Serum Protein Electrophoresis May Be Used as a Screening Tool for Antibody Deficiency in Children and Adolescents.

Background: Patients with antibody deficiency may experience exceptionally long diagnostic delays, increasing the risk of life-threatening infections, end-organ damage, mortality, and health costs. Objective: This study aimed to analyze serum protein electrophoresis and verify the correlation between calculated globulin (CG, total protein minus albumin levels) or electrophoretically determined serum gamma globulin fraction (Gamma) with IgG levels in children and adolescents under 18 years old (yo). Methods: We analyzed serum protein electrophoresis (GC or Gamma) and IgG levels from 1215 children and adolescents under 18 yo, classified into 5 age groups. We verified the correlation between CG or Gamma with serum IgG levels. Results: Serum IgG levels varied according to age groups (from 4.3 ± 2.3 g/l in children under 6 months old to 11.4 ± 3.2 g/l in adolescents in the 10-<18 yo group). CG sensitivity and specificity to detect IgG below the reference range for all patients were 93.1% and 81.8%, respectively, and varied according to age group. Gamma sensitivity and specificity for all patients were 100% and 87.8%, respectively, and varied according to age group as well. We found serum IgG levels below the age reference level in 29 patients (2.4% of the cases) using CG or Gamma levels. Conclusion: Both CG and Gamma levels may be of utility as a screening tool for earlier diagnosis of antibody deficiency in children and adolescents under 18 yo.

Immunoglobulin A Dysgammaglobulinemia Is Associated with Pediatric-Onset Obsessive-Compulsive Disorder.

Background: Inflammation and immune dysregulation have been implicated in the pathogenesis of pediatric-onset obsessive-compulsive disorder (OCD) and tic disorders such as Tourette syndrome (TS). Though few replicated studies have identified markers of immune dysfunction in this population, preliminary studies suggest that serum immunoglobulin A (IgA) concentrations may be abnormal in these children with these disorders. Methods: This observational retrospective cohort study, conducted using electronic health records (EHRs), identified 206 children with pediatric-onset OCD and 1024 adults diagnosed with OCD who also had testing for serum levels of IgA. IgA deficiency and serum IgA levels in pediatric OCD were compared with IgA levels from children diagnosed with autism spectrum disorders (ASD; n = 524), tic disorders (n = 157), attention-deficit/hyperactivity disorder (ADHD; n = 534), anxiety disorders (n = 1206), and celiac disease, a condition associated with IgA deficiency (n = 624). Results: Compared with ASD and anxiety disorder cohorts, the pediatric OCD cohort displayed a significantly higher likelihood of IgA deficiency (OR = 1.93; 95% CI = 1.18-3.16, and OR = 1.98; 95% CI = 1.28-3.06, respectively), though no difference was observed between pediatric OCD and TS cohorts. Furthermore, the pediatric OCD cohort displayed similar rates of IgA deficiency and serum IgA levels when compared with the celiac disease cohort. The pediatric OCD cohort also displayed the highest percentage of IgA deficiency (15%,) when compared with TS (14%), celiac disease (14%), ADHD (13%), ASD (8%), and anxiety disorder (8%) cohorts. When segregated by sex, boys with OCD displayed a significantly higher likelihood of IgA deficiency when compared with all comparison cohorts except for celiac disease and tic disorders; no significant difference in IgA deficiency was observed between female cohorts. Pediatric OCD subjects also displayed significantly lower adjusted serum IgA levels than the ASD and anxiety disorder cohorts. Adults with OCD were also significantly less likely than children with OCD to display IgA deficiency (OR = 2.71; 95% CI = 1.71-4.28). When compared with children with celiac disease, no significant difference in IgA levels or rates of IgA deficiency were observed in the pediatric OCD cohort. Conclusions: We provide further evidence of IgA abnormalities in pediatric-onset OCD. These results require further investigation to determine if these abnormalities impact the clinical course of OCD in children.

A prospective ten-year follow-up of patients with chronic urticaria.

BACKGROUND: Chronic urticaria can be the initial clinical presentation of a number of different diseases. The objective of the present study was to report the associated diseases during a ten-year clinical-laboratory follow-up in patients with an initial diagnosis of chronic spontaneous urticaria (CSU) of unknown cause. METHODS: A prospective, longitudinal cohort study with a ten-year clinical-laboratory follow-up was conducted. Patients with a history of urticarial plaques of over six weeks presenting as the only clinical symptom were selected. Individuals with other clinical conditions, urticaria of known causes or chronic physical urticaria were excluded. The following tests were initially performed: haemogram, urine type I, stool parasite exam and sedimentation rate. The following exams were ordered during follow-up: PPD; urine culture; serology tests; antithyroid and antinuclear antibodies, rheumatoid factor, lupus anticoagulant; thyroid hormones; serum immunoglobulin; paranasal sinus and thorax radiographs; testing for BK and Helicobacter pylori; and prick tests. RESULTS: Infections were diagnosed in 29% of patients (syphilis, parasitosis, H. pylori, urinary infection, tuberculosis, hepatitis B and C); autoimmune diseases in 21% (thyroiditis, rheumatoid arthritis and antiphospholipid antibody syndrome); primary immunodeficiencies in 4% (IgA and IgG2 deficiencies); and chronic myeloid leukaemia in 1%. At ten-years of follow-up, the urticaria diagnosis was CSU of unknown cause in 45% of the cases. CONCLUSION: This ten-year clinical-laboratory follow-up of 100 individuals with chronic urticaria as the initial diagnosis revealed the presence of associated diseases in over half of the cases. The most prevalent diseases were infections and autoimmune diseases besides primary immunodeficiencies and blood diseases.

Specific Antibody Deficiencies.

Patients with specific antibody deficiency (SAD) have a deficient immunologic response to polysaccharide antigens. Such patients experience sinopulmonary infections with increased frequency, duration, or severity compared with the general population. SAD is definitively diagnosed by immunologic challenge with a pure polysaccharide vaccine in patients 2 years old and older who have otherwise intact immunity, using the 23-valent pneumococcal polysaccharide vaccine as the current gold standard. Specific antibody deficiencies comprise multiple immunologic phenotypes. Treatment must be tailored based on the severity of symptoms. Most patients have a good prognosis. The deficiency may resolve over time, especially in children.

Immunoglobulin deficiency in patients with chronic rhinosinusitis: Systematic review of the literature and meta-analysis.

BACKGROUND: Several studies have shown a high prevalence of immunoglobulin deficiencies in patients with chronic rhinosinusitis (CRS). OBJECTIVE: We sought to perform a systematic review and meta-analysis to estimate this prevalence more precisely and to identify patients who need substitution treatment. METHODS: All case series published after 1990 describing patients with CRS, which was defined as symptomatic rhinosinusitis for more than 12 weeks and documented immunoglobulin deficiencies (including deficiencies of IgG with subclasses, IgA, and IgM; specific antibody deficiencies; and potential common variable immunodeficiency), were retrieved. A meta-analysis of the proportion of any combination of common variable immunodeficiency, IgG deficiency, IgA deficiency, and IgM deficiency in patients with CRS was performed by using logit transformation of the prevalence. Recurrent CRS was defined as rhinosinusitis not controlled by appropriate conservative management for 4 months, and difficult-to-treat CRS was defined as noncontrollable rhinosinusitis despite successful sinus surgery and appropriate conservative management for at least 1 year. RESULTS: The meta-analysis revealed a prevalence of pooled IgG, IgA, and IgM deficiencies in 13% of patients with recurrent CRS and 23% of patients with difficult-to-treat CRS. The prevalence of IgG subclass deficiency (5% to 50%) and specific antibody deficiency (8% to 34%) was increased in patients with CRS, as was the prevalence of respiratory allergies in patients with recurrent CRS (31% to 72%). CONCLUSION: Immunoglobulin deficiency is a frequent condition in patients with CRS. An even higher prevalence of atopy was observed in patients with recurrent CRS. Therefore immunoglobulin titers and accurate allergy diagnostic workups are strongly recommended in these patients to provide specific treatments for symptom alleviation. However, there is a need for larger prospective studies addressing the effect of specific therapeutic interventions for CRS.

Immunoparesis and monoclonal gammopathy of undetermined significance are disassociated in advanced age.

Immunoparesis and a skewed serum free light chain (FLC) ratio are indicators of immune dysfunction predictive of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). Previous studies have reported increased prevalence of MGUS by age, but no study has examined the relationship between immunoparesis and abnormal FLC ratios in the elderly. We screened 453 older adults (median age, 80 years; range, 65-96) to characterize the patterns of immunoparesis and abnormal FLC ratio in relation to MGUS. We defined MGUS in 4.4% of the subjects; the prevalence was 12.5% among individuals of >90 years. In MGUS (vs. non-MGUS) cases, immunoparesis and abnormal FLC ratios were detected in 70.0% (vs. 49.0%; P = 0.07) and 50.0% (vs. 12.9%; P = 0.0001), respectively. Based on small numbers, MGUS patients with abnormal FLC ratio were borderline (P = 0.07) more likely to have immunoparesis. Overall, the prevalence of immunoparesis varied in a nonlinear fashion, with lowest frequencies in the youngest and oldest groups. Our observed disassociation between MGUS prevalence and impaired immunoglobulin production suggests that separate mechanisms are involved in the development of MGUS and immunoparesis in advanced age. These findings emphasize the need for molecularly defined methods to characterize myeloma precursor states and better predict progression to MM.

Immunoglobulin deficiency in children with Hib vaccine failure.

Immunoglobulin deficiency has been reported in 21% of UK children with Hib vaccine failure but its clinical significance and long-term consequences are not known. This study aimed to estimate the prevalence of immunoglobulin deficiency in children with Hib vaccine failure several years after infection and to determine their risk of recurrent infections. The families of children who developed invasive Hib disease after prior immunisation were identified through national surveillance. A completed questionnaire and blood sample was provided by 170 children at a median of 4 years after infection, equivalent to 1035 child-years of follow-up. Nineteen (11.2%) children had immunoglobulin deficiency, including IgA (n=12), IgM (n=5) and all three immunoglobulin classes (n=2). Immunoglobulin deficiency was associated with younger age (<2 years) at initial Hib disease (12/19 [63.2%] vs. 60/151 [39.7%], P=0.05) and parental reporting of their child receiving >2 antibiotic courses annually in early childhood (11/19 [57.9%] vs. 39/151 [25.8%], P=0.004].). In a logistic regression model, Hib vaccine failure cases that had received multiple antibiotic courses in early childhood were 3.8 times (95% CI, 1.4-10.6; P=0.01) more likely to be immunoglobulin deficient at follow-up than those with fewer or no antibiotic courses. Thus, the prevalence of immunoglobulin deficiency in children with Hib vaccine failure at a median of four years after infection is half that reported at the time of the original infection. A proportion of children with Hib vaccine failure, especially where it occurs at a young age, appear to have a maturational delay in development of normal immunoglobulin concentrations.

Infants with low immunoglobulin levels: Isolated low IgA level vs other immunoglobulin abnormalities.

BACKGROUND: The International Union of Immunological Societies defined transient hypogammaglobulinemia of infancy as decreased IgG and IgA levels. Some others, however, include decreased IgA level alone. We compared infants with decreased levels of IgG and IgA, all isotypes, and IgA alone. OBJECTIVE: To determine whether infants presenting with diminished IgA only differ clinically and in time of immunoglobulin recovery, from those with decreased levels of IgG and IgA, or of all major isotypes. METHODS: Eighty-seven term infants found to have immunoglobulin isotype(s) 2 or more SDs below mean, normal antibody response, intact cellular immunity, and absence of other immunodeficiency syndrome features were evaluated between January 1, 1977 and December 31, 2008. Infants had decreased IgA level (group 1, n = 43), decreased IgA and IgG levels (group 2, n = 39), or low IgA, IgG, and IgM levels (group 3, n = 5). RESULTS: Groups had similar histories. Immunoglobulins normalized in a similar percentage of all groups during infancy but earlier for group 1 (P = .005). CONCLUSION: Little reason exists to separate infants with isolated decreased IgA levels from those with decreased levels of IgA and IgG or all isotypes.

Children with Tourette's syndrome may suffer immunoglobulin A dysgammaglobulinemia: preliminary report.

BACKGROUND: Postinfectious autoimmunity has been implicated in Tourette's syndrome and obsessive-compulsive disorder (TS/OCD), whereas increased frequency of upper respiratory tract infections (URTI) in TS/OCD patients suggests immune deficiency. We hypothesized that antineuronal antibodies may be elevated in patients (reflecting autoimmune processes), and levels of total immunoglobulins (Igs) may be decreased (reflecting immune deficiency). METHODS: We analyzed plasma of TS/OCD patients (n = 24) and healthy age- and sex-matched control subjects (n = 22) by enzyme-linked immunosorbent assay (ELISA) for the levels of total and specific IgG, IgM, and IgA against antigens previously identified in multiple sclerosis (myelin basic protein and myelin-associated glycoprotein) and Sydenham's chorea (ganglioside-GM1, lysoganglioside, and tubulin). RESULTS: Total IgA was decreased in TS/OCD patients (median 115 mg/100 mL) compared with control subjects (141 mg/100 mL; p = .02). Specific IgA against all antigens, except tubulin were also decreased in the patients (MPB 0 vs. 13 [ELISA units [EU]; myelin-associated glycoprotein 29 vs. 44 EU, p = .04; ganglioside GM1 21 vs. 35 EU, p = .01; lysoganglioside 44 vs. 56 EU, p = .03; tubulin 44 vs. 44 EU, p = .8). The levels of total IgA and anti-myelin basic protein (MBP) IgA were significantly lower in the subgroup of pediatric autoimmune neuropsychiatric disorder associated with Streptococcus (PANDAS) cases (n = 10) than in non-PANDAS cases (n = 9; total IgA 98 mg/100 mL vs. 133 mg/mL, p = .03; anti-MBP IgA 1 vs. 6 EU, p = .03) or healthy control subjects (total IgA 141 mg/100 mL, p = .02; anti-MBP IgA 13 EU, p = .005). CONCLUSIONS: At least some TS/OCD patients may suffer IgA dysgammaglobulinemia, possibly rendering the children more prone to URTI.

[IgE deficiency: a forgotten disease?]. / Deficiencia de IgE: un padecimiento olvidado?

BACKGROUND: Selective IgE deficiency is a profound deficiency (< 5 UI/mL) or absence of serum IgE levels without other immunologic abnormalities. It is usually asymptomatic, but may be associated with recurrent respiratory infections, chronic fatigue, and musculoskeletal complaints. OBJECTIVE: To describe the evolution and treatment in patients with selective IgE deficiency. PATIENTS AND METHOD: In selective IgE's deficiency patients identification note, atopy history, concurrent diseases, clinic of allergic diseases, Prick test and prior response to treatment were analyzed. RESULTS: Eleven patients were included, five women and six men within 16 months to 10 years old. The patients had serum IgE levels < 5 UI with other immunoglobulins and sub-classes in normal levels; except a patient with concomitant IgA and IgE deficiency. The treatment administered was since prophylactic antibiotic to intravenous gammaglobulin. DISCUSSION: We established the diagnosis of selective IgE deficiency in patient with serum IgE levels < 5 UI/mL associated with recurrent respiratory infections. CONCLUSIONS: We need more clinic studies to document with precision the selective IgE deficiency.

Pediatric selective IgM immunodeficiency.

OBJECTIVE: Limited information exists on features of pediatric Selective IgM immunodeficiency (SIgMID). Previously published pediatric cases and 2 new cases are reviewed. METHODS: English literature from PubMed and references from relevant articles were reviewed. Previously reported cases and 2 new cases from an allergy/immunology practice were analyzed. RESULTS: Forty-nine reported cases of SIgMID presented with respiratory infections (77.6%), gastrointestinal disease (16.3%), skin disease (12.2%), and meningitis (8.2%). Mean serum IgM level was 16.5+/-13.8 mg/dL. Two patients were identified with SIgMID among 6300 active pediatric patients (0.03%) presenting with asthma, vasomotor rhinitis, and recurrent respiratory infections. In the 51 cases reported, none developed lymphoproliferative disease nor evolved into panhypogammaglobulinemia; four fatalities were reported. CONCLUSIONS: The prevalence of SIgMID in our pediatric population was 0.03%. In general, respiratory infections are the common comorbid conditions. Death and autoimmune disease are uncommon complications of pediatric SIgMID.

Selective IgM immunodeficiency: retrospective analysis of 36 adult patients with review of the literature.

OBJECTIVE: To review and compare previously reported cases of selective IgM immunodeficiency (SIgMID) with the largest adult cohort obtained from a retrospective analysis of an allergy and immunology practice. DATA SOURCES: Publications were selected from the English-only PubMed database (1966-2005) using the following keywords: IgM immunodeficiency alone and in combination with celiac disease, autoimmune disease, malignancy, and infection. Bibliographic references of relevant articles were used. STUDY SELECTION: Reported adult SIgMID cases were reviewed and included in a comparative database against our cohort. RESULTS: Previously described patients with SIgMID include 155 adults and 157 patients of unspecified age. Thirty-six adult patients were identified with SIgMID from a database of 13,700 active adult patients (0.26%, 1:385). The mean +/- SD serum IgM level was 29.74 +/- 8.68 mg/dL (1 SD). The mean +/- SD age at the time of diagnosis of SIgMID was 55 +/- 13.5 years. Frequency of presenting symptoms included the following: recurrent upper respiratory tract infections, 77%; asthma, 47%; allergic rhinitis, 36%; vasomotor rhinitis, 19%; angioedema, 14%; and anaphylaxis, 11%. Serologically, 13% of patients had positive antinuclear antibodies (ANAs), 5% had serologic evidence of celiac disease, and nearly all had non-AB blood type. Patients also had low levels of IgM isohemagglutinins. No patients developed lymphoproliferative disease or panhypogammaglobulinemia, and none died of life-threatening infections, malignancy, or fulminant autoimmune-mediated diseases during a mean follow-up period of 3.7 years. CONCLUSIONS: The prevalence of SIgMID in our adult population was 0.26% and may be more common than previously thought. Non-life-threatening respiratory disorders were common comorbid conditions.

The prevalence of celiac disease in at-risk groups of children in the United States.

OBJECTIVE: In contrast to its prevalence in Europe, celiac disease (CD) is considered rare in the United States. We aimed to determine the prevalence of CD in children presenting with symptoms or conditions associated with CD. STUDY DESIGN: Individuals aged 6 months to 20 years were screened for IgG and IgA antigliadin (AGA-IgG and AGA-IgA) and antiendomysium (EMA) antibodies. Those with only elevated AGA-IgG were screened for selective IgA deficiency. Patients with elevated EMA, or AGA-IgG elevation and selective IgA deficiency, were advised to undergo small intestinal biopsy. RESULTS: A total of 1200 individuals were studied; 34 were EMA positive-26 (19 EMA positive) consented to biopsy and 21 had CD, giving a prevalence of 1 in 57 (21/1200). Including the 15 EMA positive patients who refused a biopsy, the prevalence of CD in this study could be as high as 1 in 33 (36/1200). CONCLUSIONS: CD is not rare in the United States and may be as common as in Europe. AGA and EMA are useful for identifying patients who should undergo a small intestinal biopsy.

Immunoglobulin deficiencies and impaired immune response to polysaccharide antigens in adult patients with recurrent community-acquired pneumonia.

The frequency of humoral immunodeficiencies was analysed in 39 patients with a history of recurrent (> or = 3) episodes of community-acquired pneumonia. Total immunoglobulin levels and/or IgG subclass levels were low in 14 patients (36%), including eight patients with IgG or IgG2 deficiency. The specific antibody activity to pneumococcal capsular polysaccharides (serotypes 3, 6A, 19F, and 23F) and to phosphorylcholine was low in the IgG/IgG2-deficient patients compared to 36 healthy controls, and they also responded poorly to vaccination with a 23-valent pneumococcal capsular polysaccharide vaccine. The remaining 25 patients, with normal immunoglobulin and IgG subclass levels, had specific anti-pneumococcal antibody levels comparable to the healthy controls, and all but 3 responded to vaccination. We conclude that immunoglobulin deficiencies and the inability to respond to polysaccharide antigens are common risk factors for recurrent pneumonia in adult patients. Immunoglobulin levels (including IgG subclasses) and antibody response to polysaccharide antigens should be investigated in these patients.