eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

X-linked Immunodeficiency With Hyper IgM

C Lucy Park, MD, Head, Division of Allergy, Immunology, and Pulmonology, Associate Professor, Department of Pediatrics, University of Illinois at Chicago

Updated: Feb 20, 2009

Introduction

Background

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) class-switching from immunoglobulin M (IgM) to immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE).

Thus, patients with XHIGM 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 XHIGM 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.

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 class-switch recombination (CSR). In 1974, a World Health Organization (WHO) working party named the syndrome immunoglobulin deficiency with increased IgM (hyper-IgM syndrome [HIGM]).¹ The most common form of HIGM is XHIGM (or HIGM1) and is inherited as an X-linked 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 (see Differentials).

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 antigen-independent.
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.

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 antigen-specific 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.

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 CD40 ligand on T cells, differentiation to plasma cells does not occur.

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

Neutropenia is also a common feature of XHIGM and may result from a defective, stress-induced, CD40-dependent granulopoiesis as myeloid progenitors express CD40 molecules.

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.  

Frequency

United States

In 2003, the US XHIGM registry reported that the minimal incidence rate of XHIGM was approximately 1 in 1,000,000 live births from 1984-1993.² This may be an underestimation because not all physicians in the United States participated in the registry.

International

Establishing reasonable estimates of XHIGM incidence has been difficult because most primary immunodeficiency disease registries combine data regarding XHIGM with data regarding genetic defects with resultant hyper-IgM. All forms of HIGM constitute 0.3-2.9% of all patients with primary immunodeficiencies in Europe, Asia, and South America. One registry in Spain reported that the incidence rate of all forms of HIGM is 1 per 20 million live births. XHIGM represents about 65-70% of all HIGMs.³

Mortality/Morbidity

A retrospective study of the Registry of the European Society for Immune Deficiency of 56 affected males showed a 20% survival rate in individuals aged 25 years.⁴ The US XHIGM Registry reported that 11 of 61 surviving patients were aged 20 years or older.²

The leading cause of death was pneumonia, encephalitis, or malignancy. Other patients died of liver failure secondary to sclerosing cholangitis and cirrhosis.

Major causes of morbidity include infection with bacteria, fungi, or viruses and opportunistic infections such as those involving Pneumocystis carinii. The respiratory (sinopulmonary) system, CNS, hepatobiliary system, and skin are commonly affected. Chronic diarrhea with or without infection has been frequently reported. Neutropenia, anemia, and thrombocytopenia are common. An increased risk of GI tract malignancies has been reported. Morbidity due to infection has markedly improved with the advent of intravenous immunoglobulin (IVIG) replacement therapy and better recognition of Pneumocystis jiroveci pneumonia and early initiation of Pneumocystis prophylaxis.

Race

Studies are inadequate to provide ethnic data regarding XHIGM incidence. The US XHIGM Registry reported the racial background of 75 patients.² Fifty two of the patients were white, 12 were black, 9 were Asian, 1 was both black and Asian, and 1 was white and Asian.

Sex

CD40 ligand deficiency affects males because it is an inherited in XR trait. Female carriers, even with extreme lyonization, have been immunocompetent and without clinical illness. Females with hypogammaglobulinemia and high IgM levels should be tested for gene mutations that affect other forms of HIGM.

Age

Most patients are diagnosed before age 4 years. Over one half of patients develop symptoms of immunodeficiency by age 1 year, and nearly all develop symptoms by age 4 years.

Clinical

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.² 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.

• 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.
• 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.
• 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.⁵ Cerebral toxoplasmosis was the very first presenting event in a middle aged man that lead to the diagnosis of XHIGM.
• 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. Some patients may need parenteral nutrition. 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.
• 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.
• Hepatocellular carcinoma and carcinoid tumor of the pancreas were reported. Lymphoma, neuroectodermal tumor of the colon, and gastroenteropancreatic neuroendocrine tumors have also been reported.
• Seronegative arthritis, degenerative encephalopathy, hypothyroidism, and autoimmune nephropathy have been reported in patients with XHIGM. In the European XHIGM Registry, generalized lymphadenopathy was reported in 7 of 56 patients. Osteopenia is a prominent and previously underappreciated feature of XHIGM.⁶ 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.

Physical

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.

Causes

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.

• 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.
• 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.⁷
• 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, CD40-dependent granulopoiesis as myeloid progenitors express CD40 molecules. Autoantibodies to neutrophils are generally absent.
• 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 antigen-driven responses to pathogenic invasion also depends on functional CD40 molecules.

Differential Diagnoses

Agammaglobulinemia
Bruton Agammaglobulinemia
Common Variable Immunodeficiency
Severe Combined Immunodeficiency
Transient Hypogammaglobulinemia of Infancy

Other Problems to Be Considered

Other forms of hyper-IgM syndrome (HIGM)

Since the first description of X-linked immunodeficiency with hyper–immunoglobulin M (XHIGM) in a patient with markedly reduced serum levels of other isotypes in 1961, numerous gene mutations that result in a similar clinical manifestation have been discovered.

The most common form is XHIGM (or HIGM1), which accounts for approximately 70% of all HIGMs and is inherited through an X-linked recessive (XR) trait.

Another XR form of the syndrome is associated with hypohidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) and is due to defects in the gene that encodes for nuclear factor (NF)-kB essential modulator (NEMO). Thus, this genetic deficiency is also referred to as NEMO syndrome. In addition, several autosomal recessive (AR) forms of HIGM have been reported, including activation-induced cytidine deaminase (AID) deficiency (HIGM2), defects in CD40 expressed on B cells (HIGM3), and uracil N glycosylase (UNG) deficiency (HIGM5). Some cases of HIGM syndrome with unknown genetic defects have been reported, including HIGM with class-switch recombination (CSR) defects and unclassified HIGM. A subtype of AID deficiency (AID with c-terminal deletions) is inherited through autosomal dominant trait.

All patients with HIGHM present with recurrent bacterial infections. Only CD40L defect (XHIGM) and CD40 defect are associated with significant T & B cell defect and are susceptible to opportunistic infections. Most HIGM cases due to intrinsic B-cell defects are not due to AID or UNG deficiency. The molecular basis of these cases has not been elucidated, but CSR defect was noted in either upstream or downstream from the DNA cleavage site. 

Table 1. Clinical and Immunologic Features of Hyper-IgM Syndromes⁸

Note.AID-Cter = Mutations in the c-terminal region of AID; AID-ΔC = AID c-terminal deletions; AD = Autosomal dominant; N = normal; EDA-ID = Hypohidrotic ectodermal dysplasia with immunodeficiency; SHM = Somatic hypermutation;UD = Undetected

Workup

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.² 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.
• 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).
• Functional antibody production that requires T-cell and B-cell 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.
• 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.
• 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.
• 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.
• 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.
• A physician consultation service is available through the Immune Deficiency Foundation.

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.

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.

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 carinii pneumonia (PCP) 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.

Histologic Findings

• Lymph node biopsy findings reveal a lack of germinal centers, attributed to ineffective CD40L-CD40 interaction in the extrafollicular areas, resulting in poor recruitment of germinal center precursors.

Treatment

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 carinii (PCP) 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.

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.

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 (see Table 2). 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.
• 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 (solvent-detergent 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.
• Adverse reactions to IVIG therapy include the following:
  • Nonanaphylactic reactions
    • 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.
    • 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.
    • 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.
    • 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.
  • Anaphylactic reactions
    • 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.
    • Exercise caution during IVIG administration in patients with no detectable IgA levels.
    • Prekallikrein activator has been associated with hypotension and circulatory collapse, and IgG aggregates may result in anaphylaxis via complement activation.
    • In patients with XHIGM, production of IgE antibodies against IgA is very rare due to a defect in class-switch recombination (CSR).
  • Transmission of infectious agents
    • 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.
    • 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.
    • 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.
    • 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.
  • Acute and chronic renal failure
    • 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.
    • 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.
    • 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.
  • 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.

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 (See Medication).
• 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.
• 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.
• 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.

P carinii prophylaxis

Patients with XHIGM also have a marked susceptibility to PCP. Initiating prophylactic treatment with trimethoprim-sulfamethoxazole as soon as the diagnosis of XHIGM is established is important.

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 G-CSF.

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.

Immunosuppressants

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

Bone marrow transplantation 

BMT may be considered in young patients without bronchiectasis or severe chronic infections who have a human leukocyte antigen (HLA)–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.

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.

Consultations

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

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.

Activity

Normal activity including regular exercise is recommended.

Medication

The mainstay of therapy for X-linked immunodeficiency with hyperimmunoglobulin M (XHIGM) is intravenous immunoglobulin (IVIG).

The overall consensus among clinical immunologists is that an IVIG dose of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels of more than 500 mg/dL is desirable. Patients with meningoencephalitis require much higher doses (1 g/kg) and, perhaps, intrathecal therapy. Measurement of preinfusion (trough) serum IgG levels every 3 months, until a steady state is achieved, and then every 6 months, if the patient is stable, may be helpful in adjusting the IVIG dose to achieve adequate serum levels.

All brands of IVIG are probably equivalent, although viral inactivation processes differ (eg, solvent detergent vs pasteurization and liquid vs lyophilized). The choice of brands may depend on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences. Recording all side effects that occur during the infusion is crucial. Monitoring liver and renal function test results periodically, approximately 3-4 times a year, is also recommended. The US Food and Drug Administration (FDA) recommends that, in patients at risk for renal failure, doses should not be exceeded and infusion rates and concentrations should be the minimum practicable levels.

The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatment is high, especially in patients with infections and in those who form immune complexes. With the new generation of IVIG products, adverse effects are greatly reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions include dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions.

Activation of complements by IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators is another cause.

Most adverse reactions are related to infusion rate. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg every 6-8 h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose, maximum 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe side effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products that use sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis suggest osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose/kg/min. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. 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. IgE antibodies to IgA have been reported to cause severe transfusion reactions in patients with IgA deficiency.

A few reports describe true anaphylaxis in patients with IgA-deficiency (<7 mg/dL) who have autoantibodies to IgA. IVIG preparations with very low concentrations of contaminating IgA are advised.

Other rare, serious adverse events include aseptic meningitis, thromboembolic events, immune hemolysis, and transfusion-related acute lung injury. These events are related to hyperosmolality, activated coagulation factor, high sodium content, or presence of anti-D antibody.

Potential for transmission of pathogens cannot be completely ruled out. In order to reduce potential contamination of pathogens, all manufactured plasma is tested at various levels and retested with 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 capreolate treatment. Viral removal is necessary to reduce the risk of nonenveloped virus transmission and includes precipitation, chromatography, and nanofiltration.

Because of the introduction of various viral inactivation and removal processes, relatively large viruses, such as HIV, and hepatitis B and C, are readily inactivated and can be effectively removed. 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 with the current manufacturing processes have been documented.

Table 2. Immune Globulin, Intravenous^9,10,11,12

Table 3. Subcutaneous Immune Globulin 

Immune globulin

These agents are used for replacement of functional antibodies in IgG isotype.

Immunoglobulin, intravenous

Neutralize circulating myelin antibodies through antiidiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG levels (10%).

Dosing

Adult

400-600 mg/kg/mo IV or a dose that maintains trough serum IgG levels >500 mg/dL

Pediatric

Administer as in adults

Interactions

Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)

Contraindications

Documented hypersensitivity; IgA deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before IVIG administration, use an IgA-depleted product if deficient (eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion)
Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory finding changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Immune globulin, subcutaneous (Vivaglobin)

IgG antibodies that neutralize a wide variety of bacterial and viral agents. Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade. Peak serum IgG levels are lower and trough IgG levels are higher than those achieved with IVIG. SC administration results in stable steady-state IgG levels when administered weekly. Available as a 160-mg/mL SC injectable.

Dosing

Adult

Do not exceed 15 mL (3200 mg) SC per injection site; administration rate not to exceed 20 mL/h per injection site
Previously on IVIG: Weekly SC dose (g/wk) = (previous IVIG dose X 1.37) divided by previous administration interval in wk; initiate 1 wk after last IVIG dose
Recommended weekly dose: 100-200 mg/kg/wk SC

Pediatric

<2 years: Not established
>2 years: Administer as in adults

Interactions

Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccination); patients with XHIGM should not receive live virus vaccine because of T-cell deficiency

Contraindications

Documented hypersensitivity; IV administration; selective IgA deficiency (serum IgA level <0.05 g/L) with known antibody against IgA

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include swelling, redness, and itching at injection site; for SC administration only; preferred SC administration sites include abdomen, thighs, upper arms, or lateral hip; initiate 1 wk after regularly scheduled IVIG infusion; does not contain preservative (discard unused portion); may cause fever, chills, nausea, or vomiting when switching from one immune globulin product to another or if > 8 wk since last administered; do not shake product

Antiprotozoal agents

These agents are used for treatment of cryptosporidiosis.

Nitazoxanide (Alinia)

Inhibits growth of Cryptosporidium parvum sporozoites and oocysts and G lamblia trophozoites. Elicits antiprotozoal activity by interfering with pyruvate-ferredoxin oxidoreductase (PFOR) enzyme–dependent electron transfer reaction, which is essential to anaerobic energy metabolism. Available as a 20-mg/mL oral susp or 500-mg tab.

Dosing

Adult

500 mg PO q12h with food

Pediatric

1-3 years: 100 mg (5 mL oral susp) q12h with food
4-11 years: 200 mg (10 mL oral susp) q12h with food
>12 years: Administer as in adults

Interactions

Tizoxanide (nitazoxanide metabolite) is >99.9% bound to plasma protein and may increase toxicity of other highly plasma protein–bound drugs; use caution when administering concurrently with other highly plasma protein–bound drugs (eg, warfarin) with narrow therapeutic indices, because competition for binding sites may occur; in vitro metabolism studies have demonstrated no significant inhibitory effect on cytochrome P450 enzymes

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Pharmacokinetics of nitazoxanide in patients with compromised renal or hepatic function have not been studied; may cause abdominal pain, diarrhea, vomiting, or headache; administer with food

Antibiotics

These agents are used for prophylaxis of PCP.

Trimethoprim and sulfamethoxazole (Septra, Bactrim)

Trimethoprim-sulfamethoxazole (TMP-SMX) is a fixed combination (1:5) of the 2 drugs and is usually bacteriostatic. The dosage ratios are set to produce a 20:1 ratio of SMX to TMP in blood and tissues, which gives maximal antibacterial activity. Both drugs block the folic acid metabolism cycle of bacteria and are much more active together than either agent alone. Sulfonamides are competitive inhibitors of the incorporation of p-aminobenzoic acid. TMP prevents reduction of dihydrofolate to tetrahydrofolate.

Dosing

Adult

Prophylaxis of Pneumocystis pneumonia : 160 mg TMP and 800 mg SMX (ie, 1 double-strength tab) PO 3 consecutive days/wk

Pediatric

Prophylaxis of Pneumocystis pneumonia:
<2 months: Contraindicated
>2 months: 150 mg/m²/d (based on TMP component) PO divided q12h on 3 consecutive d/wk; not to exceed 320 mg/d TMP; alternatively, 5 mg/kg/d PO divided q12h on 3 consecutive d/wk

Interactions

May increase the risk of toxicity of the following drugs when coadministered: digoxin, ACE inhibitors (increased hyperkalemia risk), chloral hydrate, class III antiarrhythmic agents (eg, amiodarone, flecainide, dofetilide, bretylium), or other agents that prolong QT interval (eg, amitriptyline, clarithromycin, erythromycin, fluconazole, octreotide); increase metformin plasma concentration; benzocaine or other ester-based anesthetic agents may antagonize the sulfa component
May increase PT when coadministered with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly persons; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine; coadministration may decrease cyclosporine effect and increase nephrotoxicity; leucovorin antagonizes effect

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency; G6PD-deficiency;
age <2 mo; near-term pregnancy; breastfeeding

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use during last trimester of pregnancy because of potential toxicity to newborn (eg, jaundice, hemolytic anemia, kernicterus)
Dosage adjustments (adult adjustments)
CrCl (mL/min) 80-50: Recommended IV dose q18h
CrCl 50-10: Recommended IV dose q24h
CrCl <10: Not recommended
HD: 4-5 mg/kg after HD
During peritoneal dialysis: 0.16-0.8 g q48h
Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if symptoms occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, patients with chronic alcoholism, elderly patients, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in individuals who are G-6-PD deficient; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Granulocyte-Colony Stimulating Factors (G-CSF)

These agents are used for treatment of neutropenia.

Filgrastim (Neupogen)

Recombinant human granulocyte colony-stimulating factor G-CSF. Regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation (including enhanced phagocytic ability), priming of the cellular metabolism associated with respiratory burst, antibody-dependent killing, and the increased expression of some functions associated with cell-surface antigens. G-CSF is not species specific and has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage. Daily administration has been shown to be safe and effective in causing a sustained increase in the neutrophil count and a decrease in infectious morbidity in children and adults with severe chronic neutropenia. Long-term daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patient's clinical course as well as ANC.

Dosing

Adult

Initial dose: 5 mcg/kg/d SC/IV; dose can be increased by 5 mcg/kg/d if no apparent response after 1-2 wk; obtain baseline CBC count and recheck twice weekly to guide therapy duration
Postmarketing surveillance study reported the following median daily doses:
Congenital neutropenia: 6 mcg/kg/d SC/IV; rare instances of doses >100 mcg/kg/d
Cyclic neutropenia: 2.1 mcg/kg/d SC/IV
Idiopathic neutropenia: 1.2 mcg/kg/d SC/IV

Pediatric

Not established

Interactions

Drugs which may potentiate the release of neutrophils (eg, lithium) should be used with caution

Contraindications

Known hypersensitivity to Escherichia coli– derived proteins, filgrastim, or any component of the product

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause immunogenicity; incidence of antibody development has not been adequately determined, data suggest that a small number of patients developed binding antibodies, although the nature and specificity of these antibodies has not been adequately studied; cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors; patients who develop hypersensitivity reactions may have allergic or hypersensitivity reactions to other Escherichia coli– derived proteins
May cause thrombocytopenia and anemia (regular monitoring of the hematocrit and platelet count is recommended)
Rare reports ( 1/7000 patients) of moderate-to-severe cutaneous vasculitis with long-term therapy, vasculitis symptoms generally developed simultaneously with an increase in the ANC and abated when the ANC decreased; patients may be able to continue treatment at a reduced dose

Follow-up

Further 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.

Further 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.

Inpatient & Outpatient Medications

• See Medical Care.

Transfer

• Patients should be transferred to a tertiary care medical facility where experienced clinical immunologists are available for close follow-up.

Deterrence/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, mumps-measles-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.

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.

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.

Patient Education

• Some US states have local chapters of Immune Deficiency Foundation. The Immune Deficiency Foundation
  25 W Chesapeake Ave, Suite 206
  Towson, MD 21204
  Consultation calls: 1-877-666-0866
• The Jeffrey Modell Foundation also provides educational support and raises funds for research. The Jeffrey Modell Foundation
  747 3rd Avenue
  New York, NY 10017
  Phone: 1-800-JEFF-844

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize that live virus vaccines such as mumps-measles-rubella (MMR) or varicella vaccines are strictly contraindicated because patients with X-linked immunodeficiency with hyper-IgM (XHIGM) may develop infection with vaccine-strain viruses
• Failure to start P carinii (PCP) prophylaxis
• Failure to recognize and properly treat concurrent autoimmune process or malignancy

Multimedia

Media file 1: This infant with X-linked immunodeficiency with hyper–immunoglobulin M (XHIM) developed severe diarrhea and hypoproteinemia and presented to a clinic with high fever. Blood culture grew Pseudomonas aeruginosa. Marked leukocytosis was present. The WBC count was 26,000/mL, with 67% neutrophils. Stool culture and examination findings were negative for cryptosporidia, Giardia species, bacteria, or viruses.

Media file 2: During the primary antibody response, B cells in the bone marrow produce immunoglobulin M (IgM) and immunoglobulin D (IgD) antibodies of low avidity. This process occurs largely 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 (switching from IgM to IgG, IgA, or IgE) and somatic hypermutation (introduction of point mutations in the V regions of the Ig genes, the antigen-biding sites, resulting in an expansion of the antibody repertoire to generate high-affinity antigen-specific antibodies). 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.

References

1. Cooper MD, Faulk WP, Fudenberg HH, et al. Meeting report of the Second International Workshop on Primary Immunodeficiency Disease in Man held in St. Petersburg, Florida, February, 1973. Clin Immunol Immunopathol. Apr 1974;2(3):416-45. [Medline].

2. Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). Nov 2003;82(6):373-84. [Medline].

3. Matamoros Flori N, Mila Llambi J, Espanol Boren T, et al. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. Jul 1997;17(4):333-9. [Medline].

4. Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. Jul 1997;131(1 Pt 1):47-54. [Medline].

5. Aschermann Z, Gomori E, Kovacs GG, et al. X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch Neurol. Feb 2007;64(2):273-6. [Medline].

6. Lopez-Granados E, Temmerman ST, Wu L, et al. Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis. Proc Natl Acad Sci U S A. Mar 20 2007;104(12):5056-61. [Medline].

7. Van Hoeyveld E, Zhang PX, De Boeck K, Fuleihan R, Bossuyt X. Hyper-immunoglobulin M syndrome caused by a mutation in the promotor for CD40L. Immunology. Apr 2007;120(4):497-501. [Medline].

8. Notarangelo LD, Lanzi G, Peron S, Durandy A. Defects of class-switch recombination. J Allergy Clin Immunol. Apr 2006;117(4):855-64. [Medline].

9. Garcia-Lloret M, McGhee S, Chatila TA. Immunoglobulin replacement therapy in children. Immunol Allergy Clin North Am. Nov 2008;28(4):833-49, ix. [Medline].

10. Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. Nov 2008;28(4):765-78, viii. [Medline].

11. Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. Aug 15 2005;62(16 Suppl 3):S5-11. [Medline].

12. Siegel J. The product: all intravenous immunoglobuins are not equivalent. Pharmacotherapy. 2005;25(11 Pt 2):78S-84S.

13. Cunningham CK, Bonville CA, Ochs HD, et al. Enteroviral meningoencephalitis as a complication of X-linked hyper IgM syndrome. J Pediatr. May 1999;134(5):584-8. [Medline].

14. Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med. Jul 13 2000;343(2):108-17. [Medline].

15. Durandy A, Peron S, Fischer A. Hyper-IgM syndromes. Curr Opin Rheumatol. Jul 2006;18(4):369-76. [Medline].

16. Durandy A, Schiff C, Bonnefoy JY, et al. Induction by anti-CD40 antibody or soluble CD40 ligand and cytokines of IgG, IgA and IgE production by B cells from patients with X-linked hyper IgM syndrome. Eur J Immunol. Sep 1993;23(9):2294-9. [Medline].

17. Durandy A, Taubenheim N, Peron S, Fischer A. Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies. Adv Immunol. 2007;94:275-306. [Medline].

18. Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. Aug 7 2001;135(3):165-74. [Medline]. [Full Text].

19. Etzioni A, Ochs HD. The hyper IgM syndrome--an evolving story. Pediatr Res. Oct 2004;56(4):519-25. [Medline]. [Full Text].

20. Herve M, Isnardi I, Ng YS, et al. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J Exp Med. Jul 9 2007;204(7):1583-93. [Medline].

21. Hollenbaugh D, Wu LH, Ochs HD, et al. The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIGM1. J Clin Invest. Aug 1994;94(2):616-22. [Medline]. [Full Text].

22. Lin Q, Rohrer J, Allen RC, et al. A single strand conformation polymorphism study of CD40 ligand. Efficient mutation analysis and carrier detection for X-linked hyper IgM syndrome. J Clin Invest. Jan 1 1996;97(1):196-201. [Medline]. [Full Text].

23. Ochs HD. Patients with abnormal IgM levels: assessment, clinical interpretation, and treatment. Ann Allergy Asthma Immunol. May 2008;100(5):509-11. [Medline].

24. Ochs HD, Winkelstein J. Disorders of the B-cell system. In: Immunologic Disorders in Infants and Children. 4^th ed. Philadelphia, PA: WB Saunders; 1996:311-4.

25. Ramesh N, Geha RS, Notarangelo LD. CD40 ligand and the hyper-IgM syndrome. In: Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford University Press; 1999:233-49.

26. Razanajaona D, van Kooten C, Lebecque S, et al. Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome. J Immunol. Aug 15 1996;157(4):1492-8. [Medline].

27. Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. Sep 1 2000;102(5):565-75. [Medline].

Keywords

X-linked immunodeficiency with hyperimmunoglobulin M, XHIGM, HIGM1, primary immunodeficiency disease, immunoglobulin deficiency with increased IgM, hyper-IgM syndrome, HIGM, hypohidrotic ectodermal dysplasia, humoral immunity, somatic hypermutation, SHM, CD40 ligand, CD40L, CD154, gp39, neutropenia, autoimmune disorders, pneumonia, encephalitis, Pneumocystis carinii, diarrhea, Pneumocystis jiroveci pneumonia, sinusitis, otitis, sepsis, hepatitis, sclerosing cholangitis, cellulites, subcutaneous abscesses, herpes stomatitis, oral candidiasis, parvovirus B19 infection

molluscum contagiosum, warts, Candida esophagitis, cytomegalovirus, CMV, adenovirus, species, herpesvirus type 1, respiratory syncytial virus, histoplasmosis, species, species, type b, Cryptosporidium species, rotavirus, , Yersinia enterocolitica, arthritis, hypothyroidism, osteopenia, rib fractures

Contributor Information and Disclosures

Author

C Lucy Park, MD, Head, Division of Allergy, Immunology, and Pulmonology, Associate Professor, Department of Pediatrics, University of Illinois at Chicago
C Lucy Park, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Medical Association, Chicago Medical Society, Clinical Immunology Society, and Illinois State Medical Society
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David J Valacer, MD, Consulting Staff, Hoffman La Roche Pharmaceuticals
David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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