Efficacy and safety of a new immunoglobulin G product, Gammaplex(®), in primary immunodeficiency diseases.

This open-label multi-centre study evaluated a new intravenous immunoglobulin, Gammaplex®, in the treatment of 50 patients with primary immunodeficiency and significant hypogammglobulinaemia. Patients treated previously with other intravenous immunoglobulins received Gammaplex® on their same infusion schedule for 1 year; 22 were on a 21-day and 28 on a 28-day regimen (300-800 mg/kg/infusion). There were no serious, acute bacterial infections, whereas six subjects (12·0%) had at least one such infection in the 6 months before enrollment. Forty subjects (80·0%) had at least one non-serious infection; the median number of infective episodes per subject per year was 3·07. Antibiotics were taken by 38 subjects therapeutically and prophylactically by 16 at some time. Fewer than half (46·0%) missed any time off work or school because of infection or other illness. Trough immunoglobulin (Ig)G levels were above 6·00 g/l in all subjects at all assessments after 15 weeks with two exceptions. Overall, 21·2% of infusions were associated with an adverse event up to 72 h after infusion. The frequency of adverse events increased with infusion rate. Headache was the most common product-related adverse event (7·5% of 703 infusions). In conclusion, Gammaplex® is effective in primary immunodeficiency and is well tolerated.

Allergenic components of vaccines and avoidance of vaccination-related adverse events.

Vaccines have had a dramatic effect on the prevalence of communicable diseases, but, in selected individuals, the injection presents a risk of anaphylaxis. Fortunately, most people have no allergic reactions to vaccines. In egg-allergic individuals, care must be taken before administering specific vaccines; the algorithm provided in this article gives specific recommendations for skin testing and desensitization. This algorithm is not needed for individuals receiving the measles-mumps-rubella vaccine because the risk of anaphylaxis is extremely low, even in those with known egg-protein sensitivity. Some individuals have gelatin sensitivity, which may cause anaphylaxis. Selected vaccines contain antibiotic drugs, so it is important to note if an individual has any known drug sensitivity, especially to neomycin, polymyxin B, or amphotericin B. Lastly, vaccine preservatives may cause reactions, but this occurs very infrequently.

Velocardiofacial syndrome: incidence of immune cytopenias.

BACKGROUND: Velocardiofacial syndrome (VCFS) is associated with a broad clinical spectrum that frequently overlaps the DiGeorge syndrome. Both have been linked to chromosomal microdeletions of chromosome 22 (22q11.2). DiGeorge syndrome is associated with T-cell dysfunction. What is the incidence of immune cytopenias in children with VCFS? OBJECTIVES: To (1) identify, (2) characterize, (3) quantify, and (4) follow up the immunologic deficits in children initially seen in our institution with VCFS. DESIGN: Prospective clinical evaluation of patients with the features of VCFS. PATIENTS: Twenty consecutive children with the clinical diagnoses of VCFS. SETTING: Tertiary care children's hospital. MAIN OUTCOME MEASURES: All 20 children had genetics evaluation with chromosomal analysis. Immunologic evaluations included serum immunoglobulin concentrations, lymphocyte studies, and mitogen and antigen stimulation studies. RESULTS: Five (25%) of 20 children were noted to have T-cell dysfunction with a clinical presentation marked by recurrent upper respiratory tract infections. Three of these 5 children had resolution of the T-cell dysfunction over a 2-year period. The 2 children with persistent cytopenias combined with immunoglobulin dysfunction required intravenous IgG infusions to control their infections. CONCLUSIONS: Velocardiofacial syndrome is associated with an increased incidence of immune cytopenias and, thus, warrants evaluation in any child with the clinical diagnosis of VCFS. This immune deficit may be transient and depends on the age of the evaluation of the child.

Safe administration of influenza vaccine to patients with egg allergy.

OBJECTIVES: Specific recommendations for administering the influenza vaccine to patients with egg allergy are based on limited scientific data. The objectives of this investigation were to determine the safety of a 2-dose administration of an influenza vaccine to patients with egg allergy and to evaluate the usefulness of skin testing with the influenza vaccine before administration. STUDY DESIGN: In this multicenter clinical trial, clinical histories of egg allergy were confirmed by skin testing with egg and, if possible, by oral challenges with egg. Subjects with egg allergy received the vaccine in 2 doses, 30 minutes apart; the first dose was one tenth and the second dose nine tenths of the recommended dose as determined by age. Subjects without egg allergy were recruited as control subjects and received 1 age-determined dose of the vaccine. Skin prick tests with the influenza vaccine were performed on all subjects. RESULTS: From 1994 to 1997, 83 subjects with egg allergy and 124 control subjects were evaluated. The content of ovalbumin/ovomucoid was 0.1, 1.2, and 0.02 micrograms/mL, respectively in the 1994-95, 1995-96, and 1996-97 influenza vaccines. Results of vaccine skin prick tests were positive in 4 subjects with egg allergy and in 1 control subject. All patients with egg allergy tolerated the vaccination protocol without any significant allergic reactions. CONCLUSIONS: These results demonstrate that patients with egg allergy, even those with significant allergic reactions after egg ingestion, can safely receive an influenza vaccine in a 2-dose protocol when the vaccine preparation contains no more than 1.2 micrograms/mL egg protein.

Human neutrophils express the prostaglandin G/H synthase 2 gene when stimulated with bacterial lipopolysaccharide.

Human blood neutrophils (PMN) rapidly release arachidonic acid (AA) from cellular phospholipids when stimulated in vitro with a variety of inflammatory agonists. Free AA is then metabolized via 5'-lipoxygenase to produce bioactive mediators such as leukotriene B4 and 5-hydroxyeicosatetraenoate. Arachidonic acid can also be metabolized via the cyclooxygenase or prostaglandin G/H synthase (PGHS) pathway to form prostaglandins and thromboxane. We show here that human blood PMN express the PGHS 2 gene when stimulated with bacterial lipopolysaccharide (LPS). PGHS 2 mRNA increases within 30 min after LPS stimulation and PGHS 2 immunoreactive protein is detectable by 5 h. Although PGHS 1 mRNA is detectable in PMN, no immunoreactive protein is observed in either resting or LPS-stimulated cells. Following stimulation with LPS and expression of PGHS 2, PMN increase secretion of prostaglandin E2. This phenotypic change in PMN could be an important mechanism for regulating inflammation.

Adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency in common variable immunodeficiency.

The clinical presentations of adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency are widely variable and include clinical and immunologic findings compatible with common variable immunodeficiency. The screening of 44 patients with common variable immunodeficiency failed to identify any individuals with deficiencies of these enzymes.

Skin sensitivity to allergen does not accurately predict airway response to allergen.

BACKGROUND: Allergen challenge of the asthmatic airway has become widely applied in the study of allergic asthma in humans. Skin sensitivity correlates with inhaled sensitivity in some populations. Skin test titration has been proposed as a useful tool to guide the selection of initial allergen concentration. OBJECTIVE: To determine the relationship between skin test sensitivity and inhaled reactivity to allergen. METHODS: We examined the relationship between skin test and inhaled reactivity in 22 allergic asthmatic subjects. Methacholine bronchoprovocation was performed using a standardized tidal breathing technique. Prick skin test titrations were done using serially diluted lyophilized antigen extracts reconstituted in normal saline from 1:100,000 to 1:10. Inhaled allergen challenge was routinely performed in the morning using the same allergen employed in skin test titration. RESULTS: There was no correlation between skin test threshold and the inhaled concentration required to produce a 20% fall in FEV1 (r = 0.07; P = .78). If subjects who manifested marked cutaneous reactivity (i.e., skin reactivity at dilutions greater than 1:10,000) were excluded from analysis, there was a significant correlation between cutaneous and inhaled reactivity (r = 0.84; P < .001). CONCLUSION: While a correlation between skin test threshold and inhaled reactivity is present in some subjects with allergic asthma, the relationship is inconsistent.

Phospholipase A2 and arachidonate increase in bronchoalveolar lavage fluid after inhaled antigen challenge in asthmatics.

Phospholipases A2 (PLA2) hydrolyze phospholipids resulting in the release of fatty acids including arachidonic acid (AA) and lysophospholipids. AA, in turn, serves as a substrate for the synthesis of leukotrienes which can cause bronchoconstriction and airways edema and appear to be important mediators of clinical asthma. Further, lysophospholipids may be cytotoxic and/or impair the function of surfactant. We examined the release of secretory PLA2 (sPLA2) and AA into the airways after antigen challenge in 16 subjects with allergic asthma. Asthmatic subjects underwent bronchoscopy with bronchoalveolar lavage (BAL) before and after inhaled antigen challenge; in addition, a single BAL, without inhaled antigen, was performed in 10 control subjects. BAL was obtained at 4 h (n = 7), the time of the late asthmatic response (LAR) (n = 5), or 24 h (n = 4) after challenge. There was no difference between normal and asthmatic subjects in either BAL fluid (BALF) sPLA2 activity or AA concentration at baseline. Both sPLA2 and AA increased after antigen challenge (p < 0.01 and 0.05, respectively). These changes were most marked 4 h after challenge (p < 0.03 for both). sPLA2 may play an important role in the generation of AA in patients with asthma.

Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature.

The true incidence of sarcoidosis in common variable immunodeficiency (CVID) is unknown. We report here 8 cases of sarcoidosis among 80 patients with CVID followed in our clinics, along with 22 well-documented cases reported in the literature. Sarcoidosis, therefore, represents an important entity to consider among patients with CVID who exhibit clinical, radiographic, laboratory, and biopsy findings compatible with sarcoidosis. Conversely, the diagnosis of CVID should be considered in patients with sarcoidosis who do not exhibit the characteristic hypergammaglobulinemia and who have a history of recurrent infections. Although many features of sarcoidosis are similar in patients with CVID to those in patients with sarcoidosis alone, there are many important differences. Patients with CVID in whom sarcoidosis develops present with hypogammaglobulinemia rather than hypergammaglobulinemia and have a higher prevalence of recurrent infections, thrombocytopenia, and splenic involvement. Steroids, in most cases, appeared helpful in reducing adenopathy and splenomegaly, improving uveitis, lowering serum alkaline phosphatase, and reversing hematologic abnormalities. The underlying pathophysiology responsible for the association of these 2 disorders in the same patient remains obscure. However, as more patients are identified, it may be possible to gain a better understanding of the immunologic defect responsible for the dual presentation of these 2 relatively uncommon diseases.

Alterations in arachidonic acid metabolism in mouse mast cells induced to undergo maturation in vitro in response to stem cell factor.

We studied arachidonic acid (AA) metabolism during the maturation of bone marrow-derived cultured mast cells (BMCMCs) into mast cells with phenotypic characteristics, which were more similar to those of connective tissue-type mast cells. BMCMCs were maintained in medium containing 100 ng/ml recombinant rat stem cell factor (SCF) for 1 to 6 weeks. After 3 to 4 weeks in SCF, BMCMCs acquired many phenotypic characteristics of maturation, including enlarged size, numerous electron-dense cytoplasmic granules, and a 50-fold elevation in histamine content. Maintenance in SCF for 6 weeks did not significantly alter the amounts or species of eicosanoids that were produced by BMCMCs stimulated with calcium ionophore A23187. However, SCF-treated mast cells released 2.6 +/- 0.13 times more free AA and accumulated 6.4 +/- 1.0 times higher levels of intracellular free AA than did immature BMCMCs not exposed to SCF. There was no increase in the mobilization of other fatty acids (e.g., linoleic or oleic acid), indicating specificity for AA. Moreover, there were no differences between the 5-lipoxygenase activities of SCF-treated or untreated cells, as assayed in cell homogenates prepared by nitrogen cavitation. Although the total AA content in SCF-treated cells was significantly elevated, the distribution of AA in phospholipid and neutral lipid classes was not altered by SCF treatment. Total phospholipase (PL)A2 activity increased 85% +/- 11.5% in SCF-treated cells. In homogenates of immature BMCMCs, 51.0% +/- 13.7% of the PLA2 activity was inhibited by 0.5 mmol/L dithiothreitol, whereas the same concentration of dithiothreitol caused only a 2.2% +/- 10.7% reduction in the PLA2 activity in homogenates of SCF-treated BMCMCs (p < or = 0.05, n = 4). These findings suggest that SCF treatment induces a dithiothreitol-resistant PLA2 and that this PLA2 may contribute to the mobilization of AA that is not further metabolized to eicosanoids.

Risks and benefits of intravenous immunoglobulin treatment in children.

Intravenous immunoglobulin has been used in the treatment of a variety of disorders since the 1970s. Its safety and efficacy, however, have been evaluated in only a minority of these conditions. At present, intravenous immunoglobulin is licensed for use in primary immunodeficiencies, idiopathic thrombocytopenic purpura, chronic lymphocytic leukemia, Kawasaki syndrome, bone marrow transplantation, and pediatric AIDS. Although considered to be a relatively safe product, it is costly and not without risk of adverse reactions, including transmission of infectious agents. This point has been underscored by the recent report of over 100 cases of hepatitis C infection associated with a commercially available intravenous immunoglobulin preparation. Hepatitis C represents the major risk associated with intravenous immunoglobulin, and physicians must carefully weigh both the risks and benefits of this product before initiating treatment in selected patients.

Selective induction of prostaglandin G/H synthase I by stem cell factor and dexamethasone in mast cells.

This study examines the regulatory effects of two cytokines, stem cell factor (SCF) and interleukin-3, and a glucocorticoid, dexamethasone, on lipid mediator generation in mouse bone marrow-derived mast cells (BMMC). Treatment of BMMC with SCF induced a modest, dose-dependent increase in three eicosanoids, thromboxane B2, prostaglandin D2, and leukotriene B4. These increases were accompanied by a marked elevation in cytosolic PLA2 (cPLA2). Dexamethasone blocked the induction of cPLA2 levels and the elevation in leukotriene B4 induced by SCF. By contrast, the combination of SCF and dexamethasone dramatically increased (5-8-fold) the capacity by BMMC to produce prostanoid products. This increase in prostanoid products was mirrored by an increase in prostaglandin G/H synthase I (PGHS-I) levels. Dexamethasone, alone, had no effect on PGHS-I, cPLA2, or prostanoid levels. Moreover, neither SCF or dexamethasone, alone or in combination, influenced prostaglandin G/H synthase II (PGHS-II) levels. In contrast to SCF, interleukin-3 alone or in combination with dexamethasone had no effect on prostanoid synthesis or PGHS-I or II levels. To better understand the SCF and dexamethasone effect, PGHS-I and PGHS-II mRNA expression were examined by Northern analysis. PGHS-I mRNA was markedly induced (maximal levels at 5 h) by the combination of SCF and dexamethasone. PGHS-II mRNA was undetectable in either control or SCF/dexamethasone-treated BMMC. Neither SCF or dexamethasone, alone, altered mRNA for either PGHS isotype. Taken together, these studies reveal that PGHS-I may be critical to prostanoid formation in mast cells exposed to cytokines and glucocorticoids. Moreover, they suggest that synergistic induction of PGHS-I could represent a novel mechanism for the anti-inflammatory action of glucocorticoids.

Chronic meningococcemia in a child with a deficiency of the sixth component of complement.

Chronic meningococcemia represents an uncommon manifestation of meningococcal disease. Microbial and host factors which may predispose to this form of meningococcal disease are not understood. Although acute meningococcal disease is frequently found in patients with terminal complement deficiencies, the relationship of chronic meningococcemia to complement deficiencies is unclear. We present a case report and a review of the literature describing chronic meningococcemia in association with deficiencies of the complement system. A total of eight cases were identified, all of whom were male. Six of the eight patients were children and two of the eight had a previous history of meningococcal disease. This case report, in conjunction with the previously reported cases, suggests an association between complement deficiencies and chronic meningococcemia.

A unique recombination event resulting in a C4A*Q0,C4B*Q0 double null haplotype.

The fourth component of complement (C4) is encoded by two closely linked genes (C4A and C4B) within the MHC. Null alleles at either locus (C4AQ0 or C4BQ0) are relatively common, occurring at the C4A locus in approximately 10% of normal individuals and at the C4B locus in approximately 16% of normal individuals. However, the presence of the double null haplotype (C4A*Q0,B*Q0) on the same chromosome is extremely rare. We recently studied a 7-yr-old patient with recurrent sinopulmonary infections in whom we documented the mechanism by which the C4A*Q0,B*Q0 double null haplotype arose. Evaluation revealed significantly reduced levels of both C4 antigen and C4 hemolytic activity. Analysis of extended haplotypes in the family was performed using MHC typing and genomic DNA analysis. The patient was found to have a C4A*3,B*Q0 haplotype and a C4A*Q0,B*Q0 haplotype. The C4A*3,B*Q0 haplotype was contributed by the father. The mother possessed a C4A*Q0,B*1 haplotype and a C4A*3,B*1 haplotype. The first maternal haplotype was involved in a recombination event within the C4B locus on her other chromosome and resulted in a new C4B*Q0 null allele and the patient's C4A*Q0,B*Q0 haplotype. Segregation analysis mapped the recombination to a region 3' to the unique 6.4-kb TaqI restriction fragment of the maternal C4B locus. This is the first demonstration of a recombination event producing a C4 double null haplotype.

Egg hypersensitivity and adverse reactions to measles, mumps, and rubella vaccine.

We evaluated the safety of the measles-mumps-rubella (MMR) combination vaccine in 140 children with egg hypersensitivity. All children, regardless of vaccine skin test results or severity of egg hypersensitivity, were safely immunized with the MMR vaccine. Systemic reactions to MMR vaccine in two nonallergic children were documented, indicating that reactions unrelated to egg protein can occur. With the use of a competitive enzyme-linked immunosorbent assay, the standard MMR injection was found to contain approximately 37 pg of ovalbumin-like material. This study provides 95% confidence that at least 97.5% of egg-allergic children will tolerate MMR vaccine without significant difficulty. Skin testing was not found to be helpful in predicting an adverse reaction. We recommend that the American Academy of Pediatrics consider revising its current policy regarding skin test response to MMR vaccine and administration of MMR vaccine to egg-allergic children.

Increased expression of the interleukin 1 receptor on blood neutrophils of humans with the sepsis syndrome.

Because of the potential importance of interleukin 1 (IL-1) in modulating inflammation and the observations that human blood neutrophils (PMN) express IL-1 receptors (IL-1R) and synthesize IL-1 alpha and IL-1 beta, we studied the IL-1R on blood PMN from a group of patients with the sepsis syndrome. We report a marked enhancement in the sites per cell of IL-1R expressed on sepsis-PMN of 25 consecutively studied patients compared to 20 controls (patient mean = 9,329 +/- 2,212 SE; control mean = 716 +/- 42 SE, respectively). There was no demonstrable difference in the Kd of IL-1R on sepsis-PMN (approximately 1 nM) as determined by saturation curves of 125I-IL-1 alpha binding and the IL-1R on sepsis-PMN had an apparent Mr approximately 68,000, a value like that of normal PMN. Cytofluorographic analysis indicated that the sepsis-PMN phenotype is a single homogeneous population with respect to IL-1R expression. In contrast, expression of the membrane complement receptor CR3 is not increased on sepsis-PMN. Similar increases in expression of IL-1R were not observed in various other inflammatory processes, including acute disseminated inflammation and organ failure not caused by infection, acute infection without organ failure, and immunopathologies such as active systemic lupus erythematosus and rheumatoid arthritis. Enhanced expression of IL-1R was not related simply to the state of myeloid stimulation. Increased expression of IL-1R on normal PMN was induced in vitro by incubating cells with recombinant human granulocyte-macrophage/colony-stimulating factor for 18 h and this response was inhibited by cycloheximide, suggesting the possibility that de novo synthesis of IL-1R might occur in PMN during the sepsis syndrome.