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Revision as of 20:58, 13 August 2018

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Synonyms and keywords:

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 defeiciency can be differentiated from other immunoglubiln 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^[1].
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^[2].

However, it may present as 2 types:
Primary IgM deficiency-
- There ocuurs just IgM deficiency and no other associated condition.
- It is present in children as a congenital condition.
Secondary IgM-
- Alongwith 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.^[3]^[4]^[5]^[6]
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^[7].
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^[8]:
1. B cell defect- inability of B cell differentiation into IgM secreting cells^[9]^[10].
2. 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.

- 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^[11].
There is no identified cause but risk factors which are:

- Plasmacytoma

Differentiating ((Page name)) from Other Diseases

IgM deficiency can be differentiated from other diseases of the same kind by measuring the value of other immunoglobulins^[12]^[13]^[14]^[15]^[16].
In Igm deficiency only IgM levels are defiicent while the rest are within normal limits.


Disease	IgM levels	IgG levels	IgA levels	IgE levels	B cell defect	T cell defect
IgM deficiency	↓	-	-	-	-	-
IgA deficiency	-	-	↓	-	-	-
IgG deficiency	-	↓	-	-	-	-
IgE deficiency	-	-	-	↓	-	-
Hypoproteinemia/Proteinuria	↓	↓	↓	↓	-	-
Comined Immunodeficiency	↓	↓	↓	↓	+	+
X linked agammaglobulinemia	↓	↓	↓	↓	+	-
Hyperimmunoglobulin M syndrome	↑	↓	↓	↓	+	-
Common variable immunodeficiency	↓	↓	↓	↓	+	-
Wiskott-Aldrich syndrome	↓	↓	↑	↑	-	+

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^[17]^[18]:

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) are measured.

Natural History, Complications, and Prognosis

The patient may be asysmptomatic or present with signs of chronic infections^[19].
Children born with IgM deficiency as in primary IgM deficiency present with chronic infections such as:
Adlults with IgM deficiency as in secondary IgM deficiency also present with chronic and multiple infections^[20]^[21]^[22]^[23].
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)
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^[24].

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

History and Symptoms

The majority of patients with IgM deficiency are asymptomatic^[25]^[26]^[27].
They may present with history of :
- Chronic infections
- Weight loss
- Chronic lung disease
- Chronic diarrhea
- Arthralgias
- Abscesses
- Allergic disorders
- Liver disease

Symptoms

The patients may be asymptomatic^[28].

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^[29]^[30]
- :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^[24].
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^[31].

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^[24]^[19]^[25].
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.
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.

References

↑ Black CA (1997). "A brief history of the discovery of the immunoglobulins and the origin of the modern immunoglobulin nomenclature". Immunol Cell Biol. 75 (1): 65–8. doi:10.1038/icb.1997.10. PMID 9046436.
↑ Manson JJ, Mauri C, Ehrenstein MR (2005). "Natural serum IgM maintains immunological homeostasis and prevents autoimmunity". Springer Semin Immunopathol. 26 (4): 425–32. doi:10.1007/s00281-004-0187-x. PMID 15611856.
↑ Ehrenstein MR, Cook HT, Neuberger MS (2000). "Deficiency in serum immunoglobulin (Ig)M predisposes to development of IgG autoantibodies". J Exp Med. 191 (7): 1253–8. PMC 2193170. PMID 10748243.
↑ GILBERT C, HONG R (1964). "QUALITATIVE AND QUANTITATIVE IMMUNOGLOBULIN DEFICIENCY". Am J Med. 37: 602–9. PMID 14215847.
↑ Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide LM; et al. (2008). "Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities". Clin Exp Immunol. 151 (1): 42–50. doi:10.1111/j.1365-2249.2007.03545.x. PMC 2276914. PMID 18005364.
↑ Hobbs JR (1975). "IgM deficiency". Birth Defects Orig Artic Ser. 11 (1): 112–6. PMID 50091.
↑ Baker N, Ehrenstein MR (2002). "Cutting edge: selection of B lymphocyte subsets is regulated by natural IgM". J Immunol. 169 (12): 6686–90. PMID 12471099.
↑ Inoue T, Okumura Y, Shirama M, Ishibashi H, Kashiwagi S, Okubo H (1986). "Selective partial IgM deficiency: functional assessment of T and B lymphocytes in vitro". J Clin Immunol. 6 (2): 130–5. PMID 2872228.
↑ Saini S, Dettore AJ, Bhambhani KJ, Buck S, Poulik J, Savaşan S (2011). "Selective IgM deficiency in CD30+ cutaneous lymphoproliferative disorder". J Pediatr Hematol Oncol. 33 (4): e156–9. doi:10.1097/MPH.0b013e31820150d5. PMID 21516014.
↑ De la Concha EG, Garcia-Rodriguez MC, Zabay JM, Laso MT, Alonso F, Bootello A; et al. (1982). "Functional assessment of T and B lymphocytes in patients with selective IgM deficiency". Clin Exp Immunol. 49 (3): 670–6. PMC 1536738. PMID 6983403.
↑ Takenaka T, Nakamine H, Nishihara T, Tsuda T, Tsujimoto M, Maeda J (1983). "Prolymphocytic leukemia with IgM hypogammaglobulinemia". Am J Clin Pathol. 80 (2): 237–42. PMID 6603786.
↑ Thong YH, Maxwell GM (1978). "Primary selective deficiency of immunoglobulin M." Aust N Z J Med. 8 (4): 436–8. PMID 367347.
↑ Cipe FE, Doğu F, Güloğlu D, Aytekin C, Polat M, Biyikli Z; et al. (2013). "B-cell subsets in patients with transient hypogammaglobulinemia of infancy, partial IgA deficiency, and selective IgM deficiency". J Investig Allergol Clin Immunol. 23 (2): 94–100. PMID 23654075.
↑ Fischer A (2004). "Human primary immunodeficiency diseases: a perspective". Nat Immunol. 5 (1): 23–30. doi:10.1038/ni1023. PMID 14699405.
↑ Ozen A, Baris S, Karakoc-Aydiner E, Ozdemir C, Bahceciler NN, Barlan IB (2010). "Outcome of hypogammaglobulinemia in children: immunoglobulin levels as predictors". Clin Immunol. 137 (3): 374–83. doi:10.1016/j.clim.2010.08.010. PMID 20851686.
↑ Notarangelo L, Casanova JL, Fischer A, Puck J, Rosen F, Seger R; et al. (2004). "Primary immunodeficiency diseases: an update". J Allergy Clin Immunol. 114 (3): 677–87. doi:10.1016/j.jaci.2004.06.044. PMID 15356576.
↑ Vogelzang NJ, Corwin H, Finlay JL, Pellettiere EV, Luskin AT, Di Camelli RF; et al. (1982). "Clear cell sarcoma and selective IgM deficiency: a case report". Cancer. 49 (2): 234–8. PMID 7053825.
↑ Kung SJ, Gripp KW, Stephan MJ, Fairchok MP, McGeady SJ (2007). "Selective IgM deficiency and 22q11.2 deletion syndrome". Ann Allergy Asthma Immunol. 99 (1): 87–92. doi:10.1016/S1081-1206(10)60627-8. PMID 17650836.
↑ ^19.0 ^19.1 Yocum MW, Strong DM, Chusid MJ, Lakin JD (1976). "Selective immunoglobulin M (IgM) deficiency in two immunodeficient adults with recurrent staphylococcal pyoderma". Am J Med. 60 (4): 486–94. PMID 1274982.
↑ Phuphuakrat A, Ngamjanyaporn P, Nantiruj K, Luangwedchakarn V, Malathum K (2016). "Selective IgM deficiency in an adult presenting with Streptococcus pneumoniae septic arthritis". J Microbiol Immunol Infect. 49 (1): 150–3. doi:10.1016/j.jmii.2013.01.009. PMID 23523054.
↑ Raziuddin S, Bilal N, Benjamin B (1988). "Transient T-cell abnormality in a selective IgM-immunodeficient patient with Brucella infection". Clin Immunol Immunopathol. 46 (3): 360–7. PMID 2962796.
↑ Chandra RK, Kaveramma B, Soothill JF (1969). "Generalised non-progressive vaccinia associated with IgM deficiency". Lancet. 1 (7597): 687–9. PMID 4182649.
↑ Takeuchi T, Nakagawa T, Maeda Y, Hirano S, Sasaki-Hayashi M, Makino S; et al. (2001). "Functional defect of B lymphocytes in a patient with selective IgM deficiency associated with systemic lupus erythematosus". Autoimmunity. 34 (2): 115–22. PMID 11905841.
↑ ^24.0 ^24.1 ^24.2 Conley ME, Notarangelo LD, Etzioni A (1999). "Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies)". Clin Immunol. 93 (3): 190–7. doi:10.1006/clim.1999.4799. PMID 10600329.
↑ ^25.0 ^25.1 Yel L, Ramanuja S, Gupta S (2009). "Clinical and immunological features in IgM deficiency". Int Arch Allergy Immunol. 150 (3): 291–8. doi:10.1159/000222682. PMID 19494527.
↑ Hong R, Gupta S (2008). "Selective immunoglobulin M deficiency in an adult with Streptococcus pneumoniae sepsis and invasive aspergillosis". J Investig Allergol Clin Immunol. 18 (3): 214–8. PMID 18564634.
↑ Arahata M, Tajiri K, Nomoto K, Tsuneyama K, Minami S, Shimizu Y (2013). "A novel type of selective immunoglobulin m deficiency in a patient with autoimmune liver cirrhosis with recurrent hepatocellular carcinoma: a case report and review of the literature". Int Arch Allergy Immunol. 161 (1): 91–6. doi:10.1159/000343583. PMID 23257944.
↑ Morita M, Saibara T, Nakazawa Y, Miyao M, Okazaki K, Onishi S; et al. (1984). "[A case of Crohn's disease associated with selective IgM deficiency]". Nihon Shokakibyo Gakkai Zasshi. 81 (4): 1070–5. PMID 6748317.
↑ Popa V, Colby TV, Reich SB (2002). "Pulmonary interstitial disease in Ig deficiency". Chest. 122 (5): 1594–603. PMID 12426258.
↑ Ross IN, Thompson RA (1976). "Severe selective IgM deficiency". J Clin Pathol. 29 (9): 773–7. PMC 476177. PMID 977778.
↑ Rossi UG, Owens CM (2005). "The radiology of chronic lung disease in children". Arch Dis Child. 90 (6): 601–7. doi:10.1136/adc.2004.051383. PMC 1720446. PMID 15908625.

Template:WikiDoc Sources

[pmid9046436-1] Black CA (1997). "A brief history of the discovery of the immunoglobulins and the origin of the modern immunoglobulin nomenclature". Immunol Cell Biol. 75 (1): 65–8. doi:10.1038/icb.1997.10. PMID 9046436.

[pmid15611856-2] Manson JJ, Mauri C, Ehrenstein MR (2005). "Natural serum IgM maintains immunological homeostasis and prevents autoimmunity". Springer Semin Immunopathol. 26 (4): 425–32. doi:10.1007/s00281-004-0187-x. PMID 15611856.

[pmid10748243-3] Ehrenstein MR, Cook HT, Neuberger MS (2000). "Deficiency in serum immunoglobulin (Ig)M predisposes to development of IgG autoantibodies". J Exp Med. 191 (7): 1253–8. PMC 2193170. PMID 10748243.

[pmid14215847-4] GILBERT C, HONG R (1964). "QUALITATIVE AND QUANTITATIVE IMMUNOGLOBULIN DEFICIENCY". Am J Med. 37: 602–9. PMID 14215847.

[pmid18005364-5] Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide LM; et al. (2008). "Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities". Clin Exp Immunol. 151 (1): 42–50. doi:10.1111/j.1365-2249.2007.03545.x. PMC 2276914. PMID 18005364.

[pmid50091-6] Hobbs JR (1975). "IgM deficiency". Birth Defects Orig Artic Ser. 11 (1): 112–6. PMID 50091.

[pmid12471099-7] Baker N, Ehrenstein MR (2002). "Cutting edge: selection of B lymphocyte subsets is regulated by natural IgM". J Immunol. 169 (12): 6686–90. PMID 12471099.

[pmid2872228-8] Inoue T, Okumura Y, Shirama M, Ishibashi H, Kashiwagi S, Okubo H (1986). "Selective partial IgM deficiency: functional assessment of T and B lymphocytes in vitro". J Clin Immunol. 6 (2): 130–5. PMID 2872228.

[pmid21516014-9] Saini S, Dettore AJ, Bhambhani KJ, Buck S, Poulik J, Savaşan S (2011). "Selective IgM deficiency in CD30+ cutaneous lymphoproliferative disorder". J Pediatr Hematol Oncol. 33 (4): e156–9. doi:10.1097/MPH.0b013e31820150d5. PMID 21516014.

[pmid6983403-10] De la Concha EG, Garcia-Rodriguez MC, Zabay JM, Laso MT, Alonso F, Bootello A; et al. (1982). "Functional assessment of T and B lymphocytes in patients with selective IgM deficiency". Clin Exp Immunol. 49 (3): 670–6. PMC 1536738. PMID 6983403.

[pmid6603786-11] Takenaka T, Nakamine H, Nishihara T, Tsuda T, Tsujimoto M, Maeda J (1983). "Prolymphocytic leukemia with IgM hypogammaglobulinemia". Am J Clin Pathol. 80 (2): 237–42. PMID 6603786.

[pmid367347-12] Thong YH, Maxwell GM (1978). "Primary selective deficiency of immunoglobulin M." Aust N Z J Med. 8 (4): 436–8. PMID 367347.

[pmid23654075-13] Cipe FE, Doğu F, Güloğlu D, Aytekin C, Polat M, Biyikli Z; et al. (2013). "B-cell subsets in patients with transient hypogammaglobulinemia of infancy, partial IgA deficiency, and selective IgM deficiency". J Investig Allergol Clin Immunol. 23 (2): 94–100. PMID 23654075.

[pmid14699405-14] Fischer A (2004). "Human primary immunodeficiency diseases: a perspective". Nat Immunol. 5 (1): 23–30. doi:10.1038/ni1023. PMID 14699405.

[pmid20851686-15] Ozen A, Baris S, Karakoc-Aydiner E, Ozdemir C, Bahceciler NN, Barlan IB (2010). "Outcome of hypogammaglobulinemia in children: immunoglobulin levels as predictors". Clin Immunol. 137 (3): 374–83. doi:10.1016/j.clim.2010.08.010. PMID 20851686.

[pmid15356576-16] Notarangelo L, Casanova JL, Fischer A, Puck J, Rosen F, Seger R; et al. (2004). "Primary immunodeficiency diseases: an update". J Allergy Clin Immunol. 114 (3): 677–87. doi:10.1016/j.jaci.2004.06.044. PMID 15356576.

[pmid7053825-17] Vogelzang NJ, Corwin H, Finlay JL, Pellettiere EV, Luskin AT, Di Camelli RF; et al. (1982). "Clear cell sarcoma and selective IgM deficiency: a case report". Cancer. 49 (2): 234–8. PMID 7053825.

[pmid17650836-18] Kung SJ, Gripp KW, Stephan MJ, Fairchok MP, McGeady SJ (2007). "Selective IgM deficiency and 22q11.2 deletion syndrome". Ann Allergy Asthma Immunol. 99 (1): 87–92. doi:10.1016/S1081-1206(10)60627-8. PMID 17650836.

[pmid1274982-19] 19.0 ^19.1 Yocum MW, Strong DM, Chusid MJ, Lakin JD (1976). "Selective immunoglobulin M (IgM) deficiency in two immunodeficient adults with recurrent staphylococcal pyoderma". Am J Med. 60 (4): 486–94. PMID 1274982.

[pmid23523054-20] Phuphuakrat A, Ngamjanyaporn P, Nantiruj K, Luangwedchakarn V, Malathum K (2016). "Selective IgM deficiency in an adult presenting with Streptococcus pneumoniae septic arthritis". J Microbiol Immunol Infect. 49 (1): 150–3. doi:10.1016/j.jmii.2013.01.009. PMID 23523054.

[pmid2962796-21] Raziuddin S, Bilal N, Benjamin B (1988). "Transient T-cell abnormality in a selective IgM-immunodeficient patient with Brucella infection". Clin Immunol Immunopathol. 46 (3): 360–7. PMID 2962796.

[pmid4182649-22] Chandra RK, Kaveramma B, Soothill JF (1969). "Generalised non-progressive vaccinia associated with IgM deficiency". Lancet. 1 (7597): 687–9. PMID 4182649.

[pmid11905841-23] Takeuchi T, Nakagawa T, Maeda Y, Hirano S, Sasaki-Hayashi M, Makino S; et al. (2001). "Functional defect of B lymphocytes in a patient with selective IgM deficiency associated with systemic lupus erythematosus". Autoimmunity. 34 (2): 115–22. PMID 11905841.

[pmid10600329-24] 24.0 ^24.1 ^24.2 Conley ME, Notarangelo LD, Etzioni A (1999). "Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies)". Clin Immunol. 93 (3): 190–7. doi:10.1006/clim.1999.4799. PMID 10600329.

[pmid19494527-25] 25.0 ^25.1 Yel L, Ramanuja S, Gupta S (2009). "Clinical and immunological features in IgM deficiency". Int Arch Allergy Immunol. 150 (3): 291–8. doi:10.1159/000222682. PMID 19494527.

[pmid18564634-26] Hong R, Gupta S (2008). "Selective immunoglobulin M deficiency in an adult with Streptococcus pneumoniae sepsis and invasive aspergillosis". J Investig Allergol Clin Immunol. 18 (3): 214–8. PMID 18564634.

[pmid23257944-27] Arahata M, Tajiri K, Nomoto K, Tsuneyama K, Minami S, Shimizu Y (2013). "A novel type of selective immunoglobulin m deficiency in a patient with autoimmune liver cirrhosis with recurrent hepatocellular carcinoma: a case report and review of the literature". Int Arch Allergy Immunol. 161 (1): 91–6. doi:10.1159/000343583. PMID 23257944.

[pmid6748317-28] Morita M, Saibara T, Nakazawa Y, Miyao M, Okazaki K, Onishi S; et al. (1984). "[A case of Crohn's disease associated with selective IgM deficiency]". Nihon Shokakibyo Gakkai Zasshi. 81 (4): 1070–5. PMID 6748317.

[pmid12426258-29] Popa V, Colby TV, Reich SB (2002). "Pulmonary interstitial disease in Ig deficiency". Chest. 122 (5): 1594–603. PMID 12426258.

[pmid977778-30] Ross IN, Thompson RA (1976). "Severe selective IgM deficiency". J Clin Pathol. 29 (9): 773–7. PMC 476177. PMID 977778.

[pmid15908625-31] Rossi UG, Owens CM (2005). "The radiology of chronic lung disease in children". Arch Dis Child. 90 (6): 601–7. doi:10.1136/adc.2004.051383. PMC 1720446. PMID 15908625.

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 ==Historical Perspective==
-* IgM was discovered by Waldenstrom, Pedersen and kunkel in 1944 by [[immunoelectrophoresis]] and [[Differential centrifugation|ultracentrifugation]].
+* IgM was discovered by Waldenstrom, Pedersen and kunkel in 1944 by [[immunoelectrophoresis]] and [[Differential centrifugation|ultracentrifugation]]<ref name="pmid9046436">{{cite journal| author=Black CA| title=A brief history of the discovery of the immunoglobulins and the origin of the modern immunoglobulin nomenclature. | journal=Immunol Cell Biol | year= 1997 | volume= 75 | issue= 1 | pages= 65-8 | pmid=9046436 | doi=10.1038/icb.1997.10 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9046436  }} </ref>.
 * 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.
+There is no established system for the classification of IgM deficiency<ref name="pmid15611856">{{cite journal| author=Manson JJ, Mauri C, Ehrenstein MR| title=Natural serum IgM maintains immunological homeostasis and prevents autoimmunity. | journal=Springer Semin Immunopathol | year= 2005 | volume= 26 | issue= 4 | pages= 425-32 | pmid=15611856 | doi=10.1007/s00281-004-0187-x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15611856  }} </ref>.
 * However, it may present as 2 types:
 * Primary IgM deficiency-
@@ Line 24: / Line 24: @@
 ==Pathophysiology==
-* IgM is the first antibody that is present on the surface of [[B cell|B lymphocytes]] when they come in contact with an [[Antigen|antigen.]]
+* IgM is the first antibody that is present on the surface of [[B cell|B lymphocytes]] when they come in contact with an [[Antigen|antigen.]]<ref name="pmid10748243">{{cite journal| author=Ehrenstein MR, Cook HT, Neuberger MS| title=Deficiency in serum immunoglobulin (Ig)M predisposes to development of IgG autoantibodies. | journal=J Exp Med | year= 2000 | volume= 191 | issue= 7 | pages= 1253-8 | pmid=10748243 | doi= | pmc=2193170 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10748243  }} </ref><ref name="pmid14215847">{{cite journal| author=GILBERT C, HONG R| title=QUALITATIVE AND QUANTITATIVE IMMUNOGLOBULIN DEFICIENCY. | journal=Am J Med | year= 1964 | volume= 37 | issue=  | pages= 602-9 | pmid=14215847 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14215847  }} </ref><ref name="pmid18005364">{{cite journal| author=Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide LM et al.| title=Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities. | journal=Clin Exp Immunol | year= 2008 | volume= 151 | issue= 1 | pages= 42-50 | pmid=18005364 | doi=10.1111/j.1365-2249.2007.03545.x | pmc=2276914 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18005364  }} </ref><ref name="pmid50091">{{cite journal| author=Hobbs JR| title=IgM deficiency. | journal=Birth Defects Orig Artic Ser | year= 1975 | volume= 11 | issue= 1 | pages= 112-6 | pmid=50091 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=50091  }} </ref>
 * It is the primary antibody against [[ABO blood group system|A]] and [[ABO blood group system|B]] [[Antigen|antigens]] on [[Red blood cell|red blood cells]].
-* Other [[An Bord Altranais|immunoglublins]] such as [[Immunoglobulin G|IgG]], [[Immunoglobulin A|IgA]] and [[Immunoglobulin E|IgE]] are produced after alteration in the structure of [[Immunoglobulin M|IgM]] heavy chains on the [[B cell|B lymphocytes]].
+* Other [[An Bord Altranais|immunoglublins]] such as [[Immunoglobulin G|IgG]], [[Immunoglobulin A|IgA]] and [[Immunoglobulin E|IgE]] are produced after alteration in the structure of [[Immunoglobulin M|IgM]] heavy chains on the [[B cell|B lymphocytes]]<ref name="pmid12471099">{{cite journal| author=Baker N, Ehrenstein MR| title=Cutting edge: selection of B lymphocyte subsets is regulated by natural IgM. | journal=J Immunol | year= 2002 | volume= 169 | issue= 12 | pages= 6686-90 | pmid=12471099 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12471099  }} </ref>.
 * IgM is present in the circulation as a pentamer structure. and is the largest antibody in human [[Circulatory system|circulatory system.]]
 * Presence of IgM antibodies in a patient's [[serum]] indicates recent [[infection]], or in a [[Infant|neonate]]'s serum indicates intrauterine infection (e.g. [[congenital rubella]]).
@@ Line 32: / Line 32: @@
 * In IgM deficiency there occurs deficiency of IgM but normal levels of [[Immunoglobulin G|IgG]] and [[Immunoglobulin A|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:
+* The defeciency in IgM could be due to<ref name="pmid2872228">{{cite journal| author=Inoue T, Okumura Y, Shirama M, Ishibashi H, Kashiwagi S, Okubo H| title=Selective partial IgM deficiency: functional assessment of T and B lymphocytes in vitro. | journal=J Clin Immunol | year= 1986 | volume= 6 | issue= 2 | pages= 130-5 | pmid=2872228 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2872228  }} </ref>:
-*# [[B cell]] defect- inability of B cell differentiation into IgM secreting cells.
+*# [[B cell]] defect- inability of B cell differentiation into IgM secreting cells<ref name="pmid21516014">{{cite journal| author=Saini S, Dettore AJ, Bhambhani KJ, Buck S, Poulik J, Savaşan S| title=Selective IgM deficiency in CD30+ cutaneous lymphoproliferative disorder. | journal=J Pediatr Hematol Oncol | year= 2011 | volume= 33 | issue= 4 | pages= e156-9 | pmid=21516014 | doi=10.1097/MPH.0b013e31820150d5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21516014  }} </ref><ref name="pmid6983403">{{cite journal| author=De la Concha EG, Garcia-Rodriguez MC, Zabay JM, Laso MT, Alonso F, Bootello A et al.| title=Functional assessment of T and B lymphocytes in patients with selective IgM deficiency. | journal=Clin Exp Immunol | year= 1982 | volume= 49 | issue= 3 | pages= 670-6 | pmid=6983403 | doi= | pmc=1536738 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6983403  }} </ref>.
 *# [[T cell]] defect- decreased [[T helper cell|helper T cell]] activity for IgM.
 * This results in decreased sysnthesis of IgM in the body.
@@ Line 57: / Line 57: @@
 The exact cause of IgM deficiency is not known.
 * Primary IgM deficiency ouccrs in children and is [[Congenital disorder|congenital]].
-* Secondary IgM deficiency occurs in adults and is associated with [[Autoimmunity|autoimmune disorders]] and [[Neoplasm|neoplasms]].
+* Secondary IgM deficiency occurs in adults and is associated with [[Autoimmunity|autoimmune disorders]] and [[Neoplasm|neoplasms]]<ref name="pmid6603786">{{cite journal| author=Takenaka T, Nakamine H, Nishihara T, Tsuda T, Tsujimoto M, Maeda J| title=Prolymphocytic leukemia with IgM hypogammaglobulinemia. | journal=Am J Clin Pathol | year= 1983 | volume= 80 | issue= 2 | pages= 237-42 | pmid=6603786 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6603786  }} </ref>.
 * There is no identified cause but risk factors which are:
 ** [[Glomerular disease|Autoimmune glomerulonephritis]]
@@ Line 73: / Line 73: @@
 ==Differentiating ((Page name)) from Other Diseases==
-*IgM deficiency can be differentiated from other diseases of the same kind by measuring the value of other immunoglobulins.
+*IgM deficiency can be differentiated from other diseases of the same kind by measuring the value of other immunoglobulins<ref name="pmid367347">{{cite journal| author=Thong YH, Maxwell GM| title=Primary selective deficiency of immunoglobulin M. | journal=Aust N Z J Med | year= 1978 | volume= 8 | issue= 4 | pages= 436-8 | pmid=367347 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=367347  }} </ref><ref name="pmid23654075">{{cite journal| author=Cipe FE, Doğu F, Güloğlu D, Aytekin C, Polat M, Biyikli Z et al.| title=B-cell subsets in patients with transient hypogammaglobulinemia of infancy, partial IgA deficiency, and selective IgM deficiency. | journal=J Investig Allergol Clin Immunol | year= 2013 | volume= 23 | issue= 2 | pages= 94-100 | pmid=23654075 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23654075  }} </ref><ref name="pmid14699405">{{cite journal| author=Fischer A| title=Human primary immunodeficiency diseases: a perspective. | journal=Nat Immunol | year= 2004 | volume= 5 | issue= 1 | pages= 23-30 | pmid=14699405 | doi=10.1038/ni1023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14699405  }} </ref><ref name="pmid20851686">{{cite journal| author=Ozen A, Baris S, Karakoc-Aydiner E, Ozdemir C, Bahceciler NN, Barlan IB| title=Outcome of hypogammaglobulinemia in children: immunoglobulin levels as predictors. | journal=Clin Immunol | year= 2010 | volume= 137 | issue= 3 | pages= 374-83 | pmid=20851686 | doi=10.1016/j.clim.2010.08.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20851686  }} </ref><ref name="pmid15356576">{{cite journal| author=Notarangelo L, Casanova JL, Fischer A, Puck J, Rosen F, Seger R et al.| title=Primary immunodeficiency diseases: an update. | journal=J Allergy Clin Immunol | year= 2004 | volume= 114 | issue= 3 | pages= 677-87 | pmid=15356576 | doi=10.1016/j.jaci.2004.06.044 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15356576  }} </ref>.
 *In Igm deficiency only IgM levels are defiicent while the rest are within normal limits.
@@ Line 122: / Line 122: @@
 ==Risk Factors==
-There are no established risk factors for IgM deficiency but it occurs more commonly in:
+There are no established risk factors for IgM deficiency but it occurs more commonly in<ref name="pmid7053825">{{cite journal| author=Vogelzang NJ, Corwin H, Finlay JL, Pellettiere EV, Luskin AT, Di Camelli RF et al.| title=Clear cell sarcoma and selective IgM deficiency: a case report. | journal=Cancer | year= 1982 | volume= 49 | issue= 2 | pages= 234-8 | pmid=7053825 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7053825  }} </ref><ref name="pmid17650836">{{cite journal| author=Kung SJ, Gripp KW, Stephan MJ, Fairchok MP, McGeady SJ| title=Selective IgM deficiency and 22q11.2 deletion syndrome. | journal=Ann Allergy Asthma Immunol | year= 2007 | volume= 99 | issue= 1 | pages= 87-92 | pmid=17650836 | doi=10.1016/S1081-1206(10)60627-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17650836  }} </ref>:
 * [[Clear cell tumor|Clear cell carcinoma]]
 * [[Bloom syndrome]]
@@ Line 140: / Line 140: @@
 ==Natural History, Complications, and Prognosis==
-* The patient may be asysmptomatic or present with signs of chronic infections.
+* The patient may be asysmptomatic or present with signs of chronic infections<ref name="pmid1274982">{{cite journal| author=Yocum MW, Strong DM, Chusid MJ, Lakin JD| title=Selective immunoglobulin M (IgM) deficiency in two immunodeficient adults with recurrent staphylococcal pyoderma. | journal=Am J Med | year= 1976 | volume= 60 | issue= 4 | pages= 486-94 | pmid=1274982 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1274982  }} </ref>.
 * Children born with IgM deficiency as in primary IgM deficiency present with chronic infections such as:
 ** [[Otitis media]]
@@ Line 151: / Line 151: @@
 ** [[Meningitis]]
 ** [[Gastroenteritis]]
-* Adlults with IgM deficiency as in secondary IgM deficiency also present with chronic and multiple infections.
+* Adlults with IgM deficiency as in secondary IgM deficiency also present with chronic and multiple infections<ref name="pmid23523054">{{cite journal| author=Phuphuakrat A, Ngamjanyaporn P, Nantiruj K, Luangwedchakarn V, Malathum K| title=Selective IgM deficiency in an adult presenting with Streptococcus pneumoniae septic arthritis. | journal=J Microbiol Immunol Infect | year= 2016 | volume= 49 | issue= 1 | pages= 150-3 | pmid=23523054 | doi=10.1016/j.jmii.2013.01.009 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23523054  }} </ref><ref name="pmid2962796">{{cite journal| author=Raziuddin S, Bilal N, Benjamin B| title=Transient T-cell abnormality in a selective IgM-immunodeficient patient with Brucella infection. | journal=Clin Immunol Immunopathol | year= 1988 | volume= 46 | issue= 3 | pages= 360-7 | pmid=2962796 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2962796  }} </ref><ref name="pmid4182649">{{cite journal| author=Chandra RK, Kaveramma B, Soothill JF| title=Generalised non-progressive vaccinia associated with IgM deficiency. | journal=Lancet | year= 1969 | volume= 1 | issue= 7597 | pages= 687-9 | pmid=4182649 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4182649  }} </ref><ref name="pmid11905841">{{cite journal| author=Takeuchi T, Nakagawa T, Maeda Y, Hirano S, Sasaki-Hayashi M, Makino S et al.| title=Functional defect of B lymphocytes in a patient with selective IgM deficiency associated with systemic lupus erythematosus. | journal=Autoimmunity | year= 2001 | volume= 34 | issue= 2 | pages= 115-22 | pmid=11905841 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11905841  }} </ref>.
 * With time, autoimmune and neoplastic diseases may also occur such as:
 ** Autoimmune glomerulonephritis
@@ Line 172: / Line 172: @@
 ==Diagnosis==
 ===Diagnostic Study of Choice===
-The diagnosis of IgM deficiency is made by measuring serum IgM levels.
+The diagnosis of IgM deficiency is made by measuring serum IgM levels<ref name="pmid10600329">{{cite journal| author=Conley ME, Notarangelo LD, Etzioni A| title=Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). | journal=Clin Immunol | year= 1999 | volume= 93 | issue= 3 | pages= 190-7 | pmid=10600329 | doi=10.1006/clim.1999.4799 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10600329  }} </ref>.
 * Serum IgM levels of <40mg/dl is diagnostic of IgM deficiency
 * [[Serum]] sample is taken and then anti [[Antibodies|immunoglobulins]] are added.
@@ Line 184: / Line 184: @@
 ===History and Symptoms===
-* The majority of patients with IgM deficiency are asymptomatic.
+* The majority of patients with IgM deficiency are asymptomatic<ref name="pmid19494527">{{cite journal| author=Yel L, Ramanuja S, Gupta S| title=Clinical and immunological features in IgM deficiency. | journal=Int Arch Allergy Immunol | year= 2009 | volume= 150 | issue= 3 | pages= 291-8 | pmid=19494527 | doi=10.1159/000222682 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19494527  }} </ref><ref name="pmid18564634">{{cite journal| author=Hong R, Gupta S| title=Selective immunoglobulin M deficiency in an adult with Streptococcus pneumoniae sepsis and invasive aspergillosis. | journal=J Investig Allergol Clin Immunol | year= 2008 | volume= 18 | issue= 3 | pages= 214-8 | pmid=18564634 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18564634  }} </ref><ref name="pmid23257944">{{cite journal| author=Arahata M, Tajiri K, Nomoto K, Tsuneyama K, Minami S, Shimizu Y| title=A novel type of selective immunoglobulin m deficiency in a patient with autoimmune liver cirrhosis with recurrent hepatocellular carcinoma: a case report and review of the literature. | journal=Int Arch Allergy Immunol | year= 2013 | volume= 161 | issue= 1 | pages= 91-6 | pmid=23257944 | doi=10.1159/000343583 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23257944  }} </ref>.
 * They may present with history of :
 ** Chronic infections
@@ Line 196: / Line 196: @@
 === Symptoms ===
-* The patients may be asymptomatic.
+* The patients may be asymptomatic<ref name="pmid6748317">{{cite journal| author=Morita M, Saibara T, Nakazawa Y, Miyao M, Okazaki K, Onishi S et al.| title=[A case of Crohn's disease associated with selective IgM deficiency]. | journal=Nihon Shokakibyo Gakkai Zasshi | year= 1984 | volume= 81 | issue= 4 | pages= 1070-5 | pmid=6748317 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6748317  }} </ref>.
 * 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]], [[Meningococcemia|meningitis,]] [[Sepsis|septicemia]], [[diarrhea]], and various skin infections:
 ===Physical Examination===
-* Physical examination of patients with longstanding IgM deficiency may present with
+* Physical examination of patients with longstanding IgM deficiency may present with<ref name="pmid12426258">{{cite journal| author=Popa V, Colby TV, Reich SB| title=Pulmonary interstitial disease in Ig deficiency. | journal=Chest | year= 2002 | volume= 122 | issue= 5 | pages= 1594-603 | pmid=12426258 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12426258  }} </ref><ref name="pmid977778">{{cite journal| author=Ross IN, Thompson RA| title=Severe selective IgM deficiency. | journal=J Clin Pathol | year= 1976 | volume= 29 | issue= 9 | pages= 773-7 | pmid=977778 | doi= | pmc=476177 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=977778  }} </ref>
 ** :[[Fever]]
 *** Low body mass index
@@ Line 213: / Line 213: @@
 ===Laboratory Findings===
-* Decreased levels of IgM(>40mg/dl) is considered diagnostic for IgM deficiency.
+* Decreased levels of IgM(>40mg/dl) is considered diagnostic for IgM deficiency<ref name="pmid10600329">{{cite journal| author=Conley ME, Notarangelo LD, Etzioni A| title=Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). | journal=Clin Immunol | year= 1999 | volume= 93 | issue= 3 | pages= 190-7 | pmid=10600329 | doi=10.1006/clim.1999.4799 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10600329  }} </ref>.
 * Levels of other immunoglobulins(IgA, IgG, IgE and IgD)are within normal range.
 * [[White blood cells|White blood cell]] count may be raised.
@@ Line 221: / Line 221: @@
 ===X-ray===
-There are no specific findings for IgM deficiency on x ray but signs of lung disease may be present.
+There are no specific findings for IgM deficiency on x ray but signs of lung disease may be present<ref name="pmid15908625">{{cite journal| author=Rossi UG, Owens CM| title=The radiology of chronic lung disease in children. | journal=Arch Dis Child | year= 2005 | volume= 90 | issue= 6 | pages= 601-7 | pmid=15908625 | doi=10.1136/adc.2004.051383 | pmc=1720446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15908625  }} </ref>.
 * Increased bronchovascular markings in [[bronchitis]].
 * '''lung''' hyperinflation with flattened hemidiaphragms in [[emphysema]].
@@ Line 249: / Line 249: @@
 ==Treatment==
 ===Medical Therapy===
-* Asymptomatic individuals do not require any treatment.
+* Asymptomatic individuals do not require any treatment<ref name="pmid10600329">{{cite journal| author=Conley ME, Notarangelo LD, Etzioni A| title=Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). | journal=Clin Immunol | year= 1999 | volume= 93 | issue= 3 | pages= 190-7 | pmid=10600329 | doi=10.1006/clim.1999.4799 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10600329  }} </ref><ref name="pmid1274982">{{cite journal| author=Yocum MW, Strong DM, Chusid MJ, Lakin JD| title=Selective immunoglobulin M (IgM) deficiency in two immunodeficient adults with recurrent staphylococcal pyoderma. | journal=Am J Med | year= 1976 | volume= 60 | issue= 4 | pages= 486-94 | pmid=1274982 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1274982  }} </ref><ref name="pmid19494527">{{cite journal| author=Yel L, Ramanuja S, Gupta S| title=Clinical and immunological features in IgM deficiency. | journal=Int Arch Allergy Immunol | year= 2009 | volume= 150 | issue= 3 | pages= 291-8 | pmid=19494527 | doi=10.1159/000222682 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19494527  }} </ref>.
 * [[Intravenous immunoglobulin|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 [[Neisseria meningitidis|meningococcal]] vaccine administered to prevent infections.