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.

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.

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.

B cell depletion for autoimmune diseases in paediatric patients.

Data on B cell depletion therapy in severe autoimmune diseases in paediatric patients are very limited. We conducted a retrospective cohort study and recruited patients who were treated with rituximab (RTX) and followed up for at least 6 months through the German societies of paediatric rheumatology and nephrology. The aim was to describe the spectrum of autoimmune disorders for which RTX was used and to describe the applied therapeutic regimens, the observed efficacy, as well as potential immunological side effects. The need to develop standard treatment guidelines for future trials should be discussed. Sixty-five patients were included. Nineteen patients suffered from systemic lupus erythematosus, 13 from vasculitic disorders, 12 from hematological autoimmune diseases, 5 from mixed connective tissue disorders, 4 from juvenile idiopathic arthritis, and 9 had other autoimmune diseases. Adverse, infusion-related events were reported in 12/65 (18%) patients. Considering laboratory and clinical parameters, 13 patients (22%) were in complete remission, 31 (52%) were in partial remission, 6 (10%) were unchanged and 10 (17%) had progressed after 6 months. In 46% of the patients, the steroid dose could be more than halved. IgG, IgM and IgA decreased from normal levels prior to RTX therapy to below normal levels at 6 months in 2/22 (9%), 10/21 (48%), and 4/22 (18%) patients, respectively. Immunoglobulin deficiency or prolonged CD20 depletion was reported in eight patients after an observation period longer than 12 months. RTX therapy led to a perceivable reduction in disease activity. However, long-term immunological alterations may occur in more than 10% of the patients. Guidelines and protocols for off-label therapy are desirable to document reasonable follow-up data. Controlled prospective studies for RTX therapies in children with standardised therapeutic and diagnostic protocols are urgently needed.

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.

[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.

Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century.

OBJECTIVES: To provide a review of the world literature and discuss the clinical role of subcutaneous immunoglobulin (SCIG) therapy for primary antibody deficiency. DATA SOURCES: English-language publications on SCIG therapy were identified through MEDLINE and through the reference list of the initially identified publications. STUDY SELECTION: Articles pertaining to SCIG for the treatment of immunodeficiency, particularly primary antibody deficiency, were selected. RESULTS: SCIG therapy has been shown to be effective and safe for the treatment of primary immunodeficiency. The risk of systemic reactions during infusion is generally reported to be less than 1%. Many patients prefer SCIG over conventional intravenous immunoglobulin therapy because of increased convenience and independence associated with SCIG therapy. Publications show SCIG therapy to be advantageous in selected patient populations, such as children, pregnant women, and patients with poor intravenous access. CONCLUSION: SCIG therapy has been widely used in some European countries for a number of years, but a Food and Drug Administration-approved product was only recently introduced into the United States in 2006. SCIG therapy offers unique advantages that are applicable to many patients receiving immunoglobulin therapy for primary immunodeficiency.

Immunologic reconstitution following bone marrow transplantation for X-linked hyper IgM syndrome.

X-linked hyper IgM syndrome (XHIM), caused by mutations of the CD40 ligand (CD40L) gene, is characterized by recurrent bacterial and opportunistic infections, an increased incidence of autoimmunity and malignancies, and immunodeficiency due to abnormal T/B cell interaction. Because of poor long-term prognosis, bone marrow transplantation (BMT) has been proposed as an alternative treatment. An 8-month-old boy with XHIM and a splice site mutation of CD40L underwent BMT using a fully matched sibling donor. Markers of engraftment and immunologic reconstitution were measured serially. After BMT, activated T cells expressed functional CD40L, and genomic DNA obtained from circulating white cells contained predominantly wild-type CD40L sequences. Serum immunoglobulin levels including IgE and antibody responses to recall antigens normalized, and immunization with the T-cell-dependent neoantigen, bacteriophage φX174, demonstrated amplification of the response and isotope switching. BMT provides a permanent cure for XHIM if a fully matched sibling donor is available and the procedure is performed before complications have occurred.

Follow-up of pediatric patients with recurrent infection and mild serologic immune abnormalities.

BACKGROUND: Children with recurrent infections significant enough to warrant referral to an immunologist frequently have mild abnormalities of the humoral immune system. Parents of these children are generally reassured that their child will outgrow the clinical problems that prompted their referral. OBJECTIVE: This is a retrospective study with the objective being to evaluate changes in immune measurements and clinical status of children with recurrent infections followed in an immunology clinic. METHODS: Forty-two patients (mean age 60 months) previously evaluated for recurrent infections were re-evaluated after at least 12 months (mean 37 months). Initial evaluation studies included quantitative immunoglobulins in all patients and IgG subclass determinations and pre- and postvaccination pneumococcal polysaccharide antibody titers in a subpopulation of patients. RESULTS: Patients were assigned to one of two categories: those with initial laboratory abnormalities (27 patients) and those with normal initial studies (15 patients). Among the patients with initial abnormalities, partial IgA deficiency was most commonly seen (20/27). It persisted in 15. Only 6/27 patients had studies that were completely normal on follow-up. Among patients with no initial abnormality, 9/15 developed a partial deficiency of at least one immunoglobulin isotype or IgG subclass. Eighty-six percent of the patients were clinically improved at the time of their last follow-up visit regardless of their laboratory values. CONCLUSIONS: A high proportion of children with recurrent infection have persistent, partial immunoglobulin deficiencies lasting in some cases for years. Despite this finding almost all patients demonstrate clinical improvement with time.

HCV infection in a patient with hyper IgM syndrome.

The association between an acquired form of hyper-IgM syndrome and a chronic hepatitis C virus (HCV) infection in a 71-year-old female patient is described. Both diseases were diagnosed at the age of 58 years. She was started on intramuscular and then intravenous immunoglobulin replacement therapy. HCV RNA was detected in 1992. The patient remained in well-balanced clinical condition until 1994, when total and specific anti-HCV IgM levels increased and the patient developed an IgM kappa monoclonal gammopathy. Adherent cells and B cells were HCV RNA positive, while T cells were HCV RNA negative. Anti-IgM reactivity was specifically directed to the core antigen of the HCV. The patient we describe showed a picture of a late-onset form of hypogammaglobulinemia with a progressive increase in IgM antibodies, possibly due to the concomitant HCV infection. It is possible that the immunodeficiency might also result from the HCV infection, with formation of specific antibodies belonging to the IgM class, and that the worsening of the clinical condition may be directly related to the persistent viral infection.

[Administration of intravenous immunoglobulins in adult patients with hematologic diseases]. / Primjena imunoglobulina za intravensku upotrebu kod odraslih osoba s bolestima krvi.

Abnormalities in serum immunoglobulin levels or in antibody production may develop as a result of many different diseases. Antibody deficiency may occur in previously normal persons with haematologic malignancies or who received immunosuppressive agents in treatment of cancer or in anticipation of bone marrow transplantation. Effective regimens may develop in primary immunodeficiencies and secondary immunodeficiencies as well as in idiopathic thrombocytopenic purpura. Some reports and information about the other haematological indications were published in medical literature. However, the consensus conference on IVIG at the National Institutes of Health (Bethesda--May 21, 1990) recommended treatment with IVIG in haematology only for CLL, ITP and after bone marrow transplantation, as a prevention for GVHD. The adverse effects of IVIG therapy are minimal, but they exist. The other important subject is the cost of widespread use of IVIG; therefore the indications must be carefully concerned and documented before therapy is started.

Effects of intravenous immunoglobulin on clinical and immunological findings of patients with humoral immunodeficiency diseases.

We evaluated nine patients with humoral immunodeficiency (6 immunodeficiency with hyper-IgM, 2 X-linked agammaglobulinemia, 1 common variable immunodeficiency) who were being treated with intravenous immunoglobulins (IVIG). After the use of the IVIG regimen in a dose of 250-300 mg/kg/4 weeks for one year, the severity and frequency of infections, even in patients with chronic lung disease, decreased significantly. An improvement in pulmonary function tests was observed in four patients who had airway obstruction prior to IVIG therapy. Side effects such as chills and fever were observed in 21 of 91 infusions, particularly in the early months of therapy. Preinfusion administration of aspirin and diphenhydramine prevented these side effects. The inversion of the CD4+/CD8+ ratio was detected in most patients during both intramuscular gammaglobulins (IMIG) and IVIG therapy.