Eur J Pediatr (1992) 151 : 271-273
European Journal of
Pediatrics
9 Springer-Verlag 1992
latrogenic IgG2 deficiency in a leukaemic child A case report A. W. de Boer, G . A . M . de Vaan, C . M . R . Weemaes, and J. A. J. M. Bakkeren Department of Paediatrics, Centre of Paediatric Oncology, Southeast Netherlands, University Hospital Nijmegen, P.O. Box 9101, NL-6500 HB Nijmegen, Nijmegen, The Netherlands Received April 22, 1991 / Accepted September 12, 1991
Abstract. A girl with a c u t e n o n - l y m p h o b l a s t i c l e u k a e m i a was t r e a t e d w i t h i m m u n o s u p p r e s s i v e c h e m o t h e r a p y . A f t e r c e s s a t i o n o f t h e r a p y she h a d t h r e e c o n s e c u t i v e epis o d e s of i n f e c t i o n d u e to Streptococcuspneumoniae f r o m which she r e c o v e r e d a n d was s h o w n to h a v e d e v e l o p e d a c o m b i n e d d e f i c i e n c y o f b o t h IgG2 a n d IgG4. T h e p a t i e n t e v e n t u a l l y r e l a p s e d a n d d i e d 3 y e a r s a f t e r t h e initial diagnosis. T h e i m p o r t a n c e o f m e a s u r i n g I g G subclasses in p a t i e n t s t r e a t e d with i m m u n o s u p p r e s s i v e c h e m o t h e r a p y is discussed.
Key words: A c u t e n o n - l y m p h o b l a s t i c l e u k a e m i a - I m m u n o s u p p r e s s i v e drugs - IgG2 d e f i c i e n c y
Introduction T h e o v e r a l l survival r a t e for a c u t e n o n - l y m p h o b l a s t i c l e u k a e m i a ( A N L L ) c o n t i n u e s to i m p r o v e [7], h o w e v e r t h e i n t e n s i v e c h e m o t h e r a p y r e q u i r e d f o r effective t r e a t m e n t s e v e r e l y c o m p r o m i s e s b o t h g e n e r a l a n d specific i m m u n i t y . D e p r e s s i o n o f i m m u n o g l o b u l i n (Ig) p r o d u c tion d u r i n g t h e r a p y is well d o c u m e n t e d [6, 12]. L i t t l e is k n o w n a b o u t t h e effect of t h e r a p y o n subclasses o f I g G [13]. W e p r e s e n t t h e case of a child w h o d e v e l o p e d a deficiency of IgG2 following t r e a t m e n t for A N L L .
Case report A 2 year 2 month-old girl was admitted complaining of fever, malaise and anorexia. She had been unwell for a few weeks but neither she nor her parents had a recent history of illness. Physical examination revealed hepatomegaly but there was no enlargement of the spleen and lymph nodes. Haemoglobin was 9.3 g/dl, haematocrit 29%, platelets 10 • 109/1 and a total leucocyte count of 1.8 • 109/1with 47% blasts. Bone marrow aspirate yielded a hypercellular, monotonous picture diagnosed as ANLL FAB M2, con-
Offprint requests to: A. W. de Boer Abbreviation." ANLL = acute non-lymphoblastic leukaemia
firmed by the Dutch Childhood Leukaemia Study Group. However, immunotyping showed 63% of the ceils to be positive for CD-10 (common ALL-antigen) and 0% positive for CD-11 (OKM), a monocyte marker. Spontaneous incorporation of tritiated thymidine by the leukaemic cells was low, which is more consistent with acute lymphoblastic leukaemia than ANLL [2, 5]. The karyotype of the leukaemic cells was normal: 46 XX. Her immunoglobulin levels were normal (Table 1). She was treated following the German BFM-ANLL 83 protocol [4]. Just before the cessation of the antileukaemic therapy she became severely ill with fever, vomiting and abdominal distension. A laparotomy was performed and showed a massive infiltration of the small intenstine with necrosis and multiple perforations due to a granulocytic sarcoma. Following the operation she developed an Escherichia coli sepsis and was treated with antibiotics. Because of her poor clinical condition only prednisone was given but no cytostatic treatment. The outcome was surprisingly successful: the tumour subsided and the child recovered. Thereafter, a period of 4 months followed during which she had three episodes of septicaemia due to Streptococcus pneumoniae, twice associated with osteomyelitis of the right talus and once with pneumonia. She responded promptly on each occasion to antibiotics. Her spleen appeared to function normally since the uptake of radioactively labelled red cells was normal. With radioactively labelled leukocytes, administered after healing of the talus, no loci anywhere in the body were revealed. The uptake of the spleen was completely normal. The complement components were normal. However, a deficiency of IgG2 and IgG4 was established (Table 1) and antibodies to S. pneumoniae remained low. The kappa/ lambda ratio which had been normal at the start of chemotherapy, decreased during chemotherapy but returned to normal after withdrawal of treatment. Some months later on a routine checkup, bone marrow examination showed her to have relapsed. There was, however, no evidence of any extramedullary involvement. She was given reinduction therapy but died in the induction phase from interstitial pneumonia associated with Streptococcus viridans. Autopsy was not performed.
Methods Serum IgG, IgA, IgM, kappa and lambda levels were determined by laser nephelometry using a DISC 120 Nephelometer (Hyland, Nivelles, Belgium). All values were calibrated against WHO standard serum No. 67/97. IgG subclass levels were measured by radial immunodiffusion and calibrated against reference serum containing IgG1 6.2g/1; IgG2 2.4g/1; IgG3 0.64g/1 and IgG4 0.46g/1 (H00-020, The Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam). IgG> IgG2 and IgG3 levels were corn-
272 Table 1. Serum immunoglobulinlevels of the patient
Immunoglobulin levels (g/l) IgG
IgG subclass levels (g/l)
IgA
IgM
IgGa
IgG2
IgG3
IgG4
7.32
0.49
2.13
2.50 4.20
0.09 0.75
< 0.04 0.50
2.0 4.1
0.77 < 0.24
0.08 0.31
0.15 < 0.046
0.52 0.81
1.58 2.11
9.9
- not done < 0.24 0.89
< 0.046
Kappa/ Lambda ratio
At diagnosis December 1984
- not done -
1.56
During therapy April 1985 June 1986
0.98
Therapy stopped December 1986 August 1987 October 1987
12.3 10.9
1.26
Table 2. Serum IgG and IgG subclass levels of control children during antileukaemic therapy
No.
1 2 3 4 5 6 7
Age at diagnosis (years; months)
Age at sampling (years; months)
Diagnosis
9;3 8;11 8;4 8;0 4;4 3;5 1;1
10;7 11;2 10;7 9;7 6;6 5;8 2;8
ANLL ALL ANLL ALL ALL ALL ALL
IgG level (g/l)
15.89 3.84 7.14 5.44 3.39 7.23 6.34
IgG Subclass levels (g/l) IgG1
IgG2
IgG3
IgG4
12.8 2.3b 6.2 3.9 2.0b 5.3 4.0
2.57 0.60b 0.74" 0.65b 0.55b 0.38b 0.38
0.70 0.19a 1.02 0.79 0.61 0.80 0.42
0.68 0.12 0.15 0.11 < 0.046b < 0.046b < 0.046b
ALL, Acute lymphoblastic leukaemia a 3rd Percentile b Deficient
pared to the age-related normal values recently described by Plebani et al. [9]. In this study values below the 3rd percentile (P3) were considered as an indication of deficiency of an IgG sublcass: IgG~ < 3.1g/l, IgG2
European Journal of
Pediatrics
9 Springer-Verlag 1992
latrogenic IgG2 deficiency in a leukaemic child A case report A. W. de Boer, G . A . M . de Vaan, C . M . R . Weemaes, and J. A. J. M. Bakkeren Department of Paediatrics, Centre of Paediatric Oncology, Southeast Netherlands, University Hospital Nijmegen, P.O. Box 9101, NL-6500 HB Nijmegen, Nijmegen, The Netherlands Received April 22, 1991 / Accepted September 12, 1991
Abstract. A girl with a c u t e n o n - l y m p h o b l a s t i c l e u k a e m i a was t r e a t e d w i t h i m m u n o s u p p r e s s i v e c h e m o t h e r a p y . A f t e r c e s s a t i o n o f t h e r a p y she h a d t h r e e c o n s e c u t i v e epis o d e s of i n f e c t i o n d u e to Streptococcuspneumoniae f r o m which she r e c o v e r e d a n d was s h o w n to h a v e d e v e l o p e d a c o m b i n e d d e f i c i e n c y o f b o t h IgG2 a n d IgG4. T h e p a t i e n t e v e n t u a l l y r e l a p s e d a n d d i e d 3 y e a r s a f t e r t h e initial diagnosis. T h e i m p o r t a n c e o f m e a s u r i n g I g G subclasses in p a t i e n t s t r e a t e d with i m m u n o s u p p r e s s i v e c h e m o t h e r a p y is discussed.
Key words: A c u t e n o n - l y m p h o b l a s t i c l e u k a e m i a - I m m u n o s u p p r e s s i v e drugs - IgG2 d e f i c i e n c y
Introduction T h e o v e r a l l survival r a t e for a c u t e n o n - l y m p h o b l a s t i c l e u k a e m i a ( A N L L ) c o n t i n u e s to i m p r o v e [7], h o w e v e r t h e i n t e n s i v e c h e m o t h e r a p y r e q u i r e d f o r effective t r e a t m e n t s e v e r e l y c o m p r o m i s e s b o t h g e n e r a l a n d specific i m m u n i t y . D e p r e s s i o n o f i m m u n o g l o b u l i n (Ig) p r o d u c tion d u r i n g t h e r a p y is well d o c u m e n t e d [6, 12]. L i t t l e is k n o w n a b o u t t h e effect of t h e r a p y o n subclasses o f I g G [13]. W e p r e s e n t t h e case of a child w h o d e v e l o p e d a deficiency of IgG2 following t r e a t m e n t for A N L L .
Case report A 2 year 2 month-old girl was admitted complaining of fever, malaise and anorexia. She had been unwell for a few weeks but neither she nor her parents had a recent history of illness. Physical examination revealed hepatomegaly but there was no enlargement of the spleen and lymph nodes. Haemoglobin was 9.3 g/dl, haematocrit 29%, platelets 10 • 109/1 and a total leucocyte count of 1.8 • 109/1with 47% blasts. Bone marrow aspirate yielded a hypercellular, monotonous picture diagnosed as ANLL FAB M2, con-
Offprint requests to: A. W. de Boer Abbreviation." ANLL = acute non-lymphoblastic leukaemia
firmed by the Dutch Childhood Leukaemia Study Group. However, immunotyping showed 63% of the ceils to be positive for CD-10 (common ALL-antigen) and 0% positive for CD-11 (OKM), a monocyte marker. Spontaneous incorporation of tritiated thymidine by the leukaemic cells was low, which is more consistent with acute lymphoblastic leukaemia than ANLL [2, 5]. The karyotype of the leukaemic cells was normal: 46 XX. Her immunoglobulin levels were normal (Table 1). She was treated following the German BFM-ANLL 83 protocol [4]. Just before the cessation of the antileukaemic therapy she became severely ill with fever, vomiting and abdominal distension. A laparotomy was performed and showed a massive infiltration of the small intenstine with necrosis and multiple perforations due to a granulocytic sarcoma. Following the operation she developed an Escherichia coli sepsis and was treated with antibiotics. Because of her poor clinical condition only prednisone was given but no cytostatic treatment. The outcome was surprisingly successful: the tumour subsided and the child recovered. Thereafter, a period of 4 months followed during which she had three episodes of septicaemia due to Streptococcus pneumoniae, twice associated with osteomyelitis of the right talus and once with pneumonia. She responded promptly on each occasion to antibiotics. Her spleen appeared to function normally since the uptake of radioactively labelled red cells was normal. With radioactively labelled leukocytes, administered after healing of the talus, no loci anywhere in the body were revealed. The uptake of the spleen was completely normal. The complement components were normal. However, a deficiency of IgG2 and IgG4 was established (Table 1) and antibodies to S. pneumoniae remained low. The kappa/ lambda ratio which had been normal at the start of chemotherapy, decreased during chemotherapy but returned to normal after withdrawal of treatment. Some months later on a routine checkup, bone marrow examination showed her to have relapsed. There was, however, no evidence of any extramedullary involvement. She was given reinduction therapy but died in the induction phase from interstitial pneumonia associated with Streptococcus viridans. Autopsy was not performed.
Methods Serum IgG, IgA, IgM, kappa and lambda levels were determined by laser nephelometry using a DISC 120 Nephelometer (Hyland, Nivelles, Belgium). All values were calibrated against WHO standard serum No. 67/97. IgG subclass levels were measured by radial immunodiffusion and calibrated against reference serum containing IgG1 6.2g/1; IgG2 2.4g/1; IgG3 0.64g/1 and IgG4 0.46g/1 (H00-020, The Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam). IgG> IgG2 and IgG3 levels were corn-
272 Table 1. Serum immunoglobulinlevels of the patient
Immunoglobulin levels (g/l) IgG
IgG subclass levels (g/l)
IgA
IgM
IgGa
IgG2
IgG3
IgG4
7.32
0.49
2.13
2.50 4.20
0.09 0.75
< 0.04 0.50
2.0 4.1
0.77 < 0.24
0.08 0.31
0.15 < 0.046
0.52 0.81
1.58 2.11
9.9
- not done < 0.24 0.89
< 0.046
Kappa/ Lambda ratio
At diagnosis December 1984
- not done -
1.56
During therapy April 1985 June 1986
0.98
Therapy stopped December 1986 August 1987 October 1987
12.3 10.9
1.26
Table 2. Serum IgG and IgG subclass levels of control children during antileukaemic therapy
No.
1 2 3 4 5 6 7
Age at diagnosis (years; months)
Age at sampling (years; months)
Diagnosis
9;3 8;11 8;4 8;0 4;4 3;5 1;1
10;7 11;2 10;7 9;7 6;6 5;8 2;8
ANLL ALL ANLL ALL ALL ALL ALL
IgG level (g/l)
15.89 3.84 7.14 5.44 3.39 7.23 6.34
IgG Subclass levels (g/l) IgG1
IgG2
IgG3
IgG4
12.8 2.3b 6.2 3.9 2.0b 5.3 4.0
2.57 0.60b 0.74" 0.65b 0.55b 0.38b 0.38
0.70 0.19a 1.02 0.79 0.61 0.80 0.42
0.68 0.12 0.15 0.11 < 0.046b < 0.046b < 0.046b
ALL, Acute lymphoblastic leukaemia a 3rd Percentile b Deficient
pared to the age-related normal values recently described by Plebani et al. [9]. In this study values below the 3rd percentile (P3) were considered as an indication of deficiency of an IgG sublcass: IgG~ < 3.1g/l, IgG2
