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.

Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus.

OBJECTIVES: Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM. METHODS: A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback. RESULTS: Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert-type scale) was reached for all three definitions and 18 statements. CONCLUSIONS: Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.

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.

Falsely low immunoglobulin (Ig)G4 in routine analysis: how not to miss IgG4 disease.

Immunoglobulin (Ig)G4 disease can have apparently 'normal' levels of IgG4 due to antigen excess conditions. IgG4 measurement therefore appears falsely low. UK National External Quality Assurance Scheme (UK NEQAS) data and other reports have suggested that this problem occurred despite pre-existing antigen excess detection steps. To determine the clinical relevance of the problem, we examined the prevalence and characteristics of prozoning in our laboratory and patient cohorts. We establish that the prevalence of raised IgG4 in routine IgG4 analysis is low (< 1%) using one of the two routine methods in use in the United Kingdom. We show that subsequent assay modification appears to have reduced the likelihood of misleading readings. However, the original version of the assay prozoned to low levels (below 0·64 g/l) in 41% of high IgG4 samples in our patients. This may explain the previous reports of low sensitivity of raised IgG4 for IgG4RD, and predictive values should be re-evaluated in this disease using modified prozone-resistant protocols. All laboratories providing IgG4 measurements should verify that their assays are fit for the clinical quality requirement of detection raised IgG4 levels and must verify the upper limit of their reference ranges and freedom from prozoning.

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.

Dysgammaglobulinemia Associated With Glu349del, a Hypomorphic XIAP Mutation.

BACKGROUND: X-linked lymphoproliferative syndrome type 2 is a rare hereditary immunodeficiency caused by mutations in the XIAP gene. This immunodeficiency frequently results in hemophagocytic lymphohistiocytosis, although hypogammaglobulinemia and dysgammaglobulinemia are also common. OBJECTIVE: We identified 17 patients from 12 Japanese families with mutations in XIAP. The Glu349del mutation was observed in 3 patients, each from a different family. Interestingly, these patients exhibited dysgammaglobulinemia but not hemophagocytic lymphohistiocytosis. We conducted an immunological study of patients carrying Glu349del and other mutations to elucidate the pathogenic mechanisms of dysgammaglobulinemia in patients with mutations in the XIAP gene. PATIENTS AND METHODS: We performed an immunological study of 2 patients carrying the Glu349del mutation and 8 patients with other mutations. RESULTS: Flow cytometry showed that the percentage of memory B cells in patients with a mutation in XIAP was lower than that observed in the healthy controls. The patients with the Glu349del mutation had a lower percentage of memory B cells than those with other mutations. Ig production was reduced in patients with the Glu349del mutation. Increased susceptibility to apoptosis was observed in the patients with other mutations. Susceptibility to apoptosis was normal in patients with Glu349del. Microarray analysis indicated that expression of Ig-related genes was reduced in patients with the Glu349del mutation and that the pattern was different from that observed in the healthy controls or patients with other mutations in XIAP. CONCLUSIONS: Patients carrying the Glu349del mutation in the XIAP gene may have a clinically and immunologically distinct phenotype from patients with other XIAP mutations. The Glu349del mutation may be associated with dysgammaglobulinemia.

Paediatric selective IgM deficiency and IgG4 deficiency: an extremely unusual association.

Humoral immunodeficiency disorders present in children after 6 months of age with recurrent respiratory and gastrointestinal infections. These may be due to the absence of B cells causing panhypogammaglobulinaemia, or due to selective deficiencies in immunoglobulin subfractions. We present the case of a child with selective deficiency of IgM and IgG4 resulting in chronic diarrhoea and recurrent lower respiratory infections. With appropriate treatment of infections, the child had good symptom relief. Such an unusual combination of antibody deficiency has not been previously described in children. This case serves to illustrate the need for awareness to institute timely therapy for infection along with appropriate prophylactic measures like vaccination for these children.

Hypoimmunoglobulinemia and protein C deficiency in a girl with Jacobsen syndrome: a case report.

Jacobsen syndrome is a rare contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. The typical clinical manifestations include physical growth retardation, mental retardation,facial dysmorphisms, congenital heart disease, thrombocytopenia, or pancytopenia. A Thai-Australian girl was born with multiple abnormalities. Typical features and her karyotype, 46, XX, del(ll) (q23-qter), confirmed Jacobson syndrome. She had many uncommon findings including upslanting palpebral fissures, tortuousity of retinal vessels and hypogammaglobulinemia. In addition, this case also presented with protein C deficiency, which has not been reported previously in Jacobsen syndrome. The patient was treated with phototherapy, intravenous antibiotic injection, and platelet transfusion in neonatal period. Cranioplasty was performed for prevention of the increased intracranial pressure at three months of age. Surgical correction for strabismus was in the treatment plan.

Poor specific antibody response immunodeficiency (dysgammaglobulinemia) predates systemic lupus erythematosus.

Poor specific antibody response is a well-known primary immunodeficiency that is related to hypogammaglobulinemia or common variable immunodeficiency (CVID). The co-existence of CVID or hypogammaglobulinemia and systemic lupus erythematosus (SLE) has been rarely described. In all reported cases, the diagnosis of SLE antedates CVID. We report a 15-year-old Saudi girl who was diagnosed with poor specific antibody response at age 6 years in the form of poor or no antibody response and dysgammaglobulinemia. She developed SLE with musculoskeletal and hematological manifestations, positive antinuclear antibody and high anti-dsDNA nine years later. She was treated with rituximab with good response.

Selective antibody deficiency and its relation to the IgG2 and IgG3 subclass titers in recurrent respiratory infections.

BACKGROUND: Selective antibody deficiency with normal immunoglobulins (SADNI) may be identified as part of distinct primary or secondary immunodeficiency disorders. The clinical manifestations include recurrent, often severe or prolonged, upper or lower respiratory tract infections. OBJECTIVES: To evaluate SADNI in patients with recurrent sinopulmonary infections and its relation to IgG subclass deficiencies. METHODS: In a case-control study, anti-pneumococcal antibody titer and IgG2, IgG3 levels before injection of pneumococcal vaccine and anti-pneumococcal antibody titer at least 4 weeks after vaccination were measured in 46 patients and 54 controls. The results were compared using student's t-test. RESULTS: There was a significant correlation between age and anti-pneumococcal antibody titers before and after vaccination in patients. No significant relation was found between pre and post vaccination pneumococcal antibody titer and IgG2 and IgG3 in cases and controls (p>0.05). The mean of anti-pneumococcal antibody before and after vaccination were significantly different in cases and controls and were higher in control group (p=0.01, p=0.001, respectively). Anti-pneumococcal antibody titers in 97.8% of cases and 100% of controls group were normal (>3.4 µg/ml). 34.8% of cases and 9.1% of controls had low titers of anti-pneumococcal antibody (<20 µg/ml) while 18.7% of cases and no controls failed to respond to vaccine. CONCLUSION: Evaluation of anti-pneumococcal antibody titer in patients with recurrent, chronic and severe respiratory infections with normal immunoglobulin levels seems to be necessary as early diagnosis. Treatment of such cases could prevent later sequelae such as mastoiditis and bronchiecstasia.

Immunoglobulin E deficiency: a forgotten clue pointing to possible immunodeficiency?

BACKGROUND: Patients with primary antibody deficiency often have delayed diagnosis. Very low IgE, found during investigations for allergy, may be a marker for other immunodeficiency. METHODS: We introduced a new laboratory policy of testing cases with very low IgE levels for possible linked antibody deficiency. The data represent an audit of routine results collected over two years. RESULTS: Very low IgE (≤2 IU/mL) was identified in 85/2622 (3.2%) routine patient samples. Two children and four adult patients were found to have one or more classes of immunoglobulin below the reference range for age. In 2/6, the initiative of the laboratory led to a new unsuspected diagnosis of antibody immunodeficiency. CONCLUSIONS: Common variable immunodeficiency continues to be overlooked as a primary cause of lung disease in adults. Very low serum IgE should trigger appropriate investigation (immunoglobulin quantification and serum electrophoresis).

Clinical and immunological features in IgM deficiency.

BACKGROUND: IgM deficiency is a dysgammaglobulinemia characterized by isolated low levels of serum IgM. Patients with IgM deficiency may exhibit various clinical manifestations. However, IgM deficiency still remains to be explored with regard to diagnosis and treatment. METHODS: Through a retrospective chart review, we investigated the clinical and immunological features of 15 symptomatic adult IgM-deficient patients who were referred to our immunology clinics over a 4-year period. RESULTS: The patients were comprised of 6 males and 9 females, with a mean age of 57.2 years. On initial evaluation, 12 patients (80%) presented with susceptibility to infections, 5 (33%) had atopic manifestations such as asthma and allergic rhinitis, 3 (20%) had both infections and atopy, 4 patients (28%) had fibromyalgia-like symptoms, 3 (20%) had autoimmune manifestations, and 1 patient had lymphoma. The mean serum IgM level was 27.4 mg/dl (range 14-39). Impaired specific antibody response to pneumococcal antigens in 5 out of 11 studied patients (45%) appeared to be a notable association. Subtle abnormalities in IgG subclasses, lymphocyte subsets and in vitro proliferative lymphocyte responses were observed. Five patients who were treated with intravenous immunoglobulin responded very well. CONCLUSION: We propose that a thorough immunological evaluation including specific antibody responses be undertaken in patients with IgM deficiency. IgM-deficient patients who present with recurrent/severe infections may benefit from immunoglobulin treatment particularly in the presence of impaired pneumococcal antibody responses.

Selective immunoglobulin M deficiency presenting with recurrent impetigo: a case report and review of the literature.

Selective immunoglobulin M (IgM) deficiency is a rare disorder defined by a decreased serum level of IgM and normal levels of other immunoglobulin classes. The disease has not been well described and the cause remains unknown. Patients with IgM deficiency may present with a wide spectrum of clinical manifestations, from asymptomatic to life-threatening infections, including recurrent respiratory and gastrointestinal infections, allergy and autoimmunity. Here, we report a 6.5-year-old otherwise healthy boy with selective IgM deficiency who presented with multiple recurrent impetigo. We reviewed the published data regarding selective deficiency of IgM.

[Immunoallergology in children: diagnosis and treatment]. / Immuno-allergologie chez l'enfant: diagnostic et traitement.

Atopy is the most frequent allergic disease in western countries: about 30% of children are suffering from various forms of its manifestations. During the 20th century, its frequency gradually increased. This is not only true for sensitization (presence of specific immunoglobulin E (IgE) in the skin or in the serum), but also for clinical symptoms associated with sensitization. It is usually a disease of skin and mucosae, but atopy can also become systemic (anaphylaxis). Hygienist hypothesis (reduction of infectious diseases and Th1 pressure) gives a possible explanation to the impressive increase of allergic diseases during the last decades. In the child, atopic dermatitis and food allergies are first observed (allergic march): 5 allergens explain more than 85% of cases (white egg, milk, peanuts, fish and nuts). Skin prick tests are more sensible than specific IgE measurements in the serum; they are usually done before. Provocation tests (labial and oral) can confirm the diagnosis when necessary. Four families of aeroallergens are described (pollens, house dust mites, pets and moistures). Eviction is the first line of treatment, than drugs are prescribed to reduce symptoms and inflammation (corticosteroids, antihistamine). Desensitization and immunomodulators that can induce tolerance are also proposed in defined situations.

Selective IgM deficiency and 22q11.2 deletion syndrome.

BACKGROUND: The 22q11.2 deletion syndrome is a common chromosomal disorder with highly variable phenotypic expression and immunologic defects. Humoral immunity is mostly unaffected, but selective IgA deficiency occurs in up to 13% of patients. Selective IgM deficiency associated with 22q11.2 deletion has been reported in 1 patient. OBJECTIVE: To describe another 2 patients with 22q11.2 deletion syndrome and IgM deficiency. METHODS: Patient 1 was a 6-year-old boy with recurrent otitis media, sinopulmonary infections, wheezing, and speech delay. His serum IgM level was 18 mg/dL, and his IgA and IgG levels were normal. Antibody titers to protein and carbohydrate antigens were protective. Workup for velopharyngeal insufficiency resulted in the diagnosis of 22q11.2 deletion syndrome 3 years later. Patient 2 was a 14-year-old girl diagnosed as having 22q11.2 deletion at 9 years of age after presenting with neonatal seizures, atrial and ventricular septal defects, recurrent otitis media, mental retardation, and asthma. Her serum IgM level was 11 mg/dL, with normal IgG and IgA levels. Antibody titers to protein and carbohydrate antigens were protective. Patient 3 was a previously described 15-year-old girl with persistently draining ears, 22q11.2 deletion, and an IgM level less than 6 mg/dL. Her clinical and laboratory features are summarized. RESULTS: Results of further testing on the patients, including lymphocyte enumeration, were normal. The literature is reviewed regarding decreased IgM levels in 22q11.2 deletion syndrome. CONCLUSIONS: Fluorescence in situ hybridization analysis for chromosome 22q11.2 deletion should be considered in patients with selective IgM deficiency, especially if concurrent chronic otitis media, developmental delay, velopharyngeal insufficiency, or dysmorphic features are present.