Discussion
Selective IgM deficiency has been characterized as a rare form of PID,
defined as a low serum IgM level (less than 2SDs below healthy
controls), and normal serum IgA and IgG levels [14]. There are over
300 cases published in the literature. The prevalence ranges from 0.03%
in a community-based study to 3% in allergy and immunology clinics
[15, 8, 9]. In our study, the ratio of sIgMD is found as 0.12%
among the patients that were followed up in pediatric immunology
out-patient clinic for a definite period (33 out of 27,000 patients)
[6].
SIgMD was first described by Hobbs et al in 1967 in a case report of two
patients with fulminant meningococcal meningitis [7]. Although URTI
were the most common clinical symptoms in sIgMD in literature, the
patients presented also with various other infections; such as sepsis
and meningitis [4]. In our series, URTI (60.6%) were the most
common type of infection, followed by otitis media (42,4%) and
pneumonia (36,3%).
It has been reported in the literature that sIgMD is more common in male
sex. In our series, 74% of our patient population was male in
accordance with the literature [6]. There are publications showing
that sIgMD is more common in atopic and allergic people, and IgE levels
may be high in patients with sIgMD [11]. In our study, six patients
(13%) had high IgE levels; five had atopy.
In Goldenstein’s retrospective cohort, 36 adults with sIgMD were
evaluated, the frequency of presentation symptoms were; recurrent URTI
in 77%; asthma in 47%; allergic rhinitis in 36%; vasomotor rhinitis
in 19%; angioedema in 14%; and anaphylaxis in 11%, and there was no
patient who developed lymphoproliferative disease, or
panhypogammaglobulinemia, and none died of life-threatening infections,
malignancy, or fulminant autoimmune-mediated diseases [15].
Chovancova presented another adult cohort with 17 sIgMD patients. Most
common manifestations were increased susceptibility to infections,
especially involving recurrent URTI, pneumonia, urinary tract
infections, sinusitis, otitis media and furuncles [10]. Allergic
disorders included allergic rhinitis, drug allergy, bronchial asthma,
atopic dermatitis, urticaria. Autoimmune manifestations including
Sjögren’s syndrome, systemic lupus erythematosus (SLE), thyreopathy and
alopecia; malignancies including rectal adenocarcinoma, melanoma, and
thymoma were also seen in this cohort [10]. Yel and her friends
reported 15 adult symptomatic patients, their findings were similar with
the previous studies, but they pointed out that impaired specific
antibody response to pneumococcal antigens was seen in half of the
patients, and IgM-deficient patients who present with recurrent/severe
infections may benefit from immunoglobulin treatment, particularly in
the presence of impaired pneumococcal antibody responses [16]. The
results of our cohort was compatible with these reports. We observed
infection susceptibility, chromosomal diseases, autoimmune/inflammatory,
and allergic diseases associating with sIgMD. According to our findings,
the follow-up of patients with low IgM is very important as about ¼ has
got the diagnosis of PID in the follow-up. IgM deficiency may accompany
CID [17]. The reason that we emphasized the group of 13 patients
with defined PID was to highlight the low IgM levels that we come across
in these group of patients.
Clinical associations of sIgMD with 22q11.2 deletion (DiGeorge
Syndrome), ring chromosome 18 and chromosome 1 deletion were reported in
literature [18]. The reason of the association of sIgMD and these
deletions is not yet known, their association may also be a coincidence
[11], or the genetic background of sIgMD may be related with these
genetic locations. In our study; nine patients had an atypical facial
appearance. Among five (14%) patients with syndromes, two patients had
trisomy 21, one patient was diagnosed with DiGeorge syndrome, one had
Cohen syndrome (COH-1 mutation), and one had 1p deletion.
SIgMD criteria of ESID includes normal IgG subclass levels, and normal
vaccination responses with low IgM levels [5]. In some case series
IgG subclass deficiency was detected in one fourth of patients [19,
15]. Hepatitis B vaccination response of six (18.1%) patients were
negative in our cohort. Janssen et al classifies selective IgM
deficiency as follows: “true sIgMD” who met ESID registry criteria,
“possible sIgMD” where ESID registry criteria were not fulfilled
completely because data on IgG subclasses and/or vaccination response
were not available, and “unclassified primary antibody deficiency”
since other abnormalities of antibodies, IgG subclass deficiency, and/or
impaired response to vaccine were present [20]. Patients of our
cohort meet “possible sIgMD” according to this classification due to
lack of Ig G subclass and vaccination responses. Gupta et al. explained
that terminology of “true”, “possible”, and “unclassified”
selective IgM deficiency should not be used, because this definition
would exclude a sizeable number of patients, including those with
complete absence of serum IgM, from the diagnosis of selective IgM
deficiency [21]. Thus, we think that selective IgM deficiency should
be defined only according to serum antibody levels and age [21].
In addition to providing early defense against microbes, IgM plays an
important role in immune homeostasis, and provides protection from
consequences of autoimmunity and inflammation [9]. There is an
increased prevalence of autoimmune diseases in patients with sIgMD
[7]. Autoimmune diseases associated with sIgMD are SLE, rheumatoid
arthritis, Hashimoto’s thyroiditis, autoimmune hemolytic anemia (AHA),
Celiac disease, vitiligo, polymyositis, autoimmune glomerulonephritis,
and chronic ITP [7]..In our cohort, six patients
(9,5%) with sIgMD was also diagnosed with autoimmune and inflammatory
disease, such as, Behcet’s disease, ITP, Gullian-Barre syndrome,
diabetes mellitus and Crohn disease. According to the reports,
autoimmune diseases are more common in adults rather than children
[9]. In our cohort, two out of four patients with autoimmune
diseases were older than eighteen years old; one of them had Behçet’s
diseases, the other had ITP.
A number of malignancies were described in sIgMD patients as case
series, including clear cell sarcoma, non-Hodgkin’s lymphoma,
promyelocytic leukemia and hepatocellular carcinoma [7]. In our
series, malignancy developed in three (8,8%) patients, they were AML,
neuroblastoma and tubuler adenoma in sigmoid colon.
There are also reports in the literature showing the relationship
between sIgMD and chronic inflammatory diseases, such as Crohn,
ulcerative colitis and Celiac disease associating protein-losing
enteropathy. We don’t know the reason why only IgM levels, not IgG
levels, decreased in patients with protein loosing enteropathy. All
these diseases may possibly associate with PID. Some sIgMD patients,
having IgM levels improved after treatment of primary disease (e.g.
gluten-poor diet) have also been reported. In our cohort, there was one
patient with Crohn disease, but there was no improvement in the IgM
levels after the treatment [7].
Intravenous immunoglobulin treatment’s beneficial effects on sIgMD
patients were reported [16]. Goldenstein et al. showed clinical
improvement with high dose IVIG in patients with comorbidity of asthma
and bronchiectasis. In our cohort, none of the patients with sIgMD
needed IVIG treatment.
Immunologic evaluation should be recommended to the family members who
had frequent infections and autoimmune, inflammatory and
lymphoproliferative/malign disease.
As a result, the etiology, pathogenesis, clinical course of sIgMD is not
clear yet. In the literature, only about three percent of patients with
sIgMD were completely asymptomatic both in the adult age and in
pediatric age groups; whereas in our series this rate was 24% (n=8)
[15, 11]. We observed in our series that about ¼ had PID, and 10%
had CID. These findings should be supported by further studies. Patients
should have regular follow-up in immunology clinics even if they do not
have clinical symptoms.