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 ...
Since the first description of patients with XHIGM by
Rosen et al in 1961, numerous genetic defects have
been found to be ...
Patients with HIGM have markedly reduced levels
of IgG, IgA, and IgE but have normal or elevated
levels of IgM. Because CD...
Pathophysiology
Humoral immunity, or antibody-mediated
immune responses, plays a central role in
defense against extracell...
Once IgM B cells are engaged with antigens, B
cells start the secondary antibody repertoire
generation by undergoing 2 gen...
Figure 1. The first step is generation of Ig diversity by recombination of Ig
heavy chain, known as CSR, switching from Ig...
The second step is somatic hypermutation (SHM)
and involves the introduction of point mutations
in the V regions (antigen-...
Figure 2. B cells in the bone marrow produce immunoglobulin M (IgM) and immunoglobulin D (IgD) antibodies of low avidity. ...
B cells of patients with XHIGM are intrinsically
normal, in that they can be induced to proliferate
and undergo CSR upon i...
Figure 3. CD40 activation is also necessary for B cells to act as antigen-presenting cells,
further enhancing the adaptive...
Because CD40 is also expressed on monocytes
and dendritic cells, impaired CD40L expression
leads to defective T-cell inter...
Figure 4. Antibody Dependent Cell Cytotoxicity that involve NK
Cell, Monocyte and other cell.

Monocyte

Prof Ariyanto Har...
Neutropenia is also a common feature of HIGM and may
result from a defective, stress-induced, CD40-dependent
granulopoiesi...
History
According to the US X-linked immunodeficiency
with hyper–immunoglobulin M [XHIGM] Registry
(2003), the initial pre...
Among all infections, pneumonia is the most
common, occurring in more than 80% of patients.
Other infections frequently o...
Microbial pathogens that cause pneumonia include
P jiroveci (59%), cytomegalovirus (CMV) (3%),
adenovirus (2%), Pseudomon...
 Pathogens that cause diarrhea include Cryptosporidium
species (21%), Giardia lamblia (8%), rotavirus (8%),
Clostridium d...
 Hepatitis occurred in a significant number of patients
(7 of 79 patients) in the US XHIGM Registry;
causative agents inc...
 Neutropenia was the most common hematologic
finding (63-68%). Nearly one half of patients had
chronic neutropenia, where...
 Hepatocellular carcinoma and carcinoid tumor of the
pancreas were reported. Lymphoma, neuroectodermal
tumor of the colon...
A mild phenotype presenting with neutropenia,
intermittent fever, and recurrent oral ulcerations
is associated with hemiz...
Physical Examination
Physical examination findings are related to the manifestation
of infection and/or associated conditi...
Etiology
XHIGM is caused by mutation in the gene that
codes for CD40 ligand, a T-cell surface
molecule required for T-cell...
 In most patients, activated T lymphocytes fail to
express CD40 ligand.
 About 20% of patients with XHIGM express
nonfun...
 In a minority of patients, milder mutations that
allow binding of CD40 at reduced intensity are
associated with less sev...
 CD40-CD40L interactions may be involved in the
selection of T-cell repertoire and priming of T cells, and
absence of CD4...
CD40-CD40L interactions are important in
hematopoiesis and innate/adaptive immunity.
CD40-CD40L interactions may have a c...
Differential Diagnosis
• Common variable immunodeficiency (CVID)
– may be associated with a decreased number of total T ce...
Laboratory Studies
 Most early descriptions of X-linked immunodeficiency with
hyper–immunoglobulin M (XHIGM) reported tha...
Diagnostic criteria used for the US XHIGM Registry
consisted of 2 of the following:
(1) mutation of CD40L,
(2) a positi...
 Functional antibody production that requires T-cell and Bcell interaction (T-cell dependent) is markedly impaired.
Antib...
In vitro lymphocyte stimulation with T-cell
mitogens (phytohemagglutinin or concanavalin A)
was normal in over 90% of pat...
 Neutropenia frequently accompanies XHIGM and
can be chronic, cyclic, or occasional. Bone marrow
studies show maturation ...
 Perform liver function tests at diagnosis and yearly
thereafter because subclinical hepatitis is not
uncommon. Viral hep...
About 20% of patients with XHIGM express
nonfunctional CD40 ligand on T cells that can bind
anti–CD40 ligand monoclonal a...
Imaging Studies
Chest radiographs and sinus radiographs or CT
scans are initially needed for baseline studies.
Patients w...
Other Tests
Pulmonary function tests are essential at
diagnosis and yearly thereafter to monitor for
chronic lung disease...
Procedures
 Bronchoscopy and bronchoalveolar lavage may
be required in patients with severe pulmonary
disease that does n...
Histologic Findings
Lymph node biopsy findings reveal a lack of
germinal centers, attributed to ineffective CD40LCD40 int...
Medical Care
 Medical care should be focused on treatment and
prevention of infection. Infectious episodes can be
prevent...
Ig replacement therapy, by intravenous infusion or
subcutaneous injection, remains the mainstay of
therapy. The primary g...
Intravenous immunoglobulin therapy
 Intravenous immunoglobulin (IVIG) therapy has reportedly
significantly decreased the ...
 Only one report has compared 2 IVIG products. In this
randomized, double-blind, multicenter study, patients treated
with...
Adverse reactions to IVIG therapy include the
following:
Nonanaphylactic reactions
o These are the most common reactions ...
o Febrile or phlogistic reactions are thought to be secondary to
immune aggregates that fix IgG-aggregate or IgG-antigen
c...
 Anaphylactic reactions
o True anaphylactic reactions to IVIG therapy are rare.
Patients who have selective IgA deficienc...
o Prekallikrein activator has been associated with
hypotension and circulatory collapse, and IgG
aggregates may result in ...
 Transmission of infectious agents
o The potential for transmission of pathogens cannot be
completely ruled out. In 1993 ...
o Because of the introduction of various viral inactivation and
removal processes, relatively large viruses, such as human...
 Acute and chronic renal failure
o This is most often reported in patients with preexisting
renal disease who receive suc...
Other reactions: Rare reactions to IVIG therapy
include aseptic meningitis, lymphocytic pleural
effusion, thromboembolism...
Subcutaneous immunoglobulin therapy
 Subcutaneous immunoglobulin (SCIG) is an alternative method for
patients with diffic...
 The SCIG is well accepted by patients, mostly administered
at home, and the risk of infusion reactions is even less than...
 As with all Ig products, Vivaglobin is contraindicated
in individuals with a history of anaphylactic or severe
systemic ...
P jiroveci prophylaxis
Patients with XHIGM also have a marked
susceptibility to P jiroveci pneumonia (Figure 4).
Initiati...
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 resp...
Antimicrobial treatment
 Infections should be treated early with full doses
of pathogen-specific antimicrobial agents.
Wh...
Immunosuppressants
Treatment of associated autoimmune
disorders may require immunosuppressants
such as prednisone. Therap...
Bone marrow transplantation
BMT may be considered in young patients
without bronchiectasis or severe chronic
infections w...
Experimental therapy: Recombinant CD40L
 Three patients were treated with subcutaneous
injection of human recombinant CD4...
Surgical Care
Patients may need to undergo endoscopic
sinus surgery to treat chronic sinusitis. Biopsy
samples should be ...
Consultations
Patients with XHIGM and multiple organ
system involvement may benefit from a
multidisciplinary team of cons...
Diet
Patients with chronic lung disease may require
high-calorie diet supplementation because of
high energy expenditure....
Inpatient Care

 Inpatient care may be necessary for any serious clinical
conditions associated with X-linked immunodefic...
Outpatient Care
Monitor patients who are stable every 2-3
months. More frequent observation is
appropriate for patients w...
Prevention

 PCP prophylaxis using antibiotics such as trimethoprim-sulfamethoxazole
must be started as soon as the diagn...
Complications

 Bronchiectasis is common in patients who experience
recurrent episodes of pneumonia. Bacterial
pneumonia ...
Prognosis
 Prognosis is guarded, even with aggressive IVIG therapy
and PCP prophylaxis.
 A retrospective study by the Re...
References
Notarangelo L D, Hayward A R. X-linked
immunodeficiency with hyper-IgM (XHIM).
Clin Exp Immunol. 2000; 120: 39...
Thank you

Prof Ariyanto Harsono MD PhD SpA(K)

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Hyper IgM Syndrome

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Hyper IgM Syndrome

  1. 1. Hyper IgM Syndrome Prof Ariyanto Harsono MD PhD SpA(K)
  2. 2. 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). Prof Ariyanto Harsono MD PhD SpA(K) 2
  3. 3. 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. Prof Ariyanto Harsono MD PhD SpA(K) 3
  4. 4. 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
  5. 5. 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. Prof Ariyanto Harsono MD PhD SpA(K) 5
  6. 6. 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). Prof Ariyanto Harsono MD PhD SpA(K) 6
  7. 7. 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
  8. 8. 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). Prof Ariyanto Harsono MD PhD SpA(K) 8
  9. 9. 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. Prof Ariyanto Harsono MD PhD SpA(K) 9
  10. 10. 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). Prof Ariyanto Harsono MD PhD SpA(K) 10
  11. 11. 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 Prof Ariyanto Harsono MD PhD SpA(K) 11
  12. 12. 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. Prof Ariyanto Harsono MD PhD SpA(K) 12
  13. 13. Figure 4. Antibody Dependent Cell Cytotoxicity that involve NK Cell, Monocyte and other cell. Monocyte Prof Ariyanto Harsono MD PhD SpA(K) 13
  14. 14. 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. Prof Ariyanto Harsono MD PhD SpA(K) 14
  15. 15. 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. Prof Ariyanto Harsono MD PhD SpA(K) 15
  16. 16. 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. Prof Ariyanto Harsono MD PhD SpA(K) 16
  17. 17. 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. Prof Ariyanto Harsono MD PhD SpA(K) 17
  18. 18.  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. Prof Ariyanto Harsono MD PhD SpA(K) 18
  19. 19.  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. Prof Ariyanto Harsono MD PhD SpA(K) 19
  20. 20.  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. Prof Ariyanto Harsono MD PhD SpA(K) 20
  21. 21.  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
  22. 22. 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. Prof Ariyanto Harsono MD PhD SpA(K) 22
  23. 23. 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. Prof Ariyanto Harsono MD PhD SpA(K) 23
  24. 24. 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. Prof Ariyanto Harsono MD PhD SpA(K) 24
  25. 25.  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. Prof Ariyanto Harsono MD PhD SpA(K) 25
  26. 26.  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. Prof Ariyanto Harsono MD PhD SpA(K) 26
  27. 27.  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. Prof Ariyanto Harsono MD PhD SpA(K) 27
  28. 28. 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. Prof Ariyanto Harsono MD PhD SpA(K) 28
  29. 29. 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 Prof Ariyanto Harsono MD PhD SpA(K) 29
  30. 30. 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. Prof Ariyanto Harsono MD PhD SpA(K) 30
  31. 31. 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). Prof Ariyanto Harsono MD PhD SpA(K) 31
  32. 32.  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. Prof Ariyanto Harsono MD PhD SpA(K) 32
  33. 33. 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. Prof Ariyanto Harsono MD PhD SpA(K) 33
  34. 34.  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. Prof Ariyanto Harsono MD PhD SpA(K) 34
  35. 35.  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. Prof Ariyanto Harsono MD PhD SpA(K) 35
  36. 36. 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. Prof Ariyanto Harsono MD PhD SpA(K) 36
  37. 37. 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. Prof Ariyanto Harsono MD PhD SpA(K) 37
  38. 38. 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. Prof Ariyanto Harsono MD PhD SpA(K) 38
  39. 39. 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. Prof Ariyanto Harsono MD PhD SpA(K) 39
  40. 40. 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. Prof Ariyanto Harsono MD PhD SpA(K) 40
  41. 41. 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. Prof Ariyanto Harsono MD PhD SpA(K) 41
  42. 42. 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. Prof Ariyanto Harsono MD PhD SpA(K) 42
  43. 43. 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. Prof Ariyanto Harsono MD PhD SpA(K) 43
  44. 44.  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. Prof Ariyanto Harsono MD PhD SpA(K) 44
  45. 45. 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. Prof Ariyanto Harsono MD PhD SpA(K) 45
  46. 46. 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. Prof Ariyanto Harsono MD PhD SpA(K) 46
  47. 47.  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. Prof Ariyanto Harsono MD PhD SpA(K) 47
  48. 48. 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). Prof Ariyanto Harsono MD PhD SpA(K) 48
  49. 49.  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. Prof Ariyanto Harsono MD PhD SpA(K) 49
  50. 50. 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. Prof Ariyanto Harsono MD PhD SpA(K) 50
  51. 51.  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 Prof Ariyanto Harsono MD PhD SpA(K) 51
  52. 52. 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. Prof Ariyanto Harsono MD PhD SpA(K) 52
  53. 53. 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. Prof Ariyanto Harsono MD PhD SpA(K) 53
  54. 54.  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. Prof Ariyanto Harsono MD PhD SpA(K) 54
  55. 55.  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. Prof Ariyanto Harsono MD PhD SpA(K) 55
  56. 56. 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. Prof Ariyanto Harsono MD PhD SpA(K) 56
  57. 57. Figure 4. Chest x-ray of 7 month XHIM boy presenting with P jiroveci (formerly Pneumocystis carinii) pneumonia. 57
  58. 58. 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. Prof Ariyanto Harsono MD PhD SpA(K) 58
  59. 59. 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 Prof Ariyanto Harsono MD PhD SpA(K) 59
  60. 60. Immunosuppressants Treatment of associated autoimmune disorders may require immunosuppressants such as prednisone. Therapy should be directed to the specific conditions. Prof Ariyanto Harsono MD PhD SpA(K) 60
  61. 61. 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 Prof Ariyanto Harsono MD PhD SpA(K) 61
  62. 62. 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. Prof Ariyanto Harsono MD PhD SpA(K) 62
  63. 63. 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. Prof Ariyanto Harsono MD PhD SpA(K) 63
  64. 64. 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. Prof Ariyanto Harsono MD PhD SpA(K) 64
  65. 65. 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. Prof Ariyanto Harsono MD PhD SpA(K) 65
  66. 66. 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. Prof Ariyanto Harsono MD PhD SpA(K) 66
  67. 67. 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. Prof Ariyanto Harsono MD PhD SpA(K) 67
  68. 68. 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. Prof Ariyanto Harsono MD PhD SpA(K) 68
  69. 69. 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. Prof Ariyanto Harsono MD PhD SpA(K) 69
  70. 70. 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. Prof Ariyanto Harsono MD PhD SpA(K) 70
  71. 71. 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. Prof Ariyanto Harsono MD PhD SpA(K) 71
  72. 72. Thank you Prof Ariyanto Harsono MD PhD SpA(K) 72

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