers in this country have been investigating the serum levels of the immunoglobulin in childhood and their relation to disease states, a relationship such as that described by the Swiss workers has not been reported." I tried to form a personal opinion on this matter and I did not find a statistical relationship between the levels of IgA or IgM (measured by a quantitative method) and the susceptibility of infants to infection. On this point I quite agree with Dr. West and I think that a low level of IgA is not a sufficient reason for the therapeutic use of gammaglobulin. This therapy must be reserved to cases of agammaglobulinemia, transient hypogammaglobulinemia, or dysgammaglobulinemia in which an antibody deficiency syndrome has been biologically proved. However, the isolated absence of IgA, which has been reported in a small proportion of the healthy population, may be associated in some rare cases with undue susceptibility to infection. We have reported the case of a girl 8 years old, followed up by us since early childhood for repeated infections. She presented a failure of antibody formation and IgA was always absent on her immunoelectrophoretic pattern (specific antihuman IgA antiserum was also used). In 1966, traces of IgA appeared for the first time and a quantitative determination (method of Mancini) gave a level of 10 mg. per 100 ml? -2 Some other cases were published.3 Fulginitti and associates 4 bore such a witness not only in this country but even in this JOURNAL. IgA isolated deficiency has been reported in ataxiatelangiectasia. An isolated decrease of IgM was found in cases of Wiskott-Aldrich syndrome. Evidence is therefore presented that the lack of a single immunoglobulin may in some cases be responsible for an antibody deficiency syndrome. DOCTEUR DANIEL ROSENBERG
C H E F DE CLINIQUE CLINIQUE MEDICALE I N F A N T I L E B
IgA deficiency and susceptibility to infection To the Editor: In THE JOURNAL OF PEDIATRICS, January, 1968, Dr. C. D. West commented on an article by Buser and associates, which appeared in the same issue and established a connection between
HOPITAL E. HERRIOT LYON, FRANCE
REFERENCES 1. Francois, R., Rosenberg, D., Creyssel, R., and Manuel, Y.: Syndrome d'infections k r6p6tition par carence en beta2A-globulines, Arch. fran~. p6diat. 22: 913, 1965. 2. Francois, R., Rosenberg, D., Bertrand, J., Manuel, Y., Racle, P., and Guibaud, P.: D6ficit dissoci6 en immunoglobulines et insuffisence
Volume 73 Number 4
surr~nalienne. Association possible d'une carence immunitaire et d'une affection autoimmune, Semaine des Hopitaux, Ann. P~diat. 14: 2778, 1967. 3. Williams, R. T.: Acquired dysgammaglobulinaemia in a young man, Clin. & Exper. Immunol. 1: 223, 1966. 4. Fulginitti, V. A., Sieber, O. F., Jr., Claman, H. N., and Merill, D.: Serum immunoglobulin measurement during the first year of life and in immunoglobulin deficiency states, J. PEmAT. 68: 729, 1966.
Reply To the Editor: I wish to comment on the points raised by Dr. Rosenberg concerning our study on "Susceptibility to infection and IgA deficiency" reported in this JOURNAL.x With regard to the argument about the statistical relationship between IgA deficiency and susceptibility to infection, it should be emphasized that immunity is determined by many factors, each of which may vary considerably from one individual to another. Thus, a simple relationship between deficiency of an immunoglobulin class such as IgA and susceptibility to infection cannot be expected. Although the immunoglobulin levels (which were obtained by routine immunoelectrophoretic analyses) were not quantitatively determined by us and are not therefore suitable for statistical evaluation, a difference in IgA values was nevertheless found between a group of very susceptible infants (IgA not detected in 52 percent of cases) and a resistant control group (IgA present in all cases) (see Table I in our paper). It cannot be said whether the low level of IgA per se determines susceptibility to infection, or whether the level of IgA reflects only the degree of maturity of the immune mechanism. As to methods, we fully agree about the necessity for using more quantitative procedures such as the Mancini technique. There is increasing evidence that IgA plays an important role in the immune defense mechanisms, especially of the mucous membranes.2-4 The fact that a lack of IgA is occasionally found in healthy individuals is not necessarily counterevidence, as this deficiency may be made up in other ways. 5 Besides the well-known IgA deficiency in ataxia-telangiectasia, in which there is high susceptibility to respiratory infections, there are supporting case reports, such as the careful study relating IgA deficiency with high suseep-
Letters to the editor
64 3
tibility to infection in a child, by Dr. Rosenberg himsel] and his associatesl G We do not agree with Dr. Rosenberg's proposal to limit the use of gamma globulin to antibody deficiency syndromes only. Gamma globulin applied in adequate dosage has been proved to be beneficial and to have even a lifesaving effect in severe infections regardless of the immunoglobulin pattern as revealed by immunoelectrophoresis. It is therefore an indispensable therapeutic tool for a number of indications besides the classical antibody deficiency syndrome.~ Although the illnesses of our gamma globulintreated patients did not involve danger to life, they were nevertheless troublesome and lasted for months, and only treatment with gamma globulin was effective in bringing about decisive improvement. As such therapy is easy to apply, involves no danger, and is furthermore not very costly (moderate amounts only are needed), we advocate its use in cases such as those described by us. On the other hand, a promiscuous use of gamma globulin without careful indication should be avoided, as it would lead only to apparent failures. We hope that our study will be a stimulus to further investigations in tiffs important field of pediatrics. DR. Iq'. B U S E R H I R S C H E N G R A B E N Q~ BERN~ S W I T Z E R L A N D
REFERENCES i. Buser, F., Btitler, R., and Martin Du Pan, R.: Susceptibility to infection and IgA deficiency in the infant, J. PEDmT. 72: 29, 1968. Preliminary presentation--Buser, F., and Bfitler, R.: Transactions of the Swiss Pediatric Society, Annual Meeting Winterthur, June, 1964, Basel, S. Karger AG. 2. Janeway, C. A., Rosen, F. S., Merler, E., and Alper, C. A.: The gamma globulins, New England J. Med. Progress Series, p. 86, 1967. 3. South, M. A.: Secretory IgA and the immunologic deficiency diseases, Third Developmental Immunology Workshop on the Immunologic Deficiency Diseases in Man, Fort Meyers, Fla., 1967. 4. Tomasi, T. B.: Secretory IgA system, Third Developmental Immunology Workshop on the Immunologic Deficiency Diseases in Man, Fort Meyers, Fla., 1967. 5. Hansom, L. A.: Aspects of the absence of the IgA system, Third Developmental Immunology Workshop on the Immunologic Deficiency Diseases in Man, Fort Meyers, Fla., 1967. 6. Francois, R., Rosenberg, D., Creyssel, R., and Manuel, Y.: Syndrome d'infections ?~r6p6titions