1169
and they were seen in 32 of the 175 patients treated in the Medical Research Council trial. Reactions are rare in boys with congenital agammaglobulinaemia and in pa-
secondary immunodeficiency. They happen other antibody-deficient patients and are thought to result from complement activation by IgG aggregates in the injection, rather than from an allergic response. Conventionally prepared IgG is suitable only for intramuscular injection; it can cause severe reactions when given intravenously. But, large intramuscular injections are painful, so the amount of immunoglobulin which can be given by this route is limited. This is unfortunate because the M.R.C./triaP showed that patients receiving 50 mg/kg/week of IgG had significantly tients with
sporadically in
fewer infections than those on the standard dose of 25 mg/kg/week. The smaller dose was recommended for routine prophylaxis in antibody deficiency partly out of consideration of the volume of the injection. Nolte and co-workers3 in Oregon have now shown that antibodydeficient patients given 150 mg/kg monthly had significantly fewer infections than others given about 50 mg/kg/month (the lower dose being substantially less than that routinely used in the U.K.). The higher dose was made possible through the use of a new IgG preparation, suitable for intravenous injection, in which immunoglobulin aggregation is prevented by mild reduction and alkylation. This is a considerable advance on the enzyme-digested IgG preparations, which lack the Fc region of the molecule and so have subnormal opsonising activity and a half-life in the circulation of only 5-6 days. The new intravenous preparation has a halflife of about 20 days and retains over 80% of the original antibody activity. One-third of the patients with primary antibody deficiency had transient nausea, fever, flushing, and muscle cramps after the infusions while those with secondary immunodeficiency were spared these effects. No patients had the severe reactions which sometimes follow intramuscular injections of the standard IgG. Ochs4 found that total hmmolytic complement and C3 levels fell slightly after intravenous IgG infusions and that the transient minor reactions were lessened or abolished by 600 mg of aspirin taken 30 minutes before the infusion. Ochs and co-workers will soon be reporting a two-year blind cross-over study comparing intravenous with intramuscular treatment. Meanwhile other smaller-scale studies are confirming the view that preparations of IgG suitable for intravenous use are effective and highly acceptable to patients; these include pH 4 treated material tested by Barandunsand S-sulphonated IgG used by Yamanaka et al.6 The reasons why S-sulphonation is so effective are not clear but the treated molecules reconvert to their native form within 24 hours of administration and they
1. Soothill
JF. Reactions to immunoglobulin. In: Hypogammaglobulinæmia in the United Kingdom. MRC Spec Rep Ser No. 310, 1971. LE, Mollison PL. Conclusions. In: Hypogammaglobulinæmia in the
2. Hill
United Kingdom. MRC Spec Rep Ser No. 310, 1971. 3. Nolte MT, Pirofsky B, Gerritz GA, Golding B. Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol 1979; 36: 237-43. 4. Ochs HD. Prophylactic treatment of immunodeficiency syndromes with intravenous gammaglobulin. Vox Sang 1979; 37: 126-28. 5. Barandun S. Use of intravenous gammaglobulin in the treatment of severe bacterial infection. Vox Sang 1979; 37: 117-19. 6. Yamanaka T, Abo W, Chiba S, et al. Clinical effect and metabolism of s-sulphonated immunoglobulin in 7 patients with congenital humoral immunodeficiency. Vox Sang 1979; 37: 14-20.
in the circulation with a half-life of 21 days. No reactions have been reported in the small number of patients treated. Commercial exploration of intravenous IgG preparations is doubtless undertaken in the hope that they may have wider clinical application than mere immuno-
persist
deficiency-for instance, life-threatening infections, particularly with septicaEmia, and sepsis of the newborn. Clinical trials in these areas are very difficult to organise very informative results are yet to hand. On evidence there is ’a strong case for further evaluation of intravenous IgG in treatment of antibody deficiency in the U.K. Until intravenous preparations are more widely available it may be to the patient’s ultimate advantage to be generous with intramuscular IgG, despite the added pain of injection.
and
no
existing
VARIABLE RESPONSE TO GLUTEN CHALLENGE MOST paediatricians now accept that final diagnosis of cceliac disease in childhood rests on healing of the smallintestinal mucosa when gluten is withdrawn followed by histological relapse after gluten challenge.’ Now Kumar and colleagues2 have used these diagnostic criteria when trying the reintroduction of gluten into the diet of teenagers and adults diagnosed as having coeliac disease and on a gluten-free regimen. The first group, 9 teenagers diagnosed in childhood, relapsed histologically a very variable time after gluten reintroduction, 5 taking more than 7 weeks, the longest 10 months. In the second group, all diagnosed after puberty, 18 of 19 relapsed within 7 weeks but 1 had a normal mucosa 2 years after return to a gluten-containing diet. This is the first reported instance in an adult of something now familiar in the paediatric world-namely, absence of relapse after two years’ gluten challenge, despite an earlier flat small-intestinal mucosa and response to a gluten-free diet.3-5 Most of these children have continued to do well,3,4 but one relapsed histologically after 63 months.5 This remarkable variation in histological response, especially in patients diagnosed in childhood, is quite unexplained. Kumar’s findings resembled the paediatric results in other respects. 7 patients had no symptoms whatever despite morphological relapse, and there was no correlation with duration of the gluten-free diet. They also substantiate the. observation3 that a normal mucosa after 3 months of gluten challenge does not exclude cceliac disease, as was suggested by some workers.6 Whether the same applies in most patients after two years of gluten remains to be seen.
1. Meeuwise GW. Diagnostic criteria in cæliac disease. Acta Pædiat Scand 1970; 59: 461-63. 2. Kumar PJ, Donoghue DP, Stenson K, Dawson AM. Reintroduction of gluten in adults and children with treated cæliac disease. Gut 1979; 20: 743-49. 3. Walker-Smith JA, Kilby A, France NE. Reinvestigation of children previously diagnosed as cæliac disease. In: McNicholl B, McCarthy CF, Fottrell PF, eds. Perspectives in cæliac disease. Lancaster: MTP, 1978: 267. 4. Nusslé D, Bozic C, Cox J, Deleze G, Roulet M, Fete R, Megevana A. Noncæliac gluten intolerance in infancy. In: McNicholl B, McCarthy CF, Fottrell PF, eds. Perspectives in cœliac disease. Lancaster: MTP, 1978: 277. 5. McNicholl B, Egan-Mitchell B, Fottrell PF. Variability of gluten intolerance in treated childhood cæliac disease. Gut 1979; 20: 126-32. 6. Packer SM, Charlton V, Keeling JW, Risdon RA, Ogilvie D, Rowlatt RJ, Larcher VF, Harries JT. Gluten challenge in treated cœliac disease. Arch Dis Childh 1978; 53: 449-55.
and they were seen in 32 of the 175 patients treated in the Medical Research Council trial. Reactions are rare in boys with congenital agammaglobulinaemia and in pa-
secondary immunodeficiency. They happen other antibody-deficient patients and are thought to result from complement activation by IgG aggregates in the injection, rather than from an allergic response. Conventionally prepared IgG is suitable only for intramuscular injection; it can cause severe reactions when given intravenously. But, large intramuscular injections are painful, so the amount of immunoglobulin which can be given by this route is limited. This is unfortunate because the M.R.C./triaP showed that patients receiving 50 mg/kg/week of IgG had significantly tients with
sporadically in
fewer infections than those on the standard dose of 25 mg/kg/week. The smaller dose was recommended for routine prophylaxis in antibody deficiency partly out of consideration of the volume of the injection. Nolte and co-workers3 in Oregon have now shown that antibodydeficient patients given 150 mg/kg monthly had significantly fewer infections than others given about 50 mg/kg/month (the lower dose being substantially less than that routinely used in the U.K.). The higher dose was made possible through the use of a new IgG preparation, suitable for intravenous injection, in which immunoglobulin aggregation is prevented by mild reduction and alkylation. This is a considerable advance on the enzyme-digested IgG preparations, which lack the Fc region of the molecule and so have subnormal opsonising activity and a half-life in the circulation of only 5-6 days. The new intravenous preparation has a halflife of about 20 days and retains over 80% of the original antibody activity. One-third of the patients with primary antibody deficiency had transient nausea, fever, flushing, and muscle cramps after the infusions while those with secondary immunodeficiency were spared these effects. No patients had the severe reactions which sometimes follow intramuscular injections of the standard IgG. Ochs4 found that total hmmolytic complement and C3 levels fell slightly after intravenous IgG infusions and that the transient minor reactions were lessened or abolished by 600 mg of aspirin taken 30 minutes before the infusion. Ochs and co-workers will soon be reporting a two-year blind cross-over study comparing intravenous with intramuscular treatment. Meanwhile other smaller-scale studies are confirming the view that preparations of IgG suitable for intravenous use are effective and highly acceptable to patients; these include pH 4 treated material tested by Barandunsand S-sulphonated IgG used by Yamanaka et al.6 The reasons why S-sulphonation is so effective are not clear but the treated molecules reconvert to their native form within 24 hours of administration and they
1. Soothill
JF. Reactions to immunoglobulin. In: Hypogammaglobulinæmia in the United Kingdom. MRC Spec Rep Ser No. 310, 1971. LE, Mollison PL. Conclusions. In: Hypogammaglobulinæmia in the
2. Hill
United Kingdom. MRC Spec Rep Ser No. 310, 1971. 3. Nolte MT, Pirofsky B, Gerritz GA, Golding B. Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol 1979; 36: 237-43. 4. Ochs HD. Prophylactic treatment of immunodeficiency syndromes with intravenous gammaglobulin. Vox Sang 1979; 37: 126-28. 5. Barandun S. Use of intravenous gammaglobulin in the treatment of severe bacterial infection. Vox Sang 1979; 37: 117-19. 6. Yamanaka T, Abo W, Chiba S, et al. Clinical effect and metabolism of s-sulphonated immunoglobulin in 7 patients with congenital humoral immunodeficiency. Vox Sang 1979; 37: 14-20.
in the circulation with a half-life of 21 days. No reactions have been reported in the small number of patients treated. Commercial exploration of intravenous IgG preparations is doubtless undertaken in the hope that they may have wider clinical application than mere immuno-
persist
deficiency-for instance, life-threatening infections, particularly with septicaEmia, and sepsis of the newborn. Clinical trials in these areas are very difficult to organise very informative results are yet to hand. On evidence there is ’a strong case for further evaluation of intravenous IgG in treatment of antibody deficiency in the U.K. Until intravenous preparations are more widely available it may be to the patient’s ultimate advantage to be generous with intramuscular IgG, despite the added pain of injection.
and
no
existing
VARIABLE RESPONSE TO GLUTEN CHALLENGE MOST paediatricians now accept that final diagnosis of cceliac disease in childhood rests on healing of the smallintestinal mucosa when gluten is withdrawn followed by histological relapse after gluten challenge.’ Now Kumar and colleagues2 have used these diagnostic criteria when trying the reintroduction of gluten into the diet of teenagers and adults diagnosed as having coeliac disease and on a gluten-free regimen. The first group, 9 teenagers diagnosed in childhood, relapsed histologically a very variable time after gluten reintroduction, 5 taking more than 7 weeks, the longest 10 months. In the second group, all diagnosed after puberty, 18 of 19 relapsed within 7 weeks but 1 had a normal mucosa 2 years after return to a gluten-containing diet. This is the first reported instance in an adult of something now familiar in the paediatric world-namely, absence of relapse after two years’ gluten challenge, despite an earlier flat small-intestinal mucosa and response to a gluten-free diet.3-5 Most of these children have continued to do well,3,4 but one relapsed histologically after 63 months.5 This remarkable variation in histological response, especially in patients diagnosed in childhood, is quite unexplained. Kumar’s findings resembled the paediatric results in other respects. 7 patients had no symptoms whatever despite morphological relapse, and there was no correlation with duration of the gluten-free diet. They also substantiate the. observation3 that a normal mucosa after 3 months of gluten challenge does not exclude cceliac disease, as was suggested by some workers.6 Whether the same applies in most patients after two years of gluten remains to be seen.
1. Meeuwise GW. Diagnostic criteria in cæliac disease. Acta Pædiat Scand 1970; 59: 461-63. 2. Kumar PJ, Donoghue DP, Stenson K, Dawson AM. Reintroduction of gluten in adults and children with treated cæliac disease. Gut 1979; 20: 743-49. 3. Walker-Smith JA, Kilby A, France NE. Reinvestigation of children previously diagnosed as cæliac disease. In: McNicholl B, McCarthy CF, Fottrell PF, eds. Perspectives in cæliac disease. Lancaster: MTP, 1978: 267. 4. Nusslé D, Bozic C, Cox J, Deleze G, Roulet M, Fete R, Megevana A. Noncæliac gluten intolerance in infancy. In: McNicholl B, McCarthy CF, Fottrell PF, eds. Perspectives in cœliac disease. Lancaster: MTP, 1978: 277. 5. McNicholl B, Egan-Mitchell B, Fottrell PF. Variability of gluten intolerance in treated childhood cæliac disease. Gut 1979; 20: 126-32. 6. Packer SM, Charlton V, Keeling JW, Risdon RA, Ogilvie D, Rowlatt RJ, Larcher VF, Harries JT. Gluten challenge in treated cœliac disease. Arch Dis Childh 1978; 53: 449-55.
