Role of immunoglobulin subclasses and specific antibody determinations in the evaluation of recurrent infection in children.

We studied humoral immune function in 267 children with recurrent respiratory infections referred to our immunology clinic to determine the most appropriate immunologic studies for evaluating recurrent infections in children. Of this highly selected population, 58% had a partial deficiency in one or more of the major immunoglobulin isotypes or IgG subclasses (defined as at least 2 SD below the normal age-adjusted mean). In none of the patients was there a total absence of an immunoglobulin isotype. The most common abnormality was partial IgA deficiency, which was found in one third of the patients. Twenty-six patients had only partial IgG subclass deficiencies, of which 20 were deficiencies of a single subclass. IgG1 was an isolated partial defect in three patients, IgG3 in five patients, and IgG2 and IgG4 were selective partial defects in six patients each. Tetanus toxoid and pneumopolysaccharide type 3 were the most immunogenic of the immunogens tested; hyporesponsiveness to pneumococcal polysaccharide types 7, 9, and 14 was common. Nineteen percent of the patients with normal immunoglobulin concentrations who were tested had lower-than-expected antibody titers; 42% of those tested with partial isotype deficiencies had deficient antibody responses. Of 25 patients with selective partial IgG subclass deficiencies or combined IgG subclass deficiencies, eight had antibody deficiencies. Our findings indicate that a high proportion of children referred to immunology clinics for recurrent infection have a demonstrable immunologic abnormality. Selective IgG subclass deficiency or a combined IgG subclass deficiency without an associated deficiency in a major immunoglobulin isotype is unusual. Identification of such patients is not predictive of the capacity to form antibodies to the antigens tested in this study and, in our opinion, adds little to the initial evaluation of immune function in such children.     

IgG subclasses in children with recurrent respiratory tract infections in an allergy practice

Isolated or combined deficiencies of immunoglobulin G (IgG) subclasses have been recognized in children with recurrent infections. In our allergy practice, there are a subset of children with recurrent respiratory tract infections. To investigate the presence of immunoglobulin G subclass deficiency (IgGSD), 60 children with atopy and 14 children without atopy suffering from recurrent respiratory tract infections were studied in an attempt to determine whether atopy is associated with a certain IgG subclass pattern. Ten atopic children were found to have isolated or combined IgG subclass deficiencies: one with IgG1, two with IgG2, four with IgG3 and three children had IgG2–IgG3. Neither IgG subclass concentration nor the frequency of children with high or low IgG subclasses showed any difference between atopic and non-atopic groups. Except for a week correlation with IgG3, no correlation existed between IgE and other IgG subclasses. It was concluded that childhood respiratory diseases complicated by recurrent respiratory tract infections may be associated with IgG subclass deficiencies. Although there have been reports noting some IgG subclass patterns in atopic disorders, in the present study, no distinctive feature between atopics and non-atopics with respect to IgG subclass concentrations and patterns was observed.     

Clinico-immunologic aspects of IgG subclass deficiency

Serum IgG contains 4 subclasses, IgG1 (60-66%), IgG2 (20-30%), IgG3 (less than or equal to 5%) and IgG4. Individual subclasses vary with respect to their physicochemical and biological properties. IgG subclass concentrations in serum are age dependent. IgG1 and IgG3 reach near to adult levels around the age of 3, IgG2 and IgG4 after the age of 6. Antibodies of certain specificities generally belong to a certain isotype (subclass) due to the isotype restriction. Patients with subclass deficiencies often suffer from recurrent infections. Those with IgG2 deficiency (often occurring with IgA and IgG4 deficiency) develop recurrent infection of the upper and lower respiratory tract often caused by pyogenic microorganisms (Haemophilus, Pneumococcus). Since early initiation of IVIG substitution therapy has a beneficial effect on long term prognosis the importance of early diagnosis is apparent.     

Clinico-immunologic aspects of IgG subclass deficiency

Serum IgG contains 4 subclasses, IgG1 (60-66%), IgG2 (20-30%), IgG3 (less than or equal to 5%) and IgG4. Individual subclasses vary with respect to their physicochemical and biological properties. IgG subclass concentrations in serum are age dependent. IgG1 and IgG3 reach near to adult levels around the age of 3, IgG2 and IgG4 after the age of 6. Antibodies of certain specificities generally belong to a certain isotype (subclass) due to the isotype restriction. Patients with subclass deficiencies often suffer from recurrent infections. Those with IgG2 deficiency coften occurring with IgA and IgG4 deficiency) develop recurrent infection of the upper and lower respiratory tract often caused by pyogenic microorganisms (Haemophilus, Pneumo-(occus). Since early initiation of IVIG substitution therapy has a beneficial effect on long term prognosis the importance of early diagnosis is apparent.     

IgG subclass deficiency in children with IgA deficiency presenting with recurrent or severe respiratory infections

A group of 22 children presenting with recurrent or severe respiratory tract infections who had low IgA levels (more than 2 SD below the mean for age) were examined for IgG subclass deficiency. Patients were screened for possible defects in neutrophil chemotaxis, bactericidal, fungicidal, and quantitative iodination activity, as well as for complement function. The majority of the patients showed IgG subclass levels below the mean for age. Nine of the children showed definite IgG subclass deficiency and at least two showed definite deficiency of more than one IgG subclass. The predominant subclass deficiency was found to be IgG1. While nine children showed IgG4 levels below the level detectable by the technique used, it is not possible to assess whether these patients are deficient in this isotype since some healthy subjects also give values below the level of detection. Most of the patients who had very low (1-6 mg/dl) or undetectable (less than 1 mg/dl) levels of serum IgA did not show IgG subclass deficiencies, while IgG subclass deficiencies were common among those with borderline low IgA levels (slightly more than 2 SD below the mean for age). Nine children showed total IgG levels close to 2 SD below mean for age, and at least six of these showed IgG subclass deficiency. The result suggests that patients with recurrent and/or severe respiratory infections who have borderline IgA and IgG levels may have IgG subclass deficiencies and if they do could benefit from immunoglobulin therapy.     

Isolated Immunoglobulin G4 Subclass Deficiency in a Child with Bronchiectasis

Immunoglobulin G4 subclass deficiency is the most common IgG subclass deficiency, followed by immunoglobulin G2 deficiency. However, IgG2 deficiency is the most common IgG subclass deficiency associated with recurrent infections. Immunoglobulin G4 subclass deficiency occurs in association with other isotype deficiencies. Isolated IgG4 deficiency, however, is much less common. Although respiratory tract infections are the most common manifestation in isolated IgG4 deficiency, other mucosal surfaces may also be affected in IgG4 deficiency leading to diarrhea and recurrent giardiasis. The authors herein report a case of isolated immunoglobulin G4 subclass deficiency in a young girl presenting with bronchiectasis. The diagnosis was established after ruling out other causes of secondary and primary immunodeficiency.     

IgG4 deficiency in IgA-deficient patients

IgG subclass deficiency may be an important factor in the infection proneness of some IgA-deficient subjects. Although several studies on IgG subclass deficiency in IgA-deficient subjects have been reported, most have been unable to assess the incidence of IgG4 deficiency because the limitations of the assay methods used have often made a distinction between low normal and subnormal concentrations impossible. Having developed an enzyme-linked immunosorbent assay capable of measuring concentrations of all the IgG subclasses in healthy subjects of all ages and having established age-normal ranges for IgG subclasses using this assay, we measured IgG subclass concentrations in 73 IgA-deficient patients, the majority of whom were children with recurrent respiratory infections. The results showed that IgG4 deficiency occurred in 26% of the patients and was the most common IgG subclass deficiency found. IgG1, IgG2 and IgG3 deficiencies occurred, respectively, in 10, 12 and 8% of the patients. IgA-IgG4 deficiency occurred in 16% of the patients; IgA-IgG2-IgG4 in 4%; and IgG1-IgG2-IgG4, IgA-IgG1 and IgA-IgG2-IgG3 each occurred in 3%. Other subclass deficiencies or combinations of deficiencies were less frequent. Our results suggest that IgG4 deficiency even in the absence of IgG2 deficiency may be an important but hitherto largely unrecognized factor in infection proneness in some IgA-deficient patients.     

Increases in serum immunoglobulins to age-related normal levels in children with IgA and/or IgG subclass deficiency

Immunoglobulins (Ig) A and G subclass deficiencies are common immune system disorders which cause morbidity especially between 2 and 6 yr of age. Prognosis of these defects and therapeutic approach is unclear. The aim of the present retrospective study was to review the clinical and laboratory records of 87 children with IgA and/or IgG subclass deficiency to determine whether these patients experience changes in serum Ig concentrations during follow-up and to give more clinic and laboratory information to the families about the course of these diseases. Among 87 patients studied, the most frequent defect was partial IgA deficiency combined with IgG3 subclass deficiency (41%). The other groups were as follows; partial IgA deficiency (32%), selective IgA deficiency (8%), partial IgA combined with IgG2-G4 subclass deficiency (6%), and IgG subclass deficiency (13%). The commonest clinical presentations were recurrent upper respiratory tract infections (76%), pneumonia (14%), acute gastroenteritis (3%), urinary tractus infection (3%), sinusitis (2%), and acute otitis media (2%). Atopy was widely represented in the patients studied (24%). The number of patients who were given prophylactic treatment with benzathine penicilline, prophylactic oral antibiotic, or oral bacterial extract to prevent infections was 68 (78%). Frequency of recurrent infections decreased from 7.9 +/- 4.9 per year to 2.5 +/- 2.3 in 68 patients receiving any prophylactic regimen; however, decrease in frequency of infections did not show any significant difference between different prophylactic groups. None of the patients in the selective IgA deficiency group had reached normal serum levels of IgA. At the age of 58.3 +/- 21.4 months, 52% of patients in partial IgA deficiency group and 51% of patients in partial IgA + IgG subclass deficiency group, serum IgA increased to normal ranges. Serum IgG subclass levels increased to normal range for age in 67% of patients in partial IgA + IgG subclass deficiency group and in 30% of patients in isolated IgG subclass deficiency group. The mean age for reaching age-related normal IgG subclass levels for these patients was 69.0 +/- 14.5 months. In conclusion, findings of this study suggest that IgA and/or IgG subclass deficiency may be either progressive or reversible disorders and emphasize the value of monitoring Ig levels in affected individuals.     

Clinical phenotypes associated with selective IgA deficiency: a review of 330 cases and a proposed follow-up protocol

Selective IgA deficiency is the most common Primary Immune Deficiency. Only a small proportion of these patients present during childhood, but this proportion increases over the years, and may be associated with an IgG subclass deficiency with increased susceptibility to respiratory and digestive tract infections. During childhood, IgA deficient patients may also refer to symptoms related to allergic and autoimmune diseases or tumours.AimsTo describe the relationship of selective IgA deficiency with infections, allergic diseases, autoimmune disorders and tumours. To investigate the presence of other immune disorders associated with selective IgA deficiency. To suggest a follow-up protocol for these patients.MethodsRetrospective study of paediatric patients (<18 years) being followed-up in the Clinical Immunology Department between 1992 and 2007, as well as laboratory records with IgA values below 50 mg/L. Clinical records were reviewed (frequency and intensity of diseases associated with selective IgA deficiency) along with immunology tests performed.ResultsA total of 330 paediatric patients were identified with a selective IgA deficiency: 39 (11.8%) suffered from recurrent ear infections (2 developed secondary deafness), 58 (17.5%) from recurrent upper respiratory tract infections, and 20 patients (6%) from recurrent pneumonia, 6 of whom developed secondary bronchiectasis and 2 underwent a lobectomy.A relationship with atopic disease was found in 62 (18.78%) of patients. Regarding digestive disorders, chronic diarrhoea was found in 21 (6.5%), coeliac disease in 22 (6.6%), and persistently high plasma transaminases in 3.Autoimmune manifestations were found in 38 (11.5%), juvenile chronic arthritis, type 1 diabetes, vitiligo, cytopenia, and Crohn's disease, amongst others). Tumours were identified in 5 (1.5%).An IgG sub-class deficiency was found in 5 patients (4%), and 6 patients had a confirmed deficiency in antibody production.ConclusionsIn our cohort, 56.6% of patients with IgA deficiency showed other comorbidities which were, in decreasing frequency: recurrent infections (respiratory and ear infections), allergic diseases, autoimmunity and tumours. Some patients will develop a more severe humoral defect (IgG subclass deficiency with or without antibody deficiency).     

IgG subclasses and their clinical significance

IgG are the most common isotype of Ig and include four subclasses which differ from one another in the following ways: their initial amino acid sequence, their physical and chemical properties and the different serum concentrations reached with age. Every subclass has a specific biological function: the response to proteic antigens is prevalently mediated by IgG1 and IgG3, while IgG2 mediates the response to polysaccharide antigens. It is still unclear whether IgG4 are protective or sensitising antibodies; IgG1 and IgG3 also have a major ability to bind to the cells that mediate the immune response, while only IgG4 activate the complement using an alternative route. Although low levels of IgG subclasses may be temporary, deficiencies are often associated with various diseases: 1) recidivating bacterial infections involving the respiratory and digestive tracts, primarily sustained by capsulated or pyogenic microorganisms; 2) IgA deficiency; 3) absence of immune response following vaccination; 4) allergic or autoimmune diseases; 5) diseases of the CNS. IgG subclass deficiencies must therefore be looked for every time these diseases are diagnosed, also because subjects may benefit from gammaglobulin replacement therapy.     

IgG subclass deficiency in childhood. Changes in the antigen specific immune response and significance of low IgG4 level

The definition of IgG subclass deficiency and the correlations between low IgG subclass serum concentrations and high incidence of infections in certain patients are still obscure. Therefore 260 children from 6 months to 18 years with severe recurrent infections or a known immunodeficiency were screened for IgG subclass deficiency. Nine patients with severe IgG2 deficiency (Ig2 less than 0.3 g/l) and 35 patients with non-detectable IgG4 in immunoprecipitation were detected. One of these patients had a concomitant IgA deficiency, eight revealed an additional IgA and IgG2 deficiency, two an IgA, IgG2, and IgG3 deficiency, eighteen an IgG2 deficiency and one patient an IgG2 and IgG3 deficiency. The proportion of patients with non-detectable IgG4 in immunoprecipitation was 13.5% and thus in the same order of magnitude as described in the literature for healthy people. Our data show that there is no relation between low IgG4 serum levels and the increased occurrence of severe infections. In all patients investigated with non-detectable IgG4 in immunoprecipitation the gene for the heavy chain gene constant domain C gamma 4 could be detected by Southern blotting. Using a sensitive ELISA method IgG4 could be directly demonstrated in all patients at a serum level of 0.5-29 micrograms/ml. Specific IgG4 antibodies against protein antigens could not be detected in IgG4-deficient patients. Nevertheless total IgG antibodies against diphtheria and tetanus toxoid reached protecting titers. Patients with IgG2 deficiency showed an impaired immune response against polysaccharides from pneumococci and haemophilus influenzae type b.     

Phenytoin-induced IgG2 and IgG4 deficiencies in a patient with epilepsy

A five-year-old girl with epilepsy and recurrent respiratory infections was investigated for serum IgG subclass concentrations. She was diagnosed as having a combined deficiency of IgG2 and IgG4 with a decreased serum concentration of IgA and IgG3 and was given replacement therapy with i.v. immunoglobulins. Since then, she has been free from respiratory infections. After phenytoin therapy was stopped, IgG subclass deficiency improved. This case describes the further action of phenytoin on the immune system, adding IgG subclass deficiency to the list.     

Cartilage-hair hypoplasia associated with IgG2 deficiency

We report on a 1 year old boy with cartilage-hair hypoplasia (CHH). He suffered from recurrent upper respiratory infections and short-limbed dwarfism. As with most patients with CHH, he had impaired cellular immunity as determined by lymphocyte reactivity. In addition, he had a selective IgG2 deficiency. This combination of immunodeficiencies has not previously been reported for patients with CHH. His recurrent upper respiratory infections were likely to be associated with cellular immunodeficiency and IgG2 deficiency.     

Immunoglobulin G subclass concentrations and infections in children and adolescents with severe asthma

It was the aim of this study to investigate possible dysfunctions of the humoral immune system in asthmatic children with frequent respiratory infections. Forty‐one severe asthmatics (7–15 years of age), classified according to the Second Brazilian Consensus in Asthma (1998), were divided into two groups: group I (n = 12) had recurrent respiratory infections; and group II (n = 29) were without recurrent respiratory infections. Immunoglobulin (Ig)G, IgA and IgM levels (nephelometry), and IgE (radioimmunoassay) and IgG subclasses (enzyme‐linked immunosorbent assay), were evaluated using standard methods. Asthmatics with recurrent infections presented with worse clinical evolution, an increased number of hospital admissions, and a higher need of medication than the children without recurrent infections. There were no significant differences between the mean values of IgG, IgA or IgM levels, or IgE or IgG subclasses, in patients of both groups. A complete IgA deficiency was detected in two patients of group I (one was associated with IgG subclass deficiency). Deficiency of one or more IgG subclasses was verified in eight of 12 (66%) children from group I and in 16/29 (55%) from group II. The following deficiencies were found in both groups: IgG₃ (10/41), IgG₄ (three of 41), IgG₂ (two of 41), IgG₁ (one of 41), IgG₃‐IgG₄ (four of 41), IgG₁‐IgG₃ (two of 41), and IgG₁‐IgG₃‐IgG₄ (one of 41). There were a higher proportion of children with low IgG₄ levels in group I than in group II (p = 0.01). To conclude, IgA and IgG subclass deficiencies were detected in both severely asthmatic groups, with a predominance of IgG₃ subclass deficiency. However, low IgG subclass levels appear not to be a suitable predictor of the development of infections in asthmatic children.     

Clinical correlates of response to pneumococcal immunization

OBJECTIVE: The inability to form antibodies to polysaccharide antigens may occur as a part of a more significant immunodeficiency or as an isolated defect. The latter has been reported in some children with recurrent upper and lower respiratory tract infections and evaluation of the responsiveness of such patients to polysaccharide antigens is indicated as part of their assessment. The present study evaluated the pattern of antibody responses of patients immunized with pneumococcal vaccine as part of the investigation of recurrent upper and lower respiratory tract infections to determine if any correlation exists between these responses and clinical presentation. METHODOLOGY: An analysis was performed of antibody responses to pneumococcal serotypes 3, 4 and 6 following immunization with a 23-valent vaccine in 42 children with normal IgG levels who were evaluated for recurrent infections. Antibody responses were assessed in relation to clinical features and the results of other immunological investigations. RESULTS: Of the 42 patients evaluated, 25 (59%) were responders to all serotypes tested. Failure to respond to serotype 3 alone was the least common pattern of non-response. Recurrent pneumonia, but not otitis media with discharge or chronic productive cough, was significantly associated with a lack of response to two or three serotypes. Failure to respond to serotype 3 alone or in combination with other serotypes was associated with more significant immune abnormalities. CONCLUSION: In a selected population of children with recurrent bacterial infections, pneumococcal serotype 3 is a strong immunogen. In this clinical group recurrent pneumonia is associated with a defect in response to multiple pneumococcal serotypes.     

Defects of IgG subclasses as a cause of severe, recurrent respiratory tract infection

IgG Immunoglobulins can be differentiated into four subclasses with different structures and functions. Partial or complete defects of one or two subclasses can be related to an impaired immune defence. We describe four children with severe recurrent bacterial airway infections. Two children had developed bronchiectasia following recurrent bronchopulmonary inflammation. Prior to diagnosis of IgG subclass deficiency other common causes of recurrent airway infections were excluded. Defects of IgG 2 or IgG 4 antibodies as well as of both classes were found with compensatory elevation of IgG 1 and IgG 3. In repeated sputum cultures haemophilus influenzae and staphylococcus aureus were isolated. This might be due to an impaired antibody production against special antigens as alpha-toxin of staphylococcus or capsular polysaccharide of haemophilus influenzae. The four cases demonstrate that in children with severe recurrent airway infections including bronchiectasia and otitis media defects of IgG subclasses have to be considered. Diagnosis should be proved by repeated determinations of blood levels after exclusion of other common causes for infections. Diminution of IgG subclasses without clinical symptoms of airway infections is also possible. If diagnosis seems to be certain intravenous substitution with 7 s gammaglobulin beside symptomatic antibiotic therapy is recommended.     

Selective IgA deficiency

Of 140 patients referred to the Pediatric Immunology Clinic during of 12-month period with the symptoms of recurrent infections or allergic respiratory illness, 21 (75%) were found to have selective IgA deficiency defined as serum concentration ≤ 5 mg. with normal levels of IgG and IgM. T lymphocyte number was reduced in the patients where as B cells with surface membrane IgA were increased. Autoantibodies and circulatory immune complexes were found more often in IgA-deficient subjects than in controls. Follow-up beyond the age of 9 years showed a spontaneous increase in serum IgA in 6, whereas 15 continued to have IgA deficiency. The latter group of children were characterized by more frequent infections, a higher prevalence of atopic disease, lower T cell count and serum IgG concentration, higher serum IgE level and a higher prevalence of food antibodies and immune complexes. These observations highlight the natural history and immunologic features of selective IgA deficiency.     

Immunoglobulin G subclass deficiency and predisposition to infection in Down's syndrome

Serum immunoglobulins and IgG subclasses were measured in 26 children with Down's syndrome using an enzyme-linked immunosorbent assay and monoclonal antibodies. Eighteen (69%) of the children had increased susceptibility to infection. None of the children had deficiencies of total IgG and IgM, and only one had an IgA deficiency. IgG4 deficiency was diagnosed in 14 (54%) children. One child had a deficiency of IgG2. There were no children with deficiencies of either IgG1 or IgG3. There was a significant correlation between IgG subclass deficiency and predisposition to infection (P less than 0.05). Ninety percent of the patients with severe infections had low IgG4 whereas only 25% of those with no infections had low concentrations of IgG4. These results suggest that it is important to screen patients with Down's syndrome who have frequent systemic or respiratory infections for IgG subclass deficiencies because this may not be apparent from the assay of total IgG.     

IgG subclasses in healthy children and in children with frequent respiratory tract infections

A group of 130 children presenting with frequent respiratory tract infections was examined for serum levels of IgG-subclasses IgG1, IgG2, IgG3 and IgG4 using radial immunodiffusion according to Mancini. Additionally a control group of 175 children not prone to infections was investigated. Both, low and high levels compared to controls were observed for IgG3 and IgG4. 11.5% of the children with frequent airway infections had IgG3 values below 2 SD below the mean for age compared to 2.8% in the control group (p less than 0.01). Likewise a low IgG4 level was observed more frequently in children prone to airway infections (9.8% versus 2.8% in control; p less than 0.05). IgG4 was undetectable (level less than 3.4 mg/dl) in 5 of the 175 control children. Despite an accumulation of low or undetectable IgG3 or IgG4 levels in children with frequent respiratory tract infections, no correlation between low IgG subclass-levels and the degree of the individual disease could be detected. Based on this lack of a simple causal relationship between frequent respiratory tract infections and the finding of low or undetectable IgG-subclass levels, an immunoglobulin replacement therapy has to be considered with reserve.     

IgG subclass deficiency in children with recurrent bronchitis

We studied the incidence of IgG subclass deficiency in children with recurrent bronchitis. Recurrent bronchitis was defined as three or more episodes a year during at least 2 consecutive years, of bronchopulmonary infection, productive cough with or without fever and/or diffuse rales by physical examination in the absence of asthma or atopy. Fifty three children were selected, of whom 30 (57%) were deficient in one of the IgG subclasses. None had an IgG1 deficiency. Nine (17%) were deficient in IgG2, 9 (17%) in IgG3 and 20 (38%) in IgG4. Isolated IgG subclass deficiencies were most frequently seen for IgG4 (14, 26%), less for IgG3 (6, 12%) and even less for IgG2 (4, 7%). Nine (17%) children were IgA deficient and 8 (15%) IgG deficient with a combined IgG subclass deficiency in 8 and 7 of them respectively. By subdivision into different age groups most patients were encountered in the youngest group. The mean content of IgG2, IgG3 and IgG4 in 3- to 4-year-old children with recurrent bronchitis was significantly lower than in the age matched controls. The mean value for IgG4 in the 5- to 6-year-olds was significantly lower than in the control group. This study demonstrates the correlation between recurrent bronchitis in childhood and IgG subclass deficiency. IgG subclass deficiency and recurrent bronchitis are both quite prominent phenomena in young children but rare in older children, suggesting a transient immaturity of the immune system as one of the possible pathogenetic factors. An IgA or an IgG deficiency is highly suggestive for the existence of a combined IgG subclass deficiency.