The Four Most Common Pediatric Immunodeficiencies

Abstract

The four most common immunodeficiencies in pediatric patients are transient hypogamma-globulinemia of infancy, IgG subclass deficiency, impaired polysaccharide responsiveness (partial antibody deficiency) and selective IgA deficiency. Most of these patients have normal cellular immune systems, phagocyte function and complement levels. All four illnesses are characterized by recurrent bacterial respiratory infections such as purulent rhinitis, sinusitis, otitis and bronchitis. Except for some IgA-deficient patients, the molecular basis for these illnesses is not known, and indeed each syndrome is heterogeneous, with multiple causes, including genetic factors, drug/environmental toxicant exposure, and/or prenatal physiological events. This paper describes the clinical and laboratory features, postulated causes, current management and prognosis. Only a few of these cases require the use of intravenous IgG (IVIG) and the outlook for long life is excellent.

Keywords :

• Immunodeficiency
• selective IgA deficiency
• transient hypogammaglobulinemia
• impaired polysaccharide responsiveness
• IgG subclass deficiency

INTRODUCTION

Other than the physiologic hypogammaglobulinemia of infancy (which we all have survived during the first 6 months of our lives), 80% of the confirmed immunodeficiencies in my practice, consisting of referred pediatric patients for possible or proven immunodeficiencies, consist of four syndromes, transient hypogammaglobulinemia of infancy (THI), IgG subclass deficiency, partial antibody deficiency with impaired polysaccharide responsiveness (IPR, sometimes termed partial or selective antibody deficiency), and selective IgA deficiency (IgAD). None is life threatening, all can be readily managed, and many patients recover spontaneously.

An exact incidence of these disorders is not known. A summary of immunodeficiency registries in four countries/regions (Spain, Australia, Latin America, and Norway) listed IgA deficiency in 27.5% of the patients, IgG subclass deficiency in 4.8%, and THI in 2.3% (Stiehm et al., 2004a). A 1999 United States survey of primary immunodeficiencies conducted by the Immune Deficiency foundation (1999) found that 17.5% of these patients had IgA deficiency and 24% an IgG subclass deficiency; THI and IPR were not listed (Immune Deficiency Foundation 1999) The Jeffrey Modell Foundation (2005) survey of global centers in 2004 reported IgAD in 15.5%, subclass deficiencies in 8%, and THI in 2% of their patients. Common variable immunodeficiency, the leading diagnosis in adult registries, is uncommon in children.

These registry data do not reflect the true incidence of THI, because it often does not come to the attention of the immunologists reporting cases for the registries, and because it is rarely associated with severe infection. Impaired polysaccharide responsiveness (IPR) patients likewise are unrepresented in registries, since they rarely are referred to the immunologist, and are generally underdiagnosed because most doctors are not familiar with the disease or its diagnosis.

IgG subclass deficiency is probably over-diagnosed because of the ready availability of IgG subclass analysis, and the failure to recognize that decreases of one or more subclasses is very common, and unless there is an associated antibody deficiency, is of no clinical significance

TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY

Definition and History

Gitlin and Janeway (1956) were the first to describe this disorder. It is classically considered a prolongation of physiologic hypogammaglobulinemia that occurs from age 3–6 mo as a result of disappearance of maternal transplacental IgG and slow increase of the infant's own IgG levels (Roifman, 2004; Dalal and Roifman, 2006). Despite their low IgG levels most infants are able to respond to vaccine antigens during the first 6 mo of life, with the exception of those vaccines in which high titers of maternal antibody inhibit the infants' antibody response, e.g., measles vaccine.

Although some use low levels of either IgG, IgM, or IgA below two standard deviations (SD) from the mean as diagnostic criteria, THI is best defined as low levels of IgG (< 2 SD below mean for age), with or without depression of IgA and/or IgM, in an infant beyond 6 mo-of-age in which other primary immunodeficiencies have been excluded. The condition can persist up to the age of 5 yr (Roifman, 2004; Dalal et al., 2006).

This definition will include many infants who have no increased susceptibility to infection and have normal antibody responses to vaccine antigens. Such infants rarely come to the attention of the immunologist. Thus, a clinically significant THI occurs in that subgroup of THI infants with frequent infections and/or poor antibody responses to one or more vaccine antigens.

Etiology

Various causes of this disorder have been proposed. An early study suggested that IgG genetic allotypes (Gm types) on the fetal IgG induced anti-Gm antibodies in the mother that crossed the placenta and suppressed fetal immunoglobulin production (Fudenberg and Fudernberg, 1964). This was not confirmed in another study (Nathenson et al., 1971). A genetic cause was suggested that THI represented heterozygosity for genetic hypogammaglobulinemia based on family studies (Nathenson et al 1971). Another suggested that a T-helper deficiency caused THI (Siegel et al., 1981). A final study suggested cytokine imbalance (Kowalczyk et al., 1997).

Another cause is seen among infants, usually premature, who have had prolonged stays in the neonatal ICU for a variety of illnesses. Their IgG is often low as a result of stress, loss of plasma into the GI or respiratory tract, steroid use, and frequent blood draws. This author terms this the immunodeficiency of the stressed infant.

Finally many of these children may simply be at the low end of the normal range for IgG and/or at the low end of the normal progression of immune maturation as reflected by IgG levels, thus have no immunodeficiency, and are not unlike asymptomatic patients with low CD4 cells who are designated as idiopathic CD4 lymphopenia.

Clinical Features

THI is somewhat more common in males, who usually are identified at an earlier age than females (Whelan et al., 2006). In addition, THI is rarely familial. About 25% of the symptomatic patients are identified before age 6 mo, another 50% from ages 6–12 mo, and the rest after age 12 mo.

Two groups of THI patients are recognized. The first group (Group I) of infants are asymptomatic who have immunoglobulins done routinely or because a family member has an immuno-deficiency. Most of these infants remain asymptomatic, have normal responses to vaccine antigen, and grow out of their hypogammaglobulinemia after several years.

The second group (Group II) is infants identified because of recurrent or severe infection often starting in the first weeks of life. The majority of their infections are respiratory - upper respiratory infections (URI), otitis, sinusitis, bronchitis, and occasionally pneumonitis. A rare patient has sepsis, meningitis, or soft tissue cellulitis. Other children have recurrent diarrhea, severe varicella, or prolonged oral candidiasis (thrush).

Atopic diseases with wheezing, eczema and food intolerance are not uncommon. We recently identified seven infants with severe eczema with low levels of IgG (Lin et al., unpublished data), possibly associated with protein loss through the skin. Positive skin or RAST tests, and elevated IgE levels are often seen in these patients; all were given intravenous IgG (IVIG). Hematologic abnormalites are often present, most commonly mild neutropenia; less commonly, thrombocytopenia is evident.

Physical examination is generally unrevealing, with normal growth and development normal. Chronic otitis purulent rhinitis may be noted as well as port-nasal drip may be present. Tonsil and lymph nodes are present but small. A thymic shadow on Chest X-ray excludes a T-lymphocyte deficiency. Sinus films may show maxillary or ethmoid sinusitis, even in small infants.

Laboratory Features

These patients usually have low levels of all three major immunoglobulins. An IgG level of < 200 mg/dl is noted in over half of the patients (Whelan et al., 2006). Levels of IgG < 100 mg/dl are suggestive of a permanent immunodeficiency. To date, there is no molecular test for THI.

Antibody titers to tetanus, diphtheria, hepatitis A and B, Haemophilus influenzae, and pneumococcal vaccine antigens are variable. About 15% of the patients have non-protective antibody titers to one or more of these antigens, most commonly one or more of the serotypes present in the conjugated pneumococcal vaccine (Prevnar). Under these circumstances a booster immunization is recommended followed by repeat titers after one month.

Levels of lymphocyte subsets (CD3⁺, CD4⁺, and/or CD8⁺ T-lymphocytes), CD19⁺ B-lymphocytes, and CD16⁺/CD56⁺ natural killer cells are usually normal, as are responses of the cell types in lymphoproliferative assays. Very low numbers of B-lymphocytes suggest X-linked agammaglobulinemia. As noted, allergy tests including IgE levels may be abnormal. Repeated respiratory infections may be associated with chronic sinusitis as identified by sinus film (Waters view) or limited CT scan. Repeat immunoglobulin levels are done at 6-12 mo intervals to determine recovery.

Management

Infants in Group 1 require no treatment; we repeat levels every 12 mo, sooner if infections begin to occur to document their recovery. In symptomatic patients, a conservative approach is initially warranted, such as removing the infant from day care, prompt treatment of respiratory infections, and occasionally prophylactic antibiotic therapy, particularly in the winter during respiratory infection season. Doctors at the Mattel Children's Hospital at UCLA often use Azithromycin 5 mg/kg for 2 d/wk. Some THI patients require this regimen for several years.

In the rare THI patient who has severe infections or very poor antibody responses to vaccine antigens, treatment with IVIG at 400–500 mg/kg/month are used, usually for a 6–12 mo period. IVIG is then stopped and immunoglobulin levels and antibody responses are retested 3 mo later. Doctors at this Author's hospital recommend discontinuing IVIG in the late spring or summer, not during respiratory infection season.

Prognosis

By definition, all of these patients eventually recover. Most patients recover by age 2 yr, but low IgG levels may persist in some patients until age 5 and occasionally beyond that. Patients with a combined IgG and IgA deficiency may develop selective IgA deficiency. Other patients will develop an IgG subclass deficiency, while others with poor antibody responses may normalize their IgG levels, but have persistent impaired polysaccharide responsiveness. In the Whalen et al. (2006) series, there was a striking difference in immune maturation, with females having persistently slower recovery. They also emphasize that the diagnosis of THI is usually made in retrospective, uncertain until the patient recovers. No long-term sequelae have been identified.

IgG SUBCLASS IMMUNODEFICIENCY

Definition and History

Schur et al. (1970) first described IgG subclass deficiencies in three adult patients. Since then numerous publications have identified subclass deficiencies in many patients, particularly children. Indeed it is perhaps the most common immunodeficiency described, and certainly the one for which IVIG is most often used and misused.

The definition of an IgG subclass deficiency is the presence of one or more IgG subclasses < 2 SD below the mean for age with normal or near normal total IgG levels (Stiehm et al., 2004c; Lemmon and Knutsen, 2006). Up to 20% of the population will thus have an IgG subclass deficiency of one or more IgG subclass. Since most of these subjects are asymptomatic, the previously mentioned definition only defines a clinical laboratory finding, not a disease.

A clinically-significant IgG subclass immunodeficiency is associated with recurrent infection and a significant defect in antibody responsiveness. Most of these patients present with recurrent respiratory infections. Others, often with more serious infections, may have a subclass deficiency in association with another primary immunodeficiency (e.g., selective IgA deficiency, DiGeorge syndrome), or with an secondary immunodeficiency (e.g., HIV infection, cirrhosis) or with autoimmune diseases such as immune thrombocytopenia and/or lupus (Stiehm et al., 2004c).

Etiology

The four IgG subclasses are defined by unique structures of the constant region of their heavy chains; they make up about 70, 20, 7, and 3% of the total IgG levels, respectively (Stiehm, 2004). Each subclass has unique structural, antigenic and biologic differences. The most significant biologic difference is that IgG₂ contains the preponderance of antibodies to polysac-charide antigens. Other differences include activation of the classical complement pathway by IgG₁ and IgG₃, a shorter half-life for IgG₃, and less placental passage for IgG₂. Other antibody titers are not evenly distributed, e.g., parasite antigens in schistosomiasis and filariasis are mostly in IgG₄ subclass.

Since each subclass is encoded by a different gene segment gene deletions may be responsible for some subclass deficiencies, particularly those associated with a complete absence of a subclass (Lefranc et al., 1983; Migone et al., 1984). Other abnormalities may include transcriptional defects, post-translational abnormalities or genetic association with certain genetic IgG allotypes (Gm types) (Kavanaugh and Huston 1989).

The most common subclass deficiencies among patients presenting with recurrent infections are IgG₄ deficiency (40%), IgG₂ deficiency (28%), IgG₃ deficiency (17%), and an IgG₁ deficiency (14%). Isolated IgG₁ deficiency is rare, since a deficiency of this subclass usually results in a deficiency of total IgG and thus not fitting the definition of a subclass deficiency. Combinations of one subclass deficiency with another IgG subclass or an IgA deficiency are common, notably (in order of frequency) IgG₂ and IgG₄, IgG₄ and IgA, IgG₃ and IgA, IgG₂ and IgG₄ and IgA, and IgG₂ and IgA combinations (Stiehm et al., 2004c).

Clinical Features

Subclass deficiencies are heterogeneous, and rarely familial. IgG₄ subclass deficiency may occur in as many as 20% of both adults and children, depending on the sensitivity of the assay, and thus is of rare clinical significance. In adults, IgG₃ deficiency is the second most common deficiency, and females are more likely to be affected. Adults generally have more severe infections, and indeed some of these may be developing common variable immuno-deficiency (CVID).

In children, males make up 75% of the cases, and a deficiency of IgG₂ is the second most common deficiency. Children under age 6 may be recovering from transient hypogammaglobu-linemia, so it is difficult to diagnose an IgG deficiency in children before age 4. In both adults and children, recurrent respiratory infections, including otitis, sinusitis, and bronchitis caused by common respiratory bacterial pathogens predominate. Serious systemic infections (e.g., sepsis, pneumonia, meningitis, cellulitis) are less common; many are atopic, and asthmatic bronchitis accompanies the respiratory infections.

Selective IgG₁ may be associated with more severe infections and is more common in adults. Selective IgG₂ deficiency is the most common subclass disorder associated with recurrent infection, and may be accompanied by IgA and or IgG₄ deficiencies. Many of these patients have impaired polysaccharide responsiveness (IPR) as discussed below. IgG₂ deficiency may resolve with time, especially in young children.

Most symptomatic IgG₃-deficient subjects have an associated deficiency of another class. Familial IgG₃ deficiency has been recorded. As noted, isolated IgG₄ is most common and not usually of clinical significance. However, recurrent pneumonia and bronchiectasis have been described, suggesting that it is a marker for these illnesses rather than the cause of them.

Laboratory Features

IgG subclass determinations are indicated for patients with documented antibody defects, in patients with IgA deficiencies, and in patients in which early CVID is suspected. Levels must be compared with age-matched controls, especially in the first 2 yr-of-age. For children ages 4–10 yr, an IgG₁ level < 250 mg/dl, an IgG₂ level < 50 mg/dl, an IgG₃ level < 15 mg/dl, and an IgG₄ level < 1 mg/dl are abnormal. For subjects older than age 10 yr, an IgG₁ level < 300 mg/dl, an IgG₂ level < 75 mg/dl, an IgG₃ level < 25 mg/dl, and an IgG₄ level < 1 mg/dl are abnormal.

A clinically-significant IgG subclass deficiency must be established by measuring the antibody response to a vaccine antigen, particularly pneumococcal polysaccharide vaccine. A deficient response is defined as non-protective titers to a majority of the 12 serotypes tested or failure to exhibit a twofold rise in titer to serotypes for which there were non-protective titers. Tests for cellular immunity, complement activity and phagocytic function should be done as necessary. Chest X-ray, sinus imaging, and pulmonary function studies should be considered. A search for associated illnesses should be undertaken as deemed relevant.

Management

Asymptomatic patients with normal antibody profiles need no therapy nor should they be labeled as immunodeficient. Many patients do well with prompt medical management of each infectious episode, and the use of antibiotics early in the course of respiratory exacerbation is of value. Some patients with recurrent infections or chronic infections do well on prophylactic antibiotics, particularly in the winter months. Vaccines should be kept current unless there is complete absence of antibody responses.

A failure of prolonged antibiotics, severe symptoms and persistent radiographic abnormalities may occasionally require IVIG therapy at the usual therapeutic doses (Buckley, 2002). Doctors at this Author's hospital utilize this therapy in < 10% of their patients. The presence of a subclass deficiency alone is not an indication for IVIG. Nevertheless, it is a common practice to give IVIG under such circumstances, which is a costly misuse of a scarce and potentially harmful form of therapy, and labels the patients as chronically ill and uninsurable. Its use in young children has the potential of inhibiting normal immune maturation.

Prognosis

Most patients do well on conservative therapy outlined above, but treatment is prolonged, and often, lifelong. Children under 10 yr may recover from a subclass deficiency spontaneously, particularly if there is not a complete absence of a subclass. By contrast, symptomatic adults may progress to common variable immunodeficiency. In both groups repeat subclass determinations at yearly intervals are indicated.

IMPAIRED POLYSACCHARIDE RESPONSIVENESS (SELECTIVE OR PARTIAL ANTIBODY DEFICIENCY)

Definition and History

Impaired polysaccharide responsiveness (IPS) is characterized by recurrent bacterial respiratory infection, an absent or subnormal response to a majority of polysaccharide antigens, normal or elevated immunoglobulins and IgG subclasses, and intact antibody responses to protein antigens in subjects over age 2 yr (Stiehm et al., 2004b; Sorenson and Paris, 2006). These immunologic characteristics define what occurs physiologically prior to age 24 mo, since most such infants respond poorly to pure polysaccharide antigens but mount adequate responses to protein antigens, both inactivated and live virus vaccines.

As early as 1968, patients were described who had normal immunoglobulin levels but profound deficiencies of antibodies to both protein and polysaccharide antigens (Blecher et al., 1968); Saxon et al., 1980). This entity, antibody deficiency with normal immunoglobulins, should not be confused with IPR, since such patients are considerably more susceptible to infections and more akin to common variable immunodeficiency in their prognosis.

IPR was identified in the late 1980s following the introduction of un-conjugated H. influenzae type B polysaccharide vaccines. Granoff et al. (1986b) identified children over age 2 yr that had a poor response to this vaccine despite normal responses to other vaccines. Later studies indicated that sometimes this deficiency was familial and occurred among certain ethnic groups, such as Apache Native Americans and Alaskan Eskimos (Stiehm et al., 2004b). Adults with IPR were first described by Ambrosino et al. (1987).

Since un-conjugated Haemophilus vaccine has been replaced by a protein-conjugated form that is immunogenic in infants, IPR is usually identified by a deficient response to the pneumococcal polysaccharide vaccine (Pneumovax) in children over 2 yr and adults. Sorenson and Paris (2006) have identified this disorder as the most common immunodeficiency identified among children presenting with increased susceptibility to infection

Etiology

IPR is a heterogeneous illness with several postulated causes. In younger children aged 2–6 yr, it may be an exaggeration of the physiologic non-responsiveness to polysaccharide vaccines of infants less than 2 yr-of-age; these children recover spontaneously with time. Some of these youngsters have had transient hypogammaglobulinemia of infancy (see above) with poor antibody responses. Most polysaccharide antibodies are in the IgG₂ subclass, so that selective IgG₂ subclass deficiency with or without selective IgA deficiency must be sought.

In other patients, IPR is part of another primary immunodeficiency such as Wiskott-Aldrich syndrome, DiGeorge syndrome, and mucocutaneous candidiasis. It might also be part of secondary deficiencies associated with aging, HIV disease, immunosuppressive drugs, genetic syndromes, chronic lung disease, and any splenic absence or deficiency (Stiehm et al., 2004b).

IPR may be genetic in some families and linked to certain Gm and Km IgG allotypes (Granoff et al., 1986a). Ambrosino et al. (1987) suggested a defect in the B-lymphocyte repertoire, similar to certain mice strains. Timens and Poppema (1987) suggested a splenic defect in the marginal zone where dendritic cells interacted with B-lymphocytes. One adult IPR male had few B-lymphocytes and a BTK mutation associated with X-linked agammaglobulinemia (Wood et al., 2001).

Clinical Features

IPR is somewhat more common in males, is usually not familial, but as noted above, may be more common in certain ethnic groups. Most of the patients are children age 2–7 yr, and most of these patients often recover completely from their illness. Adults with this condition are more likely to have this condition indefinitely; a few may be in the early stages of common variable immunodeficiency.

Clinically, IPR patients resemble patients with IgG subclass and selective IgA deficiencies inasmuch as they usually have recurrent bacterial respiratory infections such as sinusitis, otitis, and bronchitis: less common are systemic infections such as pneumonia, sepsis or meningitis. Many patients have asthma or wheezing with infections, often as a result of chronic sinusitis. Many have had ear tubes, tonsillectomy, decreased hearing, and multiple courses of antibiotics. The physical examination often suggests chronic respiratory allergy, with circles under the eyes, pallor, gaping mouth, pharyngeal cobblestoning, post-nasal drip, purulent nasal discharge and moderate cervical adenopathy. Growth and development are usually normal.

Laboratory Features

IPR patients by definition have normal IgG, IgM, and IgA levels and IgG subclass levels, as well as normal responses to protein antigens such as tetanus, diphtheria, and H. influenzae type B conjugated vaccines. Thus, the diagnosis rests on their antibody response to pneumo-coccal polysaccharide vaccine. Pre-immunization titers are recommended followed by retesting one month following vaccination.

A normal response is development of protective titers (> 1.3 μ g/ml) to a majority of the subtypes tested. Doctors at the Authors hospital recommend use of a 12 or 14 serotype antibody panel that will include the seven types present in a conjugated pneumococcal vaccine (Prevnar). A rise in a preexisting protective titer may not occur, and should not be considered a negative test. Sorenson and Paris (2006) suggest that a normal response for children under 6 yr-of-age consists of a majority of responses to be protective and for older individuals at least 70% of the serotypes should be protective.

Three types of responses are noted. In the severe forms there is essentially no response to any or just one or two of the serotypes, and then the titers are low but protective. In the mild/moderate form (partial responders), there is some but less than expected responses. Some of these patients, as well as some patients with an adequate response, initially proceed to the third form associated with poor immunologic memory. These patients (upon retesting in 6–12 mo) have lost some or most of their previously protective titers and continue to have continued infections. Re-immunization may stimulate their response but often this response also disappears with time.

All of these patients should be tested for T-cellular, phagocytic, and complement deficiencies. Cultures are usually non-informative: occasionally S. pneumoniae is cultured from the nose or throat. Responses to other polysaccharide vaccines such as meningococcal vaccine may be done but is often normal. In young children, repeat antibody testing is recommended at yearly intervals because spontaneous recovery often ensues. Symptomatic adults should be followed periodically to look for progression to CVID.

Treatment

Many of these patients do well with prompt and vigorous treatment of each respiratory infection, with an effort to eradicate foci of infection like the sinuses. Ancillary treatment with inhaled steroids, bronchodilators, and decongestants are often of value. Vaccines, particularly influenza vaccine, should be updated. We often give these patients two doses of the pediatric conjugated pneumococcal vaccine to boost their immunity to the serotypes in this vaccine.

If these measures are ineffective, a course of prophylactic antibiotics is tried, usually for at least 6 mo. If there is persistent infection, a trial of IVIG should be considered in full therapeutic doses. Only an occasional patient requires such therapy, but a good response has been documented in some series (Herrod, 1993).

Prognosis

Children with partial responses usually recover with time. Patients with the severe form of disease usually have lifelong problems. Some of these patients may develop IgG subclass deficiency or common variable immunodeficiency.

SELECTIVE IgA DEFICIENCY

Definition and History

Selective IgA deficiency (IgAD) is defined as the absence or very low levels (< 7 mg/dl) of serum IgA with normal levels of total IgG and IgM and no other major immune defects. This definition excludes young infants since they have low levels of IgA physiologically and do not obtain adult levels until age 3 yr. IgAD is the most common primary immunodeficiency and in many individuals, it is unassociated with any illness including an increased susceptibility to infection.

IgAD was first described in ataxia-telangiectasia (Thieffrey et al., 1961) and then in patients with frequent infections (West et al., 1962) and in normal subjects (Rockey et al., 1964). Low or absent IgA is a variable component of many other primary immunodeficiencies, notably all forms of agammaglobulinemia, ataxia-telangiectasia, mucocutaneous candidiasis (Kalfa et al., 2003) and IgG₂ subclass deficiency (Oxelius et al., 1981).

The frequency of IgAD varies in different ethnic groups, and is as high as 1:142 in Arabs (Al-Attas and Rahi, 1998) and as low as 1;15,000 in Japanese populations (Kanoh et al., 1986). Among Europeans and Americans, the frequency is about 1:500 (Hostoffer, 2006).

Etiology

IgA is the second most abundant immunoglobulin synthesized (after IgG) since it appears not only in the serum, but predominantly in secretions, including colostrum and breast milk (Goldblum and Garofalo, 2004). Much of the serum and all of the secretory IgA is synthesized in plasma cells of glandular tissues. Locally-produced monomeric IgA combines with an epithelial cell-synthesized secretory component and a joining chain and the material is secreted as a dimer (secretory IgA) into the lumen of the gland. Serum IgA does not get into the secretions, but most of the serum IgA is synthesized locally and enters the blood stream in the monomeric form.

Secretory IgA coats the mucous membranes and is a chief component of the mucosal defense system. It serves to neutralize pathogens, and prevents foreign antigens, including food antigens from entering the systemic circulation. Secretory antibodies in the breast milk have antibodies to antigens present in the maternal gastrointestinal system, the so-called entero-mammary system. Patients who lack serum IgA lack secretory IgA, and patients who have serum IgA always have secretory IgA antibodies in their secretions.

Selective IgA deficiency is occasionally familial (Koistinen, 1976); in some families, there is a shared propensity for relatives of IgAD patients to have CVID (Cunningham-Rundles, 2004). IgA deficiency occurs in thymectomized mice. Genetic defects of a tumor-necrosis factor receptor family member (termed TACI) have been identified in a few patients with IgAD and CVID, possibly causing defects in isotype switching (Castigli et al., 2005). There is an association of IgAD deficiency with certain HLA types, suggesting a linkage to the major histocompatibility complex (Lakhanpal et al., 1988). Genetic defects involving deletions of chromosome 14 (on which IgA is encoded) and abnormalities of chromosome 18, and chromosome 4 are also associated with IgAD (Cunningham-Rundles, 2004; Hostoffer, 2006).

Certain drugs, notably penicillamine, gold, hydantoin, fenclofenac, and valporate may cause depression of serum IgA levels, which sometimes are permanent. Congenital rubella and Epstein-Barr virus infections have been implicated in a few cases of acquired IgAD deficiency (Cunningham-Rundles, 2004).

Clinical Features

Up to 90% of IgAD patients are asymptomatic. Indeed, a few patients - particularly children under age 5 yr with low but measurable IgA levels - outgrow the illness; this is most unusual in adults and in patients with no detectable IgA (Blum et al., 1988). In this Author's experience, 25% of patients are identified when immunoglobulins are done routinely, another 25% are identified in a search for a cause of recurrent infection; another 25% during an allergy evaluation, and another 25% during an investigation for an autoimmune or inflammatory illnesses such as rheumatoid arthritis.

Most symptomatic IgAD patients have frequent respiratory infections similar to patients with IgG subclass deficiencies or impaired polysaccharide responsiveness. Many of these patients have a concomitant IgG₂ deficiency and/or IPS. The usual infections are otitis, sinusitis, or bronchitis. A few have recurrent pneumonia, obstructive lung disease, or bronchiectasis or other chronic lung diseases. Other IgAD patients will have chronic diarrhea, and under those circumstances; Giardia is particularly common.

Atopic patients have a high incidence of IgAD. This includes patients with asthma, rhinitis, hives, and eczema. A search for sinusitis should be done in those with asthma. Food intolerance, particularly milk allergy, is common in the infant with IgA deficiency; some of these patients have high titers of milk antibodies identified by precipitin tests. Other causes of gastrointestinal symptoms in patient with IgAD include celiac disease, inflammatory bowel disease, nodular lymphoid hyperplasia, hepatitis and many others (Goldblum et al., 2004).

Autoimmune disease is common among IgAD patients, notably rheumatoid arthritis, lupus erythematosus, and thyroiditis. At least 16 other autoimmune disorders have been identified in patients with IgA deficiency, involving all organ systems such as the skin (vitiligo), central nervous system (mental retardation), and the hematopoietic system (immune thrombocytopenic purpura, autoimmune hemolytic anemia) (Cunningham-Rundles, 2004). One theory is that absence of IgA in the serum permits cross-reactive antigens to enter the circulation and initiate autoimmune reactions.

A very rare IgAD patient may have an anaphylactic reaction to a blood product containing IgA (whole blood, plasma, immune globulin). Such patients have developed anti-IgA antibodies to a previous infusion and recognize IgA as a neo-antigen. Thus blood products should be avoided in IgAD patients, and they should wear a Medic Alert badge to this effect. If IVIG is needed, a product low in IgA should be used with caution and with pre-medication (Cunningham-Rundles, 2004).

Laboratory Features

Immunoglobulin levels and IgG subclass levels are the primary diagnostic tests. If IgA deficiency is present, its absence should be confirmed by repeat sampling. Next antibody titers to vaccine antigens should be done to determine if there is a concomitant functional antibody deficiency. Assays for cellular immunity, phagocyte function and complement are usually normal. The presence of autoimmune antibodies such as ANA and thyroid antibodies are common. Allergy tests are often positive. Milk antibodies and celiac antibodies should be done if there is evidence of food intolerance or malabsorption. Anti-IgA antibodies can be assessed, but do not correlate well with intolerance to IVIG.

Treatment

Treatment of infection consists of prolonged or even prophylactic antibiotics, particularly in winter months. Vaccines should be maintained. A Medic-Alert badge is recommended to warn about administration of IVIG or blood products. A rare patient with refractory infection may require IVIG. This should be done cautiously with a product low in IgA. Usually IVIG can be given safely.

Prognosis

Prognosis is largely dependent on the presence of antibody deficiency, allergy or autoimmune disease. IgAD is usually lifelong, but not associated with life-threatening infections or a shortened life span. Rare instances of spontaneous recovery have been recorded, particularly in young patients with some measurable IgA. If the patient has been on a medication known to cause IgA deficiency, its discontinuance may lead to recovery. A rare patient may evolve into CVID.

SUMMARY

These four syndromes probably account for 80% of the immunodeficiencies likely to be seen by the physician who looks after children with frequent infections. Their cause is generally unknown. The chronic respiratory infections present are rarely life-threatening but often require prolonged antibiotics, only rarely is IVIG therapy necessary.