# Pediatric Selective IgM Immunodeficiency

Authors: Marc F. Goldstein; Alex L. Goldstein; Eliot H. Dunsky; Donald J. Dvorin; George A. Belecanech; Kfir Shamir
Journal: Clinical and Developmental Immunology
 (2008)

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## Abstract

Objective. Limited information exists on features of pediatric Selective IgM immunodeficiency (SIgMID). Previously published pediatric cases and 2 new cases are reviewed. Methods. English literature from PubMed and references from relevant articles were reviewed. Previously reported cases and 2 new cases from an allergy/immunology practice were analyzed. Results. Forty-nine reported cases of SIgMID presented with respiratory infections (77.6%), gastrointestinal disease (16.3%), skin disease (12.2%), and meningitis (8.2%). Mean serum IgM level was 16.5±13.8 mg/dL. Two patients were identified with SIgMID among 6300 active pediatric patients (0.03%) presenting with asthma, vasomotor rhinitis, and recurrent respiratory infections. In the 51 cases reported, none developed lymphoproliferative disease nor evolved into panhypogammaglobulinemia; four fatalities were reported. Conclusions. The prevalence of SIgMID in our pediatric population was 0.03%. In general, respiratory infections are the common comorbid conditions. Death and autoimmune disease are uncommon complications of pediatric  SIgMID.


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## Body

## 1. Introduction

Selective IgM immunodeficiency
(SIgMID) is a dysgammaglobulinemia characterized by an isolated
low level of
serum IgM, usually <20 mg/dL in infants and children or <2 standard
deviations or 10% below age adjusted means [1–3].  Usually, serum IgM levels are <10–20 mg/dL [3].
The level of other immunoglobulin isotypes is typically normal, although
IgE may be increased.  It is said to be a
rare primary immunodeficiency, with the prevalence of completely deficient IgM
patients reported as approximately 0.03% in a community-based study. [1]  However, the prevalence of those with
deficient but detectable levels of IgM is closer to 0.1–3.0% in hospitalized patients
[1, 4, 5], 1.6%
in an unselected community health screening [1, 6], 0.07% in an allergy and
immunology clinic [7], and 0.26% in an adult allergy and immunology clinic [8].
There is a slightly higher penetration of SIgMID in males (1.97%) versus
females (1.42%) [1]. The prevalence in the pediatric population (<18 years
of age) has not been reported.A variety of bacterial and viral
infections have been linked with SIgMID in the pediatric and adult populations
(Table1) [8].  In children, infectious
agents have included Pneumocystis carinii [9], Giardia [10], Staphylococcus [10, 11], Salmonella [12], Listeria monocytogenes [13], meningococcus
[6, 14, 15], Pseudomonas [10, 16], molluscum
contagiosum [17], cytomegalovirus [18], and varicella [17].  These organisms account for recurrent
infectious dermatitis, diarrhea, meningitis, upper and lower respiratory
infections, sepsis, and in some cases, death.
Secondary IgMID presumptively from another cause has been associated
with an array of noninfectious diseases in children and adults, in particular,
autoimmune diseases and malignancies [8].
In children, celiac disease and autoimmune hemolytic anemia (Table 1)
have been reported but other autoimmune diseases
and malignancies have not.  We present a
review of 49 previously reported pediatric patients with SIgMID and 2 new cases
from our practice.  The relative
frequencies of various clinical, immunological and demographic features,
associations, and complications are established in this series.  These findings are also compared and
contrasted to adult cases previously reported [8].Table 1
Characteristics
of previously reported pediatric cases of SIgMID.
WNL: within normal limits, GN:  glomerulonephritis, CMV: cytomegalovirus, AD:
atopic dermatitis, N/A:  not available,
OM:  otitis media, URI: upper respiratory
infection.
ReferenceAge
of diagnosis (year)/sexPresenting
historySerum   IgM
mg/dLSerum
IgG mg/dLSerum IgA
mg/dLIgE
IU/mLComment[19]9
malePyoderma,
AD, diarrhea, cutaneous candidiasis, rudimentary auricles1/4 of normal controlsWNLWNLN/A⊕ Isohemagglutinin; Lack of IgM response to S. typhi;  “O” antigen[9]4.5 mo femaleAutoimmune
anemia, GN, failure to thrive132500390N/ADied
of PCP; diffuse lymphoid hypoplasia, thymus dysplasia[6]8
maleMeningococcal
sepsis, Waterhouse- Friderichsen syndrome456070Died
from infection[6]5
maleMeningococcal
meningitis121120190Died
from infection[20]3Celiac
disease33N/AN/AN/AIgM
level normalized after gluten free diet[20]8Celiac
disease30N/AN/AN/AIgM
level normalized after gluten free diet[20]10Celiac
disease35N/AN/AN/AIgM
level normalized after gluten free diet[20]13Celiac
disease40N/AN/AN/AIgM
level normalized after gluten free diet[20]2Celiac
disease20N/AN/AN/AIgM
level normalized after gluten free diet[21]5
maleAsymptomatic35820224N/AFamilial
cases[2]3.75 maleN/A7495172N/APartial
deletion of  long arm of chromosome 18[12]6
maleRecurrent
pneumonia, OM, AD, sinusitis61250950Received
IM gammaglobulin treatment, salmonella enteritis, pneumococcal sepsis[16]8.5 mo malePseudomonas
pneumonia, recurrent OM0WNLMildly
reducedDied
from infection[18]13
maleCMV
hepatitis26–29N/AN/AN/A[14]4Meningitis34WNLWNLN/ALow IgM hemagglutinin to meningococcus[14]1Asymptomatic36WNLWNLN/ALow IgM hemagglutinin to meningococcus[22]2.5 femaleRecurrent
OM, laryngitis, meningitis853048N/AAbsent
isohemagglutinin, chromosome #1 defect[1]3
patients, female <17N/A<23WNLWNLN/A[1]7
patients, male <16N/A<23WNLWNLN/A[23]12
femaleRecurrent
bronchitis, OM, pneumonia, bronchiectasis3468687N/ANo
response to salmonella “H” antigen[24]Young
maleN/A8150072555[10]3
femaleerythrodermic
psoriasis<4680125340OM,
diarrhea, failure to thrive, recurrent respiratory infection, eosinophilia[10]9
maleAD<49001538000Failure
to thrive, recurrent respiratory tract infection and pneumonia, skin
infections, giardiasis, eosinophilia[17]16
femaleDisseminated
molluscum contagiosum<423056888900AD,
aphthous stomatitis, varicella, recurrent respiratory infections,
eosinophilia, bronchiectasis[25]2.5 femaleFailure
to thrive, recurrent URI3786945N/A[25]5.5 femaleFailure
to thrive, recurrent OM, eyelid and GI infections38106442N/A[25]8
maleFailure
to thrive, recurrent OM, eyelid and GI infections42488100N/A[26]1 moPneumonia<6<350N/AN/ANonspecific
IgG subclass deficiency[26]11 moBronchitis,
OM<4<350N/AN/A[26]3Bronchitis,
OM5780N/AN/A[26]2OM11~2200N/AN/A[13]1 moMeningitis,
pneumonia, OM671727<10Allergic
rhinitis[13]3Bronchitis,
OM5768108<10Allergic
rhinitis[13]2OM116083312Allergic
rhinitis[13]11 moOM,
pneumonia546225<10[13]11 moBronchitis,
OM534588<10Wheezing[13]8OM,
pneumonia11925134297Allergic
rhinitis, wheezing[27]10
maleRecurrent
sinusitis, OM, pneumonia,
chronic staphylococci blepharitis2390086N/A[28]15
femaleChronic
OM<61170356N/A22q11.2
chromosome deletion[3]11
maleAsthma<5NLNLN/AFather
with SIgMID[29]17
maleRussell-Silver
Syndrome with recurrent URI1NLNLN/ANo
response to pneumococcal vaccine[30]1.5 maleRecurrent
OM28N/AN/AN/A[31]7Recurrent
OM, pneumococcal pneumonia with emphysemaDeficientNLNLElevatedLack
of protective antibody response to polysaccharide and protein antigen,
responded to IVIg[31]18
monthAsthma,
recurrent OM, pseudomonal pneumonia, sepsisDeficientNLNLElevatedMean6±4.716.5±13.8939±580183±2261814±3509


## 2. Materials and Methods

We undertook a retrospective (2002–2005) medical record review of 20000 charted
patients seen in our practice over a 3-year period.  Of these, 6300 patients were children (<18 years of age).  Charts were selected
with a diagnosis of SIgMID, selective IgA immunodeficiency (SIgAID), common
variable immunodeficiency (CVID), Bruton agammaglobulinemia, and transient
hypogammaglobulinemia of infancy and reviewed for immunoglobulin levels (IgG,
IgM, IgA, IgE, and IgG subclasses), isohemagglutinin levels, autoantibody
serologies, presenting clinical symptoms, concurrent conditions, and clinical
course.  Patients diagnosed with SIgMID
were screened serologically for celiac disease, autoimmune thyroid disease, and
autoimmune collagen vascular disease.  A
literature search was conducted of reported cases of SIgMID in the English
literature through PubMed from 1966, and from the bibliographies of related
articles.  Identified in the literature
were 361 previously reported SIgMID patients, comprised of 155 adult, 49
pediatric, and 157 age unspecified patients.
The analyses
of the 155 adult, 157 age-unspecified cases, and 36 new adult cases of SIgMID
have been previously reported [8].
Comparative analysis was made of clinical, laboratory, and demographic
data of pediatric cases to reported adult cases of SIgMID.


## 3. Statistical Analysis

The group mean and 1 SD were
calculated for group serum IgM, IgA, IgG, IgE levels and age of
presentation.  Descriptive statistics were
used to denote frequencies of occurrence of comorbid conditions.  Statistical analyses were done with Microsoft
Excel (Microsoft Corporation, Redmond, WA).


## 4. Results

### 4.1. Previously Reported Pediatric Cases

Forty-nine previously described
pediatric cases of SIgMID were identified ranging in age from 1 month to 17
years (Table1).  The mean age at the
time of diagnosis was 6.0±4.7 years.
Of these cases, where reported, presenting respiratory infections
occurred in 78.4% of cases (Table 2).
Frequencies of specific presenting respiratory infections were  otitis media (39.2%),
pneumonia/lower
respiratory infections (19.6%), bronchitis (9.8%), and upper respiratory
infections (9.8%).  Frequency of nonrespiratory
presenting illnesses included  gastrointestinal
illness (13.7%), skin disorders (9.8%) with atopic dermatitis the most common
(6.1%), failure to thrive (7.8%), asthma (7.8%), meningitis (7.8%), and
vasomotor rhinitis (3.9%).  Five patients
had celiac disease and serum IgM levels normalized in all cases on gluten free
diets.  There were no patients with
malignancies reported.  There were 2
asymptomatic cases reported.  The mean
serum IgM level was 16.5±13.8 mg/dL.
Serum IgA and IgG levels were normal in all cases.  Mean serum IgE level was elevated at 1814 ±
3509 IU/mL.  Four patients developed
respiratory allergy while 3 patients developed asthma. Two patients lacked
protective IgG responses to polysaccharide and protein antigen/vaccine
challenge and clinically responded to intravenous immunoglobulin (IVIg)
treatment.  Where tested, most patients
had low-to-normal titers
of IgM isohemagglutinins.  Infections
from pneumococcus, Staphylococcus, Pseudomonas, Salmonella, Pneumocystis
carinii, Giardia,
cytomegalovirus, Listeria monocytogenes, meningococcus, molluscum
contagiosum, and varicella were reported.Table 2
Prevalence of presenting conditions
in pediatric and adult patients with SIgMID.
ConditionPediatric  frequency percentage(n=48)Adult frequency [8]
percentage  (n=191)Pneumonia/lower respiratory tract infection19.65.2Otitis
media39.21.6Bronchitis9.83.1Meningitis7.80.5Nonspecific
bacterial respiratory infection04.7Upper
respiratory infections9.816.2Failure
to thrive7.80Otherinfections∗9.81.5Allergic
rhinitis011.5Vasomotor
rhinitis3.93.7Nasal
polyps01.5Asthma7.816.2Idiopathic
angioedema02.6Idiopathic
anaphylaxis02.1Gastrointestinal
disease13.74.2Asymptomatic3.93.1Autoimmune
disease3.911.5Skin
disease9.84.7Bronchiectasis02.6Nonrespiratory∗/nonmeningitis/nonskin.


### 4.2. Pediatric Cohort

Sex and Race: there
were 2 Caucasian males and 0 females identified in our pediatric population of
6300 patients.Age at time of
diagnosis:
age of diagnosis of SIgMID was 10
(patient 1) and 12 years of age (patient 2).
Onset of SIgMID could not be determined or estimated accurately,
although patient 1 had normal IgM, IgG, IgA levels 6 years prior to diagnosis.  Observation Period:  patient
1 had been followed for 8 years and patient 2 for 5 years post diagnosis.
Immunoglobulin Levels: two patients in
our pediatric patient population of 6300 (incidence 0.03%) were identified
with reduced serum IgM levels less than 2 SD of age-adjusted means.  Asymptomatic patients may have been missed
since only symptomatic patients with recurrent infections or unusual infection
were screened for immunodeficiency.
Neither patient had undetectable IgM levels.  The serum IgM levels were 21 mg/dL (patient
1) and 30 mg/dL (patient 2) with normal serum IgA, serum IgG levels, and IgG
subclasses.  The serum IgE level was 15 IU/ml in patient 1 [normal levels (<200 IU/ml)]. Immunoglobulin levels were repeated 6 months
and 2, 4, and 7 (patient 1) years after diagnosis and remained essentially the
same with persistence of serum IgM <30 mg/dL in both patients through time. Within the same database of
patients there were no pediatric patients with CVID, Bruton agammaglobulinemia,
transient hypogammaglobulinemia of infancy, or SIgAID. Serologic Evaluation: because of previous reports of autoimmune disease,
thyroiditis, and celiac disease in patients with SIgMID, the 2 patients were
screened for anemia, ANA, anti-endomysial antibody, anti-gliadin antibody, anti-transglutaminase
antibody, and thyroid autoantibodies.  No
autoantibodies were identified in either patient.  Neither patient was anemic. Functional
Antibodies: both patients were tested for ABO blood group and
isohemagglutinin level.  Detectable low
titer isohemagglutinins were noted (patient 1 anti-A 1:4; patient 2 anti-B
1:8). IgG antibody responses to tetanus, H.
influenzae, and pneumococcus vaccination were normal.Clinical Manifestations
Infections: our 2
patients  presented with a history of respiratory infections: patient 1 with
recurrent otitis media and patient 2 with pneumonia.  Neither patient had a severe life-threatening
infection.  Neither patient had an
unusual bacterial, viral, fungal, or parasitic infection, meningitis,
bacteremia, or abscess prior to or during the followup period. Gastrointestinal
Abnormalities:  chronic gastrointestinal illnesses
were not noted. Autoimmune Disease:  no autoimmune disorders were noted
at time of presentation or during the followup period. Other Respiratory
Conditions including Allergy:  upper respiratory allergies were
ruled out by skin testing.  Other noninfectious
respiratory conditions seen included asthma and vasomotor rhinitis in both
patients.  Neither patient had nasal
polyps. Miscellaneous Abnormalities: neither idiopathic angioedema nor
idiopathic anaphylaxis was seen.  During
the followup period of observation, neither patients transformed into CVID. Mortality:
neither patient died of serious infections, malignancies or complications of
autoimmune disease. Family History of Patients:  there were no family histories of
infantile deaths, increased susceptibility to infections, or primary
immunodeficiencies among immediate relatives.
Screenings
for immunodeficiencies in parents and siblings were recommended but compliance
was inconsistent.  Where tested, no
parent or sibling was identified with an immunoglobulin deficiency. Therapy:  neither patient was put on IVIg
therapy.  In general, infections were
successfully treated with conventional courses of antibiotics.


## 4.1. Previously Reported Pediatric Cases

Forty-nine previously described
pediatric cases of SIgMID were identified ranging in age from 1 month to 17
years (Table1).  The mean age at the
time of diagnosis was 6.0±4.7 years.
Of these cases, where reported, presenting respiratory infections
occurred in 78.4% of cases (Table 2).
Frequencies of specific presenting respiratory infections were  otitis media (39.2%),
pneumonia/lower
respiratory infections (19.6%), bronchitis (9.8%), and upper respiratory
infections (9.8%).  Frequency of nonrespiratory
presenting illnesses included  gastrointestinal
illness (13.7%), skin disorders (9.8%) with atopic dermatitis the most common
(6.1%), failure to thrive (7.8%), asthma (7.8%), meningitis (7.8%), and
vasomotor rhinitis (3.9%).  Five patients
had celiac disease and serum IgM levels normalized in all cases on gluten free
diets.  There were no patients with
malignancies reported.  There were 2
asymptomatic cases reported.  The mean
serum IgM level was 16.5±13.8 mg/dL.
Serum IgA and IgG levels were normal in all cases.  Mean serum IgE level was elevated at 1814 ±
3509 IU/mL.  Four patients developed
respiratory allergy while 3 patients developed asthma. Two patients lacked
protective IgG responses to polysaccharide and protein antigen/vaccine
challenge and clinically responded to intravenous immunoglobulin (IVIg)
treatment.  Where tested, most patients
had low-to-normal titers
of IgM isohemagglutinins.  Infections
from pneumococcus, Staphylococcus, Pseudomonas, Salmonella, Pneumocystis
carinii, Giardia,
cytomegalovirus, Listeria monocytogenes, meningococcus, molluscum
contagiosum, and varicella were reported.Table 2
Prevalence of presenting conditions
in pediatric and adult patients with SIgMID.
ConditionPediatric  frequency percentage(n=48)Adult frequency [8]
percentage  (n=191)Pneumonia/lower respiratory tract infection19.65.2Otitis
media39.21.6Bronchitis9.83.1Meningitis7.80.5Nonspecific
bacterial respiratory infection04.7Upper
respiratory infections9.816.2Failure
to thrive7.80Otherinfections∗9.81.5Allergic
rhinitis011.5Vasomotor
rhinitis3.93.7Nasal
polyps01.5Asthma7.816.2Idiopathic
angioedema02.6Idiopathic
anaphylaxis02.1Gastrointestinal
disease13.74.2Asymptomatic3.93.1Autoimmune
disease3.911.5Skin
disease9.84.7Bronchiectasis02.6Nonrespiratory∗/nonmeningitis/nonskin.


## 4.2. Pediatric Cohort

Sex and Race: there
were 2 Caucasian males and 0 females identified in our pediatric population of
6300 patients.Age at time of
diagnosis:
age of diagnosis of SIgMID was 10
(patient 1) and 12 years of age (patient 2).
Onset of SIgMID could not be determined or estimated accurately,
although patient 1 had normal IgM, IgG, IgA levels 6 years prior to diagnosis.  Observation Period:  patient
1 had been followed for 8 years and patient 2 for 5 years post diagnosis.
Immunoglobulin Levels: two patients in
our pediatric patient population of 6300 (incidence 0.03%) were identified
with reduced serum IgM levels less than 2 SD of age-adjusted means.  Asymptomatic patients may have been missed
since only symptomatic patients with recurrent infections or unusual infection
were screened for immunodeficiency.
Neither patient had undetectable IgM levels.  The serum IgM levels were 21 mg/dL (patient
1) and 30 mg/dL (patient 2) with normal serum IgA, serum IgG levels, and IgG
subclasses.  The serum IgE level was 15 IU/ml in patient 1 [normal levels (<200 IU/ml)]. Immunoglobulin levels were repeated 6 months
and 2, 4, and 7 (patient 1) years after diagnosis and remained essentially the
same with persistence of serum IgM <30 mg/dL in both patients through time. Within the same database of
patients there were no pediatric patients with CVID, Bruton agammaglobulinemia,
transient hypogammaglobulinemia of infancy, or SIgAID. Serologic Evaluation: because of previous reports of autoimmune disease,
thyroiditis, and celiac disease in patients with SIgMID, the 2 patients were
screened for anemia, ANA, anti-endomysial antibody, anti-gliadin antibody, anti-transglutaminase
antibody, and thyroid autoantibodies.  No
autoantibodies were identified in either patient.  Neither patient was anemic. Functional
Antibodies: both patients were tested for ABO blood group and
isohemagglutinin level.  Detectable low
titer isohemagglutinins were noted (patient 1 anti-A 1:4; patient 2 anti-B
1:8). IgG antibody responses to tetanus, H.
influenzae, and pneumococcus vaccination were normal.Clinical Manifestations
Infections: our 2
patients  presented with a history of respiratory infections: patient 1 with
recurrent otitis media and patient 2 with pneumonia.  Neither patient had a severe life-threatening
infection.  Neither patient had an
unusual bacterial, viral, fungal, or parasitic infection, meningitis,
bacteremia, or abscess prior to or during the followup period. Gastrointestinal
Abnormalities:  chronic gastrointestinal illnesses
were not noted. Autoimmune Disease:  no autoimmune disorders were noted
at time of presentation or during the followup period. Other Respiratory
Conditions including Allergy:  upper respiratory allergies were
ruled out by skin testing.  Other noninfectious
respiratory conditions seen included asthma and vasomotor rhinitis in both
patients.  Neither patient had nasal
polyps. Miscellaneous Abnormalities: neither idiopathic angioedema nor
idiopathic anaphylaxis was seen.  During
the followup period of observation, neither patients transformed into CVID. Mortality:
neither patient died of serious infections, malignancies or complications of
autoimmune disease. Family History of Patients:  there were no family histories of
infantile deaths, increased susceptibility to infections, or primary
immunodeficiencies among immediate relatives.
Screenings
for immunodeficiencies in parents and siblings were recommended but compliance
was inconsistent.  Where tested, no
parent or sibling was identified with an immunoglobulin deficiency. Therapy:  neither patient was put on IVIg
therapy.  In general, infections were
successfully treated with conventional courses of antibiotics.


## 5. Discussion

ImmunoglobulinM
is a pentamer
found in the intravascular compartment and on the surface of B
lymphocytes.  It is the antibody isotype
produced initially in the immune response, and the first immunoglobulin class
to be synthesized by a fetus or newborn.
IgM antibodies do not cross the placenta, and for these reasons the
demonstration of IgM specific antibody is useful in the assessment of neonatal
infection.  Dysregulation of IgM leading
to elevated or reduced serum levels has been reported in a number of conditions [8].  In children, isolated elevated levels of IgM
have been associated with acute or recurrent infections (Hyper-IgM
immunodeficiency, Epstein Barr virus infection) [32, 33].  Fluctuating levels of serum IgM associated
with secondary conditions in some adult cases may have prognostic significance,
as in adult systemic lupus erythematosus (SLE) [34].  Decreased levels of IgM have been associated
with episodes of recurrent infection, thymic hypoplasia, celiac disease,
autoimmune disease, and certain adult malignancies and several primary
immunodeficiencies (Wiskott-Aldrich Syndrome, ataxia-telangiectasia, CVID,
Bruton agammaglobulinemia, SIgMID, combined IgG and IgM immunodeficiency, and
transient hypogammaglobulinemia of infancy) and congenital disorders (Bloom
syndrome and Russell-Silver syndrome).
Isolated reduced serum IgM levels secondary to these other illnesses
should be excluded before making a diagnosis of primary SIgMID.  Primary selective IgM immunodeficiency is
less common than secondary IgM immunodeficiency.SIgMID has been characterized as a
rare primary immunodeficiency differentiated by a low serum IgM level, less
than 2 SD or <10% of age adjusted normal controls or absolute levels of 10–20 mg/dL in infants and children [3].
The earliest recognized cases were described in children in 1966
[9, 19]
. More pediatric cases
and the first adult cases were described in the late 1960s and were classified
as dysgammaglobulinemia V [2, 6, 12, 21].
Over the subsequent 40 years, small series and isolated case reports
have appeared.  Recently, a retrospective
review with a large cohort of adult SIgMID was reported further characterizing
this illness in patients ≥18 years of age [8].Heterogeneous lymphocyte abnormalities have been reported in patients
(mainly adults) with SIgMID.  Several in
vitro and in vivo immunologic, phenotypic and functional profiles have been
described, some conflicting, and are summarized in Table3.Table 3
Immunologic abnormalities in SIgMID.
T cell functionsIncreased
IgM-specific T cell suppressor function [35, 40, 41];
normal T cell suppression function [42–44]Excessive
isotype nonspecific T cell suppressive activity [40]; increased IgM specific
suppressive T cell function [35]Defect
in T cell help [10, 26];
normal
T cell help [17, 42, 44, 45]Nonspecific T cell abnormalities [26];
normal
T cell function [42]B cell
functionDefect
in B cell differentiation into IgM-immunoglobulin secreting cells [40, 46, 47]T and B cell enumeration and
phenotypeNormal
peripheral T and B cell phenotypes [42, 43, 47, 48];
increased
CD8+ cells and inverted CD4/CD8 ratios [40];
increased
CD4+ cells and decreased CD8+ cells [47]Reduced
number of IgM secreting B cells [45, 46] with a failure of secreted mu mRNA
synthesis [46];
normal
surface IgM expression on B cells [10, 17, 35, 43, 47–49]; normal
secreted mu mRNA synthesis [49]Mitogen/antigen stimulationMitogen
and antigen stimulated B cell proliferation assays with normal IgM responses
[11, 42];
decreased
antigen proliferation IgM responses [4, 17, 40, 41, 45–49]Deficient
IgM responses to viral antigens and/or endotoxin containing vaccines and
deficient isohemagglutinin antibodies [24]Failure
to respond to antigen challenge with tetanus toxoid, pneumococcal
vaccine,  meningococcus vaccine,Salmonella O and H antigens, and
typhus-paratyphus vaccine [10–12, 19, 42, 50]ComplementNo
complement deficits [10]Delayed hypersensitivityReduced
delayed cutaneous hypersensitivity [10, 17];
normal
delayed cutaneous hypersensitivity [11, 42]PhagocytosisNormal
phagocytosis and killing of encapsulated bacteria [10];  nominally affected opsonification of yeast
particles [11];
select opsonic defect against Pseudomonas [51]Heterogeneous gene impairments regulating terminal B cell
differentiation have been reported in SIgAID [35] and CVID.  Recently, mutations in the inducible T cell
costimulator gene, the transmembrane activator and calcium modulator, and
cyclophilin ligand interactor have been described in CVID and SIgAID [36].  Similar in depth in vitro studies of
lymphocyte function and molecular genetic studies have not been applied to
pediatric and adult patients with SIgMID [8].
Functional (except isohemagglutinin titers), phenotypic or molecular
genetic studies were not performed in our cohort.  The latter was not the subject of this
analysis.SIgMID is regarded as an uncommon disorder and often
neglected in the discussion of primary immunodeficiencies [36, 37].  A discussion of SIgMID is notably absent in
recently published practice parameters on primary immunodeficiencies from
expert panels [37].  The prevalence of
SIgMID has been reported to be less than SIgAID in an unselected group of 3,213
individuals ages 4–87 [1].
In the atopic population, the prevalence of both SIgAID (4.5%) and
SIgMID (ranging from 1.56–22%) may be higher than in the general
population [38].  The prevalence of
SIgMID in an adult symptomatic population of patients going to an allergy and
immunology practice (1:385) [8] may be much higher than previously thought
(1:15,000) [7].  By comparison, the
prevalence in our pediatric symptomatic patients going to an allergy and
immunology practice was 0.03%—one-tenth of the adult prevalence.  Asymptomatic patients with SIgMID have been
reported (up to 19% in some series) [14, 21, 39], but only 2 cases were
observed in children [14, 21].
Asymptomatic pediatric patients with SIgMID were not screened for or
identified in our retrospective practice database analysis.  These cases are typically found during the
investigation of other diseases (autoimmune disease or cancer) or in family
members of patients with immunodeficiency or by chance.  Screening for asymptomatic cases would be
cost prohibitive.  In our review, 1
pediatric patient with a complete deficiency of  IgM was identified, reflecting the rarity of
such an occurrence [16].  In Cassidy’s
population of 3213 unselected Caucasian individuals, only 1 patient had
undetectable serum IgM levels (0.03% incidence) [1].Common with other primary immunodeficiencies, recurrent
sinopulmonary infections were present in 74.5% of pediatric SIgMID cases
(Table4).  Although meningitis, sepsis,
atypical infections and fatalities secondary to infections have previously been
reported in pediatric SIgMID, these complications were not seen in our 2
cases.  In contrast to CVID and SIgAID
where antibiotics may be used for extended periods along with prophylactic
antibiotics, our 2 pediatric patients with recurrent respiratory infections
responded to conventional courses of antibiotics and were not treated with
prophylactic antibiotics.  Also different
from CVID and  SIgAID, our patients, and the majority of previously reported pediatric
cases, did not receive IVIg.  Two
pediatric SIgMID cases with functional IgG antibody deficiency received IVIg
[31].  Given these observations, adult
patients with SIgMID and most pediatric cases of SIgMID experience infections
with conventional organisms.  The absence
of virulent infections in most cases may be due to effective antibiotic therapy
and/or the response of other immune systems to microorganisms that may
compensate for the low level of IgM.  In
addition, earlier reported fatalities from infections (all prior to 1972) may
reflect less effective antibiotic coverage and/or hospital care than that
currently available.  Nevertheless, like
other primary immunodeficiencies. the morbidity of frequent infection in SIgMID
is high.  Appropriate immunization
(influenza, H. influenzae,
pneumococcus, pertussis), attention to concomitant treatment directed at
allergic inflammation, and good hygiene are important preventative
measures.  Aggressive antimicrobial
therapy is recommended to prevent and manage infectious complications.  IVIg may be instituted in cases of recurrent,
debilitating or life threatening infection, and/or in patients with concomitant
functional IgG deficiencies.Table 4
Frequencies of comorbid diseases in
patients with SIgMID. (n/a = not
applicable).
Disease statePreviously reported pediatric cases + 2 new cases
percent(n=51)Previously reported adults cases [8] percent   (n=191)Allergic rhinitis9.812.6Idiopathic angioedema02.6Idiopathic anaphylaxis02.1Asthma18.724Autoimmune disease*3.912Bronchiectasis02.6Failure to Thrive9.8N/AGastrointestinal disease**15.712Malignancy02.6Meningitis7.80.5Nasal polyps00.5Other infections***9.81.6Recurrent respiratory infections74.532.5Skin disease11.84.7Thyroid disease00.5Vasomotor rhinitis3.937Fatalities7.80Asymptomatic3.93.1Autoimmune∗ thyroiditis, autoimmune anemia,
autoimmune glomerulonephritis, rheumatoid arthritis, SLE.
**Includes
celiac disease, inflammatory bowel disease, diarrhea syndromes.
***Nonrespiratory/nonmeningitis/nonskin.Autoimmune phenomena are seen in association with several
immunoglobulin deficiency syndromes.  In
particular, SLE, rheumatoid arthritis, thyroiditis, and autoimmune hemolytic
anemia have been reported in CVID as well as SIgAID [5, 12].  From our review, in pediatric SIgMID cases,
autoimmune disease is distinctly uncommon (3.9%), compared to 12% in previously
reported adult SIgMID cases (Table 4) [8].Dysgammaglobulinemia has been reported with several GI
conditions including steatorrhea, nodular lymphoid hypoplasia, Crohn’s disease,
ulcerative colitis, amyloidosis, disaccharidase deficiencies, pernicious
anemia, schlerosing cholangitis, celiac disease and protein losing
enteropathies [4, 20, 50].  In
particular, celiac disease has been reported in association with several
primary immunodeficiencies including isolated severe SIgAID [52, 53] or reduced
IgA levels (20—<60 mg/100 mL) [20, 54, 55], panhypogammaglobulinemia [53] and
isolated combined IgA and IgM deficiency [53].
IgM deficiency has been more frequently reported—including 30 of 75 (37%) of adult cases, 5 of
5 childhood cases [20], 11 of 30 (37%) untreated adult patients [54], 8 of 11
untreated adult patients [55], 6 of 11 untreated, and 2 of 7 treated adult
patients [55].  Studies based on
catabolism and distribution of labeled IgM have not shown any difference in
diet controlled untreated celiac disease [55].
Where reported, SIgMID did not correlate with any specific biochemical,
hematologic or histologic abnormalities.
Jejunal biopsies of affected patients were no different than those of
celiac patients with normal immunoglobulin levels.  There was no unusual risk of infection in
these reported patients [55]. Of note, IgM levels returned to normal levels in
most pediatric and adult patients following a gluten-restricted diet [20, 55].  In one study, mean pretreatment IgM
level was 31.4 and the mean post treatment level 73.6, the difference being
statistically significant (P  = .0001) [20].  In those where the diet restriction was
removed, IgM levels fell back to subnormal levels.  It has been suggested that this secondary
form of IgM deficiency is related to reduced synthesis from lymphoreticular
dysfunction stimulated by gluten antigen exposure [54, 55].The development of lymphoproliferative disorders and/or other
malignancies is a concern with several primary immunodeficiencies, especially
CVID [37].  In SIgMID the risk is
relatively low in adults (2.6%) and negligible in children (0%).  Pediatric cases of SIgMID also differ from
adult cases in the absence of reported cases of angioedema, anaphylaxis, nasal
polyps, bronchiectasis, and thyroid disease (Table 4).  However, these conditions may become relevant
concerns as children with SIgMID mature into adults.  Vigilant followup and surveillance for these
complications may therefore be warranted.


## 6. Conclusion

Pediatric SIgMID is a rare immunodeficiency with a prevalence
of 0.03% in our symptomatic population.
In our review of 51 pediatric patients with SIgMID, most patients
presented with respiratory infections which, in general, were not severe or
life threatening.  The coexistence of
autoimmune disease was rare, malignancies were not reported, and 4 fatalities
were observed, 3 from fulminant infection, either meningitis or pneumonia.  This report should alert clinicians to the
possibility that SIgMID, although rare, may be the cause of recurrent
respiratory infections in children.  In
addition, identification of patients with SIgMID may prevent some of the
complications seen later in life with adult patients.  Larger collaborative studies will better
define the molecular genetics, pathogenesis, and clinical and immunologic
phenotypes of this disorder in children.



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*Source: 624850-2008-11-23.xml*