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Common variable immunodeficiency in children

Common variable immunodeficiency in children
Authors:
Mary Beth Hogan, MD
Meagan W Shepherd, MD
Section Editor:
Luigi D Notarangelo, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Jan 2023. | This topic last updated: Oct 19, 2020.

INTRODUCTION — Common variable immunodeficiency (CVID) is a heterogeneous disorder involving immune dysfunction of B and T cells and dendritic cells. The characteristic immunologic defect is the inability of B cells to differentiate into plasma cells capable of secreting all immunoglobulin types.

Clinical features of CVID and issues in the diagnosis and management of this disorder that are specific to pediatric patients (less than 18 years of age) will be reviewed here. Additional reviews of CVID, which emphasize adult manifestations and management, are found separately:

(See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

(See "Treatment and prognosis of common variable immunodeficiency".)

(See "Pathogenesis of common variable immunodeficiency".)

DEFINITION AND CLASSIFICATION

Definition — CVID is defined by the following [1-3]:

Age-specific reduction in serum concentrations of immunoglobulin (Ig)G, in combination with low levels of IgA and/or IgM (at least two standard deviations below mean for age)

Poor or absent response to immunizations and/or absent isohemagglutinins and/or low switched B cells (<70 percent of age-related normal value)

Absence of profound T cell immunodeficiency (low CD4: <300 for 2 to 6 years, <250 for 6 to 12 years, <200 for >12 years; low naïve CD4 (CD45RA+): <25 percent for 2 to 6 years, <20 percent for 6 to 16 years, <10 percent for over 16 years of age; absent T cell proliferation)

Absence of any other defined immunodeficiency state

EPIDEMIOLOGY — CVID is one of the more common antibody deficiency disorders. In one large series of primary immunodeficiency (PID) in children diagnosed over a 10-year period, CVID made up 17 of 189 total PID cases and 20 percent of the 87 cases of antibody deficiency [4].

Most patients with CVID present after puberty, and the disorder is usually diagnosed in the second or third decade of life. However, about 25 percent of all CVID patients present in childhood or adolescence, and there is an earlier peak of diagnosis at approximately eight years of age [5,6]. A diagnosis of CVID before six years of age should be considered preliminary because of immunologic immaturity and the persistence of transient hypogammaglobulinemia of infancy in some children. In addition, the possible presence of a monogenic defect that causes a CVID-like disorder should be considered in children who present at a very young age. (See 'Differential diagnosis' below.)

Additional information about the epidemiology of CVID is found separately. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Epidemiology'.)

CLINICAL MANIFESTATIONS AND CHARACTERISTIC PRESENTATIONS — Patients with CVID most commonly present with recurrent sinopulmonary and gastrointestinal infections. However, they are also at increased risk for other disorders of immune dysregulation and may present with a dominant autoimmune (cytopenias, thyroid disorders), gastrointestinal, allergic, or malignant disease. Children with these less common presentations may be cared for in hematology, rheumatology, gastroenterology, or endocrine clinics for a period of years before the underlying diagnosis of CVID is appreciated.

Comparison of pediatric- and adult-onset disease — The types of disorders that develop in patients with CVID are similar in adults and children, although there are some differences in the prevalence of certain manifestations of the disease. In all age groups, sinopulmonary infections and complications of infections are the most common presentation. However, children have more problems with ear infections and certain disorders, such as autoimmune cytopenias and allergic disease, compared with adults with CVID. In addition, children may present with failure-to-thrive.

Several series support these conclusions [5,7-9]. The two largest are presented here:

A series of 457 patients used the United States Immunodeficiency Network data to compare patients diagnosed with CVID before age 18 with those with adult-onset CVID [8]. Pediatric-onset CVID patients more often had recurrent otitis media, developmental delay, and failure-to-thrive compared with adult-onset CVID patients. Asthma or reactive airway disease was reported more in early-onset and adolescent CVID groups compared with adult-onset CVID patients (46 versus 34 percent). Adult CVID patients were more frequently diagnosed with bronchitis, arthritis, depression, and fatigue.

A 30-year review of 198 cases of CVID, both pediatric- and adult-onset, also found that infectious complications between groups were similar, with sinopulmonary infections and chickenpox/shingles being the most common [9]. Otitis media and autoimmune hematologic disease were more frequent in the 91 pediatric-onset CVID cases as compared to adult-onset. A common comorbidity of each group was lymphoproliferative/granulomatous disease (44 percent of pediatric-onset and 35 percent adult-onset CVID). Malignancy was present in 11 percent of the pediatric-onset cohort, compared with 22 percent of the adult-onset population.

Recurrent infections — Pediatric patients with CVID often experience recurrent pyogenic infections of the upper and lower respiratory tracts and chronic gastrointestinal infections with the same spectrum of organisms seen in adult patients (table 1). The most common presentation for the pediatric patient with CVID is recurrent otitis media, which is more common than in adults, chronic and persistent sinusitis, chronic cough, and recurrent bacterial pneumonias [5,7-9]. Older children will often have bronchiectasis and bronchial wall thickening, presumedly from recurrent infections.

In the above-mentioned study, which included 91 pediatric-onset CVID patients, a delay in diagnosis of CVID in children was associated with an increased risk of virulent organisms such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, Pseudomonas, and Clostridium difficile, which resulted in increased odds of mortality [9]. Both pediatric-onset and adult-onset CVID patients in this group (6 percent of the cohort) developed sepsis associated with indwelling catheter use, suggesting that the risk/benefits of placement should be weighed carefully. (See 'Gastrointestinal problems' below and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Gastrointestinal disease'.)

There are rare reports of chronic enteroviral infections causing neurodegenerative diseases or encephalitis. One case series described 32 children, in which two cases of poliovirus-related vaccine paresis were reported [5].

Pulmonary manifestations — A majority of CVID patients (all ages) develop chronic structural pulmonary complications, including bronchiectasis and bronchial wall thickening [10]. In a study of 54 children with either CVID or similar disorders, structural lung disease was found in more than 85 percent of patients [11]. Most children had mild bronchiectasis scores, although 5 percent were scored moderate-to-severe. Twenty-five percent of CVID children had multiple lung nodules, which tended to resolve after treatment with systemic glucocorticoids. However, in the case series of 91 pediatric-onset CVID patients, lymphocytic/granulomatous disease was common and found to be a significant cause of mortality in females, while bronchiectasis contributed to mortality in males [9].

Children with CVID frequently have obstructive airway disease that is indistinguishable from asthma, and this appears to be a more common manifestation in children compared with adults. Obstructive flow-volume curves have been found in 50 to 94 percent of patients (all ages) [7,10]. The increased prevalence of obstructive airway disease may be in part due to recurrent viral illnesses associated with childhood.

Allergic diseases — The presence of atopic disease (asthma, eczema, allergic rhinitis, and urticaria) may be a feature of pediatric-onset CVID as compared to adult-onset disease. In both children and adults, absent immunoglobulin E (IgE) is common, with undetectable allergen-specific IgE in 97 percent [12]. Despite this, in the two pediatric series mentioned above, 38 percent of patients in one of the cohorts had some evidence of an allergic disease, including asthma, food allergy, eczema, urticaria, and rhinitis [5], and 83 percent had asthma in the other [7]. In a series of 45 patients, five had atopic dermatitis and six had eosinophilic esophagitis [6].

Failure-to-thrive and endocrine abnormalities — Failure-to-thrive (FTT) is an important manifestation of immunodeficiency in children and is usually attributed to repetitive illnesses. However, primary growth hormone deficiency and hypothyroidism have also been reported in hypogammaglobulinemic children [13,14]. Additionally, in a cohort of 22 patients with adrenocorticotropic hormone (ACTH) deficiency, three patients (14 percent) were identified as having CVID, and pedigree analysis revealed a fourth patient with both ACTH and growth hormone deficiency [15]. (See "Poor weight gain in children younger than two years in resource-abundant countries: Etiology and evaluation" and "Poor weight gain in children older than two years in resource-abundant countries", section on 'Diagnostic approach'.)

Gastrointestinal problems — Diarrhea, malabsorption, and weight loss are common problems in both children and adults with CVID [16]. Gastrointestinal infections include Clostridium difficile, Giardia lamblia, and norovirus [17]. Other intestinal pathogens such as Salmonella, Shigella, and Campylobacter are also reported [18]. Crohn disease and ulcerative colitis are reported [16], although similar findings can be a manifestation of granulomatous disease associated with immune dysregulation. Nodular intestinal hyperplasia occurs relatively frequently in adolescents with CVID (picture 1) [19]. Enteropathy was found in 33 percent of the pediatric-onset population in the above-mentioned series, making it an important comorbidity [9]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Gastrointestinal disease' and "Gastrointestinal manifestations in primary immunodeficiency".)

Autoimmune disease — Autoimmunity is seen in 20 to 25 percent of patients with CVID when all ages are considered together. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Autoimmune disease' and "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

Autoimmune cytopenias and Evans syndrome — Autoimmune cytopenias are a more common presenting disorder in children than adults and may be the initial manifestation of the disease. Idiopathic thrombocytopenic purpura (ITP) and hemolytic anemia, or combinations of these disorders, were present in 33 percent of pediatric-onset CVID patients with evidence of autoimmunity in one large series [9]. Another series identified autoimmune neutropenia in a small subset of patients with both pediatric-onset and adult-onset CVID [20].

Evans syndrome is characterized by the combination of autoimmune hemolytic anemia and ITP and has been associated with immunodeficiency and lymphoproliferation. A pediatric series of seven children with Evans syndrome found Fas expression on peripheral blood T and B cells and Fas-mediated elimination of activated T cells to be elevated compared with control children with acute ITP or other nonimmune disorders [21]. Among the seven with Evans syndrome, five eventually developed CVID, indicating that elevated Fas expression and Fas-mediated apoptosis may be associated with the development of CVID in these patients. In another series of Evans syndrome patients, 3 of 35 pediatric patients were found to have CVID, and these authors suggested that immunodeficiency screening in this population may be recommended [22]. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Evans syndrome'.)

Other disorders — Insulin-dependent diabetes, psoriasis, systemic lupus erythematosus, rheumatoid arthritis, and juvenile idiopathic arthritis are also associated with CVID, although these are less common.

Central nervous system problems — Pediatric patients are susceptible to developing intracranial granulomas. Central nervous system granulomas can be present in addition to granulomas in other organs such as the gastrointestinal tract. Manifestations of this phenomenon include seizures, headaches, vision loss, weakness, ataxia, nystagmus, and coma [23].

Malignancy — In general, the risk of malignancy with pediatric CVID is increased [24,25]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Malignancies'.)

Similar to adults, the most common malignancies in children with CVID are Hodgkin and non-Hodgkin lymphoma. However, a variety of other malignancies are reported, including leukemias, astrocytoma, melanoma, and sarcoma [5-7,9,26].

In a series of 32 children, four developed a malignancy during the follow-up period [5]. Two of these children had Hodgkin lymphoma, one had non-Hodgkin lymphoma, and one patient had Burkitt lymphoma.

In another series of pediatric CVID patients, 4 of 27 developed malignancy [26]. Three developed non-Hodgkin lymphoma (two patients diagnosed with mucosa-associated lymphoid tissue lymphoma, and one malignancy was Epstein-Barr virus-associated) and one patient developed astrocytoma.

In the authors' series, one patient had undifferentiated sarcoma prior to the identification of CVID, suggesting that malignancy may also occur as a primary event prior to identification of immunodeficiency [7].

EVALUATION

In whom to suspect the diagnosis — The diagnosis of CVID should be suspected in a child with an appropriate history of recurrent sinopulmonary infections, chronic diarrhea and malabsorption, failure to thrive, and/or autoimmune diseases (especially cytopenias).

Physical findings — Many children with CVID are small and appear chronically ill. They may show signs of chronic upper or lower respiratory infections including otitis, purulent nasal discharge, or visible postnasal drainage. Tonsils and lymphoid tissue are usually present and are sometimes enlarged. Skin infections or eczema may be noted. Pulmonary findings of rales, wheezing, and digital clubbing may be present. Hepatosplenomegaly suggests gastrointestinal or autoimmune problems. Signs of arthritis, vasculitis, or vitiligo may be present.

Immunoglobulin levels — The diagnosis of CVID requires decreased immunoglobulin (Ig)G levels, in association with low levels of IgA and/or IgM. When assessing pediatric patients for hypogammaglobulinemia, it is important to use age-related normal values (table 2).

A normal IgG level for children 6 to 16 years old is about 1000 mg/dL with a 1 standard deviation range of 250, whereas children with CVID will typically have IgG levels below 500 mg/dL.

IgM and IgA levels are also reduced in CVID but are less valuable in establishing a diagnosis.

A total IgE level is also helpful, because most patients with CVID have undetectable IgE [12]. However, the presence of IgE does not preclude the diagnosis of CVID, and if found, an investigation for specific IgE functionally through skin testing or presence in serum may be performed as clinically indicated.

IgG subclass determinations are indicated if antibody titers are decreased but immunoglobulin levels are near normal. (See 'IgG subclass deficiency' below.)

Indications for referral — If the patient's history and physical examination raise concern about a possible diagnosis of CVID, immunoglobulin levels should be evaluated initially. If low, referral to a clinical immunologist is indicated, whenever possible, to assess antibody function and exclude other causes of hypogammaglobulinemia.

Following diagnosis, immunology specialists can also determine the most appropriate therapies (such as prophylactic antibiotics and immune globulin) and help monitor the patient for associated disorders. Most pediatric immunologists are versed in the care of children with CVID. In the United States, the Clinical Immunology Society [27], the American Academy of Allergy, Asthma, and Immunology [28], and the American College of Allergy, Asthma, and Immunology [29] maintain databases of clinicians who have appropriate expertise in the care of patients with immunodeficiency.

Antibody function studies — The demonstration of adequate antibody responses essentially excludes the diagnosis of CVID in young children. After obtaining a thorough vaccination history, titers to diphtheria, tetanus, Haemophilus influenzae, and serotypes in the protein conjugated pneumococcal vaccine should be measured (table 3). The challenge in assessing specific antibody formation lies in correctly interpreting the significance of an impaired response, which may be truly pathologic or simply indicative of an immature immune system, particularly in the infant or child less than six years of age.

Evaluation of polysaccharide responses can be obtained after two years of age if the patient has received the unconjugated polysaccharide pneumococcal or Neisseria meningitidis vaccines. The unconjugated polysaccharide Vi antigen Salmonella typhi vaccine can be used in lieu of the pneumococcal and N. meningitidis vaccines in those currently receiving immunoglobulin therapy [30,31]. (See "Assessing antibody function as part of an immunologic evaluation", section on 'Other polysaccharide vaccines'.)

Other testing at the time of diagnosis

Routine laboratories — A complete blood count and differential and a chemistry panel should be obtained on all patients.

Complete blood count and differential:

Persistent thrombocytopenia, especially if associated with small-sized platelets, should prompt investigations for possible Wiskott-Aldrich syndrome. Note that mean platelet volume can be difficult to measure accurately. (See "Wiskott-Aldrich syndrome" and "Automated hematology instrumentation", section on 'Mean platelet volume (platelet size)'.)

If lymphopenia is present (absolute lymphocyte count <1500 in a child over age 5), flow cytometric studies, including CD3, CD4, CD8, CD19, and CD16/56, can help identify combined immunodeficiencies. If B or T cells are decreased in number, tests of B and T cell function should be performed. (See 'B cell studies' below and 'T cell studies' below.)

Blood chemistry panel to search for other hematologic or metabolic illnesses that may increase the risk of infection (eg, diabetes or renal disorders).

Additional testing in some patients

In patients with evidence of active infections, appropriate cultures should be obtained, as well as measurements of inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein, and relevant imaging, such as sinus films, chest radiograph, or computed tomography or magnetic resonance imaging studies.

In patients with signs or symptoms of autoimmunity, antinuclear antibodies and other appropriate autoantibodies should be assessed. Patients with CVID may produce organ-specific autoantibodies (eg, including Coombs tests, thyroid peroxidase, and thyroglobulin antibodies) despite overall antibody deficiency.

Children with failure-to-thrive should be evaluated for thyroid function and growth hormone deficiency. Growth hormone replacement therapy should be offered if deficiency is identified. (See "Diagnosis of growth hormone deficiency in children" and "Treatment of growth hormone deficiency in children".)

B cell studies — B cell enumeration (CD19) should be performed if the patient has a profound deficiency of immunoglobulins to exclude congenital agammaglobulinemias. B cell numbers may be normal or low in CVID. In a small series of predominantly pediatric patients, 8 of 15 patients had low peripheral B cell counts. Children in this group had autoimmunity, bronchiectasis, and splenomegaly, as compared with the group with higher CD19+ levels [32].

The near or complete absence of B cells in general decreases the likelihood of the diagnosis of CVID, because absent B cells are more characteristic of agammaglobulinemia. However, defects in TRNT1, NFKB1, NFKB2, IKZF1, and RAC2 can lead to a CVID-like phenotype presenting with B cell lymphopenia [3]. (See 'Agammaglobulinemia' below.)

Advanced B cell phenotyping may provide prognostic information, although longer-term studies in children are needed before the use of immune markers can be recommended to guide management [33]. These studies may include CD19+CD27+ total memory B cells and CD19+CD27+IgD-IgM- class-switched memory B cells and are performable through several commercial laboratories.

Some pediatric patients with CVID have low numbers of switched (CD19+CD27+IgM-IgD-) memory B cells. In a study of 45 pediatric patients, 53 percent had lower switched memory B cells, CD19+ B cell levels, and T cell counts [6]. Those children with fewer than 5 switched memory B cells/microL had a higher incidence of meningitis, sepsis, bronchiectasis, granulomatous lung disease, autoimmune cytopenias, and hematologic malignancy. A second series confirmed this, but found that serious infectious complications were not restricted to this subgroup and also occurred in patients with higher numbers of switched memory B cells [34,35]. Thus, identification of patients with very low switched memory B cells can help the clinician identify patients at risk for serious complications, although other parameters are likely needed to find other subgroups that are also at risk. (See "Flow cytometry for the diagnosis of primary immunodeficiencies", section on 'Common variable immunodeficiency'.)

T cell studies — Evaluation of circulating T cells is not required for the diagnosis but can be useful in identifying patients at risk for more severe complications. Subsets of CVID (combined immunodeficiency) patients with low T cell numbers tend to experience more severe infectious complications [1,21,24,25]. Evaluation of T cell numbers with CD3, CD4, and CD8 should be performed. T cells often decrease with time so that periodic assessment of T cell numbers is worthwhile, especially if the patient starts to have infections despite immune globulin replacement therapy. For these patients, one must consider if a form of combined immune defect is present. For T cells, the analysis of the percentage of naïve CD45RA+CD4 T cells is the most informative parameter [36,37].

If T cell numbers are low, evaluation of cellular immunity in the form of lymphocyte proliferation studies (ie, phytohemagglutinin, concanavalin A, and pokeweed mitogens; tetanus and candida antigens; and anti-CD3/CD28 and anti-CD3/IL-2) may be useful in determining the need for prophylaxis of specific pathogens associated with combined immunodeficiency, such as Pneumocystis jirovecii. These studies are also readily obtainable through advanced immunology commercial laboratories. (See "Laboratory evaluation of the immune system", section on 'Defects in cellular immunity'.)

Genetic studies — An increasing number of genetic defects have been demonstrated in patients with CVID, each of which affects the normal processes of B cell maturation and differentiation into memory B cells (table 4). However, specific defects are only detected in 20 to 30 percent of patients using commercially available panels. This is discussed in more detail separately. (See "Pathogenesis of common variable immunodeficiency", section on 'Genetics'.)

Testing of family members — Evaluation of immunoglobulin levels in family members affected by frequent infections should be offered. CVID, as well as selective IgA deficiency, are found with increased frequency among family members of patients with CVID. (See "Pathogenesis of common variable immunodeficiency", section on 'Genetics'.)

DIAGNOSIS — Diagnosis is based on the findings of hypogammaglobulinemia, defective vaccine response, and exclusion of other causes of antibody deficiency. (See 'Definition' above.)

Children younger than six years of age — It is difficult to diagnose CVID in children younger than six years of age, because CVID may not be distinguishable from transient hypogammaglobulinemia of infancy (THI) in this age group. Both disorders involve hypogammaglobulinemia, but patients with THI ultimately produce adequate specific antibodies (in response to vaccines and infections), while those with CVID cannot. However, normal children below the age of two years and sometimes older children have impaired responses to polysaccharide antigens, and so this distinction can be challenging to make. Because of these uncertainties, it is important to follow the patient regularly and make the diagnosis as expediently as possible, because prolonged delays between the onset of symptoms and the beginning of immune globulin replacement therapy are common and are associated with more extensive lung damage and increased mortality [9,10,38].

Hypogammaglobulinemia in childhood may resolve with age. The natural history of hypogammaglobulinemia in childhood was investigated in a study of 37 patients with unclassified symptomatic hypogammaglobulinemia [39]. The mean age of clinical presentation was 21 months, and patients were followed for an average of 34 months. Approximately one-half (49 percent) of these children spontaneously corrected their immunoglobulin abnormalities. Among the remaining children, just two were eventually diagnosed with CVID.

Periodic reassessment — Children under six years of age with hypogammaglobulinemia, who are suspected to have CVID, should be periodically reevaluated to determine if their immune status has improved. We suggest repeating immunoglobulin levels and specific antibody titers on average one year after initial evaluation. If these patients have been started on immune globulin replacement therapy, the treatments must be withheld for four months prior to reevaluation, after which the patient's immunoglobulin G (IgG) should be compared with the trough level just before the final immune globulin treatment, in order to appreciate the patient's current level of antibody deficiency. Also at this time, specific antibody titers to various vaccines can be drawn, immunization with killed vaccines given (eg, pneumococcal vaccine, H. influenzae vaccine, and tetanus vaccine), and the specific antibody titers repeated in one month. Neoantigen titer studies with polysaccharide Vi antigen S. typhi vaccine can also be utilized while the patient is still receiving replacement immunoglobulin. The authors have seen both hypogammaglobulinemia and impaired specific antibody production resolve in children as old as 10 years of age.

DIFFERENTIAL DIAGNOSIS — Hypogammaglobulinemia is the primary laboratory feature of CVID. The other disorders that can cause hypogammaglobulinemia in children are reviewed in this section. Because some of these may resolve with age, the diagnosis of CVID in a child should not be considered certain until a series of evaluations has been completed over a period of years.

Secondary hypogammaglobulinemia — Hypogammaglobulinemia secondary to other disorders should be excluded. Patients with diseases that cause loss of immunoglobulins, such as protein-losing enteropathies or renal disease, will also have low total protein and albumin levels. A history of treatment with antiseizure medications or other immunosuppressive medications should be sought to exclude drug-induced hypogammaglobulinemia. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Secondary hypogammaglobulinemia'.)

Primary hypogammaglobulinemia — If no secondary cause of hypogammaglobulinemia is apparent, then other primary immunodeficiencies causing hypogammaglobulinemia should be considered. Genetic mutation analyses are available for some of these disorders, although this type of testing is generally best done in consultation with an immunodeficiency specialist. (See "Primary humoral immunodeficiencies: An overview".)

Agammaglobulinemia — Classic X-linked agammaglobulinemia with low or absent B cells is caused by defects in the gene for Bruton tyrosine kinase (Btk) that result in profound hypogammaglobulinemia. Autosomal recessive forms of this disorder also exist and are due to mutations in genes contributing to the maturation and function of B cells.

Congenital agammaglobulinemia is distinguished clinically from CVID by onset in infancy, hypoplastic lymphoid tissue, and severe reduction in all serum immunoglobulin isotypes. In addition, B cells in the peripheral blood (quantitated by flow cytometric evaluation of CD19 expression on lymphocytes) are nearly absent (<2 percent) or completely absent. In contrast, B cells in patients with CVID are usually normal or only mildly reduced. However, rare patients with CVID can have ≤1 percent B cells. In this situation, the patient should be assessed for causes of primary agammaglobulinemia. While X-linked agammaglobulinemia due to BTK gene mutation is the most common cause, females and patients with a family history of autosomal recessive inheritance should be evaluated for autosomal recessive agammaglobulinemia, including gene defects in IGHM, CD79A, CD79B, PIK3R1, BLNK, and IGLL1. Autosomal dominant disease is also possible, including gene defects in TCF3. (See "Agammaglobulinemia".)

Transient hypogammaglobulinemia of infancy — Young children with transient hypogammaglobulinemia of infancy (THI) have low levels of immunoglobulin (Ig)G, IgA, and usually IgM levels, which typically normalize by 24 months. They also ultimately demonstrate adequate vaccine responses (ie, usually by age 5) and have intact cellular immune function. In contrast, children with CVID have persistently impaired responses to protein and polysaccharide vaccines, and about 40 percent may eventually have impaired cellular function (although this may not be apparent at the time of diagnosis). (See "Transient hypogammaglobulinemia of infancy".)

Specific antibody deficiency — Specific antibody deficiency is a disorder characterized by recurrent sinopulmonary infections and normal immunoglobulin levels but an inability to produce specific antibodies to polysaccharide antigens and/or (rarely) protein antigens or premature loss of specific antibodies.

Specific antibody deficiency is distinguished from CVID by the presence of normal levels of IgG, IgA, and IgM. However, the diagnosis of specific antibody deficiency cannot be made in young children, because it is based on response to polysaccharide antigens, which can be abnormal in children until approximately the age of five years. This condition is discussed separately. (See "Specific antibody deficiency".)

IgG subclass deficiency — IgG subclass deficiency is defined as a deficit in one or more subclasses of IgG with normal or near-normal total IgG levels. Although the clinical presentation of patients with IgG1 or IgG2 subclass deficiency who also have impaired antibody production can be similar to those with CVID, levels of total IgG are normal (or near-normal) in IgG subclass deficiency, and IgA and IgM levels should be normal. IgG subclass deficiency is reviewed separately. (See "IgG subclass deficiency".)

Hyperimmunoglobulin M syndromes — Hyperimmunoglobulin M syndromes (hyper-IgM or HIGM) can arise from rare genetic defects affecting the ability of B cells to class-switch from IgM to other immunoglobulin isotypes. Patients have markedly reduced serum levels of IgG, IgA, and IgE, with normal or elevated levels of IgM. However, some patients with HIGM have decreased levels of IgM, and the two disorders can be difficult to distinguish. CVID is far more common than HIGM. Other distinguishing clinical features are discussed separately. (See "Hyperimmunoglobulin M syndromes", section on 'Differential diagnosis'.)

X-linked lymphoproliferative disease — X-linked lymphoproliferative disease (XLP) is a rare disorder of immune dysregulation, resulting in lymphoproliferation, liver failure, hypogammaglobulinemia, and/or lymphoma. The clinical and immunologic abnormalities are triggered after Epstein-Barr virus infection. Testing for XLP is appropriate in boys with a history of preceding viral hepatitis or other features suggestive of this disorder, as well as a family history of early death in males in the family. (See "X-linked lymphoproliferative disease", section on 'Diagnosis'.)

Combined immunodeficiency disorders — Combined immunodeficiency disorders are characterized by markedly decreased T cells with varying levels of circulating B cells. Various genetic abnormalities have been identified. (See "Combined immunodeficiencies".)

MANAGEMENT — The management of children with CVID involves immune globulin therapy, various measures to avoid infections, prompt and complete evaluation of infections that do occur, use of prophylactic antibiotics in refractory infections, monitoring of the patient's pulmonary function as well as physical and emotional development, and symptom-based vigilance for the various associated disorders (ie, autoimmunity and malignancy).

Immune globulin — Immune globulin replacement therapy, in subcutaneous (SCIG) or intravenous (IVIG) form, has significantly decreased the frequency of life-threatening infections in pediatric patients with CVID. If appropriate immunoglobulin (Ig)G replacement therapy is started early, the cycle of recurrent infections leading to progressive lung damage can be mitigated. However, it is not apparent that noninfectious complications of CVID, such as autoimmune cytopenias, are prevented or treated by immune globulin replacement therapy. Efficacy, dosing, and administration of immune globulin in CVID are reviewed separately. (See "Treatment and prognosis of common variable immunodeficiency", section on 'Immune globulin replacement therapy'.)

If possible, immune globulin should not be given until there has been a thorough evaluation of the patient's immune system, including specific antibody responses. Immune globulin is expensive, will negate an antibody investigation for several months, and has potential adverse effects, as reviewed separately. (See "Transient hypogammaglobulinemia of infancy", section on 'Immune globulin replacement therapy'.)

If immune globulin replacement therapy was already initiated prior to diagnosis to treat an autoimmune disorder or an infection causing critical illness, then plans should be made to discontinue the infusions for at least four months, in order to reassess the patient's current immune status. This would be especially true for children with normal levels of IgA and IgM, which suggest the presence of normal B cell functions. (See 'Periodic reassessment' above.)

The authors often stop immune globulin in the summer when there are fewer circulating respiratory tract infections. While an immune evaluation is being performed, the child with recurrent or chronic bacterial infections (eg, otitis media, rhinosinusitis, bronchitis, pneumonia) can be treated with a six-week course of antibiotic therapy (eg, cefdinir), followed by prophylactic antibiotics (eg, azithromycin 5 mg/kg orally two or three times a week, maximum dose 250 mg/kg daily). Other prophylactic regimens are reviewed separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy'.)  

Evaluation of illnesses — Children generally have a higher rate of viral infections than adults, due to increased exposure and other factors, which complicates the management of febrile episodes in children with CVID. Children with CVID and fever should be evaluated promptly. Attempts to identify responsible organisms should be undertaken, such as rapid viral identification kits for influenza or respiratory syncytial virus. IgG-based diagnostic tests will not be useful in those children receiving immune globulin due to presence of donor antibodies. Basing the choice of antibiotics on culture data and test results and using narrow-spectrum drugs whenever possible should help avoid bacterial resistance. Specific antiviral agents may be needed when applicable.

Monitoring pulmonary status — Monitoring the child for progressive but subclinical pulmonary damage is important, since patients can develop chronic pulmonary disease. Such monitoring usually takes the form of serial pulmonary function tests.

High-resolution computed tomography (HRCT) has been found to be the most sensitive method for identification of bronchiectasis and lymphocytic/granulomatous disease. It is an important diagnostic tool for pulmonary complications because it can detect abnormalities that are missed by chest radiographs or pulmonary function testing. HRCT is also important in determining future therapy, and patients should be screened if respiratory symptoms are present or after the CVID diagnosis is confirmed. In pediatric-onset CVID, there is an increased risk of mortality in patients with lung disease as defined by any persistent changes in HRCT or lung function testing [9]. However, the risks of cumulative radiation exposure should be taken into account as well. We typically do not perform "scheduled" HRCT. Instead, we reserve repeat exams for situations in which the result is likely to influence a significant management decision, such as the administration of antibiotics or an increase in the dose of immune globulin. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Pulmonary disease'.)

Below are some clinical situations in which repetition of an HRCT examination would be useful:

An older child who is being followed with repeat pulmonary function testing demonstrates reduced lung function and no bronchodilator response to account for these changes or develops a new decrease in diffusing capacity of the lungs for carbon monoxide (DLCO).

Pulmonary infections continue to occur despite ongoing adherence to immune globulin replacement therapy at standard starting doses (400 to 500 mg/kg per month).

Evaluation is required of certain abnormalities, such as nodules, under the direction of a consulting specialist (pulmonologist or infectious disease specialist).

Autoimmune cytopenias — Treatment of autoimmune cytopenias in patients with primary immunodeficiencies is difficult, because the treatments result in further immunosuppression in an already-compromised patient. Immunosuppressant medication should be used only when the benefits are clear and in those patients whose autoimmune disorders are clearly causing symptomatic disease. The lowest dose and the shortest course sufficient to treat the condition are recommended. Careful monitoring during treatment is required. The treatment of these conditions in patients without CVID, including glucocorticoid dosing, is reviewed separately. (See "Immune thrombocytopenia (ITP) in children: Initial management" and "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome".)

Systemic glucocorticoids have long been the primary treatment for cytopenias, although prolonged use can be associated with significant complications in immunocompromised patients. Specific agents and dosing are reviewed separately. (See "Immune thrombocytopenia (ITP) in children: Initial management" and "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome".)

The utility of immune globulin replacement therapy in the treatment of autoimmune cytopenias is controversial, and data are scant. It is possible that immune globulin may provide some protection against these disorders or recurrences of them, based on the observation that most cases have been reported in patients not yet on immune globulin, although prospective studies have not been done. (See "Treatment and prognosis of common variable immunodeficiency", section on 'Autoimmune cytopenias'.)

If immune thrombocytopenia occurs in a patient already on immune globulin, high doses of IVIG (eg, 1 to 2 grams/kilogram) can be administered [40] with or without glucocorticoids.

Rituximab (anti-CD20) may be useful as an adjunctive steroid-sparing agent [41,42]. In a study of eight children with immunodeficiencies (including CVID) and autoimmune cytopenias, 90 percent responded to rituximab, albeit with high relapse rates and requirement for repeat courses [43].

Allergic disease — Those children with ongoing sinopulmonary symptoms despite adequate treatment may benefit from allergy testing, as children with an allergy diathesis coincident to CVID have been described. In patients who are found to have IgE present at the time of CVID diagnosis, either allergy skin testing or serum evaluation of IgE to specific aeroallergens may be helpful in discerning the presence of ongoing atopy that may be complicating control of sinopulmonary disease. In these children, we have observed that aggressive asthma or allergy-specific treatment appears to improve outcomes and quality of life by reducing the frequency of complications, such as recurrent otitis media and sinopulmonary infections, although definitive studies have not been performed. It is the authors' impression that pediatric CVID patients follow the same general course as immunocompetent children with atopy and experience fewer complications, such as recurrent otitis media and rhinosinusitis, if allergy is addressed and managed.

Health maintenance — Issues in health maintenance include vaccination, prevention of infections, and psychosocial and educational support.

Vaccination — Vaccination in patients with CVID is discussed separately. (See "Treatment and prognosis of common variable immunodeficiency", section on 'Vaccinations' and "Immunizations in patients with primary immunodeficiency".)

Prevention of infections — Patients with CVID should take measures to avoid infection. Common sense approaches, such as handwashing, are the most practical. Patients should also avoid ingestion of untreated drinking water, if possible. Specific measures that the authors have found helpful in children with CVID are described here. General care of immunodeficient patients is reviewed separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Measures to prevent initial infections'.)

We have not limited pet ownership, largely because many children have pets prior to their diagnosis, and we have not seen infectious complications from pet ownership in our population so far. It does seem reasonable to leave clean-up of pet waste to the immunologically-intact members of the household.

Depending on the child's history, it may be better for children who normally attend school to remain home when gastroenteritis, influenza, or other infectious diseases are affecting a large number of the children at the school. The school nurse is the person best able to identify such situations.

Psychosocial and educational issues — Children with primary immunodeficiencies, including CVID, have a number of significant psychosocial concerns when compared with children with other chronic diseases, such as chronic renal disease or severe asthma [44]. These concerns include depression, anxiety, somatization, social withdrawal, and decreased social skills. Increasing severity of the immunodeficiency was associated with a number of school adjustment issues, including concomitant psychiatric diagnoses and requiring special education services. In a series of pediatric-onset CVID patients, 18 percent of children had depression as a comorbidity and this was associated with mortality, particularly in patients with a delayed diagnosis [9]. Clinicians taking care of children with CVID should be aware of these problems and make early use of available social and psychologic services in the long-term management of these patients.

One study reported elevated rates of sensorineural hearing loss in children with CVID, possibly secondary to repeated episodes of otitis media [45]. Complete audiologic examinations should be considered in patients who display signs of impaired hearing or perform poorly in school.

Despite these issues, children with CVID successfully attend school in our experience. Close communication is required with the school nurse and administration to make allowances for absences due to clinician follow-up care or hospitalizations.

Some proactive education about immunodeficiency can be tremendously helpful in ensuring that school staff fully engage with the child and participate in his/her daily care. Many people (including nurses and other staff) equate immunodeficiency with HIV infection, and it is useful to explain that CVID is not a transmittable disease. Age-appropriate education of other children can also prevent alienation and/or bullying. Parents/caregivers often take the lead in these matters, although the clinician should initiate the discussion and help the caregivers choose the information to be shared.

Our population of pediatric CVID patients has participated in a wide range of extracurricular activities. There may be a few situations in which a specific activity is not appropriate for a given patient (eg, a child with bronchiectasis should probably not spend significant time gardening with peat due to risk of Aspergillus exposure). However, in most cases, we encourage the children to pursue whatever they wish in terms of physical activities, pending consultation with general pediatricians, because of the psychosocial benefits and long-term good health habits that sports and hobbies provide.

PROGNOSIS — The lifespan of children with CVID has been significantly lengthened since immune globulin replacement therapy became standard of care. However, pediatric-onset CVID with pulmonary complications has a higher mortality rate as compared to adult-onset CVID patients, as noted in the above-mentioned review [9]. In that series, the average age of death was 31 years for the 91 patients diagnosed with CVID prior to 19 years of age. The most common cause of mortality was infection, although these patients had multiple comorbidities as outlined previously. Those children diagnosed after irreversible pulmonary disease has developed may have a shorter lifespan, based on findings in adults with CVID in both the case series mentioned above and adult studies of CVID. In addition, the authors found that pediatric mortality correlated with a delay in diagnosis of CVID. The prognosis of CVID in all age groups considered together is reviewed separately. (See "Treatment and prognosis of common variable immunodeficiency", section on 'Prognosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by the inability of B cells to differentiate into plasma cells capable of secreting all immunoglobulin types. Approximately 25 percent of all CVID patients present in childhood, with a peak in diagnosis around eight years of age. (See 'Definition and classification' above and 'Epidemiology' above.)

In all age groups, sinopulmonary infections and complications of infections are the most common presentation. However, children have more problems with ear infections and certain disorders, such as autoimmune cytopenias and allergic disease, compared with adults with CVID. In addition, children may present with failure-to-thrive. (See 'Clinical manifestations and characteristic presentations' above.)

The diagnosis of CVID is based on the findings of hypogammaglobulinemia, defective antibody formation (ie, vaccine response), and exclusion of other causes of antibody deficiency. Diagnosis in children younger than six years of age is difficult, because there are several causes of hypogammaglobulinemia that must be excluded and because response to polysaccharide antigens is normally weak in young children. Definitive diagnosis may not be possible until the child has undergone serial evaluations over a period of years. (See 'Diagnosis' above and 'Differential diagnosis' above.)

The management of CVID is similar in adults and children. Important aspects include immune globulin replacement therapy, avoidance of infection, monitoring of pulmonary status, and vigilance for known associated disorders, such as cytopenias and malignancy. Issues that are of special importance in children include monitoring of physical and emotional development, early intervention for psychosocial and educational problems, and attention to cumulative radiation exposure resulting from radiologic studies. (See 'Management' above.)

The lifespan of children with CVID has been significantly lengthened since immune globulin replacement therapy became standard of care. However, it has been demonstrated that those with pediatric-onset disease may be at increased risk for mortality as compared to adult-onset CVID. At-risk children are those who develop pulmonary manifestations, and initiation of intravenous immune globulin (IVIG) therapy may be needed to prevent a poorer prognosis. (See 'Prognosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Nevin W Wilson, MD, and E Richard Stiehm, MD, who contributed to an earlier version of this topic review.

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References

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