Common variable immunodeficiency

Common variable immunodeficiency
Classification and external resources
Specialty hematology
ICD-10 D83
ICD-9-CM 279.06
OMIM 240500
DiseasesDB 3274
eMedicine ped/444 derm/870
Patient UK Common variable immunodeficiency
MeSH D017074

Common Variable Immunodeficiency (CVID) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA.[1] It is thought to affect between 1 in 25,000 to 1 in 50,000 people worldwide. CVID is a rare primary immunodeficiency, and can take many forms due to the diverse ways in which antibody production can be impaired.[2] Generally, CVID symptoms include high susceptibility to foreign invaders, chronic lung disease, and inflammation and infection of the gastrointestinal tract.[1] However, symptoms vary greatly. The disease is not only phenotypically heterogeneous, but also hard to diagnose, taking on average 6–7 years after onset.[2] [3]

CVID is a lifelong disease, but its origin is poorly understood. Current research points to deletions in particular genetic markers encoding cell surface proteins and cytokine receptors, like CD19, CD20, CD21, and CD80, as likely sources of the disease.[2] A deletion is a mutation in which part of the chromosome is lost during DNA replication. Additionally, the disease is defined by T cell defects, namely reduced proliferative capacity.[4] Current research is aimed at studying large cohorts of CVID patients in an attempt to better understand age of onset, as well as mechanism, genetic factors, and progression of the disease.[2]

CVID was first diagnosed over 60 years ago, and since has emerged as the predominant class of primary antibody deficiencies. CVID is formally diagnosed by levels of IgG and IgA more than two standard deviations from the norm, and no other cause for hypogammaglobulinemia, an abnormally low level of immunoglobulins in the blood. Treatment options are limited, and usually include life-long immunoglobulin replacement therapy.[3] This therapy is thought to help reduce bacterial infections. This treatment alone is not wholly effective, and many patients still experience other symptoms like lung disease and noninfectious inflammatory symptoms.

Signs and symptoms

CVID is a clinically heterogeneous disease. Its main features are hypogammaglobulinemia and recurrent infections. Hypogammaglobulinemia manifests as a significant decrease in the levels of IgG antibodies, usually alongside IgA antibodies; IgM antibody levels are also decreased in about 50% of patients.[5] Infections are a direct result of the low antibody levels in the circulation of patients, which do not adequately protect them against pathogens. The microorganisms that most frequently cause infections in CVID are bacteria Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus. Pathogens less often isolated from patients include Neisseria meningitidis, Pseudomonas aeruginosa and Giardia lamblia. Infections mostly affect the respiratory tract (nose, sinuses, bronchi, lungs) and the ears; they can also occur at other sites, such as the eyes, skin and gastrointestinal tract. These infections respond to antibiotics but can recur upon discontinuation of antibiotics. Bronchiectasis can develop when severe, recurrent pulmonary infections are left untreated.

In addition to infections, CVID patients can develop complications of different kinds. These include:

Anxiety and depression can occur as a result of dealing with the other symptoms.[6]

Causes

The underlying causes of CVID are largely obscure.[3] Genetic mutations can be identified as the cause of disease in about 10% of patients, while familial inheritance accounts for 10-25% of cases.[7] Rather than arising from a single genetic mutation, CVID seems to result from variety of mutations that all contribute to a failure in antibody production.

Mutations in the genes encoding ICOS, TACI, CD19, CD20, CD21, CD80 and BAFFR have been identified as causative of CVID.[7][8][9] Susceptibility to CVID may also be linked to the Major Histocompatibility Complex (MHC) of the genome, particularly to DR-DQ haplotypes.[10] A mutation in the NFKB2 gene has recently been shown to cause CVID-like symptoms in a murine model. The frequency of this NFKB2 mutation in the CVID population is, however, yet to be established.[11]

Diagnosis

According to a European registry study, the mean age at onset of symptoms was 26.3 years old.[12] As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is diagnosed if:[13]

Diagnosis is chiefly by exclusion, i.e. alternative causes of hypogammaglobulinemia, such as X-linked agammaglobulinemia, must be excluded before a diagnosis of CVID can be made.

Diagnosis is difficult because of the diversity of phenotypes seen in CVID patients. For example, serum immunoglobulin levels in CVID patients vary greatly. Generally, patients can be grouped as follows: no immunoglobulin production, immunoglobulin (Ig) M production only, or both normal IgM and IgG production.[2] Additionally, B cell numbers are also highly variable. 12% of patients have no detectable B cells, 12% have reduced B cells, and 54% are within the normal range.[13] In general, CVID patients display higher frequencies of naive B cells and lower frequencies of class-switched memory B cells. Frequencies of other B cell populations, such as IgD memory B cells, transitional B cells, and CD21 B cells, are also affected, and are associated with specific disease features. Although CVID is often thought of as a serum immunoglobulin and B cell-mediated disease, T cells can display abnormal behavior. Affected individuals typically present with low frequencies of CD4+, a T-cell marker, and decreased circulation of regulatory T cells and iNKT cell. Notably, approximately 10% of patients display CD4+ T cell counts lower than 200 cells/mm3; this particular phenotype of CVID has been named LOCID (Late Onset Combined Immunodeficiency), and has a poorer prognosis than classical CVID.

Types

The following types of CVID have been identified, and correspond to mutations in different gene segments.

Type OMIM Gene
CVID1 607594 ICOS
CVID2 240500 TACI
CVID3 613493 CD19
CVID4 613494 TNFRSF13C
CVID5 613495 CD20
CVID6 613496 CD81

Treatment

Treatment consists of immunoglobulin replacement therapy, which replenishes Ig subtypes that patients lack. This treatment is given at frequent intervals for life, and is thought to help reduce bacterial infections and boost immune function.[14] Before therapy begins, plasma donations are tested for known blood-borne pathogens, then pooled and processed to obtain concentrated IgG samples. Infusions can be administered in three different forms: intravenously (IVIg):,[15] subcutaneously (SCIg), and intramuscularly (IMIg).

The administration of intravenous immunoglobulins requires the insertion of a cannula or needle in a vein, usually in the arms or hands. Because highly concentrated product is used, IVIg infusions take place every 3 to 4 weeks. Subcutaneous infusions slowly release the Ig serum underneath the skin, again through a needle, and takes place every week.[16] Intramuscular infusions are no longer widely used, as they can be painful and are more likely to cause patient reaction.

Patients often experience adverse side effects to immunoglobulin infusions, including:

In addition to Ig replacement therapy, treatment may also involve immune suppressants, to control autoimmune symptoms of the disease, and high dose steroids like corticosteroids.[13] In some cases, antibiotics are used to fight chronic lung disease resulting from CVID.[17] The outlook for patients varies greatly depending on their level of lung and other organ damage prior to diagnosis and treatment.

Epidemiology

CVID has an estimated prevalence of about 1:50,000 in caucasians.[18] The disease seems to be less prevalent amongst Asians and African-Americans. Males and females are equally affected; however, among children, boys predominate.[2] A recent study of European patients with primary immunodeficiencies found that 30% had CVID, as opposed to a different immunodeficiency.[7] 10-25% of patients inherited the disease, typically through autosomal-dominant inheritance. Given the rarity of the disease, it is not yet possible to generalize on disease prevalence among ethnic and racial groups. CVID shortens the life-span; the median age of death for men and women is 42 and 44 years old, respectively.[3] Those patients who suffered from accompanying disorders had the worst prognosis and those CVID patients who suffered only from frequent infections had the longest survival rates, with life expectancy almost equalling that of the general UK population.[19] Additionally, CVID patients with one or more noninfectious complications have an 11 times higher risk of death as compared to patients with only infections.

History

[13] Charles Janeway, Sr. is generally credited with the first description of a case of CVID in 1953.[20] The case involved a 39-year-old who had recurrent infections, bronchiectasis, and meningitis.[7] Though described in 1953, there was no standard definition for CVID until the 1990s, which caused wide-spread confusion during diagnosis. During the 1990s, the European Society for Immunodeficiency (ESID) and Pan-American Group for Immunodeficiency (PAGID) developed diagnostic criteria, including minimum age of diagnosis and the need to exclude other conditions, to describe the disease. These criteria were published in 1999 and since that time, some aspects, like increasing the minimum age, have been changed.

Research

Funding for research in the US is provided by the National Institutes of Health. Key research in the UK was previously funded by the Primary Immunodeficiency Association (PiA) until its closure in January 2012,[21] and funding is raised through the annual Jeans for Genes campaign. Current efforts are aimed at studying the following:[13]

References

  1. 1 2 "Common Variable Immune Deficiency". Genetics Home Reference. Retrieved 8 February 2016.
  2. 1 2 3 4 5 6 Abbott, Jordan K.; Gelfand, Erwin W. (2015). "Common Variable Immunodeficiency: Diagnosis, Management, and Treatment". Immunol Allergy Clin N Am 35: 637–658. Retrieved 8 February 2016.
  3. 1 2 3 4 Resnick, Elena S.; Cunningham-Rundles, Charlotte (2012). "The many faces of the clinical picture of common variable immune deficiency". Current Opinion 12 (6): 595–601.
  4. ↑ Strober, Warren; Chua, Kevin (2000). "Common Variable Immunodeficiency". Clinical Reviews in Allergy and Immunology 19: 157–181.
  5. ↑ Herriot R, Sewell WA (2008). "Antibody deficiency". Journal of Clinical Pathology 61 (9): 994–1000. doi:10.1136/jcp.2007.051177. PMID 18755724.
  6. ↑ Sanger, David E. "An Investigation of Coping and Psychosocial Functioning in Persons with Common Variable Immunodeficiency (CVID)", Barts and The London NHS Trust, 2003, accessed August 7, 2011.
  7. 1 2 3 4 Park, Miguel A; Ti, James T; Hagan, John B; Maddox, Daniel E; Abraham, Roshini S (2008). "Common variable immunodeficiency: a new look at an old disease". The Lancet 372 (9637): 9–15.
  8. ↑ Salzer U, Neumann C, Thiel J; et al. (2008). "Screening of functional and positional candidate genes in families with common variable immunodeficiency". BMC Immunol. 9 (1): 3. doi:10.1186/1471-2172-9-3. PMC 2268914. PMID 18254984.
  9. ↑ Blanco-Quirós A, Solís-Sánchez P, Garrote-Adrados JA, Arranz-Sanz E (2006). "Common variable immunodeficiency. Old questions are getting clearer". Allergol Immunopathol (Madr) 34 (6): 263–75. doi:10.1157/13095875. PMID 17173844.
  10. ↑ O Olerup, O; Smith, CI; Björkander, J; Hammarström, L (Nov 15, 1992). "Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency.". PNAS 89 (22): 10653–10657. doi:10.1073/pnas.89.22.10653. PMC 50399. PMID 1438261.
  11. ↑ Chen, Karin; Emily M. Coonrod; Attila Kumánovics; Zechariah F. Franks; Jacob D. Durtschi; Rebecca L. Margraf; Wilfred Wu; Nahla M. Heikal; Nancy H. Augustine; Perry G. Ridge; Harry R. Hill; Lynn B. Jorde; Andrew S. Weyrich; Guy A. Zimmerman; Adi V. Gundlapalli; John F. Bohnsack; Karl V. Voelkerding (17 October 2013). "Germline Mutations in NFKB2 Implicate the Noncanonical NF-κB Pathway in the Pathogenesis of Common Variable Immunodeficiency.". The American Journal of Human Genetics 93: 812–24. doi:10.1016/j.ajhg.2013.09.009. PMID 24140114. Retrieved 18 October 2013.
  12. ↑ Bonilla, Francisco A.; Geha, Raif S. (2009). "Common Variable Immunodeficiency". Pediatric Research 65 (5): 13R–19R.
  13. 1 2 3 4 5 Chapel, Helen; Cunningham-Rundles, Charlotte (2009). "Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions". British Journal of Haematology 145: 709–727.
  14. ↑ "Primary immunodeficiency". Mayo Clinic. Retrieved 17 February 2016.
  15. ↑ Pourpak Z, Aghamohammadi A, Sedighipour L; et al. (2006). "Effect of regular intravenous immunoglobulin therapy on prevention of pneumonia in patients with common variable immunodeficiency" (abstract). J Microbiol Immunol Infect 39 (2): 114–20. PMID 16604243.
  16. ↑ Schwartz, Robert A; Modak, Rohit; Modak, Prema. "Common Variable Immunodeficiency Treatment and Management". Medscape. Retrieved 17 February 2016.
  17. ↑ "Common Variable Immune Deficiency". Immune Deficiency Foundation. Retrieved 16 February 2016.
  18. ↑ Common Variable Immunodeficiency : Article by Robert A Schwartz at eMedicine
  19. ↑ Chapel, Helen; Cunningham-Rundles, Charlotte (2009-06-01). "Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions". British Journal of Haematology 145 (6): 709–727. doi:10.1111/j.1365-2141.2009.07669.x. ISSN 1365-2141. PMC 2718064. PMID 19344423.
  20. ↑ Janeway CA, Apt L, Gitlin D (1953). "Agammaglobulinemia". Trans Assoc Am Physicians 66: 200–2. PMID 13136263.
  21. ↑ http://www.ukpin.org.uk/home/PIA-archive/index.htm

External links

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