Immunoglobulin M deficiency
Synonyms and keywords:IgM deficiency

# Overview
Immunoglobulin M deficiency is said to be present when the levels of IgM in serum are <40mg/dl while the levels of all other immunoglobulins are within normal range. IgM deficiency was first noted in 1969 by Roy- Chawdhary from a jejunal biopsy. It is of 2 types primary and secondary IgM deficiency. IgM deficiency can occur due to a defect in B cells or T cells. IgM deficiency can lead to chronic infections, development of autoimmune disease and neoplastic diseases. IgM deficiency cab be caused in autoimmune conditions and it can itself lead to the development of autoimmune conditions. IgM deficiency can be differentiated from other immunoglobuiln deficiencies by measuring the levels of all the immunoglobulins.The incidence/prevalence of IgM deficiency is approximately 100-2000 per 100,000 individuals worldwide. The patients usually present with chronic or recurrent infections. Signs and symptoms of chronic lung disease, chronic ear and chronic sinus infections may be present.

# Historical Perspective
- IgM was discovered by Waldenstrom, Pedersen and kunkel in 1944 by immunoelectrophoresis and ultracentrifugation.
- IgM deficiency was first noted in 1969 by Roy- Chawdhary from a jejunal biopsy.

# Classification
There is no established system for the classification of IgM deficiency.However, it may present as 2 types:
- Primary IgM deficiency-
There occurs just IgM deficiency and no other associated condition.
It is present in children as a congenital condition.
- There occurs just IgM deficiency and no other associated condition.
- It is present in children as a congenital condition.
- Secondary IgM deficiency-
Along with IgM deficiency there occurs autoimmune disorders or some neoplasms.
It occurs in adults and is acquired.
- Along with IgM deficiency there occurs autoimmune disorders or some neoplasms.
- It occurs in adults and is acquired.

# Pathophysiology
- IgM is the first antibody that is present on the surface of B lymphocytes when they come in contact with an antigen.
- It is the primary antibody against A and B antigens on red blood cells.
- Other immunoglublins such as IgG, IgA and IgE are produced after alteration in the structure of IgM heavy chains on the B lymphocytes.
- IgM is present in the circulation as a pentamer structure. and is the largest antibody in human circulatory system.
- Presence of IgM antibodies in a patient's serum indicates recent infection, or in a neonate's serum indicates intrauterine infection (e.g. congenital rubella).
- IgM activates the classic pathway of complement system.
- In IgM deficiency there occurs deficiency of IgM but normal levels of IgG and IgA.
- The level of IgM in serum is less than 40mg/dl (normal value 45-150mg/dl).
- The defeciency in IgM could be due to:
B cell defect- inability of B cell differentiation into IgM secreting cells.
T cell defect- decreased helper T cell activity for IgM.
- B cell defect- inability of B cell differentiation into IgM secreting cells.
- T cell defect- decreased helper T cell activity for IgM.
- This results in decreased sysnthesis of IgM in the body.
- It can be primary or secondary.
- The primary IgM deficiency presents with chronic infections while secondary presents with associated autoimmune conditions or neoplasms.
- Due to absence of IgM, infections like otitis media, chronic sinusitis, bronchitis, bronchiectasis, pneumonia, urinary tract infections, cellulitis, meningitis, sepsis, etc. are very common.
- Most common infections are staphylococcus aureus, streptococcus pneumonia and haemophilus influenza.
- IgM deficiency increases the risk of acquiring autoimmune and some malignant conditions.
Autoimmune glomerulonephritis
Autoimmune hemolytic anemia
Autoimmune thrombocytopenia
Celiac disease
Crohns disease
Hashimoto's thyroiditis
Rheumatoid arthritis
Sarcoma
Lymphoma
Myasthenia gravis
Plasmacytoma
- Autoimmune glomerulonephritis
- Autoimmune hemolytic anemia
- Autoimmune thrombocytopenia
- Celiac disease
- Crohns disease
- Hashimoto's thyroiditis
- Rheumatoid arthritis
- Sarcoma
- Lymphoma
- Myasthenia gravis
- Plasmacytoma

# Causes
The exact cause of IgM deficiency is not known.
- Primary IgM deficiency ouccrs in children and is congenital.
- Secondary IgM deficiency occurs in adults and is associated with autoimmune disorders and neoplasms.
- There is no identified cause but risk factors which are:
Clear cell carcinoma
Bloom syndrome
Promyelocytic leukemia
Brucella
Crohn's disease
Chronic diarrhea
Whipple disease
Infants with hypothyroidism
Multiple myeloma
Chromosome 22q.11.2 deletion
- Clear cell carcinoma
- Bloom syndrome
- Promyelocytic leukemia
- Brucella
- Crohn's disease
- Chronic diarrhea
- Whipple disease
- Infants with hypothyroidism
- Multiple myeloma
- Chromosome 22q.11.2 deletion

# Differentiating IgM deficiency from Other Diseases
- IgM deficiency can be differentiated from other diseases of the same kind by measuring the value of other immunoglobulins.
- In IgM deficiency only IgM levels are deficIent while the rest are within normal limits.

# Epidemiology and Demographics
- The incidence of IgM deficiency is approximately 100-2000 per 100,000 individuals worldwide.
- Primary IgM defiicency is present congenitally in children which presents in age group 3-36 months.
- Secondary IgM deficiency occurs in adults in age group 30-40, no relation with sex or age.
- Complications such as development of autoimmune disease and neoplastic conditions occur in adult age group.

# Risk Factors
There are no established risk factors for IgM deficiency but it occurs more commonly in:
- Clear cell carcinoma
- Bloom syndrome
- Promyelocytic leukemia
- Brucella
- Crohn's disease
- Chronic diarrhea
- Whipple disease
- Infants with hypothyroidism
- Multiple myeloma
- Chromosome 22q.11.2 deletion

# Screening
- There is insufficient data to recommend screening for IgM deficiency.
- However, in patients presenting with recurrent infections, all immunologlobulins (IgM, IgG, IgA, IgE and IgD) can be measured.

# Natural History, Complications, and Prognosis
- The patient may be asysmptomatic or present with signs of chronic infections.
- Children born with IgM deficiency as in primary IgM deficiency present with chronic infections such as:
Otitis media
Chronic sinusitis
Bronchitis
Bronchiectasis
Pneumonia
Urinary tract infections
Abscesses
Meningitis
Gastroenteritis
- Otitis media
- Chronic sinusitis
- Bronchitis
- Bronchiectasis
- Pneumonia
- Urinary tract infections
- Abscesses
- Meningitis
- Gastroenteritis
- Adlults with IgM deficiency as in secondary IgM deficiency also present with chronic and multiple infections.
- With time, autoimmune and neoplastic diseases may also occur such as:
Autoimmune glomerulonephritis
Autoimmune hemolytic anemia
Autoimmune thrombocytopenia
Celiac disease
Crohns disease
Hashimoto's thyroiditis
Myasthenia gravis
Rheumatoid arthritis
Systemic lupus erythematosus
Sarcoma
Lymphoma
Plasmacytoma
Splenomegaly
Atopy (asthma, anaphylaxis and angioedema)
- Autoimmune glomerulonephritis
- Autoimmune hemolytic anemia
- Autoimmune thrombocytopenia
- Celiac disease
- Crohns disease
- Hashimoto's thyroiditis
- Myasthenia gravis
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Sarcoma
- Lymphoma
- Plasmacytoma
- Splenomegaly
- Atopy (asthma, anaphylaxis and angioedema)
- The prgnosis is good in primary IgM deficiency if diagnosed early as IgM supplements can be given.
- In secondary IgM, autoimmune and neoplastic complications occur and prognosis is poor.

# Diagnosis

## Diagnostic Study of Choice
The diagnosis of IgM deficiency is made by measuring serum IgM levels.
- Serum IgM levels of <40mg/dl is diagnostic of IgM deficiency
- Serum sample is taken and then anti immunoglobulins are added.
- The amount of IgM produced is then measured.
- Other tests include
CBC
Serum IgG, IgA, IgE and IgD levels
Complement profile
Serum and urine electrophoresis
Serum ANA levels
- CBC
- Serum IgG, IgA, IgE and IgD levels
- Complement profile
- Serum and urine electrophoresis
- Serum ANA levels

## History and Symptoms
- The majority of patients with IgM deficiency are asymptomatic.
- They may present with history of :
Chronic infections
Weight loss
Chronic lung disease
Chronic diarrhea
Arthralgias
Abscesses
Allergic disorders
Liver disease
- Chronic infections
- Weight loss
- Chronic lung disease
- Chronic diarrhea
- Arthralgias
- Abscesses
- Allergic disorders
- Liver disease

## Symptoms
- The patients may be asymptomatic.
- Symptoms of IgM deficiency may include the symptoms of recurrent sinopulmonary infections include otitis media, rhinosinusitis, pneumonia and more serious infections that can occur, include osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections:

## Physical Examination
- Physical examination of patients with longstanding IgM deficiency may present with
Fever
Low body mass index
Swelling and tenderness over maxilla and frontal sinuses.
Perforated tympanic membrane or scarring over tympanic membrane.
Chronic nasal discharge.
Chronic cough, Crepitations, clubbing and wheezing.
Abdominal dystension, tenderness
Abscesses
Ulcers.
- Fever
Low body mass index
Swelling and tenderness over maxilla and frontal sinuses.
Perforated tympanic membrane or scarring over tympanic membrane.
Chronic nasal discharge.
Chronic cough, Crepitations, clubbing and wheezing.
Abdominal dystension, tenderness
Abscesses
Ulcers.
- Fever
- Low body mass index
- Swelling and tenderness over maxilla and frontal sinuses.
- Perforated tympanic membrane or scarring over tympanic membrane.
- Chronic nasal discharge.
- Chronic cough, Crepitations, clubbing and wheezing.
- Abdominal dystension, tenderness
- Abscesses
- Ulcers.

## Laboratory Findings
- Decreased levels of IgM(>40mg/dl) is considered diagnostic for IgM deficiency.
- Levels of other immunoglobulins(IgA, IgG, IgE and IgD)are within normal range.
- White blood cell count may be raised.

## Electrocardiogram
There are no ECG findings associated with IgM defiicency.

## X-ray
There are no specific findings for IgM deficiency on x ray but signs of lung disease may be present.
- Increased bronchovascular markings in bronchitis.
- Lung hyperinflation with flattened hemidiaphragms in emphysema.
- Consolidation in pneumonia.
- Tram track opacities in bronchiectasis.

## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with IgM deficiency

## CT scan
- There are no CT scan findings associated with IgM deficiency.
- Changes of chronic lung disease, if present will be visible on CT and can help differentiate the cause and extent of the disease.
- Chronic sinusitis- mucosal thickening, complete opacification, bone remodeling and thickening due to osteitis, and polyposis.

## MRI
There are no MRI findings associated with IgM deficiency.
However, signs of chronic lung disease or chronic sinsuitis may be present.

## Other Imaging Findings
There are no other imaging findings associated with IgM deficiency.

## Other Diagnostic Studies
There are no other diagnostic studies associated with IgM deficiency.

# Treatment

## Medical Therapy
- Asymptomatic individuals do not require any treatment.
- IVIG can be used in some patients but not effective in all the patients in a dose range of 400 to 600 mg/kg infused every three to four weeks intravenously or subcutaneosly.
- Conjugated pneumococcal vaccine, conjugated haemophilus influenza B and conjugated meningococcal vaccine administered to prevent infections.
- Prohphylactic antibiotics can be used for recurrent sinopulmonary infections:
Amoxicillin
Cefuroxime
Trimethoprim/sulphamethoxazole
Clarithromycin/eryhtromycin.
- Amoxicillin
- Cefuroxime
- Trimethoprim/sulphamethoxazole
- Clarithromycin/eryhtromycin.
- Treatment of the infections with the appropriate antibiotics.
- Treatment of atopic diseases such as allergic rhinitis with antihistamines can help in reducing sinopulmonary infections.

## Surgery
Surgical intervention is not recommended for the management of IgM deficiency.

## Primary Prevention
There are no established measures for the primary prevention of IgM deficiency.

## Secondary Prevention
- Secondary prevention includes prevention of infections by:
Avoidance- reduce exposure to others with potentially contagious illnesses, proper hand washing and immunization of family members and close contacts.
Vaccination with conjugate vaccines -conjugated pneumococcal vaccine, conjugated haemophillus influenza B and conjugated meningococcal vaccine administered to prevent infections.
Use of prophylactic broad spectrum antibiotics.
- Avoidance- reduce exposure to others with potentially contagious illnesses, proper hand washing and immunization of family members and close contacts.
- Vaccination with conjugate vaccines -conjugated pneumococcal vaccine, conjugated haemophillus influenza B and conjugated meningococcal vaccine administered to prevent infections.
- Use of prophylactic broad spectrum antibiotics.