Pediatr Allergy Immunol 2007: 18: 167–173 Ó 2007 The Authors

DOI: 10.1111/j.1399-3038.2006.00491.x Journal compilation Ó 2007 Blackwell Munksgaard

PEDIATRIC ALLERGY AND

IMMUNOLOGY

Increases in serum immunoglobulins

to age-related normal levels in children
with IgA and/or IgG subclass deficiency
Kutukculer N, Edeer Karaca N, Demircioglu O, Aksu G. Increases in Necil Kutukculer, Neslihan Edeer
serum immunoglobulins to age-related normal levels in children with Karaca, Ozlem Demircioglu and
IgA and/or IgG subclass deficiency. Guzide Aksu
Pedriatr Allergy Immunol 2007: 18: 167–173. Ege University, The Medical School, Department
Ó 2007 The Authors of Pediatrics, Izmir, Turkey
Journal compilation Ó 2007 Blackwell Munksgaard

Immunoglobulins (Ig) A and G subclass deficiencies are common

immune system disorders which cause morbidity especially between 2
and 6 yr of age. Prognosis of these defects and therapeutic approach is
unclear. The aim of the present retrospective study was to review the
clinical and laboratory records of 87 children with IgA and/or IgG
subclass deficiency to determine whether these patients experience
changes in serum Ig concentrations during follow-up and to give more
clinic and laboratory information to the families about the course of
these diseases. Among 87 patients studied, the most frequent defect was
partial IgA deficiency combined with IgG3 subclass deficiency (41%).
The other groups were as follows; partial IgA deficiency (32%), selective
IgA deficiency (8%), partial IgA combined with IgG2-G4 subclass
deficiency (6%), and IgG subclass deficiency (13%). The commonest
clinical presentations were recurrent upper respiratory tract infections
(76%), pneumonia (14%), acute gastroenteritis (3%), urinary tractus
infection (3%), sinusitis (2%), and acute otitis media (2%). Atopy was
widely represented in the patients studied (24%). The number of
patients who were given prophylactic treatment with benzathine peni-
cilline, prophylactic oral antibiotic, or oral bacterial extract to prevent
infections was 68 (78%). Frequency of recurrent infections decreased
from 7.9 ± 4.9 per year to 2.5 ± 2.3 in 68 patients receiving any
prophylactic regimen; however, decrease in frequency of infections did
not show any significant difference between different prophylactic
groups. None of the patients in the selective IgA deficiency group had
reached normal serum levels of IgA. At the age of 58.3 ± 21.4 months,
52% of patients in partial IgA deficiency group and 51% of patients in
partial IgA + IgG subclass deficiency group, serum IgA increased to Key words: immunoglobulin A; IgG subclass
normal ranges. Serum IgG subclass levels increased to normal range for deficiency; specific antibody response; recurrent
age in 67% of patients in partial IgA + IgG subclass deficiency group infections; prophylaxis
and in 30% of patients in isolated IgG subclass deficiency group. The
Necil Kutukculer, Faculty of Medicine, Ege University,
mean age for reaching age-related normal IgG subclass levels for these _
Department of Pediatrics, 35100 Bornova, Izmir,
patients was 69.0 ± 14.5 months. In conclusion, findings of this study Turkey
suggest that IgA and/or IgG subclass deficiency may be either pro- E-mail: necil.kutukculer@ege.edu.tr
gressive or reversible disorders and emphasize the value of monitoring
Ig levels in affected individuals. Accepted 29 September 2006

Recurrent infections in children are common associated with recurrent infections and they
causes of morbidity and hospitalization world- have been often associated with some humoral
wide. A variety of risk factors have been immune system disorders, such as low levels of
167
Kutukculer et al.
immunoglobulins (Ig) A and G subclasses and/or
lack of specific antibody responses.
IgA deficiency is the most common congenital
immunodeficiency in humans (1, 2). The preval-
ence of IgA deficiency ranges from 1:223 to
1:1000 in community studies and from 1:400 to
1:3000 in healthy blood donors (3). IgA defici-
ency is generally considered a non-serious con-
dition requiring only normal pediatric care. The
majority of IgA-deficient individuals have no
clinical problems. One-third of them are symp-
tomatic (4). The main symptoms are recurrent
upper respiratory tract infections, such as tonsil-
litis, sinusitis, otitis, and diarrhea. These patients
may have Giardia infestation, autoimmune dis-
eases (such as systemic lupus erythematosus,
Still’s disease, thyroiditis, and rheumatoid
arthritis), atopic conditions like allergic rhino-
conjunctivitis and asthma (5–7).
Many reports have shown a high frequency of
respiratory tract infections in patients with IgG
subclass deficiency. The age at which each of the
IgG subclasses reaches adult levels varies and
every age group in childhood has its own normal
levels (8, 9). Human IgG can be subdivided into
four subclasses, IgG1, IgG2, IgG3, and IgG4.
IgG1 makes up most of the total IgG (66%),
followed by IgG2 (24%), IgG3 (7%), and IgG4
(3%) (10, 11). IgG1 and IgG3 appear early in
ontogeny, are efficient activators of the classical
complement pathway (12), and are directed
mainly against protein antigens. Deficiency of
IgG1 results in low levels of total IgG and is
often associated with susceptibility to bacterial
infections. IgG2 appears much later in develop-
ment, and adult levels of this subclass are not
reached until 5–10 yr of age. IgG2 antibodies are
mainly directed against polysaccharide antigens
whereas IgG3 are mostly constituted of antibod-
ies directed to viral antigens (13). Undetectable
IgG4 subclass levels are a common finding in
normal individuals and an accurate detection of
very low levels of IgG4 is technically difficult to
achieve, therefore the clinical relevance of IgG4
evaluation is still unclear (14).
IgA and IgG subclass deficiencies are common
immune system disorders which cause morbidity
especially between 2 and 6 yr of age. IgA
deficiency is occasionally associated with IgG
subclass deficiency, a combination that leads to
severe bacterial infections (15, 16). Parents of
these children often ask pediatricians how the
illness will go on and if complete remission will
be possible.
The aim of the present retrospective study was
to review the clinical and laboratory records of
87 children with IgA and/or IgG subclass defi-
168
ciency to determine whether these patients
experience changes in serum Ig concentrations
during follow-up and to give more clinical and
laboratory information to the families about the
course of these diseases. Clinical presentations
mostly seen in children with IgA and/or IgG
subclass deficiency and the percentage of patients
who had reached normal serum Ig levels were
also tried to be determined.
Materials and methods
We retrospectively recruited 87 children [36 girls
(41%), 51 boys (59%)] at the mean age of
46 ± 40.9 months, referred to our Pediatric
Immunology Department with a history of recur-
rent infections. Among 87 patients studied, the
most frequent defect was partial IgA deficiency
combined with IgG3 subclass deficiency (41%,
n ¼ 35). Thirty-two percent (n ¼ 28) of the
patients had isolated partial IgA deficiency, 8%
(n ¼ 7) had isolated selective IgA deficiency, 6%
(n ¼ 5) had partial IgA combined with IgG2-G4
subclass deficiency, and 13% (n ¼ 12) had just
IgG subclass deficiency (Fig. 1). Diagnostic cri-
teria for these immunodeficiencies were as follows.
IgA serum levels under 5 mg/dl are diagnostic of
selective IgA deficiency and levels at least 2 SD
(standard deviation) below normal for age are
diagnostic of partial IgA deficiency (1, 2). IgG
subclass deficiency is defined as a one or more
serum IgG subclass level that is more than 2 SD
below the normal mean for age (10). Recurrent
infection was defined as the presence of at least six
febrile infection episodes in a year. The patients
who had recurrent infections received some
prophylactic treatment to prevent infections.
Subclass
deficiency
13%
Partial IgA
+G3
Partial IgA
deficiency
deficiency
41%
32%
Partial IgA
+G2/G4 Selective IgA
deficiency
deficiency
8%
6%
Fig. 1. The distribution of diagnoses of the entire study
population.
 Increases in immunoglobulins in IgA-IgG subclass deficiency
Patients affected by severe combined immunode-
ficiencies, common variable immunodeficiency,
hyper IgM syndromes, or acquired immunodefi-
ciency syndrome were not included to this study.
The quantifications of serum IgA, IgM, IgG
and IgG1, IgG2, IgG3 had been performed by
nephelometric method on the Dade Behring BN2
Nephelometer Analyzer and commercially avail-
able kits by Dade Behring (Germany). Enyzme
immunuassay tecnique had been used for the
determination of IgG antibodies aganist poly-
ribosylribitol-phosphateofHaemophilusinfluenzae
type B (Hib) and anti-tetanus toxoid antibodies
(Immunozyme HiB IgG and Immunozyme Tet-
anus; Progen Biotechnik, Heidelberg, Germany).
Protective titers of anti-Hib antibodies have been
defined as >1 lg/ml and protective titers of
anti-tetanus antibodies have been defined as
>100 mIU/ml (17, 18).
One of the inclusion criteria was at least 2 yr of
follow-up in out-patient clinic. The mean follow-
up time for all the patients in the study was
34 ± 10 months.
Records of all patients were examined for the
following criteria:
1 The beginning age of infections.
2 Localization of infections.
3 Family history (if there is somebody in the
family who has similar symptoms).
4 Atopy (it has been diagnosed by using clinical
findings, serum IgE levels, specific IgE levels,
and food panel).
5 Autoimmune diseases or development of
autoantibodies (by clinical findings, anti-
nuclear antibodies – ANA – and ANA profile
tests; Euroimmun kits, Lübeck, Germany).
6 Type of childcare (at home or day-care center).
7 The history of adenoidectomy/tonsillectomy.
8 Type, duration, and efficacy of prophylactic
therapy against infections.
9 Serum concentrations of IgG, IgA, IgM, IgG
subclasses during follow-up and their com-
parison with age-related normals.
10 Specific antibody responses against tetanus
and Hib.
11 Evaluation of the age in which IgA or IgG
subclass had risen to age-related normal levels
and percentage of the patients whose defective
immunoglobulins reached normal levels.
Statistical analysis
Data were analyzed using v2-test (SPSS for
Windows). p < 0.05 was considered statistically
significant.
Results
The mean ages of diagnosis of partial IgA defici-
ency, selective IgA deficiency, partial IgA + G3
deficiency and IgG subclass deficiency were:
39.5 ± 41.1, 78.9 ± 53.9, 43.5 ± 35.4, and
49.6 ± 39.1 months, respectively. The mean ages
for the beginning of recurrent infections were:
23.3 ± 42 months in partial IgA deficiency
group, 30.9 ± 41.9 months in selective IgA defi-
ciency group, 21.9 ± 24.7 months in partial
IgA + IgG3 deficiency group, and
24.1 ± 21 months in IgG subclass deficiency
group. When all the patients were examined
together, the mean age for the beginning of
infections was 25 ± 32.4 months. Most of the
patients (76%) were taken care of at home while
24% of the patients were beheld at the day-care
center.
The commonest clinical presentations were
recurrent upper respiratory tract infections (ton-
sillitis/pharengitis) (76%), followed by pneu-
monia (14%), acute gastroenteritis (3%),
urinary tract infection (3%), sinusitis (2%), and
acute otitis media (2%). Family history for
immunodeficiency was observed in only 17% of
the patients. Atopy was widely represented in the
patients studied (24%). Fifty-three percent of
atopic children had bronchial hyperreactivity,
19% had allergic rhinitis, 14% conjunctivitis,
and 14% had urticeria. None of the patients had
clinical symptoms and laboratory findings of an
autoimmune disease or autoantibody formation.
Nine percent (n ¼ 10) of the study group under-
went adenotonsillectomy.
The number of patients who were given
prophylactic treatment to prevent infections
was 68 (78%). When they were examined accord-
ing to age groups, before 3 yr of age, number of
patients receiving prophylaxis was 21; between 3
and 5 yr of age there were 24 patients and after
5 yr, 23 patients received prophylaxis (31%,
35%, and 34%, respectively). Ages of the
children during first prophylactic therapy and
duration of prophylaxis against infections are
shown in Fig. 2. Benzathine penicilline (once
every 21 days) or prophylactic oral antibiotic
(such as amoxycillin, 25% of total daily dose
every night) was administered to 30% of the
patients. Oral bacterial extract (OM-85-BV-
Broncho-vaxom, Switzerland) was given to
22% of the patients. Eighteen percent of the
patients received prophylactic antibiotic and oral
bacterial extract consecutively. Intravenous
immunoglobulin was administered to 8% of the
patients receiving prophylaxis. Twenty-two
percent of the patients were not given any
169
Kutukculer et al.

Ages of he children during first prophylactic therapy 100

6 5.6
5 90
3.8 4
4 3.8

3
80
2
1
70
0 S1
Partial IgA Selective IgA Partial IgA/G3 Subclass
deficiency deficiency deficiency deficiency

IgA levels (mg/dl)

60
Duration of prophylaxis

Subclass deficiency 18.7 Ay

50

Partial IgA deficiency 24 Ay

40
Selective IgA 28.8 Ay
deficiency
Partial IgA/G3 24 Ay
30
deficiency
0 5 10 15 20 25 30 35
20
Fig. 2. Ages of the children during first prophylactic ther-
apy and duration of prophylaxis against infections. 10

0
prophylactic treatment. Frequency of recurrent 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
infections decreased from 7.9 ± 4.9 per year to Months
2.5 ± 2.3 in 68 patients receiving any prophy-
lactic regimen (p < 0.05). However, decrease in Fig. 3. Kinetics of immunoglobulin (Ig) A levels of 33
patients who have improved. Symbols represent the same
frequency of infections did not show any patient in the graph (first symbol of every patient shows
significant difference between different prophy- serum IgA level and age of the patient at diagnosis).
lactic groups (p > 0.05).
Anti-Hib antibody response was examined in
48 patients (55%). Preventive antibody titers related normal IgG subclass levels for these
(>1 lg/ml) against this polysaccharide antigene patients was 69.0 ± 14.5 months.
was found in 96% (n ¼ 46) of the patients. Anti- There was a slightly significant correlation
tetanus antibody response was analyzed in 57 between the ages of improvement for IgA and
patients (66%) and 98% of them (n ¼ 56) had IgG3 in the partial IgA + partial
normal protective response (>100 mIU/ml). In IgA + G3 + partial IgA + G2 deficiency
one patient who had IgG2-G4 subclass defici- patients (p ¼ 0.046, r ¼ 0.661, correlation
ency, anti-Hib antibody reponse was found to be analysis).
very low. In another patient who had partial Kinetics of IgA, IgG2, and IgG3 for improved
IgA + IgG2-G4 deficiency, both the specific patients (33 patients for IgA, 15 patients for
antibody responses (anti-Hib and anti-tetanus) IgG3, and 5 patients for IgG2, respectively) are
were negative. However, this patient did not have shown in Figs 3 and 4. First symbol of every
recurrent infections and did not receive any patient shows serum immunoglobulin levels and
prophylaxis. ages of the patients at diagnosis.
During follow-up, none of the serum IgA
measurements in patients with selective IgA
Discussion
deficiency (<5 mg/dl) group had risen to age-
related normal levels. Serum IgA levels of 52% of The spectrum of antibody deficiencies ranges
the patients in partial IgA deficiency group and from severe deficiencies of all immunoglobulin
51% of the patients in partial IgA + IgG isotypes (agammaglobulinemia) to milder but
subclass deficiency group increased to normal clinically relevant deficiencies of specific anti-
range for age. Mean age for reaching normal IgA bodies in patients with normal immunoglobulin
levels for these patients was 58.3 ± 21.4 months. concentrations (16). IgA and IgG subclass defi-
Serum IgG subclass levels increased to normal ciencies are considered as risk factors for fre-
range for age in 67% of the patients in partial quent infections. It has been suggested that IgA
IgA + IgG subclass deficiency group and in deficiency must be associated with those of the
30% of the patients in isolated IgG subclass IgG subclasses, especially of IgG2 and IgG4 (19,
deficiency group. The mean age for reaching age- 20).
170
 Increases in immunoglobulins in IgA-IgG subclass deficiency

200
180
160

IgG2 levels (mg/dl)

140
120
100
80
60
40
20
0
0 10 20 30 40 50 60 70 80
Months

50
45
40
IgG3 levels (mg/dl)

35
30
Fig. 4. Kinetics of immuno- 25
globulins (Ig) G2 and G3 levels
of the patients who have im- 20
proved (15 patients for IgG3 and 15
5 patients for IgG2; symbols 10
represent the same patient in
each graph. First symbol of 5
every patient shows serum IgG2 0
or G3 levels and ages of the 0 10 20 30 40 50 60 70 80
patients at diagnosis). Months

Litzman et al. (21) reported that the pre-
valance of IgA deficiency was significantly higher
in individuals, both children and adults with
frequent respiratory tract infections than in the
healthy control group in Czech population. The
frequency of IgA deficiency is increased especi-
ally in relatives of patients with immunoglobulin
deficiencies. In Litzman’s study (21), only 4/41
IgA-deficient children with frequent respiratory
tract infections had concominant IgG1, IgG2, or
IgG4 subgroup deficiencies. In our study,
although most of the children were taken care
at home and had no risk factor of day-care
centers, the beginning age of frequent infections
was very early, approximately 2 yr. Upper res-
piratory tract infections and atopic disorders
were observed in high percentages although no
signs of autoimmunity have been determined
probably because of small ages of children and
short period of follow-up. On the other hand,
just 17% of patients had parents, siblings, and
relatives with the history of a humoral immuno-
deficiency and/or recurrent infections.
Morgan and Levinsky (22) reported that more
than 50% of the children with frequent infections
owing to IgA deficiency become asymptomatic
when they grew up. In our previous prospective
and randomized study with 91 children who had
IgA and/or IgG subclass deficiency, we com-
pared the clinical efficacy and tolerability of
prophylactic therapy with either the oral
immunomodulator bacterial extract OM85-BV
or benzathine penicilline G in the prevention of
recurrent infections in symptomatic patients (23).
In that study, the number of infections and
antibiotic treatments were reduced significantly
after 12 months of prophylactic treatment by
55.8% and 55.3%, respectively (23). Similar
significant reductions were observed in different
prophylactic groups, but the between-group dif-
ference was not significant (23). In this study,
frequency of recurrent infections decreased from
7.9 ± 4.9 to 2.5 ± 2.3 per year in the entire
study population and different prophylactic reg-
imens did not show any significant difference in
reducing the number of infections, as observed
before.
Patients with IgG subclass deficiency may have
some problems in producing specific antibody
responses. In our previous study, in patients with
isolated IgG subclass deficiency and in patients
with partial IgA + IgG subclass deficiency, vac-
cine failures (not producing enough specific
antibody in IgG form) were 12.3% against
tetanus and 2.7% against H. influenza (23). In
Finocchi et al.Õs study (24), anti-Hib antibody
171
Kutukculer et al.
deficiency was present in 7% of humoral
immune-deficient patients. In this study, the
percentage of patients who could not produce
preventive amount of antibodies against tetanus
was 2% and against Hib was 4%. As a result,
during the vaccination period, the children with
these immune disorders have to be checked for
specific antibody production.
Roberton et al. (25) reported 67 children with
symptomatic IgA deficiency, 18 of them had
selective (complete-absolute) IgA deficiency at
presentation, and 49 had partial IgA deficiency.
In their study, IgA concentrations had risen to
the normal range for age in 22.2% of the children
presenting with IgA deficiency and 77.6% pre-
senting with partial IgA deficiency when restud-
ied at a median interval of 3.2 and 3.0 yr,
respectively. In our study, none of the patients
in the selective IgA deficiency group had normal
serum levels of IgA. At the age of
58.3 ± 21.4 months, 52% of the patients in the
partial IgA deficiency group and 51% of the
patients in the partial IgA + IgG subclass defi-
ciency group, serum IgA increased to normal
ranges.
Roberton et al. (25) measured IgG subclass
concentrations from 12 children with complete
IgA deficiency and 22 children with partial IgA
deficiency. IgG2 and IgG4 concentrations for
these 34 children were below the fifth percentile
for age more frequently than expected. The
prevalence of IgG2 deficiency or IgG4 deficiency
did not differ significantly between those with
complete IgA deficiency and those with partial
IgA deficiency. IgG2 concentrations remained
below the fifth percentile more frequently than
expected when retested in 31 children whose
partial IgA deficiency had resolved. In Shackel-
ford et al.Õs study (26) with nine children having
IgG2 subclass deficiency, normalization in IgG2
levels was noticed in four of them during 1–5 yr
of follow-up. In our study, at about 6 yr of age,
serum IgG subclasses increased to normal ranges
in 67% of the patients in the partial IgA + IgG
subclass deficiency group and in 30% of the
patients in the isolated IgG subclass deficiency
group, suggesting that these children also may
experience changes in serum IgG subclasses to
normal levels. Similar trend in the kinetics of
different variables, namely IgA, IgG2, and IgG3,
has been observed as shown in Figs 3 and 4. This
also indicates slightly significant correlation
between the type of the deficiency and the age
of improvement, more strikingly between IgA
and IgG3.
In conclusion, the findings of this study
suggest that IgA and/or IgG subclass deficiency
172
may be either progressive or reversible disorders
and emphasize the value of monitoring Ig levels
in affected individuals. We believe that our study
will be helpful for giving more information to the
parents of these children about the prognosis.
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