Hyper IgM Syndrome: A Rare Immunodeficiency Causing Recurrent Infections

Hyper IgM Syndrome

Prof Ariyanto Harsono MD PhD SpA(K)

Introduction
The initial terminology of Hyper IgM Syndrome is
really X-linked immunodeficiency with hyper–
immunoglobulin M (XHIGM or HIGM1) is a rare
form of primary immunodeficiency disease
caused by mutations in the gene that codes for
CD40 ligand (CD40L, also known as CD154 and
gp39). CD40 ligand is expressed on activated T
lymphocytes and is necessary for T cells to induce
B cells to undergo immunoglobulin (Ig) classswitching from immunoglobulin M (IgM) to
immunoglobulin G (IgG), immunoglobulin A (IgA),
and immunoglobulin E (IgE).

2

Since the first description of patients with XHIGM by
Rosen et al in 1961, numerous genetic defects have
been found to be responsible for defective Ig classswitch recombination (CSR). In 1974, a World Health
Organization working party named the syndrome
immunoglobulin deficiency with increased IgM (hyperIgM syndrome [HIGM]). The most common form of
HIGM is XHIGM (or HIGM1) and is inherited as an Xlinked recessive (XR) trait. Another XR form of the
syndrome is associated with hypohidrotic ectodermal
dysplasia. In addition, several autosomal recessive
forms (AR) and an autosomal dominant form of HIGM
have been reported.

3

Patients with HIGM have markedly reduced levels
of IgG, IgA, and IgE but have normal or elevated
levels of IgM. Because CD40 ligand is required in
the functional maturation of T lymphocytes and
macrophages, patients with HIGM also have a
variable defect in T-lymphocyte and macrophage
effector function. Clinically, patients with XHIGM
have increased susceptibility to infection with a
wide variety of bacteria, viruses, fungi, and
parasites. In addition, they are at increased risk for
developing autoimmune disorders and
malignancies.
Keywords: higm, immune deficiency, CD40 mutation, neutropenia,
pneumonia, IVIG
4

Pathophysiology
Humoral immunity, or antibody-mediated
immune responses, plays a central role in
defense against extracellular pathogens and
some viruses. Humoral immunity depends on
the generation of exquisite specificity and
diversity of Igs. During the primary antibody
response, B cells in the bone marrow produce
IgM and immunoglobulin D (IgD) antibodies of
low avidity. This process is largely antigenindependent.

5

Once IgM B cells are engaged with antigens, B
cells start the secondary antibody repertoire
generation by undergoing 2 genetic alterations to
improve specificity and avidity of the antibody to
specific microorganisms.
The first step is generation of Ig diversity by
recombination of Ig heavy chain, known as CSR,
switching from IgM to IgG, IgA, or IgE (Figure 1).


6

Figure 1. The first step is generation of Ig diversity by recombination of Ig
heavy chain, known as CSR, switching from IgM to IgG, IgA, or IgE

7

The second step is somatic hypermutation (SHM)
and involves the introduction of point mutations
in the V regions (antigen-binding sites) of the Ig
genes, resulting in an expansion of the antibody
repertoire to generate high-affinity antigenspecific antibodies. The secondary antibody
repertoire generation is antigen and T-cell
dependent and occurs in peripheral lymphoid
organs, mainly through the interaction between
CD40 ligand (CD154), expressed on activated CD4+
T cells, and CD40, expressed on B cells (Figure 2).

8

Figure 2. B cells in the bone marrow produce immunoglobulin M (IgM) and immunoglobulin D (IgD) antibodies of low avidity. This
process occurs in an antigen-independent way (pro-B cells, pre-B cells). Once IgM B cells are engaged with antigens, B cells start
the secondary antibody repertoire generation by undergoing 2 genetic alterations; class-switch recombination. The secondary
antibody repertoire generation is antigen and T-cell dependent and occurs in peripheral lymphoid organs, mainly through the
interaction between CD40L (CD154) expressed on activated CD4+ T cells and CD40 expressed on B cells.


9

B cells of patients with XHIGM are intrinsically
normal, in that they can be induced to proliferate
and undergo CSR upon in vitro activation by CD40
agonists and appropriate cytokines. CD40
activation is also necessary for B cells to act as
antigen-presenting cells, further enhancing the
adaptive (acquired) immune response of T cells
and other cells. Although B cells mature to express
CD19 and surface immunoglobulins in the absence
of CD40L on T cells, differentiation to plasma cells
does not occur (Figure 3).

10

Figure 3. CD40 activation is also necessary for B cells to act as antigen-presenting cells,
further enhancing the adaptive (acquired) immune response of T cells and other cells.
Although B cells mature to express CD19 and surface immunoglobulins in the absence
of CD40L on T cells, differentiation to plasma cells does not occur


11

Because CD40 is also expressed on monocytes
and dendritic cells, impaired CD40L expression
leads to defective T-cell interactions with
monocytes and dendritic cells, resulting in
abnormal cell-mediated immune function (Figure
4) and increased susceptibility to opportunistic
infections, fungal infection, malignancy, and
autoimmune diseases.


12

Figure 4. Antibody Dependent Cell Cytotoxicity that involve NK
Cell, Monocyte and other cell.

Monocyte


13

Neutropenia is also a common feature of HIGM and may
result from a defective, stress-induced, CD40-dependent
granulopoiesis as myeloid progenitors express CD40
molecules. CD40L and CD40 are widely expressed on
hematopoietic cells, and CD40 triggering on stromal cells
enhances the expression of granulopoiesis growth factors,
such as granulocyte-colony-stimulating factor (G-CSF) and
granulocyte/monocyte-colony-stimulating factor (GM-CSF).
Disruption of the CD40L/CD40-signaling pathway can lead
to neutropenia.
Increased incidence of autoimmune disorders have been
reported among patients with HIGM syndrome.
Furthermore CD40L-CD40 interactions may play an
important role in T-regulatory (T-reg) cells that are required
for the establishment and maintenance of immune
tolerance. Patients with CD40L deficiency displayed low
numbers of T-reg cells and defects in B-cell tolerance.

14

History
According to the US X-linked immunodeficiency
with hyper–immunoglobulin M [XHIGM] Registry
(2003), the initial presentation of patients with
XHIGM usually involves increased susceptibility to
infection. Two prominent clinical problems are
Pneumocystis carinii pneumonia (PCP) and
neutropenia. Nearly one half of patients with
XHIGM presented with PCP prior to, or at the
time of, diagnosis.

15

Among all infections, pneumonia is the most
common, occurring in more than 80% of patients.
Other infections frequently observed in patients
with XHIGM include sinusitis (43%), otitis (43%),
recurrent and/or protracted diarrhea (34%), CNS
infections (14%), sepsis (13%), hepatitis (9%), and
sclerosing cholangitis (6%). Other, less common,
infections include cellulites, subcutaneous
abscesses, herpes stomatitis, oral candidiasis,
parvovirus B19 infection, molluscum
contagiosum, warts, and Candida esophagitis.

16

Microbial pathogens that cause pneumonia include
P jiroveci (59%), cytomegalovirus (CMV) (3%),
adenovirus (2%), Pseudomonas species (3%),
herpesvirus type 1 (2%), respiratory syncytial virus
(2%), histoplasmosis(2%), Pneumococcus species
(2%), Staphylococcus species (2%), Haemophilus
influenzae type b (2%), and other unknown
pathogens (27%). Infections with Mycobacterium
bovis or atypical Mycobacterium species have been
reported.

17

 Pathogens that cause diarrhea include Cryptosporidium
species (21%), Giardia lamblia (8%), rotavirus (8%),
Clostridium difficile (4%), Yersinia enterocolitica (4%), and
other unknown pathogens (63%).
 Causes of CNS infection include echovirus (27%),
Cryptococcus species (9%), Pneumococcus species (9%),
and other unknown causes (55%). Neurological
deterioration in cognitive functions, ataxia, and
hemiplegia associated with progressive
meningoencephalitis has been described in patients with
CNS infection due to enteroviruses or CMV. One case with
rapidly progressing multifocal leukoencephalopathy due to
JC virus infection has been reported. Cerebral
toxoplasmosis was the very first presenting event in a
middle aged man that lead to the diagnosis of XHIGM.

18

 Hepatitis occurred in a significant number of patients
(7 of 79 patients) in the US XHIGM Registry;
causative agents included hepatitis C virus,
echovirus, histoplasmosis, and Bartonella species.
 Cryptosporidium infection was the etiology of
sclerosing cholangitis in 80% of patients.
 Chronic diarrhea without identifiable infectious
agents that leads to failure to thrive is common.
Intestinal nodular lymphoid hyperplasia and
inflammatory bowel disease have been reported.
Chronic hepatitis frequently progresses to cirrhosis
and liver failure. Oral ulcers, gingivitis, proctitis, and
perianal ulcers have also been described.

19

 Neutropenia was the most common hematologic
finding (63-68%). Nearly one half of patients had
chronic neutropenia, whereas others had cyclic or
episodic neutropenia. In 38% of patients with
neutropenia, it was present at the time of diagnosis.
Antineutrophil antibodies were negative. Bone
marrow examination revealed maturation arrest of
the myeloid lineage at the promyelocyte-myelocyte
stage. In 48% of patients with neutropenia, oral
ulcers were occasionally present. Anemia and/or
thrombocytopenia also occurred but with much less
frequency than neutropenia.

20

 Hepatocellular carcinoma and carcinoid tumor of the
pancreas were reported. Lymphoma, neuroectodermal
tumor of the colon, and gastroenteropancreatic
neuroendocrine tumors have also been reported.
Neuroendocrine carcinomas associated with XHIGM are
rapidly progressing and have been found in the pancreas,
liver, intestine, and lymph nodes.
 Seronegative arthritis, degenerative encephalopathy,
hypothyroidism, and autoimmune nephropathy have been
reported in patients with XHIGM. Generalized
lymphadenopathy was reported in 7 of 56 patients.
Osteopenia is a prominent and previously
underappreciated feature of XHIGM. CD40L mediated T-cell
priming is required in induction of osteoclast
differentiation, and CD40L deficiency may contribute to an
imbalance in bone mineral homeostasis. Patients may
present with spontaneous rib fractures without obvious
antecedent trauma history.
21

A mild phenotype presenting with neutropenia,
intermittent fever, and recurrent oral ulcerations
is associated with hemizygous sequence variant
in the CD40L gene. At age 12 years, one patient
experienced only pseudomonas sepsis and
uncomplicated bronchiolitis.


22

Physical Examination
Physical examination findings are related to the manifestation
of infection and/or associated conditions.
Patients with chronic diarrhea may present with failure to
thrive.
Patients with pulmonary infections may have cough,
tachypnea, dyspnea, retraction, accessory muscle use,
hypoxia, or abnormal breath sound on auscultation.
Lymphadenopathy may be present.
Jaundice, pruritus, and hepatomegaly may be present.
Oral mucosal and perirectal ulcerations may be present,
especially in patients with concomitant neutropenia.


23

Etiology
XHIGM is caused by mutation in the gene that
codes for CD40 ligand, a T-cell surface
molecule required for T-cell–driven
immunoglobulin class-switching by B cells.
CD40L is located on the long arm of the X
chromosome (Xq26-27.2). CD40L belongs to
the tumor necrosis factor superfamily. More
than 100 unique mutations of CD40L have
been reported.

24

 In most patients, activated T lymphocytes fail to
express CD40 ligand.
 About 20% of patients with XHIGM express
nonfunctional CD40 ligand on T cells, which can
bind anti–CD40 ligand monoclonal antibodies.
Therefore, these patients may require testing of
the capability of T cells to bind to CD40, using
CD40-Ig fusion protein. The final molecular
diagnosis may depend on sequence analysis of
CD40L using complementary DNA (cDNA) or
genomic DNA.

25

 In a minority of patients, milder mutations that
allow binding of CD40 at reduced intensity are
associated with less severe clinical course. Among
these, a few cases presented with parvovirus
B19–related anemia.
 A case report described a patient with XHIGM
due to mutation in the promotor region resulting
in decreased transcription of CD40L. Sequence
analysis of CD40L genomic DNA showed no
mutations.

26

 CD40-CD40L interactions may be involved in the
selection of T-cell repertoire and priming of T cells, and
absence of CD40-CD40L interaction may result in
defective development of regulatory T cells (T-reg).
This may cause development of autoimmune
manifestations in patients with XHIGM.
 Neutropenia is a common feature of XHIGM and may
result from a defective, stress-induced, CD40dependent granulopoiesis as myeloid progenitors
express CD40 molecules. Autoantibodies to neutrophils
are generally absent.

27

CD40-CD40L interactions are important in
hematopoiesis and innate/adaptive immunity.
CD40-CD40L interactions may have a critical role in
the development of effector cell functions on
monocytes, CD34+ multilineage progenitor cells,
and endothelial cells. The generation of dendritic
cells that prime immune reactions during antigendriven responses to pathogenic invasion also
depends on functional CD40 molecules.


28

Differential Diagnosis
• Common variable immunodeficiency (CVID)
– may be associated with a decreased number of total T cells or decreased T-cell
function

• Severe combined immunodeficiency
– usually presents with absent T-cell function, quantitative abnormalities of T
lymphocyte populations, and markedly decreased mitogen function

• Agammaglobulinemia
– XLA : recurrent bacterial infections but Opportunistic viral infections and
neutropenia are rare, absence of CD19+ B cells

• HIV infection
• Transient hypogammaglobulinemia of infancy (THI)
– normal antibody production, normal growth patterns, and lack of opportunistic
infections


29

Laboratory Studies
 Most early descriptions of X-linked immunodeficiency with
hyper–immunoglobulin M (XHIGM) reported that patients had
elevated serum immunoglobulin (Ig)M levels but markedly
reduced IgG, IgA, and IgE levels. According to the US XHIGM
Registry report in 2003, elevated IgM levels were found in less
than one third of patients. All patients had reduced levels of IgG.
More than three fourths of patients had reduced levels of IgA.
 Diagnosis is confirmed by demonstrating a deficient expression
of CD40 ligand on activated CD4+ T lymphocytes using flow
cytometric analysis with anti–CD40 ligand monoclonal antibody.
Phenotypical analysis of circulating lymphocytes (CD3, CD4,
CD8, and CD19 expression) generally shows normal counts of T
and B cells. One case report described a man with normal
expression of CD40L on activated T cells who was found to have
hypomorphic mutations of the CD40L gene.


30

Diagnostic criteria used for the US XHIGM Registry
consisted of 2 of the following:
(1) mutation of CD40L,
(2) a positive family history of a lateral male
relative with the HIGM syndrome, and
(3) defective expression of CD40 ligand on
activated T lymphocytes. Patients with reduced
CD40L expression only, without positive family
history or mutation of CD40L, cannot be included
because this reduced expression can occur in some
patients with common variable immunodeficiency
(CVID).

31

 Functional antibody production that requires T-cell and Bcell interaction (T-cell dependent) is markedly impaired.
Antibodies against T-cell–dependent antigens, such as
antibodies to tetanus-toxoid, diphtheria-toxoid, and
protein-conjugated H influenzae type b antigens, are
absent. Although pneumococcal polysaccharide antigens
are T-cell independent, IgG antibodies against these
antigens are not produced. Antibodies to T-cell–
independent antigens in the IgM class, such as
isohemagglutinin (antibodies against ABO blood group
antigens), are often normal.
 Despite decreased or absent functional antibody
production, these patients may produce a large amount of
autoantibodies against erythrocytes, platelets, and other
organs, such as antiparietal cells and antithyroid
microsomal autoantibodies.

32

In vitro lymphocyte stimulation with T-cell
mitogens (phytohemagglutinin or concanavalin A)
was normal in over 90% of patients with XHIGM.
A minority of patients had a reduced in vitro
proliferative response to tetanus toxoid.
B cells from patients with XHIGM can be driven to
secrete immunoglobulins of various isotypes in
the presence of pokeweed mitogens when
cocultured with helper T lymphoblasts from a
patient with a Sézary-like syndrome. This finding
illustrates a primary T-cell defect in XHIGM.

33

 Neutropenia frequently accompanies XHIGM and
can be chronic, cyclic, or occasional. Bone marrow
studies show maturation arrest of the myeloid
lineage at the promyelocyte-myelocyte stage.
Autoantibodies to neutrophils are not detected.
 Evaluation of infection by appropriate culture and
determination of antibiotic sensitivities are integral
to managing any immune deficiency disease.
Sputum and stool cultures are commonly needed,
and obtaining a culture at any acute infection site
before administering antibiotics is crucial.


34

 Perform liver function tests at diagnosis and yearly
thereafter because subclinical hepatitis is not
uncommon. Viral hepatitis (B and C) testing requires
antigen detection because most patients are unable
to produce antibodies. Perform biopsies on patients
with hepatic disease to best delineate the extent of
disease.
 Gene mutation analysis should be performed for the
final confirmation of diagnosis. If the precise
mutation in CD40L is known in a given family, and if
the fetus is male, a prenatal diagnosis is possible.
Women in the family can be tested to see if they
carry the mutation and are, therefore, at risk for
having an affected son.

35

About 20% of patients with XHIGM express
nonfunctional CD40 ligand on T cells that can bind
anti–CD40 ligand monoclonal antibodies.
Therefore, these patients may require testing to
determine whether their T cells can bind to CD40
molecules using CD40-Ig fusion protein. The final
molecular diagnosis may depend on sequence
analysis of CD40L using cDNA or genomic DNA.


36

Imaging Studies
Chest radiographs and sinus radiographs or CT
scans are initially needed for baseline studies.
Patients with chronic sinopulmonary disease
are customarily reevaluated at intervals with
CT imaging.
Abdominal CT imaging or MRI is indicated in
patients with hepatomegaly, cholangitis, or
abnormal liver function test findings.

37

Other Tests
Pulmonary function tests are essential at
diagnosis and yearly thereafter to monitor for
chronic lung disease. Approximately one fourth of
patients with XHIGM have bronchiectasis; the risk
of bronchiectasis is higher if the initiation of
intravenous immunoglobulin (IVIG) therapy is
delayed.


38

Procedures
 Bronchoscopy and bronchoalveolar lavage may
be required in patients with severe pulmonary
disease that does not respond to usual antibiotic
therapy or patients who may have P jiroveci
pneumonia in order to obtain a specimen for
identification of pathogens.
 Patients with chronic diarrhea may require
endoscopy and biopsy to rule out inflammatory
bowel disease.
 Patients with abnormal liver function may require
percutaneous liver biopsy.

39

Histologic Findings
Lymph node biopsy findings reveal a lack of
germinal centers, attributed to ineffective CD40LCD40 interaction in the extrafollicular areas,
resulting in poor recruitment of germinal center
precursors.


40

Medical Care
 Medical care should be focused on treatment and
prevention of infection. Infectious episodes can be
prevented with regular infusion of human immunoglobulin
(Ig) and early initiation of P jiroveci prophylaxis.
Antimicrobial therapy should be based on culture and
sensitivity results and should be pathogen-specific. Every
effort should be made to obtain a specimen for culture
and sensitivity. Prevention of Cryptosporidium infection
using boiled or filtered water is recommended. Patients
with neutropenia may benefit from treatment with
granulocyte colony-stimulating factor (G-CSF). Bone
marrow transplantation (BMT)or cord blood stem cell
transplantation has been tried in a few patients, with
variable outcome.

41

Ig replacement therapy, by intravenous infusion or
subcutaneous injection, remains the mainstay of
therapy. The primary goal is the prevention of
infection. Ig replacement therapy has significantly
decreased the frequency of life-threatening
infections in patients with X-linked
immunodeficiency with hyper–immunoglobulin M
(XHIGM). If replacement therapy is started early
and appropriate amounts are administered with
sufficient frequency, the cycle of recurrent
infections and progressive lung damage can be
arrested.

42

Intravenous immunoglobulin therapy
 Intravenous immunoglobulin (IVIG) therapy has reportedly
significantly decreased the frequency of lower respiratory tract
and severe infection; however, IVIG therapy has not changed the
frequency of nonrespiratory or upper respiratory infections.
 Regular IVIG infusions replace the IgG and often result in a
reduction or normalization of the serum IgM level. IVIG therapy
does not change the clinical course of neutropenia, chronic
diarrhea, or chronic cholangitis, hepatitis, or other autoimmune
manifestations.
 Ig products currently available in the United States are derived
from pooled human plasma. The manufacturing processes
include cold ethanol fractionation of Ig and viral inactivation and
removal steps. Biological activity of the IgG molecule, not simply
the antibody titer, but also opsonic and complement activity and
circulating half-life, may be affected by discrete steps in the
manufacturing and isolation of IgG.

43

 Only one report has compared 2 IVIG products. In this
randomized, double-blind, multicenter study, patients treated
with Gamunex (purified using caprylate treatment and
chromatography) had a significantly lower number of infections
compared with the group treated with Gamimune N (solventdetergent treated) from the same company. Annual infection
rates were 0.18 compared with 0.43, respectively (P =.023).
 Ig replacement is intravenously administered on a regular basis.
The half-life of IgG is usually longer than 18-23 days in healthy
individuals. Tailor the dose and frequency to the Ig trough levels
and to clinical symptoms. Measure the serum IgG level before
each infusion and adjust the dose of IVIG accordingly. Maintain
trough serum IgG concentrations of 400-500 mg/dL in adults, a
value close to the lower limit of the reference range. For most
patients, a dose of 400-600 mg/kg every 3-4 weeks suffices to
reduce the frequency of infection. Some patients with chronic
lung disease require up to 600-800 mg/kg/mo. Once a regular
regimen is established, IVIG can be administered at home.

44

Adverse reactions to IVIG therapy include the
following:
Nonanaphylactic reactions
o These are the most common reactions to IVIG therapy
and frequently manifest as backache, nausea, chills,
low-grade temperature, or vomiting within the first 30
minutes of infusion. Headache, chills, flushing, chest
tightness, dyspnea, fever, myalgia, nausea, and fatigue
may begin at the end of the infusion and continue for
several hours. Slowing the infusion rate or
interrupting the infusion for a few minutes can
prevent most of these reactions.

45

o Febrile or phlogistic reactions are thought to be secondary to
immune aggregates that fix IgG-aggregate or IgG-antigen
complement complexes. These reactions tend to occur more
frequently in patients with severe hypogammaglobulinemia,
particularly at the initiation of treatment, and in patients with
intercurrent infections or bronchiectasis. These symptoms may be
treated with acetaminophen, diphenhydramine, and/or
hydrocortisone.
o To minimize the risk of these reactions, treat or eradicate preexisting
infection before administering IVIG for the first time or after a hiatus
in therapy. Initiate therapy with one half of the calculated IVIG dose
and then repeat the dose 2 weeks later before changing to a 3-week
to 4-week schedule. Alternatively, antipyretics, diphenhydramine,
and/or corticosteroids may be administered prior to IVIG
administration to attenuate adverse reactions.
o Reactions caused by fluid volume, salt, or protein overload may be
problematic for patients with cardiovascular limitations, particularly
at higher doses. Closely monitor these patients during and after
infusions and administer diuretics if necessary.

46

 Anaphylactic reactions
o True anaphylactic reactions to IVIG therapy are rare.
Patients who have selective IgA deficiency (sIgAD) or
common variable immunodeficiency (CVID) with
undetectable IgA may develop IgE antibodies against
IgA following exposure to serum IgA. These patients
may develop anaphylactic reactions during
subsequent IVIG administrations.
o Exercise caution during IVIG administration in
patients with no detectable IgA levels.

47

o Prekallikrein activator has been associated with
hypotension and circulatory collapse, and IgG
aggregates may result in anaphylaxis via
complement activation.
o In patients with XHIGM, production of IgE
antibodies against IgA is very rare due to a defect
in class-switch recombination (CSR).


48

 Transmission of infectious agents
o The potential for transmission of pathogens cannot be
completely ruled out. In 1993 and 1994, transmission of
hepatitis C virus was reported in recipients of one of 2 IVIG
products that did not undergo viral inactivation steps
during manufacturing. All IVIG products currently
marketed in the United States now undergo viral
inactivation and removal.
o In order to reduce potential contamination of pathogens,
all plasma for manufacture is tested at various levels and
retested by viral marker and nucleic acid technology (NAT).
Viral inactivation is achieved using dry heat or
pasteurization or irradiation solvent-detergent treatment,
low pH exposure, or caproate treatment. Viral removal is
necessary to reduce the risk of nonenveloped virus
transmission and includes precipitation, chromatography,
and filtration, including nanofiltration.

49

o Because of the introduction of various viral inactivation and
removal processes, relatively large viruses, such as human
immunodeficiency virus (HIV) and hepatitis B and C, are
readily inactivated and can be effectively removed. No case
of HIV infection has resulted from treatment with IVIG
because retroviruses are readily inactivated by the cold
ethanol precipitation.
o The main concern is prions that transmit spongiform
encephalopathy, referred to as variant Creutzfeldt-Jacob
disease (vCJD). No blood tests or inactivation methods are
currently applicable to prions. Fortunately, prions have not
been directly detected in human blood, and the potential
for efficient removal of prions by the current manufacturing
processes has been documented.

50

 Acute and chronic renal failure
o This is most often reported in patients with preexisting
renal disease who receive sucrose-containing IVIG
solutions. IVIG products have been reported to be
associated with renal dysfunction, acute renal failure,
osmotic nephrosis, and death.
o Patients at risk for acute renal failure include patients with
any degree of preexisting renal insufficiency, diabetes
mellitus, age older than 65 years, volume depletion, sepsis,
or paraproteinemia or patients receiving known
nephrotoxic drugs. Products that contain sucrose as a
stabilizer account for a disproportionate share of the total
number of renal failure cases.
o In patients at increased risk, monitoring BUN and creatinine
levels before starting treatment and prior to each infusion
is necessary. If renal function deteriorates, the product
should be discontinued

51

Other reactions: Rare reactions to IVIG therapy
include aseptic meningitis, lymphocytic pleural
effusion, thromboembolism, coagulopathy, and
immune hemolysis. Suspected causes of these
adverse events include hyperosmolarity, presence
of activated factor XI, and high sodium content.
However, these causes are from anecdotal
observation, and establishing precise guidelines
for reducing the risk of adverse events is difficult.


52

Subcutaneous immunoglobulin therapy
 Subcutaneous immunoglobulin (SCIG) is an alternative method for
patients with difficult venous access or for those who experience serious
side effects from IVIG.
 Vivaglobin (ZLB Behring; King of Prussia, Penn) is the first SCIG product to
be approved in the United States for the prevention of serious infection
in patients with primary immune deficiency diseases.
 Vivaglobin is administered weekly using an infusion pump, allowing
patients to self-administer the injection at home.
 The recommended weekly dose of Vivaglobin is 100-200 mg/kg
administered subcutaneously. The dose may be adjusted over time to
achieve the desired clinical response and serum IgG levels. Initial dose
can be calculated by multiplying the previous IVIG dose by 1.37, and then
dividing this dose into weekly doses based on the patient's previous IVIG
treatment interval; for example, if IVIG was administered every 3 weeks,
divide by 3. This dose of Vivaglobin provides a systemic IgG exposure
comparable with that of the previous IVIG treatment. Weekly
administration of this dose leads to stable steady-state serum IgG levels,
with lower IgG peak levels and higher IgG trough levels compared with
monthly IVIG treatment.

53

 The SCIG is well accepted by patients, mostly administered
at home, and the risk of infusion reactions is even less than
for intravenous infusions. SCIG was well tolerated in
patients who had a history of severe reactions to IVIG
infusions with the same product.
 In clinical trials, the most frequent adverse event was
injection-site reaction, consisting of mild or moderate
swelling, redness, and itching. No serious local site
reactions were observed, and reactions tended to decrease
substantially after repeated use. Other adverse events
irrespective of causality included headache, GI disorder,
fever, nausea, sore throat, and rash.
 As with all Ig products, patients receiving Ig therapy for the
first time, receiving a new product, or not having received
Ig therapy within the preceding 8 weeks may be at risk for
developing reactions such as fever, chills, nausea, and
vomiting.
54

 As with all Ig products, Vivaglobin is contraindicated
in individuals with a history of anaphylactic or severe
systemic response to Ig preparations and in persons
with selective IgA deficiency who have known
antibody against IgA.
 Vivaglobin is derived from human plasma. As with all
plasma-derived products, the risk of transmission of
infectious agents, including viruses and, theoretically,
the CJD agent, cannot be completely eliminated.


55

P jiroveci prophylaxis
Patients with XHIGM also have a marked
susceptibility to P jiroveci pneumonia (Figure 4).
Initiating prophylactic treatment with
trimethoprim-sulfamethoxazole as soon as the
diagnosis of XHIGM is established is important.


56

Figure 4. Chest x-ray of 7 month XHIM boy presenting with P
jiroveci (formerly Pneumocystis carinii) pneumonia.

57

Granulocyte-colony stimulating factor therapy
for neutropenia
Patients with persistent severe neutropenia
who do not respond favorably to IVIG
infusions are candidates for treatment with GCSF.


58

Antimicrobial treatment
 Infections should be treated early with full doses
of pathogen-specific antimicrobial agents.
Whenever possible, narrow-spectrum drugs
should be used based on microbial sensitivity
testing. Prophylactic antibiotics should be
avoided because they increase the risk of
infection with fungi or drug-resistant organisms.
Antiviral agents may be useful in some patients
with persistent or severe viral infections

59

Immunosuppressants
Treatment of associated autoimmune
disorders may require immunosuppressants
such as prednisone. Therapy should be
directed to the specific conditions.


60

Bone marrow transplantation
BMT may be considered in young patients
without bronchiectasis or severe chronic
infections who have a human leukocyte
antigen–matched sibling who can serve as a
BMT donor. Cord blood stem cells (fully or
partially matched) or bone marrow from an
unrelated matched donor may be considered
if a matched sibling donor is not available

61

Experimental therapy: Recombinant CD40L
 Three patients were treated with subcutaneous
injection of human recombinant CD40L 3 times a
week. After 22 weeks of treatment, the patient
mounted delayed-type hypersensitivity reactions
and produced T helper (TH 1) effector cytokines
after activation but failed to induce
differentiation of naïve B cells in the periphery.


62

Surgical Care
Patients may need to undergo endoscopic
sinus surgery to treat chronic sinusitis. Biopsy
samples should be taken from rapidly
enlarging lymph nodes to rule out infection or
malignancy.


63

Consultations
Patients with XHIGM and multiple organ
system involvement may benefit from a
multidisciplinary team of consultants,
including a immunologist, pulmonologist,
gastroenterologist, hematologist, oncologist,
and nephrologist.


64

Diet
Patients with chronic lung disease may require
high-calorie diet supplementation because of
high energy expenditure. Patients with chronic
enteropathy may require an elemental diet
and, at times, supplemental parenteral
nutrition.


65

Inpatient Care

 Inpatient care may be necessary for any serious clinical
conditions associated with X-linked immunodeficiency with
hyper–immunoglobulin M (XHIGM). Hospitalization due to
severe infection is uncommon once intravenous
immunoglobulin (IVIG) therapy is started. IVIG can be
administered in outpatient clinics or at home to minimize
interruptions of normal living.
 Bone marrow transplantation (BMT) may be considered in
young patients without bronchiectasis or severe chronic
infections who have an human leukocyte antigen (HLA)matched sibling donor. Cord blood stem cells (fully or
partially matched) or bone marrow from an unrelated
matched donor may be considered if a matched sibling
donor is not available.


66

Outpatient Care
Monitor patients who are stable every 2-3
months. More frequent observation is
appropriate for patients with intercurrent
infection or complications such as autoimmune
disorders or viral hepatitis.
Empirical antibiotic therapy should be avoided as
much as possible. Make every effort to obtain
samples for pathogen identification and use
specific antimicrobial agents.
P carinii (PCP) prophylaxis should be started as
soon as diagnosis is established.

67

Prevention

 PCP prophylaxis using antibiotics such as trimethoprim-sulfamethoxazole
must be started as soon as the diagnosis is established.
 Patients with XHIGM should not receive live virus vaccines (eg, mumpsmeasles-rubella [MMR], varicella, or oral polio vaccine) because, although
the possibility is remote, the patient may develop infection with the
vaccine-strain viruses.
 Because exposure to Cryptosporidium may cause severe GI symptoms and
chronic liver disease, reducing the possibility of drinking contaminated
water is important. The family should contact the local water supplier and
ask if the water is tested for Cryptosporidium.
 Prenatal diagnosis is possible once the gene mutation of the index case is
identified. Polymerase chain reaction–single strand conformational
polymorphism (PCR-SSCP) screening of genomic DNA may be used to
make prenatal diagnosis. Because patients with XHIGM develop
infections, including life-threatening PCP, in the first few years of life, early
institution of IVIG and PCP prophylaxis significantly reduces morbidity and
mortality.


68

Complications

 Bronchiectasis is common in patients who experience
recurrent episodes of pneumonia. Bacterial
pneumonia is mostly preventable using regular IVIG
replacement therapy.
 Liver cirrhosis secondary to hepatitis and cholangitis
and eventual liver failure may be fatal.
Adenocarcinomas of the liver, biliary tract, and other
parts of the GI system are another complication of
chronic GI disease.
 Progressive meningoencephalitis due to
enteroviruses has been reported. Degenerative
encephalopathy without identifiable infectious
etiology has been described. Unfortunately, even
very high doses of IVIG did not prevent progression of
neurological deterioration.

69

Prognosis
 Prognosis is guarded, even with aggressive IVIG therapy
and PCP prophylaxis.
 A retrospective study by the Registry of the European
Society for Immune Deficiency of 56 affected males
revealed a 20% survival rate in persons aged 25 years or
older. The US XHIGM Registry reported that 11 of 61
surviving patients were aged 20 years or older.
 A number of patients received BMT or cord blood stem cell
transplantation, with variable outcomes. Better outcomes
are associated with BMT from an HLA-matched sibling.
Successful treatment of a patient with XHIGM using liver
transplantation followed by BMT from an HLA-matched,
unrelated donor has been reported.

70

References
Notarangelo L D, Hayward A R. X-linked
immunodeficiency with hyper-IgM (XHIM).
Clin Exp Immunol. 2000; 120: 399–405.
Park C L; Jyonouchi H (Ed).
http://emedicine.medscape.com/article/8891
04-followup#a2651 accessed 25 December
2014.


71

Thank you


72

Hyper IgM Syndrome: A Rare Immunodeficiency Causing Recurrent Infections

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