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\begin{document}

\title{SELECTIVE IGM DEFICIENCY: FOLLOW-UP AND OUTCOME}



\author[1]{Canan Caka}%
\author[1]{özlem satırer}%
\author[1]{pınar kahyaoglu}%
\author[2]{İlhan Tezcan}%
\author[1]{Deniz Cagdas}%
\affil[1]{Hacettepe University}%
\affil[2]{Hacettepe Universitesi Tip Fakultesi}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Selective IgM deficiency (sIgMD), classified under primary
immunodeficiencies, is characterized by low serum IgM(\textless{}2SD for
age), normal IgG and IgA levels. The aim of this study was to define
immunologic and clinical features of sIgMD. Method: We assessed a
retrospective medical record of patients who fullfilled the criteria for
sIgMD in a Pediatric Immunology department. Results: There were 55
patients with sIgMD. Out of 55 patients, thirteen(23.6\%) diagnosed with
a well-defined primary immunodeficiency (PID) during the follow-up.The
ratio of the sIgMD was \%0.12 in the out-patient clinic of pediatric
immunology. Out of 33 patients, 8(23.5\%) were asymtomatic during the
follow-up period. Fifteen(45.4\%) patients presented with several type
of infections). Six patients (18\%) had chromosomal anomaly, or syndrome
(trisomy 21, 22q11.2 deletion 1p deletion, CHARGE syndrome, and Cohen
Syndrome). Six (18\%) had autoimmune/inflammatory diseases, such as
Behcet's disease, immune thrombocytopenic purpura, Crohn disease,
Guillain Barre syndrome, and diabetes mellitus. Five(15\%) had allergic
disorders. Three(9\%) have developed malignancy. The diagnoses of
thirteen PID patients were combined immunodeficiency, common variable
immunodeficiency, autoimmune lymphoproliferative syndrome, chronic
granulomatous disease, adenosine deaminase deficiency, and congenital
neutropenia. Genetic disorders, autoimmune/inflammatory and allergic
diseases may accompany sIgMD. Approximately one third of the patients
were asymptomatic in our series. Malignancy risk is relatively
increased. We observed that an important ratio of patients with low IgM
(23.6\%) got sooner the diagnosis of a specific PID in the follow-up
period. Conclusion: Thus, patients with sIgMD should be followed
regularly in immunology clinics.%
\end{abstract}%



\sloppy


\section*{Introduction}

{\label{introduction}}

Selective IgM deficiency (sIgMD) is a rare form of dysgammaglobulinemia,
It is classified under primary humoral immunodeficiencies and
characterized by low serum level of IgM, normal IgG and IgA levels with
normal T cell numbers and function in the absence of a defined
immunodeficiency. Pathogenesis of sIgMD is unknown, and no genetic or
molecular basis has been defined yet. However, there are some hypothesis
suggesting that it may be due to defective B cell maturation or T cell
dysfunction {[}1, 2{]}.

The European Society for Immunodeficiencies (ESID) Registry defines
primary selective IgM deficiency (sIgMD) as serum IgM level repeatedly
below 2 standard deviations (\textless{}-2SD) of reference levels, and
normal levels of serum IgA, IgG and IgG subclasses, normal vaccination
responses, absence of T cell defects and absence of causative external
factors {[}3-5{]}. In another definition, sIgMD was defined as having
low IgM, which is usually lower than 20 mg/dL in infants and children,
or lower than 2SD. Usually, serum IgM levels are lower than10--20 mg/dL.
The levels of other immunoglobulin isotypes are typically normal,
although IgE may be increased {[}6, 7{]}. There is no definition for
IgE, and high IgE may be observed in some cases {[}8{]}. SIgMD is
observed in both children and adults {[}9{]}.

Although it may occur in asymptomatic individuals {[}10{]}, patients
with sIgMD may present with various clinical features. It may associate
with recurrent upper respiratory tract infections (URTI), atopic
manifestations (rhinitis, asthma etc.), autoimmune diseases,
malignancies, and other primary humoral immunodeficiency diseases. There
are several reports in the medical literature including diseases that
may cause decreased IgM levels, such as recurrent infections, autoimmune
diseases (Celiac disease, hemolytic anemia), and different types of
primary immunodeficiency (PID) (thymic hypoplasia, Wiskott Aldrich
syndrome, ataxia telangiectasia, common variable immunodeficiency
(CVID), Bruton agammaglobulinemia and congenital diseases (Bloom
syndrome, Russel silver syndrome, DiGeorge syndrome) {[}11{]}.

Our aim is evaluation of the demographic features, clinical
presentations, associated diseases and infections of the patients who
are followed up with sIgMD.

\section*{Patients and Methods}

{\label{patients-and-methods}}

The study was conducted in Hacettepe \selectlanguage{ngerman}Üniversity \selectlanguage{polish}İ\selectlanguage{english}hsan Dogramac\selectlanguage{polish}ı
\selectlanguage{english}Children's Hospital, Ankara, Turkey. The hospital serves as a referral
tertiary hospital. We assessed a retrospective medical record of 27,000
patients who admitted to Pediatric Immunology department. To define
selective IgM deficient patients, The European Society for
Immunodeficiencies (ESID) Registry criteria have been used {[}3-5{]}.
Patients who had repeatedly (at least twice in a 6-month period) low
serum IgM level according to age referrals were evaluated in the study.
Fifty-five patients were found in this cohort (Figure 1). Thirteen
patients who were diagnosed with a primary immunodeficiency had also low
IgM levels with normal IgG and IgA levels. Forty-two patients fulfilling
the diagnosis of sIgM deficiency were evaluated over a five-year period
(2013-2018).

As transient hypogamaglobulinemia may prolong to five years of
age{[}12{]}, we determined the patients who got the diagnosis less than
five years of age. Eighteen of 42 patients had taken the diagnosis of
sIgMD before five years of age. Out of 18, in nine patients sIgM
deficiency continued after five years of age, in two patients IgM levels
normalized, and seven patients lost follow-up. Eventually, 33 patients
were fulfilling the disease criteria {[}13{]}.

Cases of sIgMD were reviewed for the symptoms on admission, concurrent
conditions, and clinical course. Patients with genetic mutations,
chromosomal abnormalities and associated immunological disorders were
also recorded. Laboratory findings; complete blood counts, serum
immunoglobulin levels and lymphocyte subsets were noted. To evaluate
vaccination response antiHbs antibody and isohemaglutinins were used.

The patients with PID (n=13) and patients who got the diagnosis of sIgMD
at less than 5 years of age (n=9) were evaluated separately (Figure 1),
and their characteristics are given after the results of patients with
sIGMD.

The study was approved by the ethical committee of Hacettepe University
Medical School Hospital (GO 18/182-20).

\subsection*{Statistical analysis}

{\label{statistical-analysis}}

All the data collected during the study were uploaded to SPSS
statistical program. Parametrical tests (Student t-test) were used to
analyze the variables which distributed normally. The variables that did
not have normal distribution were analyzed by nonparametric tests
(Mann-Whitney U test). Categorical and qualitative variables were
analyzed by Fisher Exact test and Chi-Square test. A \emph{p} value
lower than 0.05 was considered to be statistically significant.

\section*{RESULTS}

{\label{results}}

\textbf{Demographic findings:} 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) Out of 33 patients, 25 patients (74\%) were male and 8 (26\%)
were female. The median age of onset of disease was 3 years (1-33), and
the median age of diagnosis was 8 years (1-43). Six out of 33 patients
(18.2\%) were adult, 27 of them (81.8\%) were children. Age at diagnosis
and gender of each patients were given in supplementary table 2.

\textbf{Clinical Findings:}

\textbf{Clinical Presentation:} Most common form of presentation was
pneumonia (26,4\%), skin infection (Herpes simplex, Varicella zoster,
Human papilloma virus infections) (17,6\%), URTI (11\%), lymphadenopathy
(5,8\%), meningitis (5,8 \%), and oral mucocutaneous candidiasis (2.3\%)
and lichen planus (2,9\%). Recurrent respiratory tract infection was the
most common complaint that the patients were referred to the immunology
department before we exclude patients who were under five years old.
Afterwards, frequency of presentation with recurrent URTI decreased
significantly (11 (26\%) versus 4 (12\%)). Clinical presentation
findings of patients were given in Table 1.

Four patients were asymptomatic, and diagnosed with sIgMD incidentally.
Among all, two patients have history of immunodeficiency in their
family. There were five patients who had family history of increased
susceptibility to infections or immunodeficiencies. Five patients had
syndromic facial features, and two of them were diagnosed with trisomy
21, one was diagnosed with DiGeorge syndrome, one diagnosed with Charge
syndrome, and one with Cohen syndrome (Two more patients were diagnosed
with DiGeorge syndrome among sIgMD patients who ara still under five
years of age so were not included as sIgMD) Cardiac disease (Patent
foramen ovale, mitral and aortic valve insufficiency, mitral valve
prolapse, left ventricular hypertrophy, atrial septal defect, patent
ductus arteriosus) was seen in seven (21.2\%) patients. One of the
patients admitted to hospital at the age of 2 months with chickenpox. He
is still being followed up for isolated IgM deficiency. Associating
diseases of sIgMD patients at presentation and follow-up are shown in
Table 1 and 2 respectively.

\textbf{Diseases in the Follow-up}

Infectious and noninfectious diseases of patients during follow-up
period were given in supplementary table 2.

\textbf{Infections:} During the follow-up, recurrent URTI (60.6\%) was
the most common finding followed bypneumonia (36,3 \%). The frequencies
of infections in sIgMD are shown in Table 3.

\textbf{Malignancy:} Malignancy developed in three (9\%) out of 33
patients. These were acute myeloid leukemia (n=2), and tubular adenoma
in sigmoid colon (n=1). A 4 year-old patient presented with
neuroblastoma, and after four years of follow-up, AML developed in the
same patient. He was treated successfully.

\textbf{Autoimmune and Inflammatory Diseases:} Six patients with sIgMD
was additionally diagnosed with autoimmune and inflammatory diseases,
such as, Behcet's disease (n=2), immune thrombocytopenic purpura (ITP)
(n=1), diabetes mellitus, Guillain Barre syndrome (n=1) and Crohn
disease (n=1) respectively.

\textbf{Genetic disorders:} Six (18\%) patients was found to have
genetic disorders, trisomy 21 (n=2), 22q11.2 deletion (n=1), 1p deletion
(n=1), Cohen syndrome (n=1) and CHARGE syndrome (n=1).

Among sIgMD patients who were younger than five years old, two more
patients had the diagnosis of partial DiGeorge syndrom.

\textbf{Atopy:} Five patients (15,1\%) had asthma, and one was wheezy
infant. One out of 5 patients was treated also for allergic rhinitis.

\textbf{Others:} One patient was diagnosed with osteopetrosis, 12
patients (36,3\%) had sIgMD with no additional disorder or disease.

\subsection*{Laboratory Findings}

{\label{laboratory-findings}}

\textbf{Complete blood counts:} Lymphopenia was detected in fifteen
(35,7\%), neutropenia was detected in fourteen (33,3\%), leukopenia was
seen in ten (23\%) and hypereosinophilia was seen in four patients
(9,5\%).

\textbf{Immunoglobulin levels:} The IgG and IgA levels were in normal
range as all the patients fullfilled the sIgMD criteria. Six (18\%)
patients have high IgE levels. Immunoglobulin levels of patients are
given in Supplementary Table 1.

\textbf{Lymphocyte subsets:} They were in normal range on admission in
all patients.

\textbf{Antibody Response:}

Isohemaglutinin levels were normal (above 1/8) in 21 patients (63.6\%),
and was not evaluated in others.

Anti-HBs antibody was positive in 24 (72.7\%) patients, and negative in
6 (18.1\%). Four patients were evaluated again after vaccination, two of
the patients's antiHbs results were positive and two of them were still
negative after vaccination. Two patients were not evaluated for antiHbs
antibody after vaccination.

\textbf{Treatment:} None of the patients with sIgMD required intravenous
immunoglobulin (IVIG). Nine patients (27,2\%) were given prophylactic
antibacterial therapy for recurrent infections.

\subsection*{Primary Immunodeficiency
Diseases}

{\label{primary-immunodeficiency-diseases}}

Although sIgMD is defined as isolated low levels of IgM with normal
levels of IgA and IgG without other defined immunodeficiency, we also
evaluated patients with welldefined PID. During follow-up, 13 patients
were diagnosed with other types of PID diseases. These were T cell
deficiency (n=6), combined immunodeficiency (CID) (n=3), autoimmune
lymphoproliferative disease (ALPS) (n=2), chronic granulomatous disease
(n=1), congenital neutropenia (\emph{HAX-1} gene defect) (n=1). The
molecular defects of the patients diagnosed with CID in the follow-up
were Serine-threonine kinase-4 (\emph{STK4} ) deficiency (n=2),
interleukin-2 inducible kinase (\emph{ITK} ) deficiency (n=1).
Two\emph{STK-} 4 deficient patients were initially presented with
susceptibility to infection and vasculitis; they got the molecular
diagnosis of T cell deficiency approximately 2 years after admission.
One patient developed acute EBV-associated lymphoproliferative syndrome.
Two patients who were followed up with CID developed non-Hodgkin's
lymphoma over years. Among the two patients died; one died at 22 years
of age, had \emph{STK} 4 gene mutation, lymphoma and amyloidosis; the
other patient developed secondary malignancy (acute myeloid leukemia
(AML) after treatment for lymphoma, and died at the age of 12 years.

\section*{Discussion}

{\label{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
Sj\selectlanguage{ngerman}ögren'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 (\emph{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{]}.\textsuperscript{.}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.

\section*{References}

{\label{references}}

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