Selective IgM deficiency

INTRODUCTION — Selective immunoglobulin M deficiency (sIgMD) is a rare immune disorder that has been reported in association with serious infections, such as bacteremia. The disorder can occur in infants, children, and adults. Cumulatively, there have been fewer than 300 cases reported in the literature, and understanding of this condition is therefore preliminary. This topic review discusses the normal immunophysiology of immunoglobulin M (IgM), theories of pathogenesis, and the clinical features, diagnosis, and treatment of sIgMD. More general discussions of antibody deficiency are found separately. (See "Primary humoral immunodeficiencies: An overview".)

DEFINITION — sIgMD is characterized by the following clinical and laboratory features:

●Isolated absence or deficiency of IgM

●No other identifiable immunodeficiency or external cause of low serum IgM

●Normal levels of immunoglobulin G (IgG) and immunoglobulin A (IgA)

●Recurrent infections in the majority of patients, with susceptibility to Staphylococcus aureus, encapsulated pathogens (Streptococcus pneumoniae, Haemophilus influenzae), and viral infections  

●Normal T cell numbers and function in most patients, although occasional variations are reported

The European Society for Immunodeficiencies (ESID) registry has defined primary sIgMD as a decreased serum IgM level (repeatedly ≥2 standard deviations [SD] below the mean for age) with normal levels of serum IgA, IgG and IgG subclasses, normal vaccination responses, absence of T cell defects, and absence of causative external factors. However, aspects of this definition are unclear [1]. Specifically, consensus is lacking about whether IgG subclasses and vaccination responses must be normal to make the diagnosis, and if the presence of any defect in T cell number or function excludes the diagnosis.

NORMAL IMMUNOPHYSIOLOGY OF IgM — The five classes or isotypes of immunoglobulins that contribute to humoral immunity are IgG, IgM, IgA, immunoglobulin D (IgD), and immunoglobulin E (IgE). (See "Structure of immunoglobulins".)

Naïve B lymphocytes express both IgM and IgD, and these are the only immunoglobulin isotypes produced by B lymphocytes prior to contact with antigen. Membrane-bound monomeric IgM, complexed with additional proteins, such as Ig-alpha and Ig-beta, constitute the B cell receptor for antigen. Naïve B lymphocytes use alternative messenger RNA splicing to make both IgM and IgD. The mu and delta constant region (C) genes, which code for the M and D heavy chains, respectively, are those nearest to the assembled VDJ sequence (figure 1).

Following binding of antigen by the B lymphocyte receptor, signaling occurs through immunoreceptor tyrosine-based activation motifs, leading to activation of intracellular pathways, which ultimately culminate in changes in B lymphocyte gene expression. In the presence of appropriate activation (costimulators, cytokines, etc), B lymphocytes rearrange their immunoglobulin heavy chain constant genes to switch from IgM to IgG, IgA, or IgE (figure 2) [2,3]. Immunoglobulin gene rearrangement is presented in more detail separately. (See "Immunoglobulin genetics".)

Secreted IgM exists as a pentamer and has a half-life of about 10 days (figure 3). Because of its pentameric structure, IgM is referred to as "macroglobulin." Pentameric IgM, which has 10 antigen-binding sites, readily forms antigen-antibody complexes and has high avidity, despite the fact that each individual binding site has relatively low affinity for antigen. Because of this, IgM is an exceptionally potent activator of the classical complement pathway. IgM does not activate the alternative pathway of complement, nor does it undergo transplacental transfer. The majority of IgM is intravascular in location, and accordingly, sIgMD is often associated with systemic infections and bacteremia.

The majority of natural antibodies (ie, immunoglobulins that react with multiple endogenous or exogenous antigens without prior antigenic stimulation) and autoantibodies are of the IgM class. Natural antibodies are polyspecific and of low affinity and appear to play an important role in removal of self-antigens and clearing of dead cells (housekeeping), homeostasis, and protection against microbes (especially microbes with polysaccharide components) [4-6]. IgM may regulate the selection of B lymphocyte subsets [7]. (See "An overview of the innate immune system", section on 'Homeostasis in the innate immune system'.)

IgM is the first antibody to be produced during an immune response, and most of the primary humoral immune response is mediated by IgM. The IgM response wanes as other subtypes are produced. Examples of specific disorders in which IgM responses are used in diagnosis include isohemagglutinins (which are mostly IgM but also IgG), cold agglutinins, rheumatoid factor, and the heterophile antibody [8].

EPIDEMIOLOGY — The normal concentration of IgM in the serum of adults is approximately 37 to 286 mg/dL [9]. By definition, this range includes 95 percent of the population, and 2.5 percent will fall below that range. However, some of these individuals will have low levels of other immunoglobulins, in addition to IgM. Estimates of the prevalence of isolated low serum IgM levels depend upon the population examined:

●Isolated low levels of IgM in the general population were identified in one person in a study of approximately 3000 individuals [10].

●In a series of hospitalized patients, prevalence ranged from 0.1 to 2 percent [11,12].

●In a study of approximately 14,000 adults being treated in an allergy and immunology practice, 36 individuals were identified, for a prevalence of approximately 1:385 in this selected population [13].

The European Society for Immunodeficiencies (ESID) reported on a multicenter study of sIgMD, in which 15 centers identified 98 patients [14]. Patients were excluded under three circumstances: if serum IgM was only determined once (n = 14), had normalized (n = 8), or if they also had other immunological abnormalities (n = 15). Only 10 patients completely fulfilled the ESID criteria for sIgMD and further, using the ESID diagnostic protocol reference values, only six patients were determined to have "true" sIgMD. Symptomatic adults had lower serum IgM levels (mean 0.27 g/L, 95% CI 0.22-0.31) than those without symptoms (mean 0.33 g/L, 95% CI 0.30-0.36).

There have been a small number of familial cases of sIgMD reported [15-18].

CLINICAL FEATURES — Patients with sIgMD may by asymptomatic or they may present with repeated infections or with an associated allergic, malignant, or autoimmune condition [16,19-23]. Clinical presentations of symptomatic IgM deficiency that have been reported in the published literature are summarized in the table (table 1):

●In one study of 89 hospitalized patients, associated conditions included infections (60 percent), septicemia (36 percent), atopy (22 percent), splenomegaly (11 percent), neoplasia (7 percent), and autoimmunity (3 percent) [12].

●In the series of 36 adult patients evaluated in an allergy/immunology clinic, patients presented with recurrent upper respiratory tract infections (77 percent), allergic and nonallergic rhinitis (49 percent), asthma (47 percent), angioedema (14 percent), and anaphylaxis (11 percent) [13].

●In a series of 33 children presenting to immunology clinics, 24 percent were asymptomatic and 45 percent had upper and lower respiratory tract and skin infections [19]. Autoimmune disorders were present in 18 percent, 15 percent had allergic disorders and 15 percent developed malignancies. 

Repeated infections — Based on the available studies, between 60 and 80 percent of patients with sIgMD suffer from repeated infections with both bacterial and viral pathogens. More common presentations include recurrent otitis media, bronchitis, chronic rhinosinusitis, pneumonia, and sepsis (table 2) [13,23-25]. Failure to thrive, stunted growth, and malnutrition may be observed in severely affected children with persistent infection. There have been case reports of meningococcal septicemia, pseudomonas nasopharyngitis, recurrent staphylococcal skin infections or pyoderma, recurrent hordeola, bronchiectasis, Brucella infection, and polyarticular septic arthritis [13,15,16,26-31].

Viral infections reported in patients with sIgMD include occupationally acquired smallpox, generalized nonprogressive vaccinia, disseminated molluscum contagiosum, and epidermodysplasia verruciformis [32-36]. Case reports suggest that some patients with sIgMD might also be susceptible to histoplasmosis and disseminated cutaneous (avium intracellulare) or systemic (miliary tuberculosis) mycobacterial infection, although in one of the reports, an associated T cell defect was also present [37-39].

Associated conditions — Subnormal levels of IgM may be identified in the context of another disease process (table 2). In this setting, IgM deficiency is usually less profound and may reverse with improvement of underlying disease, although this is not noted in all reports.

Malignant and hematologic disorders — Malignancies and hematologic diseases that have been reported in association with IgM deficiency include multiple myeloma and paraproteinemias, clear cell sarcoma, Bloom syndrome, lymphomatoid papulosis, immune thrombocytopenia (ITP), and lymphocytic leukemias [28,40-46]. One patient had acquired C1 inhibitor deficiency and later developed a B cell lymphoma [26]. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)

sIgMD associated with elevated levels of serum IgA and IgG were described in one patient with hepatocellular carcinoma and autoimmune liver disease with resultant cirrhosis [47]. The relationship of IgM deficiency to hepatic malignancy is unclear.

Many immunodeficiency disorders demonstrate an increased prevalence of malignancy. This may result from dysregulation of immune surveillance, infection with transforming viruses, or other poorly defined mechanisms.

Autoimmune disorders — Rheumatologic and autoimmune disorders are reported in association with sIgMD, although the cause and effect relationship is unclear [26]. It is also unknown whether sIgMD includes deficiency of natural antibodies/autoantibodies, which could predispose to pathologic autoantibody formation [4,5]. (See 'Normal immunophysiology of IgM' above.)

Associated disorders include systemic lupus erythematosus [25,48-50], Hashimoto's thyroiditis [51], ITP [28], autoimmune glomerulonephritis [52], autoimmune hepatitis [53], and adult-onset Still's disease [54]. In one review of the literature, 14 percent of individuals with sIgMD originally presented with autoimmune diseases [13]. In the series of 36 patients with sIgMD followed in an outpatient allergy/immunology clinic, 13 percent had low titers of antinuclear antibodies of uncertain clinical significance [13]. Whether this predicts the future development of autoimmune disorders is unknown.

Atopy — It is likely that an increased incidence of atopy occurs in these individuals, as has been described with IgA deficiency. Allergic rhinitis, asthma, and eczema may be presenting disorders in some patients [13,23]. Allergic disease may also represent the effects of immune dysregulation.

A high prevalence of idiopathic anaphylaxis and idiopathic angioedema was noted in the series of 36 outpatients gathered from an allergy/immunology practice [13]. This is a newly proposed association that has not been observed in earlier reported cases.

Miscellaneous conditions — Other conditions that have been described in association with sIgMD include Crohn disease, adult-onset Still's disease, gastroesophageal reflux disease, interstitial lung disease, massive splenomegaly, inflammatory multifocal osteomyelitis, and inability to train in athletes [13,54-59].

IgM deficiency may also be found in celiac disease, although it may be secondary to intestinal malabsorption in this setting, as IgM levels sometimes rise with a gluten-free diet [13,60-64].

PATHOGENESIS — Isolated IgM deficiency has been associated with serious bacterial infection and the other complications listed earlier, although it is unlikely that low or absent serum IgM, by itself, leads to increased susceptibility to infection. Rather, sIgMD is probably a manifestation of immune dysregulation, and the associated immunologic dysfunction (such as poor antibody response or other defects described below) is what results in increased infections.

The pathogenesis of sIgMD is unclear, although several mechanisms have been proposed, including B cell defects, disordered T cell help, and possibly, chromosomal defects. There are likely multiple mechanisms that can result in isolated low serum IgM:

●B lymphocyte defects – Studies have consistently found that surface levels of IgM on circulating B lymphocytes are normal in patients with sIgMD [11,65,66]. Single studies have shown normal production of messenger RNA for IgM and a lack of mutations in the mu heavy chain gene [50,67], although possible defects in IgM production by B cells were identified in other studies [50,66]. Another study showed lower numbers of nonswitched (IgM+CD27+IgD+) memory B cells in patients with sIgMD, suggesting that maturation defects of B lymphocytes might play a role in some individuals [68].

●T lymphocyte dysfunction – Although no well-defined T cell abnormalities have been consistently identified, inadequate T cell help, excessive T cell suppressive activity, abnormal CD4/CD8 ratios, and inhibitory factors have all been demonstrated in some patients with sIgMD [11,30,65,69,70].

●Chromosomal disorders – In a small number of case reports, sIgMD has been identified in patients with chromosome 22q11.2 deletion syndrome, although chromosome 22q11.2 deletions are relatively common, occurring in approximately 1 in 4000 to 6000 live births [71,72]. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis".)

EVALUATION AND DIAGNOSIS — sIgMD is usually identified when evaluating a patient for recurrent or serious infections. It is a diagnosis of exclusion, and formal diagnostic criteria have not been established. The minimal diagnostic evaluation required for the diagnosis includes the demonstration of an isolated deficiency of serum IgM and no other classifiable immunodeficiency or secondary cause of low IgM. Characteristic laboratory findings are described in the table and discussed in this section (table 3). The clinical history should be explored for the presence of associated conditions, as these may ultimately explain the low levels of IgM. (See 'Associated conditions' above.)

Initial immunologic testing — Any individual with recurrent infections, especially those with sepsis or other serious sequelae of infection, should be evaluated for immunodeficiency. Initial tests to evaluate for immunodeficiency include:

●Complete blood count with differential to look for abnormally high or low cell populations and low platelets (see 'Malignant and hematologic disorders' above)

●Quantitative serum immunoglobulin levels (IgG, IgM, IgA, and IgE)

●A measure of total hemolytic complement (CH50) to screen for complement deficiency

●Testing for HIV if the patient has any risk factors

●Flow cytometric lymphocyte analysis to quantitate B cells, T cells, and natural killer cells

●Antinuclear antibodies as an initial screen for autoimmunity in patients with concerning symptoms, with the recognition that a negative test does not exclude the possibility of autoimmune disease (see "Measurement and clinical significance of antinuclear antibodies")

●Imaging studies to rule out asplenia (see "Splenomegaly and other splenic disorders in adults", section on 'Asplenia or hyposplenia' and "Splenomegaly and other splenic disorders in adults", section on 'Imaging and biopsy')

The above studies are normal or only mildly abnormal in patients with sIgMD, as shown in the table (table 3). Note that consensus is lacking about the importance of certain laboratory features (ie, vaccine response, T cell numbers and function, and IgG subclasses). (See 'Definition' above.)

Low or absent serum IgM levels — The normal serum concentration of IgM for patients >18 years of age is between 37 and 286 mg/dL [9]. Although there are no strict numeric cutoff values for defining IgM deficiency, a level of IgM less than 2 standard deviations from the mean or less than 10 percent from the mean for age, is generally accepted as deficient [21]. Thus, IgM levels less than 10 to 15 mg/dL in infants and children and less than 20 to 30 mg/dL in adults are compatible with IgM deficiency. Immunoglobulin levels should be measured on a least two separate occasions.

Lymphocyte analysis — Numbers of circulating B cells are normal in sIgMD, but an increase of CD21^low and of IgM memory B cells has been reported [73]. T cell numbers are usually normal, although the count of CD4+ T cells may be low and that of CD8+ cells may be high. For some complicated patients, referral to a specialty center for further study of B lymphocyte biology and function may be indicated (table 4). Flow cytometry to assess lymphocyte subsets is reviewed separately. (See "Laboratory evaluation of the immune system", section on 'Flow cytometry for cell populations'.)

Vaccine response — Specific antibody responses are variable in sIgMD, although they should be assessed to exclude other immunodeficiency disorders and to determine if the patient is a candidate for prophylactic treatment to prevent infections (see 'Measures to prevent infections' below) Note that vaccine response is one of the features of sIgMD about which consensus is lacking, with some groups stipulating that it should be normal, but other experts disagreeing. (See 'Definition' above.)

●Titers for protective IgG against tetanus and diphtheria can be measured to assess response to protein antigens in vaccinated individuals.

●Titers for the serotype-specific IgG to the carbohydrate antigens in the polysaccharide pneumococcal vaccine (usually a commercially available panel of 14 to 23 serotypes) can be measured in children and adults over the age of two years.

If titers are low to either tetanus/diphtheria or to pneumococcus and the patient was not vaccinated within the past three to five years, then a dose of an age-appropriate vaccine should be given and titers repeated one month later. The interpretation of a patient's immune response to vaccination is reviewed separately. (See "Assessing antibody function as part of an immunologic evaluation".)

Vaccine responses to protein and polysaccharide antigens have not been systematically studied in patients with sIgMD. Case reports and small series suggest that they may be normal or impaired [24,74]. Depressed IgG responses to diphtheria-tetanus were reported in two of six patients with sIgMD in one series, despite normal levels of total IgG [63]. Impaired responses to pneumococcal polysaccharide vaccine were reported in five of eight patients in another series [26].

Evaluation of infections — For patients presenting with acute infections during the diagnostic evaluation, attempts should be made to document the infection, as well as the responsible organism, whenever possible. This may involve radiologic evaluation for rhinosinusitis and pneumonia, lumbar puncture for meningitis, serologies, and tissue/secretion cultures, as indicated by the clinical presentation.

Further laboratory evaluation — Once an isolated deficiency of serum IgM has been identified, further evaluation may be considered, although these studies are not needed for the diagnosis (table 4). Rather, they are included here to relay what is known about this disorder. Not all of the studies discussed below are readily available, and some are only performed at speciality centers or research laboratories.

Other antibody studies — IgG subclasses may be measured for the purpose of fully assessing the patient's immune system, although the clinical significance of a concomitant IgG subclass deficiency is unclear, as management of IgG subclass deficiency and sIgMD are similar. (See "IgG subclasses: Physical properties, genetics, and biologic functions" and "Overview and clinical assessment of the complement system".)

●Isohemagglutinins, which are comprised of both IgM and IgG, have been variably reported in patients with sIgMD [13,63]. The largest available series reported isohemagglutinins in 33 patients and found a mean titer of anti-A of 1:50±92 and a mean titer of anti-B of 1:12±13 (normal controls were ≥1:64 for both) [13].

●Vaccination with neoantigens may be helpful in uncommon instances where pneumococcal vaccination is either contraindicated (such as an earlier adverse reaction) or ineffective. Neoantigens are only available in some research laboratories.

Additional lymphocyte testing — Immunophenotyping of B cells and in vitro stimulation studies of B and T lymphocytes are commercially available and also performed by specialty centers (table 4). B lymphocytes display normal levels of surface IgM, although this measurement is not commercially available.

Evaluation for associated conditions — Patients with sIgMD should be evaluated for the conditions that have been reported in association with it, if indicated by a careful history and physical examination. In some cases (although not all), the IgM deficiency may be secondary to the other condition and may improve as the primary condition is treated (table 1).

DIFFERENTIAL DIAGNOSIS

Other immunodeficiencies — Subnormal serum levels of IgM (although not isolated IgM deficiency) may be seen in other immunodeficiency disorders, including:

●Common variable immunodeficiency (in association with low IgG levels and impaired vaccine response ± low IgA). (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

●Other antibody deficiency syndromes, although other isotypes should be affected as well. (See "Primary humoral immunodeficiencies: An overview".)

●Wiskott-Aldrich syndrome (characterized by eczema, thrombocytopenia, and an associated elevation of IgA and IgE). (See "Wiskott-Aldrich syndrome".)

Similarly, SCID syndromes, which are associated with both cellular and humoral defects, may also demonstrate IgM hypogammaglobulinemia [75]. In all of these conditions, IgM deficiency is accompanied by either abnormal levels of other immunoglobulin classes or by reduced T cell numbers. (See "Combined immunodeficiencies: An overview" and "Severe combined immunodeficiency (SCID): An overview".)

Drug-induced hypogammaglobulinemia — Subnormal immunoglobulin levels have been reported with medications, such as antiepileptic medications, gold, and d-penicillamine, although IgA deficiency or deficiency of multiple immunoglobulin classes is more typical. Clozapine use to treat schizophrenia was associated in one study with a higher than expected, statistically significant occurrence of sIgMD [76]. Causality remains to be determined. (See "Primary humoral immunodeficiencies: An overview", section on 'Differential diagnosis'.)

TREATMENT AND MONITORING — Patients with sIgMD and recurrent infections are managed similarly to individuals with other humoral immune defects, although there are no studies to evaluate the effectiveness of these interventions specifically in patients with sIgMD. Our approach to management is described here.

Patient education — We explain to patients that information about sIgMD is limited and that although some patients appear to have no specific problems related to the lack of IgM, others are at increased risk for serious infections. We advise patients to seek medical care promptly for fevers or infections that seem to be worsening. We provide them with a letter signed by the evaluating clinician, which states that the patient has sIgMD, a disorder that is sometimes associated with serious infections, such as bacteremia and sepsis. We do this to encourage a thorough evaluation in urgent care and emergency department settings and to increase the likelihood that providers will err on the side of caution when treating these individuals. We counsel patients in this manner, even if they are asymptomatic.

Prompt evaluation and treatment of infections — If infection is suspected, we evaluate patients promptly, obtain cultures when possible, and have a low threshold for initiating antimicrobials. We follow these individuals closely to assure the infections are fully cleared before terminating treatment. Patients with immunodeficiencies are less likely to clear minor infections without antimicrobials and more likely to require prolonged courses of treatment to eradicate established infections. We provide patients with an informational handout about seeking prompt evaluation for infections (table 5).

Measures to prevent infections — Measures to prevent recurrent infections include vaccinations, aggressive management of allergic respiratory disease, and in some cases, prophylactic antibiotics or immune globulin therapy.

●Patients who respond immunologically to vaccination, even if the response is partial, should be fully vaccinated. We administer pneumococcal polysaccharide vaccine during the immune evaluation and administer meningococcal vaccine subsequently if there is adequate polysaccharide responsiveness. (See "Meningococcal vaccination in children and adults", section on 'Indications and schedules in the United States'.)

●Aggressive management of atopic diseases, such as asthma and allergic rhinitis, may be helpful in reducing the incidence of complicating sinopulmonary infections. (See "An overview of asthma management" and "Pharmacotherapy of allergic rhinitis".)

●Prophylactic antibiotics can be administered to those patients who continue to have frequent infections despite the above measures. Specific regimens are discussed separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'.)

●Immune globulin contains very little IgM and hence is not advocated as a standard treatment for sIgMD. However, the propensity of patients with sIgMD to get infections is likely not simply related to low serum IgM. Accordingly, one report described five patients with frequent infections, despite preventative measures, who were treated with intravenous immune globulin and had an excellent clinical response [26]. Other case series also support benefit [77]. Consultation with an immunologist is advised. (See "Immune globulin therapy in inborn errors of immunity".)

Monitoring — We monitor patients for changes in clinical status. New signs or symptoms should be evaluated for evidence of associated conditions. Periodic measurements of IgM, IgG, and IgA may be performed.

PROGNOSIS — In some infants, sIgMD may be transient [78]. In a series of 48 children, 16 were followed for a mean duration of four years, and 87 percent continued to have low levels of IgM, while two also developed low IgA [23]. Beyond this, there is insufficient information to allow generalizations about the prognosis of patients with sIgMD, as the numbers of patients are small, and prospective studies are lacking.

RESOURCES FOR PATIENTS — General information for patients with immunodeficiency disorders is available from several sources:

●Immune Deficiency Foundation

●International Patient Organisation for Primary Immunodeficiencies

●National Institutes of Health

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●Definition – Selective immunoglobulin M deficiency (sIgMD) is a rare immune disorder that has been reported in association with bacteremia and other serious infections. There have been fewer than 200 to 300 cases reported. (See 'Definition' above.)

●Clinical manifestations – Patients with immunoglobulin M (IgM) deficiency may be asymptomatic, have repeated infections, and/or present with associated conditions, such as atopic diseases, autoimmune disorders, or malignant and hematologic disorders (table 1). (See 'Clinical features' above.)

●Reduced serum IgM levels – IgM deficiency is defined in terms of standard deviations from a population mean, which correlates to levels less than 10 to 15 mg/dL in infants and children and less than 20 to 30 mg/dL in adults. It is essential to measure the IgM level at least twice to confirm the deficiency. (See 'Low or absent serum IgM levels' above.)

●Diagnosis – sIgMD is characterized by deficiency of serum IgM, in association with infection and with normal levels of other immunoglobulin isotypes. Other aspects of the diagnosis, such as vaccine response and T cell findings, are controversial. sIgMD is a diagnosis of exclusion, and other immunologic disorders should be excluded. (See 'Evaluation and diagnosis' above and 'Differential diagnosis' above.)

●Management – Patients with sIgMD and recurrent infections are managed similarly to individuals with other antibody defects and deficiencies, although there are no studies to evaluate the effectiveness of these interventions specifically in patients with sIgMD. (See 'Treatment and monitoring' above.)

•For patients who are shown to be either partially or fully vaccine responsive during immune evaluation, we suggest vaccination with pneumococcal and meningococcal vaccines to provide protection against these organisms (Grade 2C).

•We suggest administration of prophylactic antibiotics to patients who continue to experience recurrent infections (Grade 2C).

•For patients with impaired vaccine response and severe or refractory recurrent infections despite antibiotic prophylaxis, we suggest immune globulin replacement therapy, but this should be guided by consultation with an immunologist (Grade 2C).

●Prognosis – Information on prognosis is limited. sIgMD may be transient in infants, but, in older children, it appears to be persistent in most. Information on adults is even more limited. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.