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,

In contrast to many other "primary immune deficiency syndromes", CVID is often diagnosed in adulthood, mostly between the ages of 20 and 40, with a typical latency between first manifestation and first diagnosis of about 4 years.

Affected patients usually suffer from an accumulation of bacterial infections, especially of the respiratory tract. Furthermore: disorders of the gastrointestinal tract (diarrhea about 1/3 of the patients, malabsorption), chronic respiratory diseases (bronchiectasis), changes of lymphatic tissues (hepato-splenomegaly), thymomas and malignant lymphomas).

The classic early warning symptoms of CVID have been grouped under the acronym "ELVIS." They also apply to acquired immune deficiency syndromes (see HIV infection below):

• Pathogen: Infections caused by opportunistic germs (e.g. Pneumocystis spp, see opportunistic infections).
• Localization: Atypical localization of infection sites (e.g., brain abscess due to Aspergillus spp.).
• Course: Unusually severe or unusually recurrent infections.
• Intensity: Unusually severe infections (e.g., severe refractory pyoderma, unusual cytomegalovirus or zoster infection of the skin).
• Sum ofinfections: For young children, >8 minor infections/year; for adults, >3 bacterial infections lasting longer than 4 weeks.

Furthermore, autoimmune phenomena are observed such as: reactive arthritis, immune thrombocytopenia (approx. 20% of patients), autoimmune hemolytic anemia, pernicious anemia (approx. 10% of patients).

The skin symptoms are manifold and cannot be assigned to a specific group:

• In the foreground are "atypical" infections (see also ELVIS), which suggest a disturbed immune situation.
• Generalized, non-infectious granulomas (sarcoidosis-like) are regularly observed, which can manifest themselves in the skin but also in other organs, such as the lungs, liver, spleen and eye (conjunctiva). These can appear even before the diagnosis of CVID (Ma Chia-Man 2018). In most cases, these granulomas behave harmlessly with a high spontaneous remission rate. Only rarely do they take a tissue-destructive course and then require treatment (systemic corticosteroids, immunoglobulins, mycophenolate, cyclosporine A, etanercept, and others).
• Furthermore observed are:
  • Pyoderma gangraenosum
  • Necrobiosis lipoidica
  • Leukocytoclastic vasculitis with IgA glomerulonephritis (CVID6 with mutaion in CD81)
  • Effluvium, partly 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.

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