Letter to the editor regarding the use of intravenous immunoglobulin (IVIG) in asthma.
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Asthma↗
Biomedical subjects
C Cunningham-Rundles
Publications and source records attributed to C Cunningham-Rundles.
Sensitization to Aspergillus species in the congenital neutrophil disorders chronic granulomatous disease and hyper-IgE syndrome.
BACKGROUND: Hyper-IgE syndrome (HIE) and chronic granulomatous disease (CGD) are congenital immunodeficiency diseases with increased susceptibility to bacterial and fungal infections. Both carry significant morbidity and mortality rates because of invasive infections by Aspergillus species. We encountered 2 patients, one with HIE and one with CGD, in whom detection of sensitization to Aspergillus species preceded the diagnosis of immunodeficiency. With high-dose systemic corticosteroids for allergic bronchopulmonary aspergillosis (ABPA), an inflammatory disorder caused by sensitization to Aspergillus species, pulmonary abscesses developed in the patient with HIE, and the patient with CGD succumbed to an overwhelming Aspergillus species-induced pneumonia. OBJECTIVE: We sought to assess the prevalence of sensitization to Aspergillus fumigatus and the presence of diagnostic criteria for ABPA in patients with CGD and HIE. METHODS: We measured A fumigatus-specific serum IgE, IgG, and precipitating antibodies as indicators for A fumigatus sensitization in the sera of 18 patients with neutrophil disorders (7 with HIE and 11 with CGD). Hospital records were reviewed for the presence of other diagnostic criteria for ABPA (asthma, elevated total serum IgE concentration, and radiographic abnormalities). RESULTS: Twelve (67%) of 18 patients were sensitized to A fumigatus, as evidenced by precipitating A fumigatus-specific antibodies. Six (33%) of 18 patients had serologic evidence of ABPA. Five of those 6 patients had radiologic abnormalities consistent with a diagnosis of ABPA. One patient with HIE also had asthma, thus fulfilling minimal essential criteria for concurrent ABPA. CONCLUSIONS: Patients with HIE syndrome and CGD have a high incidence of sensitization to Aspergillus species. A clinical picture indistinguishable from ABPA may coexist or emerge in patients with CGD or HIE and create a major management dilemma because systemic corticosteroids may accelerate tissue damage and invasive fungal infections. It is important to distinguish individuals with congenital neutrophil disorders from uncomplicated classic ABPA.
Adult↗
Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism.
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Autistic Disorder↗
Treatment of idiopathic CD4 T lymphocytopenia with IL-2.
Idiopathic CD4 T lymphocytopenia (ICL) is an unusual immune defect in which there is an unexplained deficit of CD4 T cells, leading to fungal, parasitic or other serious opportunistic infections. Current treatment efforts are directed at eliminating infections. Here we describe the use of a novel treatment, subcutaneous polyethylene glycol (PEG)-IL-2 injections, in a woman with this disorder, who had chronic severe mycobacterial disease which led to repeated hospitalizations, and advancing respiratory insufficiency. For this patient, PEG-IL-2, 50 000 U/m2, has been given by weekly subcutaneous injections for 5.5 years. This treatment has resulted in marked (and still continuing) long-term immunological improvement with normalized T cell functions and increased CD4 cell numbers. She has had substantial clinical improvement with clearing of mycobacterial disease, reducing hospitalizations and improved lung functions. The improvement seen in this patient suggests that low-dose IL-2 is a safe and practical therapy, which might be useful in other subjects with this potentially serious immune defect.
Aged↗
B lymphocyte antigen D8/17 and repetitive behaviors in autism.
OBJECTIVE: Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in rheumatic fever, Sydenham's chorea, and subgroups of obsessive-compulsive disorder and Tourette's syndrome with repetitive behaviors. The authors examined the rate of D8/17 expression in children with autism and its correlation with severity of repetitive behaviors. METHOD: Blood samples from 18 patients with autism and 14 comparable medically ill children were evaluated for percentage of D8/17-positive B cells by immunofluorescence and for streptococcal antibodies. Severity of repetitive behaviors was also determined. RESULTS: The frequency of individuals with > or =11% D8/17-positive cells was significantly higher in the autistic patients (78%) than the comparison subjects (21%), severity of repetitive behaviors significantly correlated with D8/17 expression, and D8/17-positive patients had significantly higher compulsion scores than D8/17-negative patients. CONCLUSIONS: D8/17 expression is high in patients with autism and may serve as a marker for compulsion severity within autism.
Adolescent↗
Pneumocystis carinii pneumonia in a 15-year-old with chronic mucocutaneous candidiasis.
A 15-y-old male patient with chronic mucocutaneous candidiasis (CMCC) and new onset adrenal insufficiency developed Pneumocystis carinii pneumonia (PCP). The literature on infectious complications of CMCC is reviewed and clinical and laboratory characteristics of the only previously described case of PCP in CMCC are compared with those of the patient reported here.
Adolescent↗
IL-10 production in common variable immunodeficiency.
Common variable immunodeficiency, (CVI) is a heterogeneous primary immunodeficiency disease in which there are T and B cell defects. Since IL-10 in conjunction with anti-CD40 promotes secretion of IgG, IgA, and IgM by CVI B cells, these studies were performed to investigate IL-10 production in CVI. Mitogen or anti-CD3 stimulated CVI peripheral blood mononuclear cells, or isolated T cells produced an insignificant amount of IL-10 over background levels. CVI monocyte IL-10 production was substantial and greater than that of normal controls. Anti-IL-10-neutralizing antibody strongly enhanced CVI T cell proliferative responses to PHA, but only to an insignificant extent, soluble antigens. IL-2 plus anti-IL-10 enhanced CVI proliferative responses to antigens significantly more over baseline than for cells of similarly tested normal controls. These data suggest that CVI T cell secretion of IL-10 is deficient, but that monocyte-derived IL-10, plus a relative lack of IL-2 production, could contribute to the defects of cell proliferation in this disorder.
Adolescent↗
Analysis of cytokine signaling in patients with extrinsic asthma and hyperimmunoglobulin E.
BACKGROUND: Recent data suggest that the regulation of class switching to IgE by cytokines is mediated by STAT transcription factors. The induction of IgE by IL-4 and IL-13 occurs through the activation of the intracellular signal-transducing protein Stat6, whereas the inhibition of IgE class switching by interferon-y (IFN-gamma) occurs through the activation of Statl. OBJECTIVE: We hypothesized that in extrinsic asthma or in cases of markedly elevated IgE (ie, hyperimmunoglobulin E [HIE]) increased levels of IgE may be associated with alterations in the cytokine levels or the activation of Stat6. METHODS: PBMCs and sera from 8 patients with extrinsic asthma (mean IgE, 285+/-100 IU/mL), 3 patients with HIE (mean IgE, 7050+/-1122 IU/mL), and 14 nonatopic control subjects (mean IgE, 112+/-28 IU/mL) were analyzed. RESULTS: The mean IL-4 level detected by ELISA was much greater in patients with HIE than control subjects (88.6+/-11.5 pg/mL vs 11.5+/-7.1 pg/mL, P = .005), and increased IL-4 levels among patients with both asthma and HIE correlated with the increased IgE levels. In contrast, IL-13 levels were not elevated. Levels of Stat6 protein present in PBMCs did not differ in the patients and control subjects. Examination of Stat6 DNA-binding activity demonstrated no activation of IL-4 signaling in patients with either HIE or acute asthma. Interestingly, evidence for the presence of B cells that have already switched to IgE was seen in PBMCs of several patients with asthma or HIE. CONCLUSION: These results indicate that (1) IgE production in asthma and HIE usually is associated with elevated levels of IL-4, but not IL-13, in the peripheral blood; (2) the increased sera IL-4 levels in asthma and HIE are not sufficient to induce Stat6 activation in PBMCs; and (3) evidence of switch recombination to epsilon may be detected in isolated cases of elevated IgE. This implies that high levels of IgE in these patients either results from B cells that have already undergone class switching, from Ig class switching that is localized to target tissues, or both.
Adult↗
Outcome analysis and cost assessment in immunologic disorders.
A number of novel biologic agents are being introduced to replace, enhance, or modulate immune responses in medical illnesses. The use of these therapies has become crucial in treating some of these diseases, yet there is relatively little available information about their cost-effectiveness. Two examples are presented. Interferon gamma, used in chronic granulomatous disease, costs about $140 for a 100-microg vial; yearly costs average $21840 per patient. Study data estimated a 69% to 76% reduction in serious illness with interferon gamma treatment; a reduced incidence of infections could cover drug costs. Intravenous immunoglobulin is used lifelong in antibody deficiency and clearly reduces the number of serious illnesses. Projected savings derive from fewer hospital admissions and reduced organ damage, but infusion costs vary widely because of the prices charged for the drug and infusion services.
Adjuvants, Immunologic↗
Granulomatous disease in common variable immunodeficiency.
BACKGROUND: Granulomatous lesions are occasionally found in the lymphoid or solid organs of patients with common variable immunodeficiency. OBJECTIVE: To examine the clinical and immunologic conditions in patients with common variable immunodeficiency who have granulomas. DESIGN: Case series. SETTING: Large tertiary care medical center. PATIENTS: 17 hypogammaglobulinemic patients with common variable immunodeficiency whose organ or tissue biopsy samples contained noncaseating granulomas. MEASUREMENTS: Results of lymphocyte function tests. RESULTS: Eight of 17 patients had granulomas at some point before hypogammaglobulinemia was diagnosed. Sixteen of the 17 had deficient T-cell proliferation to mitogens. Although 14 patients received standard treatment with intravenous immunoglobulin, they have had substantial illness, including frequent autoimmune disease. CONCLUSIONS: Dysregulated T-cell function or macrophage activation may have been involved in formation of granulomas and increased illness in hypogammaglobulinemic patients with common variable immunodeficiency. Delay in recognition of antibody deficiency may have contributed to the severity of illness in these patients.
Adolescent↗
B-cell proliferation and differentiation in common variable immunodeficiency patients produced by an antisense oligomer to the rev gene of HIV-1.
The immunostimulatory activity of a phosphorothioate oligodeoxynucleotide (27 mer) that is antisense to the rev gene of HIV-1 was studied on normal human lymphocytes and on cells from patients with common variable immunodeficiency (CVI). For peripheral blood mononuclear cells from nine normal individuals, the proliferation index (16.8 +/- 12.5) after anti-rev oligomer exposure was proportional to the percentage of peripheral B-cells (r = 0.76, P = 0.02). In five experiments, enriched B- or T-cell populations had proliferation indices of 47.2 +/- 32.9 and 2.4 +/- 1.9, respectively. The addition of T-cells to anti-rev oligomer treated B-cells had no effect (proliferation index = 47.5 +/- 38.1). After anti-rev oligomer stimulation, autoradiography, and counterstaining for B- and T-cell markers, all detectable [3H]thymidine uptake was by CD19-positive cells. Eight of the 14 CVI patients had a proliferation index and secreted levels of IgM and IgG comparable to cells from normal individuals. In contrast to normal cells, the direct correlation between proliferation of peripheral blood mononuclear cells and the percentage of peripheral B-cells was weak in samples from 13 CVI patients (r = 0.4, P = 0.2). These findings indicate that peripheral blood B-cells from about half of CVI patients proliferate and produce immunoglobulin after exposure to anti-rev oligomer. These data demonstrate that under the appropriate circumstances, B-cells of some CVI patients can proliferate and differentiate normally.
B-Lymphocytes↗
Hodgkin's disease associated with IgA and IgG subclass deficiency.
Cases of cancer have been reported in patients with primary humoral immunodeficiency syndromes, mainly non-Hodgkin's lymphoma and gastric adenocarcinoma. Two cases of Hodgkin's disease complicating IgA and IgG subclass deficiency are reported. This association is probably more than mere coincidence. A review of the literature is presented.
Adult↗
Encephalomyelitis in primary hypogammaglobulinaemia.
The neurological features of 13 patients with primary hypogammaglobulinaemia are described. Seven patients had X-linked agammaglobulinaemia (XLA) and six had common variable immunodeficiency (CVID). Three clinical pictures emerged: (i) a progressive myelopathy (one case); (ii) a myelopathy progressing to an encephalopathy (four cases); (iii) a pure encephalopathy (eight cases). In four patients the encephalopathy was temporarily reversible; the relationship of this to immunoglobulin therapy is unclear. Additional features occurred in some patients. Three had retinopathy interpreted as retinitis pigmentosa, in one of whom the retinopathy resolved. Two patients had a sensori-neural hearing loss and three had features of dermatomyositis; a variable pleocytosis was found in the CSF of nine patients. Imaging revealed atrophic changes in the cerebral hemispheres in eight cases. Ten patients have died, 1-11 years after the onset of the CNS manifestations, and in four autopsies were obtained. Two patients had encephalopathy, one with XLA had evidence of end-stage encephalitis and the other with CVID had a multi-focal leucoencephalopathy. The other two with XLA had leptomeningitis without evidence of encephalitis. Enteroviral infection is probably an important cause of neurological disease in these patients as CSF from seven patients was either positive by polymerase chain reaction (PCR) or by culture for enteroviruses. Other possible mechanisms are discussed.
Adolescent↗
Allergy and immunology.
The actual role of cytokines in the pathogenesis of disease remains unknown but intensely investigated. Oral tolerance therapy has recently been applied to several human autoimmune diseases.
Allergy and Immunology↗
Immunologic effects of low-dose polyethylene glycol-conjugated recombinant human interleukin-2 in common variable immunodeficiency.
Children or adults with the primary immunodeficiency disease, common variable immunodeficiency (CVI), have abnormally low levels of at least two of the three serum Ig isotypes. Although there appear to be intrinsic B cell defects, many have poor T cell proliferation and deficient secretion of IL-2, IL-4, IL-5 interferon-gamma, and B cell differentiation factor. Because the addition of various T cell factors can enhance Ig secretion in vitro in CVI, we have hypothesized that the B cells in this disease may be defective because they lack appropriate investigating the in vivo effects of recombinant IL-2 using a new biologic, polyethylene glycol-conjugated recombinant IL-2 (PEG-IL-2). In these studies, CVI patients were treated with weekly subcutaneous injections of PEG-IL-2. After 12 weeks, each patient had enhanced T cell proliferation, normal IL-2 production, boosted BCDF secretion, and B cells responsive to differentiation signals. During PEG-IL-2 treatment, four of five patients produced detectable serum antibody to keyhole limpet hemocyanin. These data suggest that CVI, which has the phenotype of B cell deficiency, may be caused by a lack of appropriate T cell signals for B cell maturation.
Adolescent↗
Brief report: enhanced humoral immunity in common variable immunodeficiency after long-term treatment with polyethylene glycol-conjugated interleukin-2.
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Antibody Formation↗
Clinical and immunologic studies of common variable immunodeficiency.
Common variable immunodeficiency is a complex primary immuno-deficiency disease that has as its hallmark subnormal amounts of at least two of the three main serum immunoglobulin isotypes. About 45% of cases are diagnosed before the patients reach 21 years of age, but the time of diagnosis may be delayed until even the sixth or seventh decade of life. The main clinical manifestations include sinopulmonary or gastrointestinal infections, autoimmunity, and neoplasia. The molecular defects of this disease are unknown and may involve intrinsic B-cell or T-cell defects, or both. At present, the mainstay of treatment is intravenous immunoglobulin, but experimental methods have shown that other in vivo methods might ultimately be found to ameliorate this immune deficiency disease.
Child↗
NIH conference. New insights into common variable immunodeficiency.
Common variable immunodeficiency (CVI) is a heterogenous immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and various immunologic abnormalities. In addition to recurrent infections, patients with this syndrome also have an increased incidence of autoimmune disease and malignancy. Because the spectrum of associated diseases is broad, patients with CVI are seen by various medical specialists. This review discusses the pathogenesis, clinical manifestations, diagnosis, and treatment of CVI.
B-Lymphocytes↗