Continuing Education Activity

Common variable immunodeficiency is a disorder characterized by defective B cell function leading to impaired immunoglobulin production. It can present with heterogeneous clinical manifestations such as recurrent infections, chronic lung disease, autoimmune disorders, gastrointestinal disease, or increased risk of malignancy. While some researchers have identified some genetic defect, the fundamental cause of CVID has been challenging to determine.

Objectives:

• Identify the pathophysiology of common variable immunodeficiency disease.

• Review the evaluation of common variable immunodeficiency disease, especially to avoid a delayed diagnosis.

• Describe the treatment and management options available for common variable immunodeficiency disease.

• Outline interprofessional team strategies for improving care coordination and communication to improve short-term and long-term outcomes.

Introduction

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.[1][2]

It is the most frequent symptomatic primary immunodeficiency disorder worldwide.[2][3] 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),[1] named “variable” because of its heterogeneous clinical manifestations.[4]

Etiology

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.[5][6][7][8]

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.[9]

Epidemiology

CVID affects approximately 1 of 25000 individuals, with a higher prevalence in northern Europe.[10][1][11] It is typically most diagnosed after puberty, being the majority between 20 and 45 years of age.[1][11][4] It does not show any predilection for race or gender.

Pathophysiology

The clinical variability of CVID suggests that multiple immunoregulatory defects can result in the final common pathway of hypogammaglobulinemia.[1]

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[12]:

• B Cells abnormalities: The number of B cells is normal in the majority of patients, but many of them have reduced percentages of isotype-switched memory B cells capable of producing immunoglobin isotypes that are critical toward antibody response recall. The abnormalities that appear to occur in the bone marrow include aberrant gene rearrangement, decreased V gene replacements, reduced diversity of the naïve B cell repertoire, impaired somatic hypermutation, and abnormal expansion of unmutated B cell clones.[13]
  • Toll-like receptor signaling: B cell maturation is defective, and the action of toll-like receptors 7 and 9 (TLR7 and TLR9) becomes impaired because of a yet unknown mechanism. Defective signaling of TLR7 and TLR9 in B cells and plasmacytoid dendritic cells, along with deficient IFN-a, impairs B cell functions and prevents TLR-mediated augmentation of humoral immunity in vivo.[14][15] The binding of viral RNA to TLR7 or bacterial DNA to TLR9 leads to B cell activation, cytokine secretion, proliferation, and survival; in CVID, the loss of these stimuli functions may contribute to the B cell defects mentioned.[16][17]
  • Memory B cells: determining the number of isotype-switched memory B cells is of utmost interest because it provides information about the immaturity of the B cell, relates to the numbers of plasma cells in the bone marrow, and gives information about the possible clinical outcomes.[18] Various studies tried to classify CVID patients based on numbers of isotype-switched memory B cells[19][20][21][22][23]:
    • Patients that switched CD27+IgM-IgD- memory B cells had a higher prevalence of splenomegaly and autoimmune cytopenias. This proposed a fast and reliable new classification for CVID patients with flow cytometric quantification of class-switched memory and immature B cells.
    • Certain disorders were more prevalent in patients with the lowest count of memory B cells (splenomegaly, lymphoid proliferation, granulomatous disease).
    • Lower levels of IgM memory B cells were associated with chronic pulmonary disease (bronchiectasis).
    • Research has determined that the percentages of switched memory B cells changed in some patients over time. Based on these findings, the suggestion is that immunologic characteristics have to be evaluated several times after diagnosis.[24]
  • Decreased T lymphocyte proliferation to mitogens and antigens,[1] reduced T regulatory cells,[25] T cell receptor excision circles that suggest thymic dysregulation,[26] defective T cell receptor signal transduction.
  • Decrease in CD4+ cell count or increase in CD8+ cell count, altering the CD4/CD8 ratio.[27] Increase in CD26 and CD30 levels (the last ones associated with splenomegaly and malignancy)[28].
  • The minor capacity of dendritic cells to secrete interleukin-12.[29]
  • A drop of plasma cells in the gastrointestinal tract and bone marrow.[18]

History and Physical

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[30]:

• Uncomplicated (patients usually suffer only infections)
• Autoimmunity
• Polyclonal lymphocytic infiltration (this includes lymphoid interstitial pneumonitis, unexplained granulomas, unexplained hepatomegaly and/or splenomegaly, and lymphadenopathy)
• Enteropathy (biopsy-proven lymphocytic infiltration in lamina propria and interepithelial mucous with villous atrophy)
• Lymphoid malignancy

In any patient with newly diagnosed CVID, two complications have to be considered when assessing the clinical presentation: infectious and non-infectious.

Patients may suffer the following clinical manifestations at disease onset or throughout life[31][32][33][34][35]:

• Infections: common organisms like Haemophilus influenzae, Streptococcus, Moraxella catarrhalis, and Staphylococcus aureus; and uncommon organisms like Pneumocystis jirovecii and Mycoplasma pneumoniae:
  • Sinopulmonary infections that can be recurrent and result in bronchiectasis: pneumonia, bronchitis, sinusitis
  • Otitis
  • Conjunctivitis
  • Septic arthritis
  • Bacterial meningitis
  • Sepsis
  • Cutaneous infections
• Lung Disease
  • Obstructive lung disease, generally because of bronchiectasis (resulting in chronic productive cough and dyspnea, especially in flares)
  • Restrictive lung disease: normally due to diffuse interstitial lung disease or organizing pneumonia
  • Primary malignancy (lymphoma) or metastatic gastric carcinoma
  • Granulomatous disease: manifested as parenchymal nodules and/or ground glass abnormalities
• Autoimmune disorders (hematologic disorders are the most common form of autoimmunity, with a prevalence of around 20%)[36]:
• Immune thrombocytopenia (10 to 12%)
• Coombs-positive autoimmune hemolytic anemia (5 to 7%)
• Evans syndrome
• Others:
  • Rheumatoid arthritis: 1% to 10% of patients - usually, with negative antinuclear antibodies or rheumatoid factor due to lack of antibodies production.[37]
  • Systemic lupus erythematosus (SLE): a very uncommon finding (less than 1% of patients) but with a curiously predisposal to clinical remission due to loss of B cells or functional antibodies in almost 70% of patients.[38] On the other hand, suggesting more than one mechanism involved between these two associations, there are reports of SLE exacerbations after the development of hypogammaglobulinemia.
  • Sicca syndrome, Sjogren’s syndrome, autoimmune thyroiditis, vitiligo
• Gastrointestinal (GI) infections and other GI disorders
  • Persistent diarrhea and malabsorption caused by giardiasis, Clostridium difficile infection, bacterial enterocolitis, CMV (cytomegalovirus) colitis, Helicobacter pylori infection
  • Severe diarrhea caused by other infections and autoimmunity (inflammatory colitis)
  • Inflammatory bowel-like disease, sprue-like illness, pernicious anemia (10% of patients),[39] protein-losing enteropathy
  • Malignancies (the risk of gastric carcinoma is almost 50 times greater in patients with CVID)
  • Liver disease
• Dermatologic manifestations[40]
  • Alopecia areata or alopecia universalis
  • Atopic dermatitis
  • Cutaneous vasculitis (including polyarteritis nodosa)

Physical examination may be normal in these patients. However, there could be signs and symptoms of chronic illness like[41]:

• Nasal congestion due to chronic sinusitis.
• Scars in the tympanic membranes due to recurrent otitis
• Weight loss, nocturnal fever, and sweats (B symptoms) due to lymphoid malignancy
• Digital clubbing, chronic productive cough, and dyspnea due to chronic pulmonary disease
• Lymphadenopathy, splenomegaly, arthritis, conjunctivitis, oral thrush, etc.

Evaluation

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[42]:

Laboratory Tests

• Blood counts (every 3 to 6 months; especially along with autoimmune cytopenia)
• Coombs test in case of new anemia (on-demand)
• Bone marrow biopsy + beta-2-microglobulin  in case of suspicion of lymphoma or myelodysplasia (on-demand at diagnosis or during follow-up)
• Plasma IgG, IgA, IgM (at diagnosis and every 6 months in patients with IVIG replacement; every 1 to 3 months in patients with SCIG replacement)
• Flow cytometry for CD3, CD4, CD8, CD19, CD56 lymphocyte subsets (initially and in case of suspicion of a combined immunodeficiency) and T/B cell evaluation
• Vaccination responses: tetanus, diphtheria, hepatitis, pneumococcal (at diagnosis)
• Sputum: determine pathogens and resistance to antibiotics (on-demand and every 6 to 12 months in case of bronchiectasis)
• Sinus simple computed tomography (on-demand)

Lungs

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)[43][44][45]:

• Patients should have a regular evaluation for pulmonary symptoms and characteristics of sputum (color and volume)
• Lung function with spirometry, CO diffusion test, and blood gases must be monitored every 6 or 12 months because of its proven decline over time, even in asymptomatic patients; and repeated after every flare or bronchiectasis
• Lung volume to assess restrictive disease is for patients who have an intolerance to exercise or who show diffuse parenchymal lung disease on imaging
• A chest radiograph is mandatory in all patients that complain about new symptoms
• High-resolution computed tomography (HRCT) is recommended in all patients as the initial diagnostic workup to assess existing lung damage (only 6% of patients have entirely normal HRCT images) and repeated every five years
• Thoracic computed tomography is the recommendation in patients with lung volume and pulmonary function abnormalities, or when the chest radiography demands further identification
• Lung magnetic resonance Imaging is viable as a radiation-sparing alternative
• Bronchoscopy and bronchoalveolar lavage are recommended  procedures in the case of suspected pulmonary granulomas

Lymphoproliferation

• Sonography, CT, or magnetic resonance (MR) of the abdomen (on-demand and in case of suspected lymphoma)
• Lymph node biopsy (on-demand and in case of suspected lymphoma)

Gastrointestinal Tract

• Upper endoscopy with biopsy to search for Helicobacter pylori infection (in case of clinical symptoms and every 24 months in case of increased risk for developing intestinal malignancy, as the general population)
• Lower endoscopy (on-demand)

Central Nervous System

• Magnetic resonance, cerebrospinal fluid analysis in case of neurological symptoms, especially infectious ones (on-demand).

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).[46][21] 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.[47]

Biopsies are frequently done to discard malignancy or autoimmunity in the case of gastrointestinal disorders, pulmonary nodules, and dermatologic findings.

Treatment / Management

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.[48] 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 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.[49]

Adverse Reactions:

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.

• Inflammatory reactions can occur during IVIG administration. The management is generally symptomatic.
• Anaphylaxis is rare but may be life-threatening. The treatment basis is on common protocols (securing the airway, administration of epinephrine, oxygen, salbutamol, antihistamine agents, and glucocorticoids).
• Thromboembolic risk events (as myocardial infarction, stroke, and venous thromboembolism) can be diminished by adequate hydration, avoiding prolonged immobilization, spacing larger doses, slowing infusions.
• Headache is common and treatable with normal painkillers.
• Acute kidney injury risk can be minimized with adequate hydration and avoiding concentrated or sucrose-containing products in those with existing renal disease.
• Hemolytic anemia can occur due to passive antibodies in the IVIG product. Reactions can vary from a positive direct Coombs test, mild extravascular hemolysis, and infrequently, intravascular hemolysis.
• Neutropenia can occur but is normally mild and transient.

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.[50]

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.[36] In glucocorticoid-refractory cases, rituximab should be considered,[51] maintaining immune globulin replacement therapy; however, in severe refractory cases, splenectomy is the last option.[52]

Treatment for rheumatologic diseases is the same as for patients who are not immunocompromised, along with the addition of immunoglobulin replacement.

4. Malignancies

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.[53][48] However, all patients must be tested for Helicobacter pylori infection and pernicious anemia laboratory features, because of their relation to gastric malignancy.[39]

5. Vaccinations

Recommendations for vaccination is based on the antibody deficiency severity[54]:

• Routine schedule for inactivated or subunit vaccines in mild deficiency:
  • DTaP (diphtheria, tetanus toxoid, acellular pertussis vaccine)
  • HAV (Hepatitis A virus)
  • HBV (hepatitis B virus)
  • HIB (Haemophilus influenzae type B)
  • HPV (human papillomavirus)
  • Influenza
  • Meningococcal
  • Pneumococcal
  • Polio (intramuscular)
  • Anthrax
  • JE (Japanese encephalitis)
  • Typhoid (intramuscular).
  • Rabies
• Routine schedule for inactivated or subunit vaccines in severe deficiency:
  • HPV
  • Influenza
  • Anthrax
  • Rabies
• Recommended administration of live-attenuated vaccines in mild deficiency (likely benefit but possible harm):
  • MMR (measles-mumps-rubella)
  • Rotavirus
  • Varicella
  • Herpes Zoster
  • Smallpox (for pre-exposure)
  • BCG (Bacille Calmette-Guerin)
• Live-attenuated vaccines are not recommended in severe deficiency.

6. Other recommendations

• Pulmonary diseases should be treated individually since there are no specific indications in CVID patients.
• Patients should no be given blood or blood components without testing for Cytomegalovirus.
• Regular dental care is mandatory. Prophylactic antibiotics are crucial before invasive dental procedures.
• Mental health following is crucial because patients are sometimes disintegrated from normal life activities.
• Audition care is essential given the fact that sensorineural loss frequently occurs probably because of recurrent bacterial otitis media, viral infections, periodic use of ototoxic antibiotics, and central nervous system infections.[55]
• The patient's parents must receive genetic counseling about the possibility of future children with the same disease.

Differential Diagnosis

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.

• Secondary hypogammaglobulinemia can be due to decreased production (drugs, disorders that cause bone marrow suppression, Goodpasture syndrome, malignancy) or increased loss (protein-losing disorders such as enteropathies, nephrotic syndrome, burns).
• Primary hypogammaglobulinemia can be due to deficiency in IgG1 and IgG2, hyper-immunoglobulin M syndromes, and other combined immunodeficiencies.

Prognosis

The basis of medical complications and mortality statistics is from the largest series of 473 patients, followed over 40 years in New York.[4]

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.[56][57]

Non-infectious complications have a prevalence of around 60 to 70%, and the risk of death because of them is 11 times higher.

Deaths due to bacterial infection have been reduced dramatically with the rise of immune globulin therapy.[4][30] The risk of death is 95% lower among patients with only infectious complications.

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.[58]

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.[59]

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[60]:

• Bronchiectasis (approximately 20% of patients)[56]: a common pathologic response to recurrent bacterial infections and/or lower airway inflammation.
• Bronchospasm
• Obstructive and restrictive pulmonary disease
• Granulomas

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.[61] The most frequent malignancies are described in order of frequency[30]:

• Non-Hodgkin lymphoma: mostly with an extranodal origin (patients could have a lifetime risk of possibly 2% to 8%), and more likely in females over 30 years.[1][4] B cell is the most common type as expected, and they are usually well differentiated.
• Gastric carcinoma: associated with Helicobacter pylori infection and gastritis (incidence of less than 1%). Diagnosed in individuals younger than the overall gastric cancer population. Generally, it consists of a moderately to poorly differentiated intestinal-type adenocarcinoma with a high count of intra-tumoral lymphocytes.[62]

Pearls and Other Issues

• Delayed recognition of this disease is common.
• CVID may result from various gene defects.
• Opportunistic infections are rare but can occur.
• Several causes of hypogammaglobulinemia have to be excluded before determining the diagnosis of CVID.
• Higher doses of immune globulin are recommended for those patients with persistent infections.
• There is not much evidence of immune globulin therapy and its protection against malignancy. However, evidence shows that treatment can reduce the progression of pulmonary disease and the frequency of several infections. Also, it may offer protection against autoimmunity.

Enhancing Healthcare Team Outcomes

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 5]