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]
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