Common variable immunodeficiency disorder (CVID) is diverse, both in its clinical presentation and in the types of deficiency. It is a primary humoral immunodeficiency disorder characterized by reduced serum levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) or immunoglobulin M (IgM), recurrent sinopulmonary infections, autoimmune disorders, granulomatous diseases, enhanced risk of malignancy, and impaired antibody response despite the adequate number of B cells.
It is the most frequent symptomatic primary immunodeficiency disorder worldwide. Rather than a disease, it is a collection of hypogammaglobulinemia syndromes resulting from various genetic defects (almost all of them are specific molecular defects with as yet an unknown cause), named “variable” because of its heterogeneous clinical manifestations.
The main cause of CVID remains unknown despite more than four decades of investigation. It is known that environmental and genetic factors may be involved: approximately, 20% of CVID patients have a first-degree family member with a selective IgA deficiency; while the specific environmental factors are unclear, the genetic influence in CVID is believed to cause an intrinsic B cell defect (CD19-deficiency by mutations in CD19; 16p11.2), an intrinsic T cell defect (ICOS-deficiency by mutations in ICOS; 2q33), and mutations in TNF receptors (TACI-deficiency or BAFFR- deficiency by mutations in TNFRSF13B and TNFRSF13C respectively; 17p11.2 and 22q13.1-q13.31). Other monogenic defects reported include MSH5, CD81, and CD20 deficiencies; however, CVID can be present without a known genetic defect.
There is no observable, clear pattern of inheritance. Different modes of inheritance, such as autosomal dominant with variable penetrance, autosomal recessive, and X-linked forms, have been reported.
The clinical variability of CVID suggests that multiple immunoregulatory defects can result in the final common pathway of hypogammaglobulinemia.
Reports exist of numerous immune-system abnormalities, the most common of which is defective antibody formation. As a consequence, humoral and cell-mediated lymphocytic responses are affected, and some patients may have a defect in the T-cell ability to help B cells, and/or B-cell response to T-cell help:
Chapel et al. have delineated five clinical phenotypes for CVID. Around 80% of their patients had only one of these phenotypes, and 12.6% had criteria for two:
In any patient with newly diagnosed CVID, two complications have to be considered when assessing the clinical presentation: infectious and non-infectious.
Physical examination may be normal in these patients. However, there could be signs and symptoms of chronic illness like:
If the patient’s history and physical examination raise a concern about a possible diagnosis of CVID, the evaluation must begin with the laboratory measurement of immunoglobulin levels, demonstration of impaired vaccination response, and exclusion of other abnormalities. The following summarizes some diagnostic procedures according to systems:
Evaluation of pulmonary disease is essential. There are no international consensus guidelines about pulmonary disease screening. However, there are some recommendations based on clinical experience cited in some publications (European Respiratory Review, Archives of Disease in Childhood, Clinical and Experimental Immunology):
Central Nervous System:
Generally, there are no uncommon findings in routine laboratories. Serum IgG should be below the normal limits and normally under 400mg/dL. Also, IgM and/or IgA should be below the normal limits.
The patient’s response to vaccines based on protein (IgG antibodies to tetanus and diphtheria) and polysaccharide (IgG antibodies to serotypes of the polysaccharides in the pneumococcal vaccine) requires assessment unless the antibody levels are deficient.
Flow cytometry can be used to determine levels of circulating memory B cells, and levels of isotype switched memory B cells (as mentioned before). On the other hand, molecular analysis is not required for the diagnosis of CVID but might be an option if there are other affected family members.
Biopsies are frequently done to discard malignancy or autoimmunity in the case of gastrointestinal disorders, pulmonary nodules, and dermatologic findings.
1. Immunoglobulin replacement
The mainstay of treatment is immunoglobulin replacement for those patients who have substantial impairments in its production (generally two standard deviations below the normal range for IgG) and a lack of response to protein and polysaccharide vaccines. Despite the high cost, immunoglobulin replacement can decrease the burden of recurrent infections and their complications. For patients who have higher levels of IgG and slight impairment in vaccine response, the clinician can postpone therapy but should follow the patient closely.
Generally, after treating an active infection, therapy begins with adequate hydration. Subsequently, a slow infusion load of intravenous immune globulin (IVIG) must be administered until tolerance is appropriate, followed by maintenance doses.
In patients prone to reactions, diphenhydramine and acetaminophen (and sometimes hydrocortisone) can be a premedication. The subcutaneous route is an optional alternative in maintenance therapy (normally, weekly or every other week). The initial dose for IVIG is 300 to 600 mg/kg every three to four weeks.
The monitoring of IgG levels should take place every six months. Therefore, dosing adjustments may occur according to the patient's weight and IgG production.
Intravenous immune globulin adverse reactions can be seen in 20 to 50% of patients, most likely during the first infusion, but they depend on the dose, infusion rate, organ dysfunction, prothrombotic stimuli, and brand.
Subcutaneous immune globulin systemic adverse reactions are much lower than the first ones. Local reactions, such as pain and swelling are the most frequent ones.
2. Infections and antimicrobials
Generally, active bacterial infections are treated with longer courses of antibiotics (sometimes 2 or 3 times longer).
Sputum examination or bronchoalveolar lavage is mandatory in all patients with sinopulmonary infections before antibiotic treatment.
Prophylactic antimicrobials are not a routine recommendation. However, exacerbation of sinopulmonary infections could be less frequent with the administration of 250 mg of azithromycin three times weekly in susceptible individuals who receive replacement therapy.
High-risk immunodeficient patients should be considered during seasonal influenza. Prophylactic treatment may include antiviral therapy.
3. Autoimmune disorders
Glucocorticoids are the first-line treatment for immune thrombocytopenia and autoimmune hemolytic anemia. Higher doses are deliverable in patients that are currently on immune globulin replacement therapy. In glucocorticoid-refractory cases, rituximab should be considered, maintaining immune globulin replacement therapy; however, in severe refractory cases, splenectomy is the last option.
Treatment for rheumatologic diseases is the same as for patients who are not immunocompromised, along with the addition of immunoglobulin replacement.
Treatment for malignancies has as its basis for general population protocols.
Unfortunately, there are no standardized monitoring protocols for cancer risk in these patients, therefore current recommendations of screening procedures must be age-appropriate, according to each country’s guidelines. However, all patients must be tested for Helicobacter pylori infection and pernicious anemia laboratory features, because of their relation to gastric malignancy.
Recommendations for vaccination is based on the antibody deficiency severity:
6. Other recommendations:
The basis for differential diagnosis is on the main laboratory characteristic of CVID: hypogammaglobulinemia.
Hypogammaglobulinemia can be primary or secondary. The primary causes are more common in children.
The basis of medical complications and mortality statistics is from the largest series of 473 patients, followed over 40 years in New York.
Prognosis in these patients is determined by the existence of pulmonary complications (respiratory failure due to chronic pulmonary disease) and malignancy (especially lymphoid), in which the appropriate and early therapy can prevent or slow down their development.
Non-infectious complications have a prevalence of around 60 to 70%, and the risk of death because of them is 11 times higher.
Overall mortality in CVID patients, according to age and sex-matched population controls, is around 20%.
Malignant cells in these patients do not show greater resistance to standard protocols of treatment, but are more likely to widespread and, therefore, determine the need for a more aggressive therapy, which could bring poorly tolerated adverse effects.
On the other hand, the lower amounts of serum immunoglobulin G (IgG) and circulating class-switched memory B cells, and increased amount of serum immunoglobulin M (IgM) can be used to predict the risk for mortality because of a higher prevalence of autoimmune disease, granuloma formation, recurrent bacterial pneumonia, and lymphoid hyperplasia.
It is unclear to what range IgG replacement could prevent complications.
Complications of CVID are sometimes the clinical presentation onset of CVID patients. However, early-diagnosed and early-treated patients can develop complications in the future, which could shorten their life expectancy.
The most frequent complications are associated with pulmonary disease. Therefore most patients with respiratory symptoms must be initially evaluated through HRCT.
Pulmonary complications by descending order of frequency are:
The overall risk for developing cancer is estimated to range from 4% to 25%, and estimates of the incidence of malignancy are at around 10%, with a higher risk in adult-diagnosed CVID. The most frequent malignancies are described in order of frequency:
Patients with CVID require an integrated interprofessional team approach to improve short-term and long-term patient outcomes. They need frequent specialized clinical provider evaluations, including an infectious disease specialist and immunologist. A dedicated nurse can assess and educate the patient as well as his family about potential complications and symptoms to monitor. A specialized pharmacist is required to ensure proper dosing of IVIG as well as appropriate dosing and duration of antibiotics for infection episodes. Above all, the clinical provider, the nursing staff, as well as the clinical pharmacist, need to provide an integrated interprofessional approach to patient education to minimize complications of the disease and to improve patient outcomes. Preventive care with appropriate vaccination (avoiding live vaccines such as oral polio, smallpox, influenza, yellow fever, oral typhoid), dental, auditive, and mental care requires attention, as mentioned previously. Close communication between the team members is vital to ensure good outcomes. [Level V]
|||Cunningham-Rundles C,Bodian C, Common variable immunodeficiency: clinical and immunological features of 248 patients. Clinical immunology (Orlando, Fla.). 1999 Jul; [PubMed PMID: 10413651]|
|||Bonilla FA,Barlan I,Chapel H,Costa-Carvalho BT,Cunningham-Rundles C,de la Morena MT,Espinosa-Rosales FJ,Hammarström L,Nonoyama S,Quinti I,Routes JM,Tang ML,Warnatz K, International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. The journal of allergy and clinical immunology. In practice. 2016 Jan-Feb; [PubMed PMID: 26563668]|
|||Chapel H,Cunningham-Rundles C, Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. British journal of haematology. 2009 Jun; [PubMed PMID: 19344423]|
|||Resnick ES,Moshier EL,Godbold JH,Cunningham-Rundles C, Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012 Feb 16; [PubMed PMID: 22180439]|
|||Al-Herz W,Bousfiha A,Casanova JL,Chapel H,Conley ME,Cunningham-Rundles C,Etzioni A,Fischer A,Franco JL,Geha RS,Hammarström L,Nonoyama S,Notarangelo LD,Ochs HD,Puck JM,Roifman CM,Seger R,Tang ML, Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Frontiers in immunology. 2011; [PubMed PMID: 22566844]|
|||Al-Herz W,Bousfiha A,Casanova JL,Chatila T,Conley ME,Cunningham-Rundles C,Etzioni A,Franco JL,Gaspar HB,Holland SM,Klein C,Nonoyama S,Ochs HD,Oksenhendler E,Picard C,Puck JM,Sullivan K,Tang ML, Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Frontiers in immunology. 2014; [PubMed PMID: 24795713]|
|||Bogaert DJ,Dullaers M,Lambrecht BN,Vermaelen KY,De Baere E,Haerynck F, Genes associated with common variable immunodeficiency: one diagnosis to rule them all? Journal of medical genetics. 2016 Sep; [PubMed PMID: 27250108]|
|||Chapel H, Common Variable Immunodeficiency Disorders (CVID) - Diagnoses of Exclusion, Especially Combined Immune Defects. The journal of allergy and clinical immunology. In practice. 2016 Nov - Dec; [PubMed PMID: 27836061]|
|||Nijenhuis T,Klasen I,Weemaes CM,Preijers F,de Vries E,van der Meer JW, Common variable immunodeficiency (CVID) in a family: an autosomal dominant mode of inheritance. The Netherlands journal of medicine. 2001 Sep; [PubMed PMID: 11583829]|
|||Hammarström L,Vorechovsky I,Webster D, Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clinical and experimental immunology. 2000 May; [PubMed PMID: 10792368]|
|||Oksenhendler E,Gérard L,Fieschi C,Malphettes M,Mouillot G,Jaussaud R,Viallard JF,Gardembas M,Galicier L,Schleinitz N,Suarez F,Soulas-Sprauel P,Hachulla E,Jaccard A,Gardeur A,Théodorou I,Rabian C,Debré P, Infections in 252 patients with common variable immunodeficiency. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2008 May 15; [PubMed PMID: 18419489]|
|||Rezaei N,Wing JB,Aghamohammadi A,Carlring J,Lees A,Asgarian-Omran H,Pourpak Z,Sarrafnejad A,Kardar GA,Shahrestani T,Masoumi F,Zare A,Saghafi S,Sarrafzadeh S,Foster RA,Heath AW,Read RC, B-cell-T-cell activation and interaction in common variable immunodeficiency. Human immunology. 2010 Apr; [PubMed PMID: 20097245]|
|||Roskin KM,Simchoni N,Liu Y,Lee JY,Seo K,Hoh RA,Pham T,Park JH,Furman D,Dekker CL,Davis MM,James JA,Nadeau KC,Cunningham-Rundles C,Boyd SD, IgH sequences in common variable immune deficiency reveal altered B cell development and selection. Science translational medicine. 2015 Aug 26; [PubMed PMID: 26311730]|
|||Cunningham-Rundles C,Radigan L,Knight AK,Zhang L,Bauer L,Nakazawa A, TLR9 activation is defective in common variable immune deficiency. Journal of immunology (Baltimore, Md. : 1950). 2006 Feb 1; [PubMed PMID: 16424230]|
|||Yu JE,Knight AK,Radigan L,Marron TU,Zhang L,Sanchez-Ramón S,Cunningham-Rundles C, Toll-like receptor 7 and 9 defects in common variable immunodeficiency. The Journal of allergy and clinical immunology. 2009 Aug; [PubMed PMID: 19592080]|
|||Bernasconi NL,Traggiai E,Lanzavecchia A, Maintenance of serological memory by polyclonal activation of human memory B cells. Science (New York, N.Y.). 2002 Dec 13; [PubMed PMID: 12481138]|
|||Escobar D,Pons J,Clemente A,Iglesias J,Regueiro V,Bengoechea JA,Matamoros N,Ferrer JM, Defective B cell response to TLR9 ligand (CpG-ODN), Streptococcus pneumoniae and Haemophilus influenzae extracts in common variable immunodeficiency patients. Cellular immunology. 2010; [PubMed PMID: 20171611]|
|||Ochtrop ML,Goldacker S,May AM,Rizzi M,Draeger R,Hauschke D,Stehfest C,Warnatz K,Goebel H,Technau-Ihling K,Werner M,Salzer U,Eibel H,Schlesier M,Peter HH, T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency. Blood. 2011 Jul 14; [PubMed PMID: 21576700]|
|||Warnatz K,Denz A,Dräger R,Braun M,Groth C,Wolff-Vorbeck G,Eibel H,Schlesier M,Peter HH, Severe deficiency of switched memory B cells (CD27( )IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood. 2002 Mar 1; [PubMed PMID: 11861266]|
|||Piqueras B,Lavenu-Bombled C,Galicier L,Bergeron-van der Cruyssen F,Mouthon L,Chevret S,Debré P,Schmitt C,Oksenhendler E, Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. Journal of clinical immunology. 2003 Sep; [PubMed PMID: 14601647]|
|||Wehr C,Kivioja T,Schmitt C,Ferry B,Witte T,Eren E,Vlkova M,Hernandez M,Detkova D,Bos PR,Poerksen G,von Bernuth H,Baumann U,Goldacker S,Gutenberger S,Schlesier M,Bergeron-van der Cruyssen F,Le Garff M,Debré P,Jacobs R,Jones J,Bateman E,Litzman J,van Hagen PM,Plebani A,Schmidt RE,Thon V,Quinti I,Espanol T,Webster AD,Chapel H,Vihinen M,Oksenhendler E,Peter HH,Warnatz K, The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008 Jan 1; [PubMed PMID: 17898316]|
|||Sánchez-Ramón S,Radigan L,Yu JE,Bard S,Cunningham-Rundles C, Memory B cells in common variable immunodeficiency: clinical associations and sex differences. Clinical immunology (Orlando, Fla.). 2008 Sep; [PubMed PMID: 18620909]|
|||Carsetti R,Rosado MM,Donnanno S,Guazzi V,Soresina A,Meini A,Plebani A,Aiuti F,Quinti I, The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. The Journal of allergy and clinical immunology. 2005 Feb; [PubMed PMID: 15696104]|
|||Ballegaard V,Permin H,Katzenstein TL,Marquart HV,Schejbel L, Long-term follow-up on affinity maturation and memory B-cell generation in patients with common variable immunodeficiency. Journal of clinical immunology. 2013 Aug; [PubMed PMID: 23649616]|
|||Horn J,Manguiat A,Berglund LJ,Knerr V,Tahami F,Grimbacher B,Fulcher DA, Decrease in phenotypic regulatory T cells in subsets of patients with common variable immunodeficiency. Clinical and experimental immunology. 2009 Jun; [PubMed PMID: 19438597]|
|||Serana F,Airò P,Chiarini M,Zanotti C,Scarsi M,Frassi M,Lougaris V,Plebani A,Caimi L,Imberti L, Thymic and bone marrow output in patients with common variable immunodeficiency. Journal of clinical immunology. 2011 Aug; [PubMed PMID: 21491094]|
|||Malphettes M,Gérard L,Carmagnat M,Mouillot G,Vince N,Boutboul D,Bérezné A,Nove-Josserand R,Lemoing V,Tetu L,Viallard JF,Bonnotte B,Pavic M,Haroche J,Larroche C,Brouet JC,Fermand JP,Rabian C,Fieschi C,Oksenhendler E, Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009 Nov 1; [PubMed PMID: 19807277]|
|||Mahmoudi M,Hedayat M,Aghamohammadi A,Rezaei N, Soluble CD26 and CD30 levels in patients with common variable immunodeficiency. Journal of investigational allergology [PubMed PMID: 23654079]|
|||Cunningham-Rundles C,Radigan L, Deficient IL-12 and dendritic cell function in common variable immune deficiency. Clinical immunology (Orlando, Fla.). 2005 May; [PubMed PMID: 15885637]|
|||Chapel H,Lucas M,Lee M,Bjorkander J,Webster D,Grimbacher B,Fieschi C,Thon V,Abedi MR,Hammarstrom L, Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008 Jul 15; [PubMed PMID: 18319398]|
|||Busse PJ,Farzan S,Cunningham-Rundles C, Pulmonary complications of common variable immunodeficiency. Annals of allergy, asthma [PubMed PMID: 17225714]|
|||Kainulainen L,Suonpää J,Nikoskelainen J,Svedström E,Vuorinen T,Meurman O,Ruuskanen O, Bacteria and viruses in maxillary sinuses of patients with primary hypogammaglobulinemia. Archives of otolaryngology--head [PubMed PMID: 17576911]|
|||Cadranel J,Bouvry D,Wislez M, [Respiratory manifestations of common variable immunodeficiency in adults]. Revue des maladies respiratoires. 2003 Feb; [PubMed PMID: 12709641]|
|||Aghamohammadi A,Allahverdi A,Abolhassani H,Moazzami K,Alizadeh H,Gharagozlou M,Kalantari N,Sajedi V,Shafiei A,Parvaneh N,Mohammadpour M,Karimi N,Sadaghiani MS,Rezaei N, Comparison of pulmonary diseases in common variable immunodeficiency and X-linked agammaglobulinaemia. Respirology (Carlton, Vic.). 2010 Feb; [PubMed PMID: 20051045]|
|||Agarwal S,Mayer L, Pathogenesis and treatment of gastrointestinal disease in antibody deficiency syndromes. The Journal of allergy and clinical immunology. 2009 Oct; [PubMed PMID: 19665769]|
|||Wang J,Cunningham-Rundles C, Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). Journal of autoimmunity. 2005 Aug [PubMed PMID: 15994061]|
|||Swierkot J,Lewandowicz-Uszynska A,Chlebicki A,Szmyrka-Kaczmarek M,Polańska B,Jankowski A,Szechinski J, Rheumatoid arthritis in a patient with common variable immunodeficiency: difficulty in diagnosis and therapy. Clinical rheumatology. 2006 Feb [PubMed PMID: 15940551]|
|||Fernández-Castro M,Mellor-Pita S,Citores MJ,Muñoz P,Tutor-Ureta P,Silva L,Vargas JA,Yebra-Bango M,Andreu JL, Common variable immunodeficiency in systemic lupus erythematosus. Seminars in arthritis and rheumatism. 2007 Feb [PubMed PMID: 17276173]|
|||Dhalla F,da Silva SP,Lucas M,Travis S,Chapel H, Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme. Clinical and experimental immunology. 2011 Jul [PubMed PMID: 21470209]|
|||Pagnini I,Simonini G,Lippi F,Azzari C,Cimaz R, Cutaneous polyarteritis nodosa and common variable immunodeficiency: a previously unreported association. Clinical and experimental rheumatology. 2012 Jan-Feb; [PubMed PMID: 22260879]|
|||Urschel S,Kayikci L,Wintergerst U,Notheis G,Jansson A,Belohradsky BH, Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation. The Journal of pediatrics. 2009 Jun; [PubMed PMID: 19230900]|
|||Salzer U,Warnatz K,Peter HH, Common variable immunodeficiency: an update. Arthritis research & therapy. 2012 Sep 24 [PubMed PMID: 23043756]|
|||Rich AL,Le Jeune IR,McDermott L,Kinnear WJ, Serial lung function tests in primary immune deficiency. Clinical and experimental immunology. 2008 Jan [PubMed PMID: 18005259]|
|||Stafler P,Carr SB, Non-cystic fibrosis bronchiectasis: its diagnosis and management. Archives of disease in childhood. Education and practice edition. 2010 Jun [PubMed PMID: 20501530]|
|||Cinetto F,Scarpa R,Rattazzi M,Agostini C, The broad spectrum of lung diseases in primary antibody deficiencies. European respiratory review : an official journal of the European Respiratory Society. 2018 Sep 30 [PubMed PMID: 30158276]|
|||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, Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. Journal of clinical immunology. 2007 May; [PubMed PMID: 17510807]|
|||Orange JS,Glessner JT,Resnick E,Sullivan KE,Lucas M,Ferry B,Kim CE,Hou C,Wang F,Chiavacci R,Kugathasan S,Sleasman JW,Baldassano R,Perez EE,Chapel H,Cunningham-Rundles C,Hakonarson H, Genome-wide association identifies diverse causes of common variable immunodeficiency. The Journal of allergy and clinical immunology. 2011 Jun; [PubMed PMID: 21497890]|
|||Cunningham-Rundles C, How I treat common variable immune deficiency. Blood. 2010 Jul 8; [PubMed PMID: 20332369]|
|||Lucas M,Lee M,Lortan J,Lopez-Granados E,Misbah S,Chapel H, Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. The Journal of allergy and clinical immunology. 2010 Jun [PubMed PMID: 20471071]|
|||[PubMed PMID: 30910492]|
|||[PubMed PMID: 21981575]|
|||[PubMed PMID: 18520327]|
|||[PubMed PMID: 30219982]|
|||[PubMed PMID: 27836056]|
|||[PubMed PMID: 18639734]|
|||Gathmann B,Mahlaoui N,Gérard L,Oksenhendler E,Warnatz K,Schulze I,Kindle G,Kuijpers TW,van Beem RT,Guzman D,Workman S,Soler-Palacín P,De Gracia J,Witte T,Schmidt RE,Litzman J,Hlavackova E,Thon V,Borte M,Borte S,Kumararatne D,Feighery C,Longhurst H,Helbert M,Szaflarska A,Sediva A,Belohradsky BH,Jones A,Baumann U,Meyts I,Kutukculer N,Wågström P,Galal NM,Roesler J,Farmaki E,Zinovieva N,Ciznar P,Papadopoulou-Alataki E,Bienemann K,Velbri S,Panahloo Z,Grimbacher B, Clinical picture and treatment of 2212 patients with common variable immunodeficiency. The Journal of allergy and clinical immunology. 2014 Jul; [PubMed PMID: 24582312]|
|||[PubMed PMID: 30419968]|
|||[PubMed PMID: 21120868]|
|||[PubMed PMID: 20568383]|
|||[PubMed PMID: 16431351]|
|||[PubMed PMID: 28411962]|
|||[PubMed PMID: 29393912]|