Fred S. Rosen

The Treatment of Kawasaki Syndrome with Intravenous Gamma Globulin

We compared the efficacy of intravenous gamma globulin plus aspirin with that of aspirin alone in reducing the frequency of coronary-artery abnormalities in children with acute Kawasaki syndrome in a multicenter, randomized trial. Children randomly assigned to the gamma globulin group received intravenous gamma globulin, 400 mg per kilogram of body weight per day, for four consecutive days; both treatment groups received aspirin, 100 mg per kilogram per day, through the 14th day of illness, then 3 to 5 mg per kilogram per day. Two-dimensional echocardiograms were interpreted blindly and independently by two or more readers. Two weeks after enrollment, coronary-artery abnormalities were present in 18 of 78 children (23 percent) in the aspirin group, as compared with 6 of 75 (8 percent) in the gamma globulin group (P = 0.01). Seven weeks after enrollment, abnormalities were present in 14 of 79 children (18 percent) in the aspirin group and in 3 of 79 (4 percent) in the gamma globulin group (P = 0.005). No child had serious adverse effects from receiving gamma globulin. We conclude that high-dose intravenous gamma globulin is safe and effective in reducing the prevalence of coronary-artery abnormalities when administered early in the course of Kawasaki syndrome.

A Single Intravenous Infusion of Gamma Globulin as Compared with Four Infusions in the Treatment of Acute Kawasaki Syndrome

BACKGROUND Treatment of acute Kawasaki syndrome with a four-day course of intravenous gamma globulin, together with aspirin, has been demonstrated to be safe and effective in preventing coronary-artery lesions and reducing systemic inflammation. We hypothesized that therapy with a single, very high dose of gamma globulin would be at least as effective as the standard regimen. METHODS We conducted a multicenter, randomized, controlled trial involving 549 children with acute Kawasaki syndrome. The children were assigned to receive gamma globulin either as a single infusion of 2 g per kilogram of body weight over 10 hours or as daily infusions of 400 mg per kilogram for four consecutive days. Both treatment groups received aspirin (100 mg per kilogram per day through the 14th day of illness, then 3 to 5 mg per kilogram per day). RESULTS The relative prevalence of coronary abnormalities, adjusted for age and sex, among patients treated with the four-day regimen, as compared with those treated with the single-infusion regimen, was 1.94 (95 percent confidence limits, 1.01 and 3.71) two weeks after enrollment and 1.84 (95 percent confidence limits, 0.89 and 3.82) seven weeks after enrollment. Children treated with the single-infusion regimen had lower mean temperatures while hospitalized (day 2, P less than 0.001; day 3, P = 0.004), as well as a shorter mean duration of fever (P = 0.028). Furthermore, in the single-infusion group the laboratory indexes of acute inflammation moved more rapidly toward normal, including the adjusted serum albumin level (P = 0.004), alpha 1-antitrypsin level (P = 0.007), and C-reactive protein level (P = 0.017). Lower IgG levels on day 4 were associated with a higher prevalence of coronary lesions (P = 0.005) and with a greater degree of systemic inflammation. The two groups had a similar incidence of adverse effects (including new or worsening congestive heart failure in nine children), which occurred in 2.7 percent of the children overall. All the adverse effects were transient. CONCLUSIONS In children with acute Kawasaki disease, a single large dose of intravenous gamma globulin is more effective than the conventional regimen of four smaller daily doses and is equally safe.

Defective B cell development and function in Btk-deficient mice

Mutations in the Brutons tyrosine kinase (Btk) gene have been linked to severe early B cell developmental blocks in human X-linked agammaglobulinemia (XLA), and to milder B cell activation deficiencies in murine X-linked immune deficiency (Xid). To elucidate unequivocally potential Btk functions in mice, we generated mutations in embryonic stem cells, which eliminated the ability to encode Btk pleckstrin homology or kinase domains, and assayed their effects by RAG2-deficient blastocyst complementation or introduction into the germline. Both mutations block expression of Btk protein and lead to reduced numbers of mature conventional B cells, severe B1 cell deficiency, serum IgM and IgG3 deficiency, and defective responses in vitro to various B cell activators and in vivo to immunization with thymus-independent type II antigens. These results prove that lack of Btk function results in an Xid phenotype and further suggest a differential requirement for Btk during the early stages of murine versus human B lymphocyte development.

Wiskott-Aldrich Syndrome Protein-Deficient Mice Reveal a Role for WASP in T but Not B Cell Activation

The Wiskott-Aldrich syndrome (WAS) is a human X-linked immunodeficiency resulting from mutations in a gene (WASP) encoding a cytoplasmic protein implicated in regulating the actin cytoskeleton. To elucidate WASP function, we disrupted the WASP gene in mice by gene-targeted mutation. WASP-deficient mice showed apparently normal lymphocyte development, normal serum immunoglobulin levels, and the capacity to respond to both T-dependent and T-independent type II antigens. However, these mice did have decreased peripheral blood lymphocyte and platelet numbers and developed chronic colitis. Moreover, purified WASP-deficient T cells showed markedly impaired proliferation and antigen receptor cap formation in response to anti-CD3epsilon stimulation. Yet, purified WASP-deficient B cells showed normal responses to anti-Ig stimulation. We discuss the implications of our findings regarding WASP function in receptor signaling and cytoskeletal reorganization in T and B cells and compare the effects of WASP deficiency in mice and humans.

The Gamma Globulins

IN 1952 Bruton reported the remarkable finding of the absence of gamma globulin from the serum of an eight-year boy who had been followed for a number of years in the pediatric section of the Walte...

Hereditary Angioneurotic Edema: Two Genetic Variants

Serums of patients with hereditary angioneurotic edema lack inhibitory activity against the esterase derived from the first component of complement. In one group of patients this lack appears to result from failure to synthesize the esterase inhibitor of the first component of complement, whereas in another group of patients an abnormal, nonfunctional protein is synthesized.

N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility.

The Wiskott–Aldrich syndrome protein (WASP) family of molecules integrates upstream signalling events with changes in the actin cytoskeleton. N-WASP has been implicated both in the formation of cell-surface projections (filopodia) required for cell movement and in the actin-based motility of intracellular pathogens. To examine N-WASP function we have used homologous recombination to inactivate the gene encoding murine N-WASP. Whereas N-WASP-deficient embryos survive beyond gastrulation and initiate organogenesis, they have marked developmental delay and die before embryonic day 12. N-WASP is not required for the actin-based movement of the intracellular pathogen Listeria but is absolutely required for the motility of Shigella and vaccinia virus. Despite these distinct defects in bacterial and viral motility, N-WASP-deficient fibroblasts spread by using lamellipodia and can protrude filopodia. These results imply a crucial and non-redundant role for N-WASP in murine embryogenesis and in the actin-based motility of certain pathogens but not in the general formation of actin-containing structures.

Treatment of Hereditary Angioedema with a Vapor-Heated C1 Inhibitor Concentrate

BACKGROUND Hereditary angioedema results from a congenital deficiency of functional C1 inhibitor and is characterized by episodic bouts of edema, which may be life-threatening when they involve the larynx. We evaluated the effectiveness of a C1 inhibitor concentrate in the prevention and treatment of attacks of hereditary angioedema. The concentrate was vapor-heated to inactivate hepatitis and human immunodeficiency viruses. METHODS We conducted two double-blind, placebo-controlled studies. The first was a crossover study consisting of two 17-day trials in which prophylactic infusions of either C1 inhibitor (25 plasma units per kilogram of body weight) or placebo were given intravenously every third day to six patients with hereditary angioedema. The second study was conducted in patients with acute attacks of hereditary angioedema and assessed the length of time to a clinical response after infusions of either 25 plasma units of C1 inhibitor per kilogram (55 infusions in 11 patients) or placebo (49 infusions in 11 patients). RESULTS The infusions of C1 inhibitor concentrate resulted in close to normal functional levels of C1 inhibitor and C4. As compared with placebo, prophylactic infusions of C1 inhibitor resulted in significantly lower daily symptom scores for the severity of edema of the extremities (P<0.01), larynx (P<0.05), abdomen (P<0.05), and genitourinary tract (P<0.05). Likewise, during the treatment study the time from the start of an infusion to the beginning of improvement in symptoms was shorter for the C1 inhibitor infusions than the placebo infusions (55 vs. 563 minutes, P<0.001). There was no evidence of toxicity. CONCLUSIONS Infusions of a vapor-heated C1 inhibitor concentrate are a safe and effective means of both preventing attacks of hereditary angioedema and treating acute attacks.

Increased Susceptibility to Infection Associated with Abnormalities of Complement-Mediated Functions and of the Third Component of Complement (C3)

Abstract In a patient with Klinefelters syndrome and lifelong increased susceptibility to infection, no abnormalities were found in humoral antibody production, cellular immunity or leukocyte function. In contrast, the patients serum complement-mediated functions were grossly deficient. The concentrations of serum complement components were normal except for that of C3 (β1C-globulin), which was less than one-third normal. The bulk of this was in the form of the inactive conversion product, C3b, at all times that the patients serum or plasma was examined over a two-year period. Addition of small amounts of normal serum, but not purified C3, to the patients serum improved all complement-mediated functions in vitro. This disorder, which may represent an inborn deficiency of a protein necessary for C3 stability in vivo and in vitro, is detected by the lowered serum C3 concentration and a positive non-gamma (C3) Coombs antiglobulin test.

Aberrations of Suppressor T Cells in Human Graft-versus-Host Disease

To determine whether imbalances in immunoregulatory T-cell subsets exist in patients with graft-versus-host disease, we analyzed T cells in three patients with acute and in six patients with chronic graft-versus-host disease after bone-marrow transplantation. The normal human peripheral-blood T-cell compartment is composed of 80 per cent TH2-and 20 per cent TH2+ T cells, and defined by reactivity with subset-specific heteroantiserums. Human suppressor cells are TH2+, whereas helper cells are TH2-. Patients with acute and chronic graft-versus-host disease had abnormalities in these populations, and their T cells frequently bore la-like antigens. Patients with acute disease lacked TH2+ cells, and the reappearance of this subset preceded the cessation of disease activity. Chronic disease, in contrast, was more heterogeneous. Suppressor cells were lacking in two patients but increased in the other four. Two of these four patients had TH2+, la+ T cells, suggesting in vivo activation of suppressor cells. Studies showing that these TH2+, la+ cells actively suppressed the in vitro immune response support this hypothesis and suggest that the immunoregulatory cells may profoundly affect the overall immune response.