CVID

同

common variable immunodeficiency

同

common variable immunodeficiency

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/05/16 21:10:02」(JST)

wiki en

[Wiki en表示]

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. 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. Generally, CVID symptoms include high susceptibility to foreign invaders, chronic lung disease, and inflammation and infection of the gastrointestinal tract. However, symptoms vary greatly. The disease is not only phenotypically heterogeneous, but also hard to diagnose, taking on average 6–7 years after onset.

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. 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. 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.

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. 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. 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:

• autoimmune manifestations, e.g. pernicious anemia, autoimmune haemolytic anemia (AHA), idiopathic thrombocytopenic purpura (ITP), psoriasis, vitiligo, rheumatoid arthritis, primary hypothyroidism, atrophic gastritis. Autoimmunity is the main type of complication in CVID patients, appearing in some form in up to 50% of individuals;
• malignancies, particularly Non-Hodgkin's lymphoma and gastric carcinoma;
• enteropathy, which manifests with a blunting of intestinal villi and inflammation, and is usually accompanied by symptoms such as abdominal cramps, diarrhea, constipation and, in some cases, malabsorption and weight loss. Symptoms of CVID enteropathy are similar to those of celiac disease, but don't respond to a gluten-free diet. Infectious causes must be excluded before a diagnosis of enteropathy can be made, as CVID patients are more susceptible to intestinal infections, e.g. by Giardia lamblia;
• lymphocytic infiltration of tissues, which can cause enlargement of lymph nodes (lymphadenopathy), of the spleen (splenomegaly) and of the liver (hepatomegaly), as well as the formation of granulomas.

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

Causes

The underlying causes of CVID are largely obscure. Genetic mutations can be identified as the cause of disease in about 10% of patients, while familial inheritance accounts for 10-25% of cases. 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. Susceptibility to CVID may also be linked to the Major Histocompatibility Complex (MHC) of the genome, particularly to DR-DQ haplotypes. 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.

Diagnosis

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

• the patient presents with a marked decrease of serum IgG levels (<4.5 g/L) and a marked decrease below the lower limit of normal for age in at least one of the isotypes IgM or IgA;
• the patient is four years of age or older;
• the patient lacks antibody immune response to protein antigens or immunization.

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. 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. 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. 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):, 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. 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:

• swelling at the insertion site (common in SCIG)
• chills
• headache
• nausea (common in IVIG)
• fatigue (common in IVIG)
• muscle aches and pain, or joint pain
• fever (common in IVIG and rare in SCIG)
• hives (rare)
• thrombotic events (rare)
• aseptic meningitis (rare, more common in patients with SLE)
• anaphylactic shock (very rare)

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. In some cases, antibiotics are used to fight chronic lung disease resulting from CVID. 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. The disease seems to be less prevalent amongst Asians and African-Americans. Males and females are equally affected; however, among children, boys predominate. A recent study of European patients with primary immunodeficiencies found that 30% had CVID, as opposed to a different immunodeficiency. 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. 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. 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

Charles Janeway, Sr. is generally credited with the first description of a case of CVID in 1953. The case involved a 39-year-old who had recurrent infections, bronchiectasis, and meningitis. 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, and funding is raised through the annual Jeans for Genes campaign. Current efforts are aimed at studying the following:

• Causes of complications. Little is known about why such diverse complications arise during treatment
• Underlying genetic factors. Though many polymorphisms and mutations have been identified, their respective roles in CVID development are poorly understood, and not represented in all CVID patients.
• Finding new ways to study CVID. Given that CVID arises from more than one gene, gene knock-out methods are unlikely to be helpful. It is necessary to seek out disease related polymorphisms by screening large populations of CVID patients, but this is challenging given the rarity of the disease.

References

• Moris G., Garcia-Monco JC (1999). "The Challenge of Drug-Induced Aseptic Meningitis". Archives of Internal Medicine 159 (11): 1185–1194. doi:10.1001/archinte.159.11.1185. PMID 10371226.  (IVIG and Aseptic Meningitis, association with SLE)

External links

• Immune Deficiency Foundation (US)
• Michigan Immunodeficiency Foundation (US)
• Immune Deficiencies Foundation of Australia
• Immune Deficiencies Foundation of New Zealand
• IPOPI (International Patient Organisation for Patients with Primary Immunodeficiency)
• Canadian Immunodeficiencies Patient Organization (Canada)
• Primary Immunodeficiency UK (United Kingdom and Northern Ireland)
• Dutch Patient Organisation for Primary Immunodeficiencies (SAS)
• GeneReviews/NCBI/NIH/UW entry on Common Variable Immune Deficiency Overview
• Maker of SCIG product
• Support and Discussion Forum for Primary Immunodeficiency including CVID, XLA, SCID, IgA Deficiency, Neutropenia, Goods Syndrome and Other Primary Immunodeficiencies

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 成人における分類不能型免疫不全の臨床症状、疫学、および診断 clinical manifestations epidemiology and diagnosis of common variable immunodeficiency in adults
• 2. 分類不能型低ガンマグロブリン血症の治療および予後 treatment and prognosis of common variable immunodeficiency
• 3. 小児における分類不能型免疫不全症 common variable immunodeficiency in children
• 4. 分類不能型低ガンマグロブリン血症の病因 pathogenesis of common variable immunodeficiency
• 5. 原発性の体液性免疫不全：概要 primary humoral immunodeficiencies an overview

English Journal

• Successful Hematopoietic Stem Cell Transplantation in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation.

• Tesi B1,2, Priftakis P3, Lindgren F3,4, Chiang SC5, Kartalis N4,6, Löfstedt A7,8, Lörinc E9,10, Henter JI7, Winiarski J3,4, Bryceson YT5, Meeths M11,12.
• Journal of clinical immunology.J Clin Immunol.2016 Jul;36(5):480-9. doi: 10.1007/s10875-016-0289-y. Epub 2016 May 4.
• PURPOSE: Autosomal recessive mutations in LRBA, encoding for LPS-responsive beige-like anchor protein, were described in patients with a common variable immunodeficiency (CVID)-like disease characterized by hypogammaglobulinemia, autoimmune cytopenias, and enteropathy. Here, we detail the clinical,
• PMID 27146671

• Use of Thrombopoietin-Receptor Agonist in CVID-Associated Immune Thrombocytopenia.

• Carrabba M1, Barcellini W2, Fabio G3,4.
• Journal of clinical immunology.J Clin Immunol.2016 Jul;36(5):434-6. doi: 10.1007/s10875-016-0282-5. Epub 2016 Apr 12.
• PMID 27072856

• Bone marrow transplantation for CVID-like humoral immune deficiency associated with red cell aplasia.

• Sayour EJ1,2, Mousallem T3,4, Van Mater D5, Wang E6, Martin P7, Buckley RH4, Barfield RC5.
• Pediatric blood & cancer.Pediatr Blood Cancer.2016 Jun 8. doi: 10.1002/pbc.26092. [Epub ahead of print]
• Patients with common variable immunodeficiency (CVID) have a higher incidence of autoimmune disease, which may mark the disease onset; however, anemia secondary to pure red cell aplasia is an uncommon presenting feature. Here, we describe a case of CVID-like humoral immune deficiency in a child who
• PMID 27273469

Japanese Journal

• WS5-4　全身性エリテマトーデスと免疫不全

• 日本臨床免疫学会会誌 40(4), 271b-271b, 2017
• NAID 130006219379

• Intravenous Immunoglobulin Monotherapy for Granulomatous Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency

• Internal Medicine 56(21), 2899-2902, 2017
• NAID 130006191932

• Diffuse Nodular Lymphoid Hyperplasia of the Intestine Caused by Common Variable Immunodeficiency and Refractory Giardiasis

• Internal Medicine 56(3), 283-287, 2017
• NAID 130005310322

Related Links

• 分類不能型免疫不全症（CVID）-Part2- | e-免疫.com -原発性 ...

CVIDでは現在までにCD19, CD21, CD81, CD20, BAFF-R, TACI, ICOSなどが責任遺伝子として同定され、新たな疾患として独立したが、未だに分類上はCVIDの範疇に入っている。ICOSを除き、B細胞上に発現する分子である。

• 分類不能型免疫不全症（CVID）-Part1- | e-免疫.com -原発性 ...

CVIDではすべての免疫グロブリン値が著減するが、末梢血Bリンパ球数はリンパ球の1％以上である。末梢血Bリンパ球はナイーブB細胞とメモリーB細胞に分けることができ、臍帯血B細胞はほとんどナイーブB細胞で占められるが、健常者で ...

Related Pictures

---

★リンクテーブル★

リンク元	「分類不能型原発性免疫不全症」「common variable immunodeficiency」
関連記事	「CV」

「分類不能型原発性免疫不全症」

　　[★]

英

common variable immunodeficiency, common variable immunodeficiency CVID

関

分類不能型免疫不全症

「common variable immunodeficiency」

　　[★]

同

CVID

同

CVID

同

CVID

同

CVID

「CV」

　　[★]

• クリオグロブリン血症性血管炎 cryoglobulinemic vasculitis
• クロージングボリューム closing volume
• 変動係数 coefficient of variation
• 興奮伝導速度 conduction velocity