CVID D83.0, D83.1, D83.2 , D83.8, D83.9

The disease name CVID "Common Variable Immunodeficiency" refers to a group of diseases from the group of"primary immunodeficiency diseases (PID)". CVID is characterized by a more or less pronounced deficiency of the three antibody classes IgG, IgA and IgM . The antibody deficiency leads to recurrent and often severe infections , mainly affecting the ears, sinuses, respiratory tract and skin. In the majority of cases, the diagnosis is not made until the third to fourth decade of life. Severe and recurrent infections can cause permanent damage to the airways (bronchiectasis).

The prevalence of variable immunodeficiency syndrome is estimated at 1:25,000 persons (figures vary between 1:10,000 and 1:100,000).

The cause of the disease is unknown. It is not one entity but a heterogeneous group of different diseases.

Mutations in the 4 genes ICOS, LRBA, BAFF-R and TNFRSF13B (encodes TACI) together are associated with 10-15% of CVID cases.

Other mutations affect the costimulatory molecules of the B cell series: CD19(CVID3), CD81 (CVID6), CD20(CVID5).

There are two "peaks" in the age distribution at the time of diagnosis: the early form is usually diagnosed in infancy, the late form in young adulthood. w:m = 1:1

Papules, plaque, ulcers, crusts,

Unlike many other immunodeficiency syndromes, CVID is often not diagnosed until adulthood, mostly between the ages of 20 and 40, with a typical latency period of about 4 years between the initial manifestation and the initial diagnosis.

Affected patients usually suffer from a cluster of bacterial infections, particularly of the respiratory tract. Furthermore: gastrointestinal disorders (diarrhea in about one-third of patients, malabsorption), chronic respiratory diseases (bronchiectasis), and changes in lymphoid tissue (hepatosplenomegaly, thymomas, and malignant lymphomas).

The classic early warning symptoms of CVID have been summarized under the acronym“ELVIS.”They also apply to acquired immunodeficiency syndromes (see below: HIV infection):

• Pathogens: Infections caused by opportunistic pathogens (e.g., Pneumocystis spp., see opportunistic infections)
• Location: Atypical location of sites of infection (e.g., brain abscess caused by Aspergillus spp.)
• Course: Unusually severe or unusually recurrent infections.
• Severity: Unusually severe infections (e.g., severe, treatment-resistant pyoderma; unusual cytomegalovirus or herpes zoster infections of the skin)
• Total numberof infections: For infants, >8 minor infections per year; for adults, >3 bacterial infections lasting longer than 4 weeks.  

In addition, autoimmune phenomena are observed, such as: reactive arthritis, immune thrombocytopenia (approximately 20% of patients), autoimmune hemolytic anemia, and pernicious anemia ( approximately 10% of patients).

Skin manifestations are diverse and cannot be classified into a specific group:

• The primary focus is on “atypical” infections (see also ELVIS), which suggest an impaired immune system.  
• Generalized, non-infectious granulomas (sarcoidosis-like) are commonly observed; these can manifest in the skin as well as in other organs, such as the lungs, liver, spleen, and eyes (conjunctiva). These may occur even before a diagnosis of CVID is made (Ma Chia-Man 2018). In most cases, these granulomas are benign and have a high rate of spontaneous remission. Only rarely do they follow a tissue-destructive course, in which case they require treatment (systemic corticosteroids, immunoglobulins, mycophenolate, cyclosporine A, etanercept, etc.).   
• The following are also observed:
  • Pyoderma gangraenosum
  • Necrobiosis lipoidica
  • Leukocytoclastic vasculitis with IgA glomerulonephritis (CVID6 with a mutation in CD81)   
  • Effluvium, sometimes diffuse effluvium
  • Alopecia areata
  • Vitiligo

Serum electrophoresis with reduction of the gamma globulin fraction. Furthermore, a quantitative determination of the immunoglobulins is to be carried out: IgG < 3 g/l. IgA and IgM are also often reduced.

First, the antibodies IgG, IgA and IgM are determined in the blood. In addition, it is checked whether antibodies are formed during vaccinations (vaccine antibodies). In order to clearly distinguish the disease from other diseases such as agammaglobulinemia, the number and function of B and T cells in the blood are also determined.

All acquired immune deficiency syndromes can lead to analogous "reactive" changes in the skin. In this respect, the described skin changes are not conclusive for CVID, but are to be considered as clinical leading symptoms of general immunodeficiency (see also Immunodeficiencies).

Differential diagnosis should exclude:

• Selective IgA deficiency (more frequently encountered, often an incidental diagnosis, since lifelong often asymptomatic; IgA deficiency usually occurs in isolation, but may in some cases precede the development of CVID or occur in family members of CVID patients.
• Silvery Hair Syndrome
• Agammaglobulinemia congenital type Bruton
• Agammaglobulinemia congenital type Schweizer
• Hyper-IgM syndrome (immunodeficiency associated with elevated immunoglobulin M (D80.5)
• Transient hypogammaglobulinemia in childhood
• Combined immunodeficiencies (SCID etc.)
• Multiple myeloma (especially Bence-Jones myeloma)
• Nephrotic syndrome (protein loss through the kidneys)
• Exudative enteropathy (protein loss via the intestine)
• Sarcoidosis

CVID is associated with autoimmune diseases in about half of the patients. These are characterized by leuopenias, thrombopenias, anemias or arthritides, and endocrine disorders. About 20% of CVID patients develop complicating interstitial lung disease called granulomatous lymphocytic interstitial lung disease (GLILD). Granulomatous changes are also found in other organs such as the lymph nodes, liver, skin (Cha Chia-Man et al. 2018). Furthermore, gastrointestinal problems such as chronic diarrhea, weight loss, nausea, vomiting, and abdominal pain are observed.

A causal therapy is not possible. Regular intravenous administration (every 2-6 weeks 200 to 600 mg/KG) of IVIG. For subcutaneous application 0.1g/kg bw are administered weekly. Target: IgG in serum > 5 g/l.

Furthermore: Targeted treatment of bacterial infections with antibiotics. Cave: Dosages of antibiotics significantly higher; application time longer than normal.

The granulomatous changes in the skin usually disappear spontaneously. Consequently, they do not require special treatment.

Observance of general hygienic measures with regular hand disinfection, careful dental care, use of an early local therapy for infections of the upper respiratory tract.

CVID is also known as hypogammaglobulinemia, adult-onset agammaglobulinemia, late-onset hypogammaglobulinemia, and acquired agammaglobulinemia.

Cave: live vaccinations are contraindicated. With immunoglobulin substitution, there is good passive protection against tetanus and diphtheria.

1. Barouti N et al (2013) Successful treatment of ulcerative and diabeticorum necrobiosis lipoidica with intravenous immunoglobulin in a patient with common variable immunodeficiency. JAMA Dermatol 149:879-881
2. Bergler-Czop B et al (2013) Pyoderma gangrenosum in a patient with common variable primary immunodeficiency. Postepy Dermatol Allergol 30:188-191
3. Boursiquot JN et al (2013) DEFI study group. Granulomatous disease in CVID: retrospective analysis of clinical characteristics and treatment efficacy in a cohort of 59 patients. J Clin Immunol 33:84-95
4. Cha Chia-Man et al. (2018) Cutaneous granulomas in a patient with variable immunodeficiency.J Dtsch Dermatol Ges 16: 216-218
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