Selective immunoglobulin M (SIgM) deficiency is a rare form of dysgammaglobulinemia characterized by an isolated low level of serum immunoglobulin M (IgM).[1] Reported IgM concentrations in SIgM deficiency vary from 40 mg/dL (though some sources say 20 mg/dL) to undetectable levels (reference range 45-150 mg/dL in adults).[2] Recent series report IgM levels of 29.7±8.7 mg/dL (mean±SD) for adults and 16.5±13.8 (mean±SD) in children.[3, 4] In this context, remember that 2.1% of "normal" individuals have values < 2 SD below the mean and that values in children must be compared with reference range values for age.[5] The levels of other immunoglobulin classes are within reference ranges.
SIgM deficiency may occur as a primary or secondary condition.[6] Secondary SIgM deficiency is much more common than primary SIgM deficiency and may be seen in association with malignancy, autoimmune disease, gastrointestinal disease, and immunosuppressive treatment.[1]
Some patients are asymptomatic, whereas others (often infants and small children) develop serious infections. Patients may develop prolonged or life-threatening infections caused by both encapsulated bacteria and viruses, especially in infancy. In older children and adults, SIgM deficiency is usually discovered during the investigation of other conditions, such as autoimmune disease or malignancy.[1]
Serum immunoglobulin levels are controlled by intricate immunological regulatory mechanisms, and heterogeneity is believed to exist in the pathogenesis of SIgM deficiency. Little is known about the pathological features of SIgM deficiency at a cellular level, given that the condition is so uncommon. Processes that control the survival of IgM in the circulation and may otherwise regulate its concentration in serum have not been well described; alterations in clearance mechanisms, in addition to altered production of IgM by lymphocytes, may contribute to selective deficiency of this immunoglobulin isotype.
The cause of SIgM deficiency is unknown. Increased regulatory T-cell activity specific for IgM has been described.[7] The absence of IgM in the presence of normal levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) has yet to be explained, as this appears to contradict the theory of sequential immunoglobulin gene rearrangement. Normal mature B cells are expected to have IgM and immunoglobulin D (IgD) on their surfaces, and, with proper stimulation, rearrange their immunoglobulin genes to switch from expressing IgM to IgG, IgA, or immunoglobulin E (IgE).
Having normal levels of IgG and IgA in the face of low IgM is thus counterintuitive. One could speculate that failure to regenerate B-cell precursors could lead first to depletion of IgM, with gradual loss of IgG and other isotypes occurring later as class-switched memory B-cells and plasma cells fail to be replaced. This hypothesis has not been tested, and few studies are available to determine whether only the serum IgM level is low or whether the number of B cells with surface IgM is also decreased in patients with selective IgM deficiency. Gradually, current state-of-the-art laboratory technology is being applied in studying patients with SIgM deficiency, though much remains to be learned.
The currently available literature suggests a heterogeneous population of patients of SIgM deficiency. Some patients are capable of normal antibody responses of other immunoglobulin classes following specific immunization, whereas others respond poorly. Certain patients with decreased helper T-cell activity have been described.[8] Cell-mediated immunity appears to be intact, but an insufficient number of detailed studies are available to confirm this. Suggested etiologies include rapid isotype switching of B cells from production of IgM to production of other isotypes and hypercatabolism of IgM.
United States
In a retrospective study of a large allergy practice (20,000 patients) database, Goldstein et al reported prevalences of SIgM deficiency of 0.26% among adults and 0.03% among children.[3, 4]
International
SIgM deficiency is rare, with an incidence of less than 0.03% in the general population and 1% in hospitalized patients.[9]
Since IgM may have a different range of specificities than placentally-transferred maternal IgG, infants can succumb to overwhelming infections such as meningitis, pneumonia, and gram-negative sepsis.
Patients with SIgM deficiency are susceptible to recurrent sepsis and overwhelming infection with encapsulated bacteria (eg, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae).[10, 11, 12] They may also have autoimmune disease including glomerulonephritis and osteomyelitis from which organisms are not recoverable,[13, 14, 15] as well as malignancies, chronic dermatitis, diarrhea, and upper respiratory infections.
The incidence of SIgM deficiency in various races has not been reported, given the low overall incidence.
The disorder occurs in both males and females, with no known discrepancies between the sexes.
Infants can present with severe and overwhelming infections. Older children may present with recurrent sinopulmonary infections secondary to encapsulated organisms and an increased incidence of gram-negative septicemia.
Patients may be asymptomatic, with a decreased IgM level noted during the investigation of other diseases, such as malignancies or autoimmune diseases.
Prolonged or life-threatening infections also occur, especially in infancy. Recurrent infections (eg, sinusitis and pneumonia) are often caused by encapsulated bacteria, and pneumococcal sepsis has been reported.[10] Infections with gram negative bacteria are also more common than in normal individuals, especially with Pseudomonas aeruginosa.
Associated disorders or symptoms may include atopic or chronic dermatitis, impetigo,[16] wheezing, and diarrhea. Patients may have a history of splenectomy.
Failure to thrive may be present, due at least in part to frequent infections. Other associated signs may include features of dermatitis, allergic rhinitis, wheezing, and splenomegaly, as well as those of other primary conditions associated with secondary SIgM deficiency, such as malignant or autoimmune disorders.
The cause of SIgM deficiency is unknown, and no clear pattern of inheritance has been suggested. The stability of the finding of selective deficiency of IgM, vs progression to deficiency of other immunoglobulin isotypes, has not been well characterized.
Patients with malignant neoplasms (eg, clear cell sarcoma, Bloom syndrome, promyelocytic leukemia), autoimmune diseases (eg, rheumatoid arthritis, Hashimoto thyroiditis, systemic lupus erythematosus, autoimmune hemolytic anemia), infections (eg, Brucella), or those given immunosuppressive agents may develop secondary SIgM deficiency.[17, 18]
Two case reports of epidermodysplasia verruciformis (caused by human papillomavirus) associated with SIgM deficiency are reported. One of these patients developed squamous cell carcinoma.[19, 20]
As cited by Zaka-ur-Rab, associations exist between SIgM deficiency and gastrointestinal conditions, including Crohn disease, chronic diarrhea, lymphoid nodular hyperplasia, Whipple disease, and splenomegaly.[21]
Infants with permanent congenital hypothyroidism were shown to have undetectable or lower concentrations of IgA and lower concentrations of IgM than normal controls.[22]
A report of 13 multiple myeloma patients in a phase 2 study showed that the 7 patients who received rituximab following autologous stem cell transplantation developed severely depressed levels of IgM that were persistent with continued rituximab therapy. When compared to the 6 myeloma patients who had received autologous stem cell transplantation without rituximab, not only were IgM levels significantly decreased, but those in the rituximab group experienced far more infections, including 21 cases of pneumonia, 2 cases of sepsis, and one death during the first 12 months.[23]
Three cases of 22q11.2 deletion syndrome associated with SIgM deficiency have been reported. The diagnoses were made at ages 9, 10, and 14 years. All 3 patients presented with recurrent otitis media, velopharyngeal insufficiency, speech delay, and learning disability, and 1 patient also had atrial septal defect/ventricular septal defect.[24, 25]
A 13-year-old African American boy with local lymph node involvement showed, after diagnosis and even 4 years after the chemotherapy, a low and decreasing level of both peripheral memory B cells and blood IgM-positive B lymphocytes. This case report highlights a possible association between SIgM deficiency and chronic CD30+ cutaneous lymphoproliferative disorder.[26]
Quantitative levels of IgM, IgG, IgA, and IgE, along with IgG subclasses, are measured. This is done to exclude more common immunodeficiency disorders, such as common variable immunodeficiency and IgA deficiency. Particularly in adults, serum immunoelectrophoresis should be done to rule out the possibility of a concomitant clonal B-cell disorder such as multiple myeloma or chronic lymphocytic leukemia.
The biological significance of a seemingly isolated low IgM level may be assessed by immunizing the patient with protein (eg, tetanus) and polysaccharide (eg, unconjugated Streptococcus pneumoniae) vaccines and assessing whether antigen-specific IgG responses are normal.
Imaging studies are not required routinely for SIgM deficiency. However, if patients report a history of recurrent sinopulmonary infection, CT scans of the sinuses and chest may be helpful for diagnosing chronic sinusitis and bronchiectasis, respectively.
Flow cytometry for B cells with surface IgM may be helpful.
Other tests are not required routinely for SIgM deficiency. However, other tests may be needed for further evaluation of associated diseases.
Diagnostic procedures are not routinely required for SIgM deficiency. They may be needed for diagnosis of infections, complications, or associated diseases.
Replacement of IgM is not an option, as IgM is not a significant component of therapeutic preparations of intravenous immunoglobulin. However, defective antigen-specific IgG responses have been demonstrated in some patients. For such patients, intravenous immunoglobulin (IVIG) replacement may be an option.[27]
Prophylactic and/or rigorous therapeutic antibiotic treatments may be beneficial.
Fresh frozen plasma may be considered for severe infections.[21]
In a patient who is asymptomatic and in whom a decreased IgM level has been noted incidentally, prophylactic antibiotics are not needed. However, the IgM level should be determined and specific antibody studies should be performed if recurrent infections develop.
Patients with SIgM deficiency should be under the care of a clinical immunologist, as a workup to exclude other immunodeficiencies is essential.
Consultation with an infectious disease specialist may also be helpful in a patient with recurrent infections.
Infections should be treated promptly with appropriate antibiotics, depending on the suspected pathogen. Empiric broad-spectrum therapy may be necessary before specific organisms are isolated. Some patients with selective IgM deficiency may also have increased susceptibility to fungal infections, so excessive use of broad spectrum antibiotics should be avoided, and anti-fungals should be added when appropriate.
Intravenous immunoglobulin is a therapeutic consideration for patients with SIgM deficiency who have demonstrated findings of defective antigen-specific IgG responses, particularly if they lack IgG against encapsulated bacteria and have chronic or recurrent sinopulmonary infection.[27]
Determination of quantitative immunoglobulins (IgM, IgG, IgA, IgE) and IgG subclasses should be performed at periodic intervals (ie, every 1-2 y).
Patients with severe life-threatening infections clearly have poor prognoses. Other patients who are asymptomatic may have excellent prognoses.