Common variable immunodeficiency: Difference between revisions

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{{Infobox_Disease |
  Name          = {{PAGENAME}} |
  Image          = |
  Caption        = |
  DiseasesDB    = 3274 |
  ICD10          = {{ICD10|D|83||d|80}} |
  ICD9          = {{ICD9|279.06}} |
  ICDO          = |
  OMIM          = 240500 |
  MedlinePlus    = |
  eMedicineSubj  = |
  eMedicineTopic = |
  eMedicine_mult = |
  MeshID        = D017074 |
}}
{{SI}}
{{SI}}


{{CMG}}'''; Associate Editor-In-Chief:''' {{CZ}}
{{CMG}}''' {{shyam}}; Associate Editor-In-Chief:''' {{M.B}} {{HK}}


{{SK}} CVID; common variable hypogammaglobulinaemia; non-familial hypogammaglobulinaemia
{{SK}} CVID; common variable hypogammaglobulinaemia; non-familial hypogammaglobulinaemia; acquired hypogammaglobulinemia; immunodeficiency, common variable; late-onset immunoglobulin deficiency


==Overview==
==Overview==
Common variable immunodeficiency (CVID) is a [[Primary immunodeficiency|primary immunodeficiency disorder]]. CVID is the most common [[antibody]] deficiency affecting both children and adults. The characteristic immunological defect in CVID is impaired [[B cell]] differentiation with defective production of [[Antibody|immunoglobulin]]. Impaired [[B cell]] differentiation leads to low serum concentrations of [[immunoglobulin G]] ([[Immunoglobulin G|IgG]]), low [[immunoglobulin A]] ([[Immunoglobulin A|IgA]]) and/or [[immunoglobulin M]] ([[Immunoglobulin M|IgM]]), as well poor or absent response to [[Vaccination|immunization]]. The majority of patients are diagnosed between the ages of 20 and 40 years. Recurrent bacterial infections of the [[Respiratory tract|sino-pulmonary tract]] ([[Rhinosinusitis|sinusitis]] and [[pneumonia]]) are most common manifestations of patients with CVID. [[Opportunistic infection|Opportunistic]] and unusual infections are uncommon, but may occur. In addition to recurrent infections, patients with CVID have evidence of immune dysregulation leading to [[autoimmunity]]. Patients may suffer from [[Chronic (medical)|chronic]] [[Respiratory disease|lung disease]], gastrointestinal and liver disorders, granulomatous infiltrations, lymphoid [[hyperplasia]], [[splenomegaly]], or [[Cancer|malignancy]]. Various forms of primary and secondary [[hypogammaglobulinemia]] must be excluded before the diagnosis of CVID. The diagnosis of CVID requires a suggestive clinical history, a reduced total serum concentration of [[Immunoglobulin G|IgG]], plus low [[Immunoglobulin A|IgA]] or [[Immunoglobulin M|IgM]], and poor responses to both protein- and polysaccharide-based vaccines.


'''Common variable immunodeficiency''' (CVID) is a group of 20-30 primary [[immunodeficiency|immunodeficiencies]] (PIDs) which have a common set of symptoms but with different underlying causes.
==Historical Perspective==
* In 1953, Charles Janeway was the first to describe CVID as a separate entity.
* In 1990, the European Society for Immunodeficiency (ESID) and Pan-American Group for Immunodeficiency (PAGID) determined the diagnostic criteria, including minimum age of diagnosis and the need to rule out other diseases, to determine CVID.<ref>Janeway CA, Apt L, Gitlin D. Agammaglobulinemia. ''Trans Assoc Am Physicians'' 1953;66:200-2. PMID 13136263</ref>


==Historyical Perspective==
==Classification==
Charles Janeway ''et al'' (1953) is generally credited with the description of the first case of CVID.<ref>Janeway CA, Apt L, Gitlin D. Agammaglobulinemia. ''Trans Assoc Am Physicians'' 1953;66:200-2. PMID 13136263</ref>
Common variable immunodeficiency (CVID) is a heterogeneous immune disorder characterized by recurrent [[Rhinosinusitis|sinopulmonary infections]], [[Autoimmune disease|autoimmune diseases]], and granulomatous disease. A [[Phenotype|phenotypic]] approach to classify CVID has been suggested, based upon the type of complications the patient demonstrates. Five phenotypic categories were proposed:<ref>{{Cite journal
| author = [[Helen Chapel]], [[Mary Lucas]], [[Martin Lee]], [[Janne Bjorkander]], [[David Webster]], [[Bodo Grimbacher]], [[Claire Fieschi]], [[Vojtech Thon]], [[Mohammad R. Abedi]] & [[Lennart Hammarstrom]]
| title = Common variable immunodeficiency disorders: division into distinct clinical phenotypes
| journal = [[Blood]]
| volume = 112
| issue = 2
| pages = 277–286
| year = 2008
| month = July
| doi = 10.1182/blood-2007-11-124545
| pmid = 18319398
}}</ref>
* CVID patients with no [[Complication (medicine)|complications]].
* CVID patients with [[autoimmune disease]].
* CVID patients with lymphocytic organ infiltration i.e. [[Enteropathy-associated T-cell lymphoma|lymphocytic enteropathy]], [[Granuloma|granulomas]], [[hepatomegaly]], [[lymphadenopathy]], and [[splenomegaly]].
* CVID patients with predominant [[enteropathy]].
* CVID patients with [[Lymphoma|lymphoid malignancy]].


==Classification==
==Pathophysiology==
Types of CVID include:
* The exact pathophysiology of CVID is not fully understood. 
* Defective [[Antibody|immunoglobulin]] [[secretion]] leading to dysregulated immune function is believed to be main pathophysiological mechanism of CVID.
** Defective [[B cell]] [[differentiation]] into [[Plasma cell|plasma cells]], results in inability to produce specific [[Antibody|immunoglobulins]]. 
* Multiple immuno-regulatory dysfunction leads to [[hypogammaglobulinemia]].<ref>{{Cite journal
| author = [[C. Cunningham-Rundles]] & [[C. Bodian]]
| title = Common variable immunodeficiency: clinical and immunological features of 248 patients
| journal = [[Clinical immunology (Orlando, Fla.)]]
| volume = 92
| issue = 1
| pages = 34–48
| year = 1999
| month = July
| doi = 10.1006/clim.1999.4725
| pmid = 10413651
}}</ref>
* CVID is associated with a high occurrence of [[Autoimmune disease|autoimmune]], inflammatory, and malignant disorders, whereas these conditions are not observed in  [[X-linked agammaglobulinemia]] ([[X-linked agammaglobulinemia|XLA]]), a disease that affects early [[B cell]] development.<ref>{{Cite journal
| author = [[C. Cunningham-Rundles]] & [[C. Bodian]]
| title = Common variable immunodeficiency: clinical and immunological features of 248 patients
| journal = [[Clinical immunology (Orlando, Fla.)]]
| volume = 92
| issue = 1
| pages = 34–48
| year = 1999
| month = July
| doi = 10.1006/clim.1999.4725
| pmid = 10413651
}}</ref>


* CVID appears to result from a number of gene defects. which may be either [[Recessive gene|recessive in inheritance]] or [[Autosomal dominant inheritance|autosomal dominant]]. Some of these are due to defects of B cell [[Signal (biology)|signalling molecules]] but additional genes affecting immune regulation may also lead to the CVID [[phenotype]].<ref>{{Cite journal
| author = [[Emanuela Castigli]] & [[Raif S. Geha]]
| title = Molecular basis of common variable immunodeficiency
| journal = [[The Journal of allergy and clinical immunology]]
| volume = 117
| issue = 4
| pages = 740–746
| year = 2006
| month = April
| doi = 10.1016/j.jaci.2006.01.038
| pmid = 16630927
}}</ref><ref>{{Cite journal
| author = [[O. Kopecky]] & [[S. Lukesova]]
| title = Genetic defects in common variable immunodeficiency
| journal = [[International journal of immunogenetics]]
| volume = 34
| issue = 4
| pages = 225–229
| year = 2007
| month = August
| doi = 10.1111/j.1744-313X.2007.00681.x
| pmid = 17627754
}}</ref>
{| class="wikitable"
{| class="wikitable"
|+
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Type         
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Gene       
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Immunoglobulin Deficiency 
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Phenotype 
|-
|-
! Type
|ICOS deficiency
! Gene
|''[[ICOS]]''
|Low IgG and IgA
|Recurrent infections, autoimmunity, gastroenteritis.
|-
|-
| CVID1
|CD19 deficiency
| ''[[CD278|ICOS]]''
|   ''[[CD19]]''
|Low IgG and IgA
|Recurrent infections.
 
May be associated with glomerulonephritis.
|-
|-
| CVID2
|CD81 deficiency
| ''[[TACI]]''
|   ''[[CD81]]''
|Low IgG, low or normal IgA and IgM
|Recurrent infections.
May be associated with glomerulonephritis.
|-
|-
| CVID3
|CD20 deficiency
| ''[[CD19]]''
|   ''[[CD20]]''
|Low IgG, normal or elevated IgM, and IgA
|Recurrent infections.
|-
|-
| CVID4
|CD21 deficiency
| ''[[TNFRSF13C]]''
|   ''CD21''
|Low IgG; impaired antipneumococcal response
|Recurrent infections.
|-
|-
| CVID5
|TACI deficiency
| ''[[CD20]]''
| ''[[TNFRSF13B]]''
|Low IgG and IgA and/or IgM
|Variable clinical expression
|-
|-
| CVID6
|BAFF-receptor
| ''[[CD81]]''
deficiency
|''[[TNFRSF13C]]''
|Low IgG and IgM
|Variable clinical expression
|-
|TWEAK deficiency
|  ''TWEAK''
|Low IgM and IgA; lack of antipneumococcal antibody
|Recurrent infections such as Pneumonia, bacterial infections, warts;
and  thrombocytopenia; neutropenia
|-
|NF-kappa-B2
deficiency
|  ''[[NFKB2]]''
|Low IgG and IgA and IgM; very low B cells in some
|Recurrent infections; adrenal insufficiency;
 
ACTH deficiency; alopecia
|-
|NF-kappa-B1
deficiency
| ''[[NFKB1]]''
|Low IgG and IgA and IgM; low B cells in some
|Recurrent infections
|-
|IKAROS
|  ''[[IKZF1]]''
|Low IgG and IgA and IgM, very low B cells
|Recurrent infections
|}
|}


==Pathophysiology==
==Causes==
The cause of common variable immunodeficiency has not been identified. [[Mutations|Genetic mutations]] may be recognized as the cause of CVID in about 10% of patients, and familial [[Heredity|inheritance]] accounts for 10-25% of the affected population. Rather than arising from a single genetic mutation, CVID is due to numerous [[Mutation|mutations]] that all are associated with dysfunction in antibody regulation and production.<ref name="ParkLi2008">{{cite journal|last1=Park|first1=Miguel A|last2=Li|first2=James T|last3=Hagan|first3=John B|last4=Maddox|first4=Daniel E|last5=Abraham|first5=Roshini S|title=Common variable immunodeficiency: a new look at an old disease|journal=The Lancet|volume=372|issue=9637|year=2008|pages=489–502|issn=01406736|doi=10.1016/S0140-6736(08)61199-X}}</ref>
 
==Differentiating Common Variable Immunodeficiency from other Diseases==
Common variable immunodeficiency should be differentiated from other disorders leading to [[hypogammaglobulinemia]] and defects of [[humoral immunity]]. The following conditions may be considered as differentials:<ref name="pmid17910333">{{cite journal |vauthors=Agarwal S, Cunningham-Rundles C |title=Assessment and clinical interpretation of reduced IgG values |journal=Ann. Allergy Asthma Immunol. |volume=99 |issue=3 |pages=281–3 |date=September 2007 |pmid=17910333 |pmc=3099256 |doi=10.1016/S1081-1206(10)60665-5 |url=}}</ref><ref name="pmid7679206">{{cite journal |vauthors=Korthäuer U, Graf D, Mages HW, Brière F, Padayachee M, Malcolm S, Ugazio AG, Notarangelo LD, Levinsky RJ, Kroczek RA |title=Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM |journal=Nature |volume=361 |issue=6412 |pages=539–41 |date=February 1993 |pmid=7679206 |doi=10.1038/361539a0 |url=}}</ref><ref name="pmid9255191">{{cite journal |vauthors=Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, Resnick I, Fasth A, Baer M, Gomez L, Sanders EA, Tabone MD, Plantaz D, Etzioni A, Monafo V, Abinun M, Hammarstrom L, Abrahamsen T, Jones A, Finn A, Klemola T, DeVries E, Sanal O, Peitsch MC, Notarangelo LD |title=Clinical spectrum of X-linked hyper-IgM syndrome |journal=J. Pediatr. |volume=131 |issue=1 Pt 1 |pages=47–54 |date=July 1997 |pmid=9255191 |doi= |url=}}</ref><ref name="pmid14663287">{{cite journal |vauthors=Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME |title=The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients |journal=Medicine (Baltimore) |volume=82 |issue=6 |pages=373–84 |date=November 2003 |pmid=14663287 |doi=10.1097/01.md.0000100046.06009.b0 |url=}}</ref><ref name="pmid10352287">{{cite journal |vauthors=Subauste CS, Wessendarp M, Sorensen RU, Leiva LE |title=CD40-CD40 ligand interaction is central to cell-mediated immunity against Toxoplasma gondii: patients with hyper IgM syndrome have a defective type 1 immune response that can be restored by soluble CD40 ligand trimer |journal=J. Immunol. |volume=162 |issue=11 |pages=6690–700 |date=June 1999 |pmid=10352287 |doi= |url=}}</ref><ref name="pmid8993019">{{cite journal |vauthors=Hayward AR, Levy J, Facchetti F, Notarangelo L, Ochs HD, Etzioni A, Bonnefoy JY, Cosyns M, Weinberg A |title=Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM |journal=J. Immunol. |volume=158 |issue=2 |pages=977–83 |date=January 1997 |pmid=8993019 |doi= |url=}}</ref><ref name="pmid20180797">{{cite journal |vauthors=Davies EG, Thrasher AJ |title=Update on the hyper immunoglobulin M syndromes |journal=Br. J. Haematol. |volume=149 |issue=2 |pages=167–80 |date=April 2010 |pmid=20180797 |pmc=2855828 |doi=10.1111/j.1365-2141.2010.08077.x |url=}}</ref><ref name="pmid20101521">{{cite journal |vauthors=Yel L |title=Selective IgA deficiency |journal=J. Clin. 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Immunol. |volume=111 |issue= |pages=47–107 |date=2011 |pmid=21970952 |doi=10.1016/B978-0-12-385991-4.00002-7 |url=}}</ref><ref name="pmid16007087">{{cite journal |vauthors=Salzer U, Chapel HM, Webster AD, Pan-Hammarström Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schäffer AA, Hammarström L, Grimbacher B |title=Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans |journal=Nat. Genet. |volume=37 |issue=8 |pages=820–8 |date=August 2005 |pmid=16007087 |doi=10.1038/ng1600 |url=}}</ref><ref name="pmid17510807">{{cite journal |vauthors=Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, Claudio P, Franco D, Maria Pesce A, Borghese F, Guerra A, Rondelli R, Plebani A |title=Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency |journal=J. Clin. Immunol. |volume=27 |issue=3 |pages=308–16 |date=May 2007 |pmid=17510807 |doi=10.1007/s10875-007-9075-1 |url=}}</ref><ref name="pmid26564081">{{cite journal |vauthors=Nissenkorn A, Ben-Zeev B |title=Ataxia telangiectasia |journal=Handb Clin Neurol |volume=132 |issue= |pages=199–214 |date=2015 |pmid=26564081 |doi=10.1016/B978-0-444-62702-5.00014-7 |url=}}</ref><ref name="pmid27884168">{{cite journal |vauthors=Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM |title=Ataxia telangiectasia: a review |journal=Orphanet J Rare Dis |volume=11 |issue=1 |pages=159 |date=November 2016 |pmid=27884168 |pmc=5123280 |doi=10.1186/s13023-016-0543-7 |url=}}</ref><ref name="pmid9874856">{{cite journal |vauthors=Crawford TO |title=Ataxia telangiectasia |journal=Semin Pediatr Neurol |volume=5 |issue=4 |pages=287–94 |date=December 1998 |pmid=9874856 |doi= |url=}}</ref><ref name="pmid2415689">{{cite journal |vauthors=Boder E |title=Ataxia-telangiectasia: an overview |journal=Kroc Found Ser |volume=19 |issue= |pages=1–63 |date=1985 |pmid=2415689 |doi= |url=}}</ref><ref name="pmid22614068">{{cite journal |vauthors=Hoche F, Seidel K, Theis M, Vlaho S, Schubert R, Zielen S, Kieslich M |title=Neurodegeneration in ataxia telangiectasia: what is new? What is evident? |journal=Neuropediatrics |volume=43 |issue=3 |pages=119–29 |date=June 2012 |pmid=22614068 |doi=10.1055/s-0032-1313915 |url=}}</ref><ref name="pmid13542097">{{cite journal |vauthors=BODER E, SEDGWICK RP |title=Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection |journal=Pediatrics |volume=21 |issue=4 |pages=526–54 |date=April 1958 |pmid=13542097 |doi= |url=}}</ref><ref name="pmid24683014">{{cite journal |vauthors=Sahama I, Sinclair K, Pannek K, Lavin M, Rose S |title=Radiological imaging in ataxia telangiectasia: a review |journal=Cerebellum |volume=13 |issue=4 |pages=521–30 |date=August 2014 |pmid=24683014 |doi=10.1007/s12311-014-0557-4 |url=}}</ref><ref name="pmid23886747">{{cite journal |vauthors=Lin DD, Barker PB, Lederman HM, Crawford TO |title=Cerebral abnormalities in adults with ataxia-telangiectasia |journal=AJNR Am J Neuroradiol |volume=35 |issue=1 |pages=119–23 |date=January 2014 |pmid=23886747 |pmc=4106125 |doi=10.3174/ajnr.A3646 |url=}}</ref><ref name="pmid15069401">{{cite journal |vauthors=Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM |title=Immunodeficiency and infections in ataxia-telangiectasia |journal=J. Pediatr. |volume=144 |issue=4 |pages=505–11 |date=April 2004 |pmid=15069401 |doi=10.1016/j.jpeds.2003.12.046 |url=}}</ref>
{| class="wikitable"
|+
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Disorder
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Defect (Mechanism of Development)
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Characteristic Features
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Clinical Presentation
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Laboratory Findings
|-
|[[X-linked agammaglobulinemia|'''X-Linked (Bruton) Agammaglobulinemia''']]
|
* Defect in [[tyrosine kinase]] [[gene]] ([[Bruton's tyrosine kinase|BTK]])
* [[B cells]] fail to mature
|
* [[X-linked recessive]] pattern of inheritance
* Increased [[prevalence]] in [[males]]
|
* Recurrent [[bacterial]] and [[enteroviral]] [[infections]] after 6 months of age
* Pre-disposition to development of [[infections]] by [[encapsulated organisms]]
* Pre-disposition to development of Giardia infections
* Absent lymph nodes and tonsils
|
* Normal [[CD19|CD19+ B cell]] count
* Decreased pro-[[B cells]]
* Increased pre-[[B cells]]
* Decreased [[immunoglobulins]] of all classes
|-
|[[IgA deficiency|'''Selective IgA Deficiency''']]
|
* [[Stem cell]] defect (Transferrable with [[Bone marrow transplant|marrow transplant]])
* Lack of [[Interleukin 4|IL-4]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 10|IL-10]], [[TGF beta|TGF-β]], and [[Interleukin 21|IL-21]]
* [[Mutations]] in [[transmembrane]] activator and calcium-modulator and [[cyclophilin]] ligand interactor ([[TACI]], [[TNFRSF13B]])
|
* Most common primary [[immune deficiency]]
|
* Majority of the cases are [[asymptomatic]]
* Respiratory and [[gastrointestinal]] infections ([[mucosal]] infections)
* Associated with [[autoimmune diseases]]
* [[Atopy]]
* [[Anaphylaxis]] to [[IgA]] containing products
|
* Serum [[IgA]] < 7 mg/dl
* Normal [[IgG]] and [[IgM]] levels
|-
|[[Common variable immunodeficiency|'''Common Variable Immunodeficiency''']]
|
* Defective [[B cell]] differentiation
|
* May be acquired in 20-30 years of age
|
* May present with other [[autoimmune diseases]]
* Associated with [[bronchiectasis]]
* Associated with [[lymphoma]]
* Associated with sinopulmonary infections ([[Bacterial]], [[enteroviral]] and [[parasitic]] such as [[Giardia]])
|
* Decreased [[plasma cells]]
* Decreased [[immunoglobulins]]
|-
|[[Job's syndrome|'''Autosomal dominant hype IgE syndrome (Job's Syndrome)''']]
|
* Defieciency of [[T helper 17 cell|Th17 cells]] due to [[STAT3]] [[mutation]]
* Impaired [[neutrophils]] to sites of [[infection]]
|
* Distinctive coarse facies
* Cold (non-inflammatory) Staphylococcal abscesses
* Retained primary teeth
* Eczema
|
|
* Increased levels of [[IgE]]
* Decreased levels of [[interferon gamma]] (IFN-gamma)
|-
|[[Severe combined immunodeficiency|'''Severe combined immunodeficiency (SCID)''']]
|
* Defective [[Interleukin-2 receptor|interleukin-2 receptor gamma chain]]
* [[Adenosine deaminase]] deficiency
* Reg 1 and Reg 2 [[nonsense mutations]]
|
* [[Interleukin 20 receptor, alpha subunit|IL-2R]] disease is [[X-linked]]
* [[Adenosine deaminase|ADA]] deficiency and reg mutations are typically [[autosomal recessive]]
|
* [[Failure to thrive]]
* [[Chronic diarrhea]]
* [[Thrush]]
* Recurrent [[bacterial]], [[viral]] and [[protozoal]] infections
* Treatment is [[bone marrow]] [[transplant]]
|
* Decreased [[T cell]] receptor excision circles (TRECs)
* Abscence of [[thymic]] shadow on [[Chest X-ray|chest X-Ray]]
* Absent [[germinal centers]] of [[lymph node biopsy]]
* Absent [[T cells]] on [[flow cytometry]]
|-
|[[Ataxia telangiectasia|'''Ataxia Telangiectasia''']]
|
* Defect in [[ATM|ATM gene]] which encodes a kinase necessary for ''TP53'' activity
* [[DNA]] double stranded breaks leading to [[cell cycle]] arrest
|
* Hypersensitivity to [[X-Ray|X-Rays]]
|
* Triad of:
** [[Ataxia]]
** Spider [[Angioma|angiomas]] (Nests of distended [[capillaries]])
** [[IgA deficiency]]
|
* Increased [[alpha fetoprotein]] ([[Alpha-fetoprotein|AFP]])
* Decreased [[IgA]], [[IgG]] and [[IgE]]
* [[Lymphopenia]]
* [[Cerebellar]] atrophy
|-
|[[Hyper IgM Syndrome Type 1|'''Hyper IgM Syndrome''']]
|
* Defective [[CD40L]] ([[CD40L|CD40 ligand]]) on [[T helper cell|Th cells]] leading to [[class switching]] defect
|
* [[X-linked recessive]] pattern of inheritance
|
* Severe pyogenic infections in early life
* Opportunistic infection with:
** [[Pneumocystis jiroveci]]
** [[Cryptosporidium]]
** [[Cytomegalovirus]] ([[Cytomegalovirus infection|CMV]])
|
* Increased [[Immunoglobulin M|IgM]]
* Decreased [[Immunoglobulin G|IgG]], [[IgA]] and [[Immunoglobulin E|IgE]]
* No [[germinal centers]]
|-
|[[Wiskott-Aldrich syndrome|'''Wiskott-Aldrich Syndrome''']]
|
* [[Mutation]] in [[WAS]] [[gene]]
* [[T cells]] unable to reorganize [[actin]] [[microfilaments]] ([[microfilament]] defect)
|
* [[X-linked recessive]] pattern of inheritance
* Increased risk of [[autoimmune disease]] and [[malignancy]]
|
* [[Thrombocytopenic purpura]]
* [[Eczema]]
* Recurrent [[infections]]
|
* Decreased to normal [[Immunoglobulin G|IgG]] and [[Immunoglobulin M|IgM]]
* Increased [[Immunoglobulin E|IgE]] and [[IgA]]
* Fewer and smaller [[platelets]]
|}
:*Malignancy: can cause the reduction in the immunoglobulin production.<ref>{{Cite journal
| author = [[T. Zenone]], [[P. J. Souquet]], [[C. Cunningham-Rundles]] & [[J. P. Bernard]]
| title = Hodgkin's disease associated with IgA and IgG subclass deficiency
| journal = [[Journal of internal medicine]]
| volume = 240
| issue = 2
| pages = 99–102
| year = 1996
| month = August
| pmid = 8810936
}}</ref>
*Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
*Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.<ref>{{Cite journal
| author = [[W. B. Klaustermeyer]], [[M. E. Gianos]], [[M. L. Kurohara]], [[H. T. Dao]] & [[D. C. Heiner]]
| title = IgG subclass deficiency associated with corticosteroids in obstructive lung disease
| journal = [[Chest]]
| volume = 102
| issue = 4
| pages = 1137–1142
| year = 1992
| month = October
| pmid = 1343817
}}</ref>
*Other causes of primary humoral immunodeficiencies.
*Smoking: may cause IgG2 subclass deficiency.<ref>{{Cite journal
| author = [[I. Qvarfordt]], [[G. C. Riise]], [[B. A. Andersson]] & [[S. Larsson]]
| title = IgG subclasses in smokers with chronic bronchitis and recurrent exacerbations
| journal = [[Thorax]]
| volume = 56
| issue = 6
| pages = 445–449
| year = 2001
| month = June
| pmid = 11359959
}}</ref>
*Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.


CVID is believed to be a genetically determined primary immune defect; however, the underlying causes are different.  The result of these defects is  that the patient doesn't produce sufficient antibodies in response to exposure to pathogens.  As a result, the patient's immune system fails to protect them against common bacterial and viral (and occasionally parasitic and protozoan) infections. The net result is that the patient is susceptible to illness. Both parts of the immune system (the cellular and humoral system) are affected, hence its classification as a ''combined'' immunodeficiency.
==Epidemiology and Demographics==
===Prevalence===
[[CVID]] has an estimated prevalence ranging from a low of 2 per 100,000 to a high of 4 per 100,000 with an average of 3 per 100,000.<ref>{{Cite journal
  | author = [[L. Hammarstrom]], [[I. Vorechovsky]] & [[D. Webster]]
  | title = Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)
  | journal = [[Clinical and experimental immunology]]
| volume = 120
| issue = 2
| pages = 225–231
| year = 2000
| month = May
| pmid = 10792368
}}</ref>


CVID appears to include a number of defects, some of which have been identified. For the majority, the genetic causes are still unknown.  It is possible that environmental agents provoke the immune defect, due to genetic predisposition, but this has not been clarified.
===Age===
* The typical patient is after [[puberty]] and between 20 and 40 years age.
* About 20% of patients are diagnosed in childhood.
* In an analysis of the CVID data from the ESID about 35 percent of patients were diagnosed before 10 years of age; and in studies from United States centers, 20 percent of patients are diagnosed before the age of 20 years. The majority of patients are diagnosed between the ages of 20 and 45. <ref>{{Cite journal
| author = [[C. Cunningham-Rundles]] & [[C. Bodian]]
| title = Common variable immunodeficiency: clinical and immunological features of 248 patients
  | journal = [[Clinical immunology (Orlando, Fla.)]]
| volume = 92
| issue = 1
| pages = 34–48
| year = 1999
| month = July
| doi = 10.1006/clim.1999.4725
| pmid = 10413651
}}</ref> <ref>{{Cite journal
| author = [[R. A. Hermaszewski]] & [[A. D. Webster]]
| title = Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications
| journal = [[The Quarterly journal of medicine]]
| volume = 86
| issue = 1
| pages = 31–42
| year = 1993
| month = January
| pmid = 8438047
}}</ref>


See also [[X-linked agammaglobulinemia]], a similar disorder, better characterised than CVID.
===Gender===
[[Hypogammaglobulinemia]] (CVID) and [[X-linked agammaglobulinemia]] (XLA) are often intermixed by physicians, as their clinical conditions and treatment are almost identical.
There is no gender predilection to common variable immunodeficiency.


==Epidemiology==
===Race===
Race is not associated with an increased risk of common variable immunodeficiency. However, there is some evidence of higher prevalence among individuals of northern European descent.<ref>{{Cite journal
| author = [[L. Hammarstrom]], [[I. Vorechovsky]] & [[D. Webster]]
| title = Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)
| journal = [[Clinical and experimental immunology]]
| volume = 120
| issue = 2
| pages = 225–231
| year = 2000
| month = May
| pmid = 10792368
}}</ref>


===Prevalence===
==Natural History, Complications and Prognosis==
CVID has an estimated prevalence ranging from a low of 2 per 100,000 to a high of 4 per 100,000.
===Natural History===
* All patients have several histories of [[Acute (medicine)|acute]] and recurrent [[Infection|infections]].
* The majority of patients with CVID have evidence of immune dysregulation leading to [[autoimmunity]], inflammatory disorders, and [[Cancer|malignant disease]].
* Accordingly, CVID  Patients may suffer from chronic lung disease, gastrointestinal and liver disorders, granulomatous infiltrations of several organs, lymphoid [[hyperplasia]], splenomegaly, or malignancy.<ref>{{Cite journal
| author = [[L. Hammarstrom]], [[I. Vorechovsky]] & [[D. Webster]]
| title = Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)
| journal = [[Clinical and experimental immunology]]
| volume = 120
| issue = 2
| pages = 225–231
| year = 2000
| month = May
| pmid = 10792368
}}</ref>
* The clinical manifestations of CVID affect multiple organ systems, and patients often have the history of several specialists visits by the time they are recognized. It may be partly for this reason, delayed diagnosis of this condition is common. in the European Society for Immunodeficiencies (ESID) database, and other studies, there was an average of five to seven years between the beginning of symptoms and diagnosis<ref>{{Cite journal
| author = [[C. Cunningham-Rundles]] & [[C. Bodian]]
| title = Common variable immunodeficiency: clinical and immunological features of 248 patients
| journal = [[Clinical immunology (Orlando, Fla.)]]
| volume = 92
| issue = 1
| pages = 34–48
| year = 1999
| month = July
| doi = 10.1006/clim.1999.4725
| pmid = 10413651
}}</ref><ref>{{Cite journal
| author = [[Benjamin Gathmann]], [[Nizar Mahlaoui]], [[Laurence Gerard]], [[Eric Oksenhendler]], [[Klaus Warnatz]], [[Ilka Schulze]], [[Gerhard Kindle]], [[Taco W. Kuijpers]], [[Rachel T. van Beem]], [[David Guzman]], [[Sarita Workman]], [[Pere Soler-Palacin]], [[Javier De Gracia]], [[Torsten Witte]], [[Reinhold E. Schmidt]], [[Jiri Litzman]], [[Eva Hlavackova]], [[Vojtech Thon]], [[Michael Borte]], [[Stephan Borte]], [[Dinakantha Kumararatne]], [[Conleth Feighery]], [[Hilary Longhurst]], [[Matthew Helbert]], [[Anna Szaflarska]], [[Anna Sediva]], [[Bernd H. Belohradsky]], [[Alison Jones]], [[Ulrich Baumann]], [[Isabelle Meyts]], [[Necil Kutukculer]], [[Per Wagstrom]], [[Nermeen Mouftah Galal]], [[Joachim Roesler]], [[Evangelia Farmaki]], [[Natalia Zinovieva]], [[Peter Ciznar]], [[Efimia Papadopoulou-Alataki]], [[Kirsten Bienemann]], [[Sirje Velbri]], [[Zoya Panahloo]] & [[Bodo Grimbacher]]
| title = Clinical picture and treatment of 2212 patients with common variable immunodeficiency
| journal = [[The Journal of allergy and clinical immunology]]
| volume = 134
| issue = 1
| pages = 116–126
| year = 2014
| month = July
| doi = 10.1016/j.jaci.2013.12.1077
| pmid = 24582312
}}</ref>


===Age===
===Complications===
The typical patient is between 20 and 40.  About 20% of patients are diagnosed in childhood.
Numerous complications are possible in CVID. They include:<ref>{{Cite journal
| author = [[L. Hammarstrom]], [[I. Vorechovsky]] & [[D. Webster]]
| title = Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)
| journal = [[Clinical and experimental immunology]]
| volume = 120
| issue = 2
| pages = 225–231
| year = 2000
| month = May
| pmid = 10792368
}}</ref><ref>{{Cite journal
| author = [[R. A. Hermaszewski]] & [[A. D. Webster]]
| title = Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications
  | journal = [[The Quarterly journal of medicine]]
| volume = 86
| issue = 1
| pages = 31–42
| year = 1993
| month = January
| pmid = 8438047
}}</ref><ref>{{Cite journal
| author = [[Elena S. Resnick]], [[Erin L. Moshier]], [[James H. Godbold]] & [[Charlotte Cunningham-Rundles]]
| title = Morbidity and mortality in common variable immune deficiency over 4 decades
| journal = [[Blood]]
| volume = 119
| issue = 7
| pages = 1650–1657
| year = 2012
| month = February
| doi = 10.1182/blood-2011-09-377945
| pmid = 22180439
}}</ref>
* Recurrent [[infections]] in the sinopulmonary, gastrointestinal, septic arthritis, bacterial meningitis/sepsis
* Autoimmune phenomena - [[Vitiligo]], [[autoimmune hepatitis]], [[primary biliary cirrhosis]], [[hemolytic anemia]]
* Malignancy - [[Lymphoma]]s, [[gastric cancer]], [[malignant melanoma]]
* [[Rheumatoid arthritis]]
* [[Vitiligo]]
* [[Thrombocytopenia]]
* [[Neutropenia]]
* [[Hemolytic anemia]]
* [[Pernicious anemia]]
* [[Malabsorption]]
* [[Autoimmune hepatitis]]
* [[Primary biliary cirrhosis]]
* [[Atrophic gastritis]]
* The mainstay of treatment for [[Inflammatory bowel disease]]


===Gender===
===Prognosis===
Males and females are equally affected
* The prognosis with the advent of immune globulin treatment is generally good, and the incidence of death associated with [[Bacterial infection|acute bacterial infection]] in CVID decreased dramatically.<ref>{{Cite journal
| author = [[Elena S. Resnick]], [[Erin L. Moshier]], [[James H. Godbold]] & [[Charlotte Cunningham-Rundles]]
| title = Morbidity and mortality in common variable immune deficiency over 4 decades
| journal = [[Blood]]
| volume = 119
| issue = 7
| pages = 1650–1657
| year = 2012
| month = February
| doi = 10.1182/blood-2011-09-377945
| pmid = 22180439
}}</ref>
* Afterwards, the leading causes of death are owing to complications of [[Chronic (medical)|chronic]] [[Respiratory disease|lung disease]] and [[Cancer|malignancies]].
* In the several large series of following patients with CVID, the leading causes of death were respiratory failure due to [[bronchiectasis]], [[lymphoma]], and liver disease.<ref>{{Cite journal
| author = [[Helen Chapel]], [[Mary Lucas]], [[Martin Lee]], [[Janne Bjorkander]], [[David Webster]], [[Bodo Grimbacher]], [[Claire Fieschi]], [[Vojtech Thon]], [[Mohammad R. Abedi]] & [[Lennart Hammarstrom]]
| title = Common variable immunodeficiency disorders: division into distinct clinical phenotypes
| journal = [[Blood]]
| volume = 112
| issue = 2
| pages = 277–286
| year = 2008
| month = July
| doi = 10.1182/blood-2007-11-124545
| pmid = 18319398
}}</ref><ref>{{Cite journal
| author = [[Isabella Quinti]], [[Carlo Agostini]], [[Stefano Tabolli]], [[Grazia Brunetti]], [[Francesco Cinetto]], [[Antonio Pecoraro]] & [[Giuseppe Spadaro]]
| title = Malignancies are the major cause of death in patients with adult onset common variable immunodeficiency
| journal = [[Blood]]
| volume = 120
| issue = 9
| pages = 1953–1954
| year = 2012
| month = August
| doi = 10.1182/blood-2012-05-431064
| pmid = 22936739
}}</ref>


==Diagnosis==
==Diagnosis==
===Symptoms===
===History and Symptoms===
Symptoms of CVID are:
Symptoms of CVID are:<ref>{{Cite journal
* [[hypogammaglobulinemia]], or low levels of [[immunoglobulin G]] (IgG),  IgA and/or IgM.
| author = [[Elena S. Resnick]], [[Erin L. Moshier]], [[James H. Godbold]] & [[Charlotte Cunningham-Rundles]]
*lack of normal levels of antibody in the serum is part of the diagnosis
  | title = Morbidity and mortality in common variable immune deficiency over 4 decades
* [[polyarthritis]], or joint pain, spread across most joints, but specifically [[finger]]s, [[wrist]]s, [[Elbow-joint|elbow]]s, [[toe]]s, [[ankle]]s and [[knee]]s
| journal = [[Blood]]
* chronic infections. (most common symptom) Specifically: [[upper respiratory tract infection - e.g. bronchitis, sinusitis which respond to [[antibiotic]]s but return or reoccur.   
| volume = 119
* Viral infections that usually respond to [[antiviral]]s, (URTIs), [[sinusitis]], [[tonsilitis]], [[epiglottitis]], dermatological [[abscess]]es/boils (often, but not exclusively, facial and axillary), [[pneumonia]], [[bronchitis]], [[pleurisy]], stomach/intestinal infections, colds, [[influenza]], [[shingles]], [[conjunctivitis]]
| issue = 7
* Tiredness
| pages = 1650–1657
* Chronic swelling of the lymph glands
| year = 2012
* [[splenomegaly|Enlarged spleen]]
| month = February
* [[atrophic gastritis]] with pernicious anemia 
| doi = 10.1182/blood-2011-09-377945
* nodular lymphoid hyperplasia of the intestine. This finding can be mistaken for intestinal lymphoma
| pmid = 22180439
* bacterial overgrowth of the intestine.
}}</ref><ref>{{Cite journal
* villous atrophy in the small intestine, which can resemble [[coeliac disease]] and cause diarrhoea and malabsorption
| author = [[Simon Urschel]], [[Lale Kayikci]], [[Uwe Wintergerst]], [[Gundula Notheis]], [[Annette Jansson]] & [[Bernd H. Belohradsky]]
* chronic diarrhoea (often arises as a result of "minor" intestinal infections, including protozoan and [[parasite|parasitic]] infections)
| title = Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation
* increased incidence of inflammatory bowel disease
| journal = [[The Journal of pediatrics]]
* [[bronchiectasis]] (lung tissue damage as a result of repeated chest infections) leading to shortness of breath
| volume = 154
* poor [[titer]] levels in response to vaccination. Responsiveness may be tested after administration of polysaccharide and non-polysaccharide coated pathogens (e.g. streptococci and tetanus respectively)
| issue = 6
* children may show a "[[failure to thrive]]" - they may be underweight and underdeveloped compared with "normal" peers
| pages = 888–894
* patients may lose weight
| year = 2009
| month = June
| doi = 10.1016/j.jpeds.2008.12.020
| pmid = 19230900
}}</ref>
 
* Chronic infections (most common symptom) specifically [[upper respiratory tract infection]] e.g. [[bronchitis]], [[sinusitis]] which respond to [[antibiotic]]s but return or reoccur.  Common infective organisms include:
** [[Haemophilus influenzae]]
** [[Streptococcus pneumoniae]]
** [[Moraxella catarrhalis]]
** [[Staphylococcus aureus]]
* Viral infections that usually respond to [[antiviral]]s, ([[URTI]]s), [[sinusitis]], [[tonsilitis]], [[epiglottitis]], dermatological [[abscess]]es/[[boils]] (often, but not exclusively, facial and axillary), [[pneumonia]], [[bronchitis]], [[pleurisy]], stomach/intestinal infections, [[cold]]s, [[influenza]], [[shingles]], [[conjunctivitis]]
* [[Tiredness]]
* [[Shortness of breath]] - due to [[bronchiectasis]] (lung tissue damage as a result of repeated chest infections)
* [[Polyarthritis]], or [[joint pain]], spread across most joints, but specifically [[finger]]s, [[wrist]]s, [[Elbow-joint|elbow]]s, [[toe]]s, [[ankle]]s and [[knee]]s
* Patients may [[lose weight]]
* Children may show a "[[failure to thrive]]" - they may be [[underweight]] and [[underdeveloped]] compared with "normal" peers
* [[Diarrhoea]] and [[malabsorption]] - due to [[villous atrophy]] in the [[small intestine]], which can resemble [[coeliac disease]], intestinal infections, including protozoan and [[parasite|parasitic]] infections, bacterial overgrowth of the intestine
* Increased incidence of [[inflammatory bowel disease]]
* [[Abdominal pain]], [[bloating]], [[nausea]], [[vomiting]], [[diarrhea]], [[weight loss]].
 
===Physical Examination===
Physical examination of patients with longstanding immune defects may be remarkable for''':'''
* Low [[body mass index]]
* Scarring of [[Tympanic cavity|tympanic membranes]] or skin
* Signs of [[Chronic (medical)|chronic]] [[Respiratory disease|lung disease]] such as [[chronic cough]], absent [[gag reflex]], clubbing, [[Rales|crackles]], or [[Wheeze|wheezing]] to suggest [[bronchiectasis]]
* Ongoing infection signs of [[Rhinosinusitis|chronic sinusitis]], [[Oral candidiasis|oral thrush]], [[Wart|warts]], or [[Dermatophyte|dermatophyte infections]]
 
* [[Swelling of the lymph glands]] - [[lymphadenopathy]]


[[Diagnosis]] is often delayed; and diagnosis is often made in the second or third decade of life after referral to an immunologist.
* [[Splenomegaly|Enlarged spleen]]


As with several other immune cell disorders, CVID may predispose to [[lymphoma]] or possibly stomach cancer. There also appears to be a predilection for [[autoimmune disease]]s, with a risk of up to 25%. Autoimmune destruction of platelets or red cells are the commonest of these.
===Laboratory Findings===
Patients with CVID do not usually present abnormalities in routine laboratories, such as complete blood counts, serum chemistries, and electrolytes. In the presence of infection and associated condition some abnormalities which may develop include:
* [[Lymphocytopenia]]
* [[Hypoalbuminemia]]
* Elevated [[C-reactive protein]]
* Elevated [[Transaminase|liver transaminases]]
* Positive [[blood culture]] and/or [[urine culture]]
Laboratory findings consistent with the diagnosis of CVID are reduced concentrations of serum immunoglobulins levels and include:<ref>{{Cite journal
| author = [[Isabella Quinti]], [[Annarosa Soresina]], [[Giuseppe Spadaro]], [[Silvana Martino]], [[Simona Donnanno]], [[Carlo Agostini]], [[Pignata Claudio]], [[Dammacco Franco]], [[Anna Maria Pesce]], [[Federica Borghese]], [[Andrea Guerra]], [[Roberto Rondelli]] & [[Alessandro Plebani]]
| title = Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency
| journal = [[Journal of clinical immunology]]
| volume = 27
| issue = 3
| pages = 308–316
| year = 2007
| month = May
| doi = 10.1007/s10875-007-9075-1
| pmid = 17510807
}}</ref>
* [[Immunoglobulin G|IgG]] of 258 mg/dL
* [[Immunoglobulin A|IgA]] of 28 mg/dL
* [[Immunoglobulin M|IgM]] of 40 mg/dL


==Treatment==
Evaluation of [[vaccine]] response  to both protein and polysaccharide-based [[vaccination|vaccines]] is part of the diagnosis and should be evaluated. [[Immunoglobulin G|IgG]] responsiveness to [[Tetanus, Diphtheria, and Pertussis (Tdap) Vaccine (patient information)|tetanus]] and [[Diphtheria, Tetanus, and Pertussis (DTaP) Vaccine (patient information)|diphtheria]] and [[Pneumococcal vaccine|polysaccharide pneumococcal vaccine]] provide an estimate of the patient's responsiveness.<ref>{{Cite journal
Treatment usually consists of immunoglobulin therapy, which is an injection of human antibodies harvested from blood donations: [[intravenous immunoglobulin]] (IVIG, most common treatment), subcutaneous immunoglobulin G (SCIG, relatively new therapy) or intramuscular immunglobulin (IMIG, less effective, painful). This is not a cure, but it strengthens [[immunity (medical)|immunity]] by ensuring that the patient has "normal" levels of antibodies, which helps to prevent recurrent upper respiratory infections.  IG therapy can't be used if the patient has anti-IgA antibodies but in this case, products low in IgA can be used; subcutaneous delivery also is a means of permitting such patients to have adequate antibody replacement.  
| author = [[Jordan S. Orange]], [[Mark Ballow]], [[E. Richard Stiehm]], [[Zuhair K. Ballas]], [[Javier Chinen]], [[Maite De La Morena]], [[Dinakantha Kumararatne]], [[Terry O. Harville]], [[Paul Hesterberg]], [[Majed Koleilat]], [[Sean McGhee]], [[Elena E. Perez]], [[Jason Raasch]], [[Rebecca Scherzer]], [[Harry Schroeder]], [[Christine Seroogy]], [[Aarnoud Huissoon]], [[Ricardo U. Sorensen]] & [[Rohit Katial]]
  | title = Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology
| journal = [[The Journal of allergy and clinical immunology]]
| volume = 130
| issue = 3 Suppl
| pages = S1–24
| year = 2012
| month = September
| doi = 10.1016/j.jaci.2012.07.002
| pmid = 22935624
}}</ref>


Some CVID patients may experience reactions to IG therapies; reactions may include:
[[Diagnosis]] is often delayed,and diagnosis is often made in the second or third decade of life after referral to an immunologist. As with several other immune cell disorders, [[CVID]] may predispose to [[lymphoma]] or possibly [[stomach cancer]]. There also appears to be a predilection for [[autoimmune disease]]s, with a risk of up to 25%.  Autoimmune destruction of [[platelets]] or [[red blood cells]] are the commonest of these.
* [[anaphylactic shock]] (very rare)
* [[hives]] (rare)
* difficulty breathing
* [[headache]] (relatively common, may be relieved by an antihistamine, paracetamol/acetaminophen, or an anti-inflammatory (naproxen, advil, aspirin)
* nausea (common)
* fever (common)
* aseptic meningitis (rare)
* severe fatigue
* muscle aches and pain, or joint pain
* thrombotic events  (rare)
Patients should not receive therapy if they are fighting an active infection as this increases the risk of reaction.  Also, patients changing from one brand of product to another may be at higher risk of reaction for the first couple of treatments on the new brand.


Reactions can be minimised by taking an [[antihistamine]] and/or [[hydrocortisone]] and some paracetamol/acetaminophen/anti-inflammatory (naproxen, advil, aspirin) prior to treatment; patients should also be thoroughly hydrated and continue to drink water before, after and during treatment (if possible).
==Treatment==
===Medical Therapy===
The mainstay of treatment for CVID is immune globulin replacement therapy. In addition, management also includes monitoring and screening for other associated conditions, such as [[Rhinosinusitis|sinopulmonary]], [[Granuloma|granulomatous]], [[Gastrointestinal tract|gastrointestinal]], and [[Autoimmune disease|autoimmune]] diseases, and [[Cancer|malignancy]].  


==Research==
==== '''Immune Globulin Replacement Therapy''' ====
Research is currently focussing on genetic analysis, and in differentiating between the various different disorders in order to allow a cure to be developed.  Cures are likely to be genetic in nature, repairing faulty genes and allowing the individual to start producing antibodies.  Funding for research in the US is provided by the National Institutes of Health. Key research in the UK is funded by the Primary Immunodeficiency Association (PiA), and funding is raised through the annual Jeans for Genes campaign.
* Human antibodies harvested from blood donations are administered either [[Intravenous therapy|intravenously]] or [[Subcutaneous tissue|subcutaneously]].
* Immune globulin replacement therapy reduces the number of [[Infection|infections]] and decreases [[antibiotic]] use and hospitalizations.<ref>{{Cite journal
| author = [[Paula Jane Busse]], [[Samiya Razvi]] & [[Charlotte Cunningham-Rundles]]
| title = Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency
| journal = [[The Journal of allergy and clinical immunology]]
| volume = 109
| issue = 6
| pages = 1001–1004
| year = 2002
| month = June
| pmid = 12063531
}}</ref>
* This therapy is not a cure, but it strengthens [[immunity (medical)|immunity]] in [[Hypogammaglobulinemia|hypogammaglobulinemic]] patients, which helps to [[Prevention (medical)|prevent]] recurrent [[Upper respiratory tract infection|upper respiratory infections]], and fewer serious [[Infection|infections]] and days of hospitalization among patients with [[primary immunodeficiency]] . However, immune globulin therapy does not completely eliminate [[Infection|infections]] in most patients, and the sinopulmonary and [[Gastrointestinal tract|gastrointestinal systems]], in particular, remain susceptible.<ref>{{Cite journal
  | author = [[Benjamin Gathmann]], [[Nizar Mahlaoui]], [[Laurence Gerard]], [[Eric Oksenhendler]], [[Klaus Warnatz]], [[Ilka Schulze]], [[Gerhard Kindle]], [[Taco W. Kuijpers]], [[Rachel T. van Beem]], [[David Guzman]], [[Sarita Workman]], [[Pere Soler-Palacin]], [[Javier De Gracia]], [[Torsten Witte]], [[Reinhold E. Schmidt]], [[Jiri Litzman]], [[Eva Hlavackova]], [[Vojtech Thon]], [[Michael Borte]], [[Stephan Borte]], [[Dinakantha Kumararatne]], [[Conleth Feighery]], [[Hilary Longhurst]], [[Matthew Helbert]], [[Anna Szaflarska]], [[Anna Sediva]], [[Bernd H. Belohradsky]], [[Alison Jones]], [[Ulrich Baumann]], [[Isabelle Meyts]], [[Necil Kutukculer]], [[Per Wagstrom]], [[Nermeen Mouftah Galal]], [[Joachim Roesler]], [[Evangelia Farmaki]], [[Natalia Zinovieva]], [[Peter Ciznar]], [[Efimia Papadopoulou-Alataki]], [[Kirsten Bienemann]], [[Sirje Velbri]], [[Zoya Panahloo]] & [[Bodo Grimbacher]]
| title = Clinical picture and treatment of 2212 patients with common variable immunodeficiency
| journal = [[The Journal of allergy and clinical immunology]]
| volume = 134
| issue = 1
| pages = 116–126
| year = 2014
| month = July
| doi = 10.1016/j.jaci.2013.12.1077
| pmid = 24582312
}}</ref>
* IG therapy should not be used if the patient has anti-IgA antibodies but in these cases, products low in [[Immunoglobulin A|IgA]] can be used; subcutaneous delivery also is a means of permitting such patients to have adequate antibody replacement.
* [[IVIG]] treatment can be received by patients with a complete [[IgA deficiency]] if the [[Immunoglobulin A|IgA]] is completely removed from the treatment.
* Preferred regimen: [[Intravenous immunoglobulin]] 300 to 600 mg/kg every three to four weeks.
* Alternative regimen (1):Subcutaneous immunoglobulin G administered weekly or every other week. Dose depends on body weight and immune globulin requirements.
* Alternative regimen (2): Intramuscular immunoglobulin (IMIG, less effective, painful).  


==== Adverse reactions ====
Some CVID patients may experience reactions to  immune globulin replacement therapies; reactions may include:
* [[Anaphylactic shock]] (very rare)
* [[Hives]] (rare)
* [[Difficulty breathing]]
* [[Headache]] (relatively common, may be relieved by an [[antihistamine]], [[paracetamol]] / [[acetaminophen]], or an anti-inflammatory ([[naproxen]], [[advil]], [[aspirin]])
* [[Nausea]] (common)
* [[Fever]] (common)
* [[Aseptic meningitis]] (rare)
* Severe [[fatigue]]
* [[Muscle aches]] and pain, or [[joint pain]]
* [[Thrombotic events]]  (rare)


Reactions can be minimized by taking an [[antihistamine]] and/or [[hydrocortisone]] and some paracetamol/acetaminophen/anti-inflammatory ([[naproxen]], [[advil]], [[aspirin]]) prior to treatment; patients should also be thoroughly hydrated and continue to drink water before, after and during treatment (if possible).


==== '''Antimicrobial Therapy''' ====
[[Antibiotic|Antibiotics]] may be administered prophylactically, as well as for the treatment of [[Acute (medicine)|acute]] [[Infection|infections]] or exacerbations of [[Chronic (medical)|chronic]] [[Infection|infections]].
* [[Prophylaxis of bacterial infections|Prophylactic antibiotics]] do not routinely administer to all patients with CVID. In CVID patients with ongoing [[Respiratory disease|lung disease]], and with recurrent [[Rhinosinusitis|sinopulmonary infections]], this approach is helpful. Evidence in support of this approach is largely derived from benefits observed in retrospective studies of children with this and similar antibody deficiencies.<ref>{{Cite journal
| author = [[Julie Wang]] & [[Charlotte Cunningham-Rundles]]
| title = Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID)
| journal = [[Journal of autoimmunity]]
| volume = 25
| issue = 1
| pages = 57–62
| year = 2005
| month = August
| doi = 10.1016/j.jaut.2005.04.006
| pmid = 15994061
}}</ref>
*[[Antibiotic|Antibiotics]] are required for management of [[Acute (medicine)|acute]] [[Infection|infections]] among patients with [[immunodeficiency]].  CVID patients typically do not clear common [[Infection|infections]] without the use of proper [[Antibiotic|antibiotics]]. Thus, immediate recognition and treatment with antibiotics can help prevent [[Chronic (medical)|chronic]] [[Infection|infections]] and infectious [[Complication (medicine)|complications]]. It is important to ensure that the infection has treated completely at the end of a course of [[Antibiotic|antibiotics]], as patients with [[immunodeficiency]] sometimes necessitate longer duration of therapy. Antibiotic resistance does not seem to be a serious problem in patients with CVID, for causes which are not clearly understood, then the same antibiotics continue to be useful, regardless of prolonged or frequent exposure.<ref>{{Cite journal
| author = [[A. Samuelson]], [[S. Borrelli]], [[R. Gustafson]], [[L. Hammarstrom]], [[C. I. Smith]], [[J. Jonasson]] & [[A. A. Lindberg]]
| title = Characterization of Haemophilus influenzae isolates from the respiratory tract of patients with primary antibody deficiencies: evidence for persistent colonizations
| journal = [[Scandinavian journal of infectious diseases]]
| volume = 27
| issue = 4
| pages = 303–313
| year = 1995
| month =
| pmid = 8658061
}}</ref>


==Prevention==
* There are no [[Prevention (medical)|primary preventive]] measures available for common variable immunodeficiency.
* [[Prevention (medical)|Secondary]] and [[Prevention (medical)|tertiary prevention]] strategies following CVID include avoidance measures, [[vaccination]], [[Prophylaxis|prophylactic]] [[Antibiotic|antibiotics]], immune globulin therapy, and when infections do occur, broader spectrum and more prolonged antibiotics are often recommended.
** Avoidance to reduce exposure to others with potentially contagious illnesses: proper hand-washing and use of alcohol-based [[Disinfectant|disinfectants]] should be provided to patients and their families; Co-sleeping among family members should be minimized, and [[Vaccination|immunization]] of family members and close contacts is required.
** Careful attention should be paid to patient's [[oral hygiene]] and dental health.
** The efficiency of killed or inactivated [[Vaccine|vaccines]] in patients with CVID is not fully understood because of the impaired responses to of patients to [[vaccination]] due to dysregulated , however, vaccination might augment [[T cell|T cell immunity]] to viral agents, in addition to inducing the formation of specific [[antibodies]]. Certain live [[Vaccine|vaccines]] i.e. oral [[polio]], [[Smallpox vaccine|smallpox]], live-attenuated [[influenza vaccine]], [[yellow fever]], or live oral [[Typhoid vaccine (Patient information)|typhoid vaccines]] should not be given to patients with CVID , particularly those with significantly impaired [[T cell]] function.<ref>{{Cite journal
| author = [[William T. Shearer]], [[Thomas A. Fleisher]], [[Rebecca H. Buckley]], [[Zuhair Ballas]], [[Mark Ballow]], [[R. Michael Blaese]], [[Francisco A. Bonilla]], [[Mary Ellen Conley]], [[Charlotte Cunningham-Rundles]], [[Alexandra H. Filipovich]], [[Ramsay Fuleihan]], [[Erwin W. Gelfand]], [[Vivian Hernandez-Trujillo]], [[Steven M. Holland]], [[Richard Hong]], [[Howard M. Lederman]], [[Harry L. Malech]], [[Stephen Miles]], [[Luigi D. Notarangelo]], [[Hans D. Ochs]], [[Jordan S. Orange]], [[Jennifer M. Puck]], [[John M. Routes]], [[E. Richard Stiehm]], [[Kathleen Sullivan]], [[Troy Torgerson]] & [[Jerry Winkelstein]]
| title = Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts
| journal = [[The Journal of allergy and clinical immunology]]
| volume = 133
| issue = 4
| pages = 961–966
| year = 2014
| month = April
| doi = 10.1016/j.jaci.2013.11.043
| pmid = 24582311
}}</ref>


==References==
==References==
Line 132: Line 709:
* [http://www.pia.org.uk Primary Immunodeficiency Association (UK)]
* [http://www.pia.org.uk Primary Immunodeficiency Association (UK)]
* [http://www.primaryimmune.org Immune Deficiency Foundation (US)]
* [http://www.primaryimmune.org Immune Deficiency Foundation (US)]
* [http://www.midf.org/ Michigan Immunodeficiency Foundation (US)]
* [http://www.idfaustralia.org Immune Deficiencies Foundation of Australia]
* [http://www.idfaustralia.org Immune Deficiencies Foundation of Australia]
* [http://www.idfnz.org.nz Immune Deficiencies Foundation of New Zealand]
* [http://www.idfnz.org.nz Immune Deficiencies Foundation of New Zealand]
Line 140: Line 716:
{{Immune disorders}}
{{Immune disorders}}


[[Category:Disease]]
[[Category:Immunology]]
[[Category:Immune system disorders]]
[[Category:Hematology]]
 


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]; Associate Editor-In-Chief: Mohsen Basiri M.D. Syed Hassan A. Kazmi BSc, MD [3]

Synonyms and keywords: CVID; common variable hypogammaglobulinaemia; non-familial hypogammaglobulinaemia; acquired hypogammaglobulinemia; immunodeficiency, common variable; late-onset immunoglobulin deficiency

Overview

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder. CVID is the most common antibody deficiency affecting both children and adults. The characteristic immunological defect in CVID is impaired B cell differentiation with defective production of immunoglobulin. Impaired B cell differentiation leads to low serum concentrations of immunoglobulin G (IgG), low immunoglobulin A (IgA) and/or immunoglobulin M (IgM), as well poor or absent response to immunization. The majority of patients are diagnosed between the ages of 20 and 40 years. Recurrent bacterial infections of the sino-pulmonary tract (sinusitis and pneumonia) are most common manifestations of patients with CVID. Opportunistic and unusual infections are uncommon, but may occur. In addition to recurrent infections, patients with CVID have evidence of immune dysregulation leading to autoimmunity. Patients may suffer from chronic lung disease, gastrointestinal and liver disorders, granulomatous infiltrations, lymphoid hyperplasia, splenomegaly, or malignancy. Various forms of primary and secondary hypogammaglobulinemia must be excluded before the diagnosis of CVID. The diagnosis of CVID requires a suggestive clinical history, a reduced total serum concentration of IgG, plus low IgA or IgM, and poor responses to both protein- and polysaccharide-based vaccines.

Historical Perspective

  • In 1953, Charles Janeway was the first to describe CVID as a separate entity.
  • In 1990, the European Society for Immunodeficiency (ESID) and Pan-American Group for Immunodeficiency (PAGID) determined the diagnostic criteria, including minimum age of diagnosis and the need to rule out other diseases, to determine CVID.[1]

Classification

Common variable immunodeficiency (CVID) is a heterogeneous immune disorder characterized by recurrent sinopulmonary infections, autoimmune diseases, and granulomatous disease. A phenotypic approach to classify CVID has been suggested, based upon the type of complications the patient demonstrates. Five phenotypic categories were proposed:[2]

Pathophysiology

Type Gene Immunoglobulin Deficiency Phenotype
ICOS deficiency ICOS Low IgG and IgA Recurrent infections, autoimmunity, gastroenteritis.
CD19 deficiency CD19 Low IgG and IgA Recurrent infections.

May be associated with glomerulonephritis.

CD81 deficiency CD81 Low IgG, low or normal IgA and IgM Recurrent infections.

May be associated with glomerulonephritis.

CD20 deficiency CD20 Low IgG, normal or elevated IgM, and IgA Recurrent infections.
CD21 deficiency CD21 Low IgG; impaired antipneumococcal response Recurrent infections.
TACI deficiency TNFRSF13B Low IgG and IgA and/or IgM Variable clinical expression
BAFF-receptor

deficiency

TNFRSF13C Low IgG and IgM Variable clinical expression
TWEAK deficiency TWEAK Low IgM and IgA; lack of antipneumococcal antibody Recurrent infections such as Pneumonia, bacterial infections, warts;

and thrombocytopenia; neutropenia

NF-kappa-B2

deficiency

NFKB2 Low IgG and IgA and IgM; very low B cells in some Recurrent infections; adrenal insufficiency;

ACTH deficiency; alopecia

NF-kappa-B1

deficiency

NFKB1 Low IgG and IgA and IgM; low B cells in some Recurrent infections
IKAROS IKZF1 Low IgG and IgA and IgM, very low B cells Recurrent infections

Causes

The cause of common variable immunodeficiency has not been identified. Genetic mutations may be recognized as the cause of CVID in about 10% of patients, and familial inheritance accounts for 10-25% of the affected population. Rather than arising from a single genetic mutation, CVID is due to numerous mutations that all are associated with dysfunction in antibody regulation and production.[7]

Differentiating Common Variable Immunodeficiency from other Diseases

Common variable immunodeficiency should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials:[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][31][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]

Disorder Defect (Mechanism of Development) Characteristic Features Clinical Presentation Laboratory Findings
X-Linked (Bruton) Agammaglobulinemia
Selective IgA Deficiency
  • Serum IgA < 7 mg/dl
  • Normal IgG and IgM levels
Common Variable Immunodeficiency
  • Defective B cell differentiation
  • May be acquired in 20-30 years of age
Autosomal dominant hype IgE syndrome (Job's Syndrome)
  • Distinctive coarse facies
  • Cold (non-inflammatory) Staphylococcal abscesses
  • Retained primary teeth
  • Eczema
Severe combined immunodeficiency (SCID)
Ataxia Telangiectasia
  • Defect in ATM gene which encodes a kinase necessary for TP53 activity
  • DNA double stranded breaks leading to cell cycle arrest
Hyper IgM Syndrome
Wiskott-Aldrich Syndrome
  • Malignancy: can cause the reduction in the immunoglobulin production.[58]
  • Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
  • Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.[59]
  • Other causes of primary humoral immunodeficiencies.
  • Smoking: may cause IgG2 subclass deficiency.[60]
  • Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

Epidemiology and Demographics

Prevalence

CVID has an estimated prevalence ranging from a low of 2 per 100,000 to a high of 4 per 100,000 with an average of 3 per 100,000.[61]

Age

  • The typical patient is after puberty and between 20 and 40 years age.
  • About 20% of patients are diagnosed in childhood.
  • In an analysis of the CVID data from the ESID about 35 percent of patients were diagnosed before 10 years of age; and in studies from United States centers, 20 percent of patients are diagnosed before the age of 20 years. The majority of patients are diagnosed between the ages of 20 and 45. [62] [63]

Gender

There is no gender predilection to common variable immunodeficiency.

Race

Race is not associated with an increased risk of common variable immunodeficiency. However, there is some evidence of higher prevalence among individuals of northern European descent.[64]

Natural History, Complications and Prognosis

Natural History

  • All patients have several histories of acute and recurrent infections.
  • The majority of patients with CVID have evidence of immune dysregulation leading to autoimmunity, inflammatory disorders, and malignant disease.
  • Accordingly, CVID Patients may suffer from chronic lung disease, gastrointestinal and liver disorders, granulomatous infiltrations of several organs, lymphoid hyperplasia, splenomegaly, or malignancy.[65]
  • The clinical manifestations of CVID affect multiple organ systems, and patients often have the history of several specialists visits by the time they are recognized. It may be partly for this reason, delayed diagnosis of this condition is common. in the European Society for Immunodeficiencies (ESID) database, and other studies, there was an average of five to seven years between the beginning of symptoms and diagnosis[66][67]

Complications

Numerous complications are possible in CVID. They include:[68][69][70]

Prognosis

  • The prognosis with the advent of immune globulin treatment is generally good, and the incidence of death associated with acute bacterial infection in CVID decreased dramatically.[71]
  • Afterwards, the leading causes of death are owing to complications of chronic lung disease and malignancies.
  • In the several large series of following patients with CVID, the leading causes of death were respiratory failure due to bronchiectasis, lymphoma, and liver disease.[72][73]

Diagnosis

History and Symptoms

Symptoms of CVID are:[74][75]

Physical Examination

Physical examination of patients with longstanding immune defects may be remarkable for:

Laboratory Findings

Patients with CVID do not usually present abnormalities in routine laboratories, such as complete blood counts, serum chemistries, and electrolytes. In the presence of infection and associated condition some abnormalities which may develop include:

Laboratory findings consistent with the diagnosis of CVID are reduced concentrations of serum immunoglobulins levels and include:[76]

  • IgG of 258 mg/dL
  • IgA of 28 mg/dL
  • IgM of 40 mg/dL

Evaluation of vaccine response to both protein and polysaccharide-based vaccines is part of the diagnosis and should be evaluated. IgG responsiveness to tetanus and diphtheria and polysaccharide pneumococcal vaccine provide an estimate of the patient's responsiveness.[77]

Diagnosis is often delayed,and diagnosis is often made in the second or third decade of life after referral to an immunologist. As with several other immune cell disorders, CVID may predispose to lymphoma or possibly stomach cancer. There also appears to be a predilection for autoimmune diseases, with a risk of up to 25%. Autoimmune destruction of platelets or red blood cells are the commonest of these.

Treatment

Medical Therapy

The mainstay of treatment for CVID is immune globulin replacement therapy. In addition, management also includes monitoring and screening for other associated conditions, such as sinopulmonary, granulomatous, gastrointestinal, and autoimmune diseases, and malignancy.

Immune Globulin Replacement Therapy

  • Human antibodies harvested from blood donations are administered either intravenously or subcutaneously.
  • Immune globulin replacement therapy reduces the number of infections and decreases antibiotic use and hospitalizations.[78]
  • This therapy is not a cure, but it strengthens immunity in hypogammaglobulinemic patients, which helps to prevent recurrent upper respiratory infections, and fewer serious infections and days of hospitalization among patients with primary immunodeficiency . However, immune globulin therapy does not completely eliminate infections in most patients, and the sinopulmonary and gastrointestinal systems, in particular, remain susceptible.[79]
  • IG therapy should not be used if the patient has anti-IgA antibodies but in these cases, products low in IgA can be used; subcutaneous delivery also is a means of permitting such patients to have adequate antibody replacement.
  • IVIG treatment can be received by patients with a complete IgA deficiency if the IgA is completely removed from the treatment.
  • Preferred regimen: Intravenous immunoglobulin 300 to 600 mg/kg every three to four weeks.
  • Alternative regimen (1):Subcutaneous immunoglobulin G administered weekly or every other week. Dose depends on body weight and immune globulin requirements.
  • Alternative regimen (2): Intramuscular immunoglobulin (IMIG, less effective, painful).

Adverse reactions

Some CVID patients may experience reactions to immune globulin replacement therapies; reactions may include:

Reactions can be minimized by taking an antihistamine and/or hydrocortisone and some paracetamol/acetaminophen/anti-inflammatory (naproxen, advil, aspirin) prior to treatment; patients should also be thoroughly hydrated and continue to drink water before, after and during treatment (if possible).

Antimicrobial Therapy

Antibiotics may be administered prophylactically, as well as for the treatment of acute infections or exacerbations of chronic infections.

  • Prophylactic antibiotics do not routinely administer to all patients with CVID. In CVID patients with ongoing lung disease, and with recurrent sinopulmonary infections, this approach is helpful. Evidence in support of this approach is largely derived from benefits observed in retrospective studies of children with this and similar antibody deficiencies.[80]
  • Antibiotics are required for management of acute infections among patients with immunodeficiency. CVID patients typically do not clear common infections without the use of proper antibiotics. Thus, immediate recognition and treatment with antibiotics can help prevent chronic infections and infectious complications. It is important to ensure that the infection has treated completely at the end of a course of antibiotics, as patients with immunodeficiency sometimes necessitate longer duration of therapy. Antibiotic resistance does not seem to be a serious problem in patients with CVID, for causes which are not clearly understood, then the same antibiotics continue to be useful, regardless of prolonged or frequent exposure.[81]

Prevention

  • There are no primary preventive measures available for common variable immunodeficiency.
  • Secondary and tertiary prevention strategies following CVID include avoidance measures, vaccination, prophylactic antibiotics, immune globulin therapy, and when infections do occur, broader spectrum and more prolonged antibiotics are often recommended.
    • Avoidance to reduce exposure to others with potentially contagious illnesses: proper hand-washing and use of alcohol-based disinfectants should be provided to patients and their families; Co-sleeping among family members should be minimized, and immunization of family members and close contacts is required.
    • Careful attention should be paid to patient's oral hygiene and dental health.
    • The efficiency of killed or inactivated vaccines in patients with CVID is not fully understood because of the impaired responses to of patients to vaccination due to dysregulated , however, vaccination might augment T cell immunity to viral agents, in addition to inducing the formation of specific antibodies. Certain live vaccines i.e. oral polio, smallpox, live-attenuated influenza vaccine, yellow fever, or live oral typhoid vaccines should not be given to patients with CVID , particularly those with significantly impaired T cell function.[82]

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  68. ↑ L. Hammarstrom, I. Vorechovsky & D. Webster (2000). "Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID)". Clinical and experimental immunology. 120 (2): 225–231. PMID 10792368. Unknown parameter |month= ignored (help)
  69. ↑ R. A. Hermaszewski & A. D. Webster (1993). "Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications". The Quarterly journal of medicine. 86 (1): 31–42. PMID 8438047. Unknown parameter |month= ignored (help)
  70. ↑ Elena S. Resnick, Erin L. Moshier, James H. Godbold & Charlotte Cunningham-Rundles (2012). "Morbidity and mortality in common variable immune deficiency over 4 decades". Blood. 119 (7): 1650–1657. doi:10.1182/blood-2011-09-377945. PMID 22180439. Unknown parameter |month= ignored (help)
  71. ↑ Elena S. Resnick, Erin L. Moshier, James H. Godbold & Charlotte Cunningham-Rundles (2012). "Morbidity and mortality in common variable immune deficiency over 4 decades". Blood. 119 (7): 1650–1657. doi:10.1182/blood-2011-09-377945. PMID 22180439. Unknown parameter |month= ignored (help)
  72. ↑ Helen Chapel, Mary Lucas, Martin Lee, Janne Bjorkander, David Webster, Bodo Grimbacher, Claire Fieschi, Vojtech Thon, Mohammad R. Abedi & Lennart Hammarstrom (2008). "Common variable immunodeficiency disorders: division into distinct clinical phenotypes". Blood. 112 (2): 277–286. doi:10.1182/blood-2007-11-124545. PMID 18319398. Unknown parameter |month= ignored (help)
  73. ↑ Isabella Quinti, Carlo Agostini, Stefano Tabolli, Grazia Brunetti, Francesco Cinetto, Antonio Pecoraro & Giuseppe Spadaro (2012). "Malignancies are the major cause of death in patients with adult onset common variable immunodeficiency". Blood. 120 (9): 1953–1954. doi:10.1182/blood-2012-05-431064. PMID 22936739. Unknown parameter |month= ignored (help)
  74. ↑ Elena S. Resnick, Erin L. Moshier, James H. Godbold & Charlotte Cunningham-Rundles (2012). "Morbidity and mortality in common variable immune deficiency over 4 decades". Blood. 119 (7): 1650–1657. doi:10.1182/blood-2011-09-377945. PMID 22180439. Unknown parameter |month= ignored (help)
  75. ↑ Simon Urschel, Lale Kayikci, Uwe Wintergerst, Gundula Notheis, Annette Jansson & Bernd H. Belohradsky (2009). "Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation". The Journal of pediatrics. 154 (6): 888–894. doi:10.1016/j.jpeds.2008.12.020. PMID 19230900. Unknown parameter |month= ignored (help)
  76. ↑ Isabella Quinti, Annarosa Soresina, Giuseppe Spadaro, Silvana Martino, Simona Donnanno, Carlo Agostini, Pignata Claudio, Dammacco Franco, Anna Maria Pesce, Federica Borghese, Andrea Guerra, Roberto Rondelli & Alessandro Plebani (2007). "Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency". Journal of clinical immunology. 27 (3): 308–316. doi:10.1007/s10875-007-9075-1. PMID 17510807. Unknown parameter |month= ignored (help)
  77. ↑ Jordan S. Orange, Mark Ballow, E. Richard Stiehm, Zuhair K. Ballas, Javier Chinen, Maite De La Morena, Dinakantha Kumararatne, Terry O. Harville, Paul Hesterberg, Majed Koleilat, Sean McGhee, Elena E. Perez, Jason Raasch, Rebecca Scherzer, Harry Schroeder, Christine Seroogy, Aarnoud Huissoon, Ricardo U. Sorensen & Rohit Katial (2012). "Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology". The Journal of allergy and clinical immunology. 130 (3 Suppl): S1–24. doi:10.1016/j.jaci.2012.07.002. PMID 22935624. Unknown parameter |month= ignored (help)
  78. ↑ Paula Jane Busse, Samiya Razvi & Charlotte Cunningham-Rundles (2002). "Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency". The Journal of allergy and clinical immunology. 109 (6): 1001–1004. PMID 12063531. Unknown parameter |month= ignored (help)
  79. ↑ Benjamin Gathmann, Nizar Mahlaoui, Laurence Gerard, Eric Oksenhendler, Klaus Warnatz, Ilka Schulze, Gerhard Kindle, Taco W. Kuijpers, Rachel T. van Beem, David Guzman, Sarita Workman, Pere Soler-Palacin, Javier De Gracia, Torsten Witte, Reinhold E. Schmidt, Jiri Litzman, Eva Hlavackova, Vojtech Thon, Michael Borte, Stephan Borte, Dinakantha Kumararatne, Conleth Feighery, Hilary Longhurst, Matthew Helbert, Anna Szaflarska, Anna Sediva, Bernd H. Belohradsky, Alison Jones, Ulrich Baumann, Isabelle Meyts, Necil Kutukculer, Per Wagstrom, Nermeen Mouftah Galal, Joachim Roesler, Evangelia Farmaki, Natalia Zinovieva, Peter Ciznar, Efimia Papadopoulou-Alataki, Kirsten Bienemann, Sirje Velbri, Zoya Panahloo & Bodo Grimbacher (2014). "Clinical picture and treatment of 2212 patients with common variable immunodeficiency". The Journal of allergy and clinical immunology. 134 (1): 116–126. doi:10.1016/j.jaci.2013.12.1077. PMID 24582312. Unknown parameter |month= ignored (help)
  80. ↑ Julie Wang & Charlotte Cunningham-Rundles (2005). "Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID)". Journal of autoimmunity. 25 (1): 57–62. doi:10.1016/j.jaut.2005.04.006. PMID 15994061. Unknown parameter |month= ignored (help)
  81. ↑ A. Samuelson, S. Borrelli, R. Gustafson, L. Hammarstrom, C. I. Smith, J. Jonasson & A. A. Lindberg (1995). "Characterization of Haemophilus influenzae isolates from the respiratory tract of patients with primary antibody deficiencies: evidence for persistent colonizations". Scandinavian journal of infectious diseases. 27 (4): 303–313. PMID 8658061.
  82. ↑ William T. Shearer, Thomas A. Fleisher, Rebecca H. Buckley, Zuhair Ballas, Mark Ballow, R. Michael Blaese, Francisco A. Bonilla, Mary Ellen Conley, Charlotte Cunningham-Rundles, Alexandra H. Filipovich, Ramsay Fuleihan, Erwin W. Gelfand, Vivian Hernandez-Trujillo, Steven M. Holland, Richard Hong, Howard M. Lederman, Harry L. Malech, Stephen Miles, Luigi D. Notarangelo, Hans D. Ochs, Jordan S. Orange, Jennifer M. Puck, John M. Routes, E. Richard Stiehm, Kathleen Sullivan, Troy Torgerson & Jerry Winkelstein (2014). "Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts". The Journal of allergy and clinical immunology. 133 (4): 961–966. doi:10.1016/j.jaci.2013.11.043. PMID 24582311. Unknown parameter |month= ignored (help)

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