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An evaluation of the safety of three intravenous immunoglobulin preparations in patients with primary hypogammaglobulinaemia
Journal of Infection (I986) I2, 5-IO
An evaluation of the safety of three intravenous i m m u n o g l o b u l i n preparations in patients with p r i m a r y hypogammaglobulinaemia P. L. Yap* a n d D. B. L. M c C l e l l a n d
Edinburgh & S.E. Scotland Blood Transfusion Service, Lauriston Place, Edinburgh EH3 9HB, Scotland Accepted for publication 4 April I985 Summary In an open study, three different immunoglobulin preparations for intravenous use (Iv IgG), namely pH 4 and pepsin treated immunoglobulin (' Sandoglobulin'); reduced and alkylated immunoglobulin (' Gamimune') as well as ultrafiltered, pH 4 and pepsin treated immunoglobulin manufactured by the Scottish National Blood Transfusion Service (' SNBTS IV IgG'), were compared with intramuscular immunoglobulin (IM IgG) in five patients with primary hypogammaglobulinaemia, by treating each patient consecutively with each immunoglobulin preparation for 3 months. Few adverse reactions were noted with any of the intravenous immunoglobulin preparations and these mainly consisted of mild fever (< 38 °C). Concentrations of serum IgG were higher with all intravenous immunoglobulin preparations compared with IM IgG. Furthermore, all the patients preferred IV to IM IgG therapy. As higher doses of immunoglobulin are associated with a reduction in infections in hypogammaglobulinaemic patients, we conclude that intravenous immunoglobulin therapy should be considered for the prophylaxis of infection in patients with primary hypogammaglobulinaemia. Introduction Patients with primary hypogammaglobulinaemia suffer from recurrent infections of the respiratory tract, particularly due to Haemophilus influenzae and Streptococcus pneumoniae. Treatment with immunoglobulin prepared by the cold ethanol method (Cohn fractionation) and administered by the intramuscular (IM) route has been available for the prophylaxis of infections in such patients for many years. 1 T h e recommended dose is IOO m g / k g / m o n t h and although this treatment has been associated with a lower rate of morbidity in this group of patientsfl some are better maintained on a higher dose of 2oo mg/kg/month.3 T h e volume of immunoglobulin that can be administered, however, is limited by pain from the injection. Although intravenous immunoglobulin therapy is recommended in patients with severe chest disease and those who cannot tolerate IM injection, 4 various intravenous immunoglobulin preparations are available in the U.K. and elsewhere. Previously, only single intravenous immunoglobulin preparations have been compared with IM immunoglobulin. Comparative evaluation of different immunoglobulin preparations for intravenous use in primary hypogammaglobulinaemia has not been reported. We describe the results of such a study. Correspondence to: Dr P. L. Yap. oi63-4453/86/oiooo5 +06 802.00/0
~) I986 The British Society for the Study of Infection
P. L. YAP AND D. B. L. MCCLELLAND T a b l e I Mean pre-infusion IgG concentrations during therapy with each
immunoglobulin preparation Patient
IM IgG* (g/l)
' Sandoglobulin'# (g/l)
r 2 3 4 5
5'8 1'42 2"55 4"r4 3'5I
6"4 2"54 3"34 5"4x 3"88
'Garnimune't ' SNBTS IV IgG't" (g/l) (g/l) 8'52 2'75 3"89 4"88 5"o6
9"26 2"85 6"7I 4"95 3"93
* IgG concentration before each ua IgG injection. t IgG concentration before each Iv IgG infusion. SNBTS, Scottish National Blood Transfusion Service. Table II Immunoglobulin preparations used and adverse reactions Immunoglobulin preparations
Manufacturer
rM IgG
SNBTS
' Sandoglobulin' ' Gamimune'
Sandoz (Swiss Red Cross) Cutter
'SNBTS IV IgG'
SNBTS
Method of production
Adverse reactions*
Standard Cohn fractionation pH 4 + pepsin
o
DTT treatment + iodoacetamide ultrafiltration + pH 4 + pepsin
3
8
r
* Total adverse reactions for five patients. These consisted of mild fever (< 38 °C) and shivering. SNBTS, Scottish National Blood Transfusion Service.
Patients and methods
One patient with X-linked p r i m a r y h y p o g a m m a g l o b u l i n a e m i a and four patients with late-onset p r i m a r y h y p o g a m m a g l o b u l i n a e m i a were studied. At the time of initial diagnosis all patients had serum I g G concentrations of < I g/1 except for patient 4 who had an I g G concentration of 2.2 g/1. T w o patients (patients I and 5, Table I) had previously been treated with plasma (I5 m l / k g b o d y weight every 3 weeks) until 5 weeks before the beginning of the study. T h e remaining patients had been treated with weekly doses of IM I g G (25 m g / k g b o d y weight). Approval of the hospital ethical committee was obtained for this study. T h e four i m m u n o g l o b u l i n preparations were assessed sequentially over periods of I2 weeks with an interval o f 4 weeks between each preparation. Details o f the nature and dates o f administration of each i m m u n o g l o b u l i n preparation are shown in Table II. I m m u n o g l o b u l i n G (25 m g / k g b o d y weight) was administered IM weekly; all three intravenous i m m u n o g l o b u l i n preparations (20o m g / k g b o d y weight)
Safety of intravenous IgG preparations ~M
Ig
7
Sandoglobulin \\\\
I0
r .... l'-.../
,,/,,
0 u
I
I
I
I
I
.E 0
g E E
Gamimune
I0
l\ \
NN,,x\~
"_"
0
0
SNBTS tv Ig
/""
\.,\N
.,q
t 6
I I 12 0
....
6
__.,
""
I
12
Weeks of treatment Fig. I. S e r u m I g G concentrations before each Ibl I g G injection (o) as well as before and immediately after each intravenous i m m u n o g l o b u l i n infusion ( O - - O ) in patient 4. T h e arrows indicate administration of i m m u n o g l o b u l i n and the horizontal broken line the lower limit of the normal range.
were administered every 3 weeks according to each manufacturer's instructions. Patients' preferences for the m e t h o d of administering the immunoglobulin was determined at the end of each period of treatment with intravenous immunoglobulin. Blood samples for measuring serum immunoglobulin were obtained before each TM injection of I g G as well as before and immediately after each intravenous infusion of i m m u n o g l o b u l i n ; post infusion blood samples were obtained from the arm not used for the infusion; samples for measuring complement (CH5o, C4 and C3) were collected before and after the first infusion for each of the intravenous immunoglobulin preparations studied. I m m u n o g l o b u l i n G, IgA, IgM, C3 and C4 concentrations were measured by laser nephelometry; ~ haemolytic complement (CH5o) was measured by an automated method. 8 Results
Adverse reactions were noted in I2 of the 60 infusions of intravenous immunoglobulin mostly in relation to the first intravenous immunoglobulin preparation assessed (i.e.,' Sandoglobulin' - Table II). T h e y usually consisted of mild fever ( < 38 °C) towards the end of the intravenous immunoglobulin
8
P. L. Y A P A N D D. B. L. M C C L E L L A N D I0 IM Ig
gu .E o
g~
'°[ 0 1 0
Sandoglobulin
I 6
I L 12 0
Gamimune
i 12
6 SNBTS w Ig
2 E
\\
0 0
[ 6
I L 12 0
I 6
12
Weeks of freotment
Fig. 2. Serum IgG concentrations before each XM IgG injection (e) as well as before and immediately after each intravenous immunoglobulin infusion ( e - - o ) in patient 2. The arrows indicate administration of immunoglobulin and the horizontal broken line the lower limit of the normal range.
infusion or within 3-4 h of its completion. A mild rigor was recorded after one ' S a n d o g l o b u l i n ' infusion. Patients 2 and 4 did not experience any adverse reactions with any of the intravenous infusions of immunoglobulin. Apart from pain at the site of injection no adverse reactions were noted with any of the IM I g G injections. In all five patients in this study, the mean serum I g G concentrations immediately before each infusion of the three preparations of intravenous immunoglobulin was higher than the mean serum I g G concentration before each IM I g G injection. In four of the patients, serum concentrations rose above 5 g/1 (the lower limit of the normal range) during treatment with intravenous immunoglobulin (Fig. I). In one patient (patient 2), serum I g G concentrations remained below the normal range (Fig. 2; Table I). Serum IgA and I g M concentrations were not altered by intravenous immunoglobulin or IM I g G therapy (not shown). T h e relatively high serum I g G concentrations in patients I and 5 during the period of IM I g G therapy reflect the fact that these two patients had received replacement therapy in the form of fresh frozen plasma prior to the study. Consistent decreases in complement values were not seen during any of the intravenous immunoglobulin infusions (not shown). All the patients in this study preferred intravenous immunoglobulin therapy to IM I g G because of the absence of painful injections. One of the five patients, however, preferred the convenience of self-administration of IM I g G at home.
Safety of intravenous IgG preparations
9
Discussion
Higher doses of intramuscular immunoglobulin administered as replacement therapy in primary hypogammaglobulinaemia are associated with a reduced infection rate. ~ With newer immunoglobulin preparations suitable for intravenous use, serum I g G concentrations approaching or within the normal range can be maintained in many patients. 7An increasing n u m b e r of immunoglobulin preparations suitable for intravenous use, b u t manufactured by different methods are now available, s We have evaluated two commercial preparations with a good record for safety (' Sandoglobulin' and ' G a m i m u n e ' ) as well as a new immunoglobulin preparation manufactured at the Scottish National Blood Transfusion Service Protein Fractionation Centre and have compared these preparations with standard IM I g G manufactured by C o h n fractionation. In our study, only mild adverse reactions with the intravenous i m m u n o globulin preparations were noted. We did not observe, in our smaller group of patients, the severe adverse reactions reported for ' S a n d o g l o b u l i n ' by C u n n i n g h a m - R u n d l e s and colleagues 7 nor the high incidence of chills, lower back pain, nausea and vomiting reported by Ochs and colleagues for Gamimune.9 T h e mild adverse reactions did not seem to be related to the concentration of serum IgG. O u r patients, however, did not have serious infections at the time of intravenous immunoglobulin infusion. This difference may explain the lower incidence of adverse reactions we observed. In view of the mildness of the reactions and the high concentrations of serum I g G in four of our five patients, we now r e c o m m e n d intravenous immunoglobulin, when it is available, for all patients with primary hypogammaglobulinaemia particularly since viral infections may be transmitted with immunoglobulin replacement therapy by means of whole plasma. T h e lack of an increase in serum I g G in patient 4, was probably due to malabsorption. Intravenous immunoglobulin preparations with high concentrations of antibody against specific infectious agents such as cytomegalovirus 1° or Pseudomonas (Dr R. Roussel, Cutter Labs; personal communication) or against bacterial endotoxin (Dr H. Lissner, Biotest; personal communication) are now becoming available. Although it has been previously demonstrated that patients with primary hypogammaglobulinaemia are more likely to suffer adverse reactions to immunoglobulin preparations administered intravenously, 11 our study would suggest that large quantities of antibody may be safely administered intravenously for the prophylaxis and treatment of severe infections in i m m u n o c o m p r o m i s e d patients. (We gratefully acknowledge the co-operation of our patients in this study as well as Sandoz Pharmaceuticals, Cutter Laboratories and the Scottish National Blood Transfusion Service Protein Fractionation Centre for the Immunoglobulin preparations; also the technical staff at the Blood Transfusion Service, Edinburgh for immunoglobulin and complement measurements.)
IO
P. L. YAP AND D. B. L. MCCLELLAND
References I. Cohn EJ, Strong LE, Hughes WL Jr, Mulford D J, Ashworth JN, Melin M, Taylor HL. Preparation and properties of serum and plasma proteins, IV. A system for the separation into the fractions of the protein and lipo-protein components of biological tissues and fluids. J Am Chem Soc I946; 68: 459-475. 2. Medical Research Council Special Report Series 3Io. I97I. Hypogammaglobulinaemia in the United Kingdom. 3. Thompson RA, Rees-Jones A. The antibody deficiency syndrome: a report on management. ff Infect I979; x : 49-60. 4. So A, Brenner MK, Hill ID, Asherson GL, Webster ADB. Intravenous gammaglobulin treatment in patients with hypogammaglobulinaemia. Br Med J r984; 289: t I77-I r78. 5. Whicher JT, Perry DE, Hobbs JR. An evaluation of the Hyland laser nephelometer PDQ for the measurement of immunoglobulin. Ann Clin Biochem x978; IS: 77-85. 6. Fischer J. Automatic registration of complement haemolysis and some applications. Int Syrup on lmmunol methods of Biological Standardisation. Karger x967; 4: 221-228. 7. Curmingham-Rundles C, Smithwick EM, Siegal FP, Day NK, Cunningham-Rundles S, Koziner B, Lion A, Barandun S, O'Malley J, Good RA. Treatment of primary humoral immunodeficiency disease with intravenous (pH 4 treated) immunoglobulin. In: Nydegger, VE, Ed. Immunohaemotherapy. A Guide to Prophylaxis and Therapy London: Academic Press. .I98I : 283-290, 8. McClelland DBL, Yap PL. Clinical use of Immunoglobulins. Clinics in Haematol x984; I3: 39-74. 9. Ochs HD, Buckley RH, Priofsky B, Fischer SH, Rousell RH, Anderson CJ, Wedgewood RH. Safety and patient acceptability of intravenous immune globulin in Io% maltose. Lancet x98o; ii: I I58-I x59. xo. Nicholls AJ, Brown CB, Edward N, Cuthbertson B, Yap PL, McClelland DBL. Hyperimmune immunoglobulin for cytomegalovirus infections. Lancet I983; i: 532-533. I L Barandun S, Kistler P, Jeunet F, Isliker H. Intravenous administration of human immunoglobulin. Vox Sang x962; 7: x57-I74.
An evaluation of the safety of three intravenous i m m u n o g l o b u l i n preparations in patients with p r i m a r y hypogammaglobulinaemia P. L. Yap* a n d D. B. L. M c C l e l l a n d
Edinburgh & S.E. Scotland Blood Transfusion Service, Lauriston Place, Edinburgh EH3 9HB, Scotland Accepted for publication 4 April I985 Summary In an open study, three different immunoglobulin preparations for intravenous use (Iv IgG), namely pH 4 and pepsin treated immunoglobulin (' Sandoglobulin'); reduced and alkylated immunoglobulin (' Gamimune') as well as ultrafiltered, pH 4 and pepsin treated immunoglobulin manufactured by the Scottish National Blood Transfusion Service (' SNBTS IV IgG'), were compared with intramuscular immunoglobulin (IM IgG) in five patients with primary hypogammaglobulinaemia, by treating each patient consecutively with each immunoglobulin preparation for 3 months. Few adverse reactions were noted with any of the intravenous immunoglobulin preparations and these mainly consisted of mild fever (< 38 °C). Concentrations of serum IgG were higher with all intravenous immunoglobulin preparations compared with IM IgG. Furthermore, all the patients preferred IV to IM IgG therapy. As higher doses of immunoglobulin are associated with a reduction in infections in hypogammaglobulinaemic patients, we conclude that intravenous immunoglobulin therapy should be considered for the prophylaxis of infection in patients with primary hypogammaglobulinaemia. Introduction Patients with primary hypogammaglobulinaemia suffer from recurrent infections of the respiratory tract, particularly due to Haemophilus influenzae and Streptococcus pneumoniae. Treatment with immunoglobulin prepared by the cold ethanol method (Cohn fractionation) and administered by the intramuscular (IM) route has been available for the prophylaxis of infections in such patients for many years. 1 T h e recommended dose is IOO m g / k g / m o n t h and although this treatment has been associated with a lower rate of morbidity in this group of patientsfl some are better maintained on a higher dose of 2oo mg/kg/month.3 T h e volume of immunoglobulin that can be administered, however, is limited by pain from the injection. Although intravenous immunoglobulin therapy is recommended in patients with severe chest disease and those who cannot tolerate IM injection, 4 various intravenous immunoglobulin preparations are available in the U.K. and elsewhere. Previously, only single intravenous immunoglobulin preparations have been compared with IM immunoglobulin. Comparative evaluation of different immunoglobulin preparations for intravenous use in primary hypogammaglobulinaemia has not been reported. We describe the results of such a study. Correspondence to: Dr P. L. Yap. oi63-4453/86/oiooo5 +06 802.00/0
~) I986 The British Society for the Study of Infection
P. L. YAP AND D. B. L. MCCLELLAND T a b l e I Mean pre-infusion IgG concentrations during therapy with each
immunoglobulin preparation Patient
IM IgG* (g/l)
' Sandoglobulin'# (g/l)
r 2 3 4 5
5'8 1'42 2"55 4"r4 3'5I
6"4 2"54 3"34 5"4x 3"88
'Garnimune't ' SNBTS IV IgG't" (g/l) (g/l) 8'52 2'75 3"89 4"88 5"o6
9"26 2"85 6"7I 4"95 3"93
* IgG concentration before each ua IgG injection. t IgG concentration before each Iv IgG infusion. SNBTS, Scottish National Blood Transfusion Service. Table II Immunoglobulin preparations used and adverse reactions Immunoglobulin preparations
Manufacturer
rM IgG
SNBTS
' Sandoglobulin' ' Gamimune'
Sandoz (Swiss Red Cross) Cutter
'SNBTS IV IgG'
SNBTS
Method of production
Adverse reactions*
Standard Cohn fractionation pH 4 + pepsin
o
DTT treatment + iodoacetamide ultrafiltration + pH 4 + pepsin
3
8
r
* Total adverse reactions for five patients. These consisted of mild fever (< 38 °C) and shivering. SNBTS, Scottish National Blood Transfusion Service.
Patients and methods
One patient with X-linked p r i m a r y h y p o g a m m a g l o b u l i n a e m i a and four patients with late-onset p r i m a r y h y p o g a m m a g l o b u l i n a e m i a were studied. At the time of initial diagnosis all patients had serum I g G concentrations of < I g/1 except for patient 4 who had an I g G concentration of 2.2 g/1. T w o patients (patients I and 5, Table I) had previously been treated with plasma (I5 m l / k g b o d y weight every 3 weeks) until 5 weeks before the beginning of the study. T h e remaining patients had been treated with weekly doses of IM I g G (25 m g / k g b o d y weight). Approval of the hospital ethical committee was obtained for this study. T h e four i m m u n o g l o b u l i n preparations were assessed sequentially over periods of I2 weeks with an interval o f 4 weeks between each preparation. Details o f the nature and dates o f administration of each i m m u n o g l o b u l i n preparation are shown in Table II. I m m u n o g l o b u l i n G (25 m g / k g b o d y weight) was administered IM weekly; all three intravenous i m m u n o g l o b u l i n preparations (20o m g / k g b o d y weight)
Safety of intravenous IgG preparations ~M
Ig
7
Sandoglobulin \\\\
I0
r .... l'-.../
,,/,,
0 u
I
I
I
I
I
.E 0
g E E
Gamimune
I0
l\ \
NN,,x\~
"_"
0
0
SNBTS tv Ig
/""
\.,\N
.,q
t 6
I I 12 0
....
6
__.,
""
I
12
Weeks of treatment Fig. I. S e r u m I g G concentrations before each Ibl I g G injection (o) as well as before and immediately after each intravenous i m m u n o g l o b u l i n infusion ( O - - O ) in patient 4. T h e arrows indicate administration of i m m u n o g l o b u l i n and the horizontal broken line the lower limit of the normal range.
were administered every 3 weeks according to each manufacturer's instructions. Patients' preferences for the m e t h o d of administering the immunoglobulin was determined at the end of each period of treatment with intravenous immunoglobulin. Blood samples for measuring serum immunoglobulin were obtained before each TM injection of I g G as well as before and immediately after each intravenous infusion of i m m u n o g l o b u l i n ; post infusion blood samples were obtained from the arm not used for the infusion; samples for measuring complement (CH5o, C4 and C3) were collected before and after the first infusion for each of the intravenous immunoglobulin preparations studied. I m m u n o g l o b u l i n G, IgA, IgM, C3 and C4 concentrations were measured by laser nephelometry; ~ haemolytic complement (CH5o) was measured by an automated method. 8 Results
Adverse reactions were noted in I2 of the 60 infusions of intravenous immunoglobulin mostly in relation to the first intravenous immunoglobulin preparation assessed (i.e.,' Sandoglobulin' - Table II). T h e y usually consisted of mild fever ( < 38 °C) towards the end of the intravenous immunoglobulin
8
P. L. Y A P A N D D. B. L. M C C L E L L A N D I0 IM Ig
gu .E o
g~
'°[ 0 1 0
Sandoglobulin
I 6
I L 12 0
Gamimune
i 12
6 SNBTS w Ig
2 E
\\
0 0
[ 6
I L 12 0
I 6
12
Weeks of freotment
Fig. 2. Serum IgG concentrations before each XM IgG injection (e) as well as before and immediately after each intravenous immunoglobulin infusion ( e - - o ) in patient 2. The arrows indicate administration of immunoglobulin and the horizontal broken line the lower limit of the normal range.
infusion or within 3-4 h of its completion. A mild rigor was recorded after one ' S a n d o g l o b u l i n ' infusion. Patients 2 and 4 did not experience any adverse reactions with any of the intravenous infusions of immunoglobulin. Apart from pain at the site of injection no adverse reactions were noted with any of the IM I g G injections. In all five patients in this study, the mean serum I g G concentrations immediately before each infusion of the three preparations of intravenous immunoglobulin was higher than the mean serum I g G concentration before each IM I g G injection. In four of the patients, serum concentrations rose above 5 g/1 (the lower limit of the normal range) during treatment with intravenous immunoglobulin (Fig. I). In one patient (patient 2), serum I g G concentrations remained below the normal range (Fig. 2; Table I). Serum IgA and I g M concentrations were not altered by intravenous immunoglobulin or IM I g G therapy (not shown). T h e relatively high serum I g G concentrations in patients I and 5 during the period of IM I g G therapy reflect the fact that these two patients had received replacement therapy in the form of fresh frozen plasma prior to the study. Consistent decreases in complement values were not seen during any of the intravenous immunoglobulin infusions (not shown). All the patients in this study preferred intravenous immunoglobulin therapy to IM I g G because of the absence of painful injections. One of the five patients, however, preferred the convenience of self-administration of IM I g G at home.
Safety of intravenous IgG preparations
9
Discussion
Higher doses of intramuscular immunoglobulin administered as replacement therapy in primary hypogammaglobulinaemia are associated with a reduced infection rate. ~ With newer immunoglobulin preparations suitable for intravenous use, serum I g G concentrations approaching or within the normal range can be maintained in many patients. 7An increasing n u m b e r of immunoglobulin preparations suitable for intravenous use, b u t manufactured by different methods are now available, s We have evaluated two commercial preparations with a good record for safety (' Sandoglobulin' and ' G a m i m u n e ' ) as well as a new immunoglobulin preparation manufactured at the Scottish National Blood Transfusion Service Protein Fractionation Centre and have compared these preparations with standard IM I g G manufactured by C o h n fractionation. In our study, only mild adverse reactions with the intravenous i m m u n o globulin preparations were noted. We did not observe, in our smaller group of patients, the severe adverse reactions reported for ' S a n d o g l o b u l i n ' by C u n n i n g h a m - R u n d l e s and colleagues 7 nor the high incidence of chills, lower back pain, nausea and vomiting reported by Ochs and colleagues for Gamimune.9 T h e mild adverse reactions did not seem to be related to the concentration of serum IgG. O u r patients, however, did not have serious infections at the time of intravenous immunoglobulin infusion. This difference may explain the lower incidence of adverse reactions we observed. In view of the mildness of the reactions and the high concentrations of serum I g G in four of our five patients, we now r e c o m m e n d intravenous immunoglobulin, when it is available, for all patients with primary hypogammaglobulinaemia particularly since viral infections may be transmitted with immunoglobulin replacement therapy by means of whole plasma. T h e lack of an increase in serum I g G in patient 4, was probably due to malabsorption. Intravenous immunoglobulin preparations with high concentrations of antibody against specific infectious agents such as cytomegalovirus 1° or Pseudomonas (Dr R. Roussel, Cutter Labs; personal communication) or against bacterial endotoxin (Dr H. Lissner, Biotest; personal communication) are now becoming available. Although it has been previously demonstrated that patients with primary hypogammaglobulinaemia are more likely to suffer adverse reactions to immunoglobulin preparations administered intravenously, 11 our study would suggest that large quantities of antibody may be safely administered intravenously for the prophylaxis and treatment of severe infections in i m m u n o c o m p r o m i s e d patients. (We gratefully acknowledge the co-operation of our patients in this study as well as Sandoz Pharmaceuticals, Cutter Laboratories and the Scottish National Blood Transfusion Service Protein Fractionation Centre for the Immunoglobulin preparations; also the technical staff at the Blood Transfusion Service, Edinburgh for immunoglobulin and complement measurements.)
IO
P. L. YAP AND D. B. L. MCCLELLAND
References I. Cohn EJ, Strong LE, Hughes WL Jr, Mulford D J, Ashworth JN, Melin M, Taylor HL. Preparation and properties of serum and plasma proteins, IV. A system for the separation into the fractions of the protein and lipo-protein components of biological tissues and fluids. J Am Chem Soc I946; 68: 459-475. 2. Medical Research Council Special Report Series 3Io. I97I. Hypogammaglobulinaemia in the United Kingdom. 3. Thompson RA, Rees-Jones A. The antibody deficiency syndrome: a report on management. ff Infect I979; x : 49-60. 4. So A, Brenner MK, Hill ID, Asherson GL, Webster ADB. Intravenous gammaglobulin treatment in patients with hypogammaglobulinaemia. Br Med J r984; 289: t I77-I r78. 5. Whicher JT, Perry DE, Hobbs JR. An evaluation of the Hyland laser nephelometer PDQ for the measurement of immunoglobulin. Ann Clin Biochem x978; IS: 77-85. 6. Fischer J. Automatic registration of complement haemolysis and some applications. Int Syrup on lmmunol methods of Biological Standardisation. Karger x967; 4: 221-228. 7. Curmingham-Rundles C, Smithwick EM, Siegal FP, Day NK, Cunningham-Rundles S, Koziner B, Lion A, Barandun S, O'Malley J, Good RA. Treatment of primary humoral immunodeficiency disease with intravenous (pH 4 treated) immunoglobulin. In: Nydegger, VE, Ed. Immunohaemotherapy. A Guide to Prophylaxis and Therapy London: Academic Press. .I98I : 283-290, 8. McClelland DBL, Yap PL. Clinical use of Immunoglobulins. Clinics in Haematol x984; I3: 39-74. 9. Ochs HD, Buckley RH, Priofsky B, Fischer SH, Rousell RH, Anderson CJ, Wedgewood RH. Safety and patient acceptability of intravenous immune globulin in Io% maltose. Lancet x98o; ii: I I58-I x59. xo. Nicholls AJ, Brown CB, Edward N, Cuthbertson B, Yap PL, McClelland DBL. Hyperimmune immunoglobulin for cytomegalovirus infections. Lancet I983; i: 532-533. I L Barandun S, Kistler P, Jeunet F, Isliker H. Intravenous administration of human immunoglobulin. Vox Sang x962; 7: x57-I74.