Impact of a pediatric asthma clinical pathway on hospital cost and length of stay.

This study sought to determine if a clinical pathway developed and executed by specialists in pediatric asthma would reduce hospital costs and length of stay (LOS). The study design was a retrospective, nonrandomized, controlled trial. Subjects were children aged 2-18 years (N = 1,004) with a history of recurrent wheezing, hospitalized with a diagnosis of acute asthma exacerbation between 1995-1998 at the New York Hospital-Weill Cornell Medical Center and treated via the pathway, as well as a control group of 206 children ages 2-18 hospitalized for acute asthma exacerbation in 1994, the year prior to pathway implementation. Patients were treated via the pathway under the supervision of an asthma specialist. The pathway provided guidelines for: 1) frequency of patient assessment; 2) bronchodilator usage; 3) corticosteroid use; 4) laboratory evaluation; 5) vital signs, oxygen saturation, and peak flow measurements; 6) chest x-rays; 7) social work intervention; and 8) discharge planning. The main outcome measures were hospital length of stay, cost per hospitalization, nursing, medication, laboratory and radiology costs, and relapse rate. Total charges for admission and average LOS for 1995-1998 were calculated, and compared with 1994, the year preceding implementation of the pathway. LOS decreased from 4.2 days to 2.7 days (P < 0.0001). The annual total charges for pediatric asthma admissions decreased from 2 million dollars to 1.4 million dollars (P < 0.005). Nursing and laboratory costs showed a statistically significant decrease. Follow-up study at 8 months showed a readmission rate of 0.02%. The implementation of a pediatric asthma clinical pathway, directed by specialists, resulted in significantly decreased length of stay and overall cost, without an increased rate of readmission.

Childhood asthma: causes, epidemiological factors and complications.

Asthma is common in children and its prevalence in this age group is increasing. While the reasons for this reported increase, and indeed the true magnitude of the increase, remain unclear, there can be no doubt that asthma is now a major health problem in children worldwide. Fortunately, our knowledge of the pathophysiology of asthma is also increasing. It is now known that asthma is a chronic inflammatory disease regulated by a variety of mediators, of which perhaps the leukotrienes are among the most important. This new understanding of the pathophysiology of the disease has spurred the development of the antileukotriene agents, which can be expected to play an increasingly important role in the management of childhood asthma.

A multicenter, randomized, double-blind, placebo-controlled trial of high-dose intravenous immunoglobulin for oral corticosteroid-dependent asthma.

To determine the efficacy of high doses of intravenous gammaglobulin (IVIG) for the treatment of severe, steroid-dependent asthma in patients between 6 and 68 years of age, a randomized, double-blind, placebo-controlled multicenter clinical trial was conducted in private and university hospitals in the United States. Patients were randomized to one of three treatment arms: 2 g IVIG/kg/month (16 patients); 1 g IVIG/kg/month (9 patients); or 2 g iv albumin (placebo)/kg/month (15 patients). The treatment consisted of seven monthly infusions followed by a posttreatment observation period. The primary outcome measurement was mean daily prednisone-equivalent dose requirements, determined during the observation month preceding initiation of treatment and compared to the month preceding the seventh infusion. Secondary clinical endpoints measured were pulmonary function, frequency of emergency room visits or hospitalizations, and number of days absent from school or work. When adjusted for body weight, the mean dose requirements fell by 33, 39, and 33% in the placebo, IVIG (1 g/kg), and IVIG (2 g/kg) treatment arms, respectively. The differences between therapies were not statistically different (P = 0.9728). The mean percentage-of-predicted FEV1 fell in all three treatment groups during the treatment period but there was no significant difference between treatment groups (P = 0.8291). There was also no significant difference in the percentage of subjects requiring emergency room visits or hospitalizations or missing days of work/school, among the three treatment groups. The trial was terminated prematurely after interim analysis determined the adverse experience rate was different between the three groups. Three patients, all randomized to the 2-g/kg IVIG dose group, were hospitalized with symptoms consistent with aseptic meningitis. In summary, in this randomized, double-blind, placebo-controlled multicenter study, high doses of IVIG did not demonstrate a clinically or statistically significant advantage over placebo (albumin) infusions for the treatment of corticosteroid-dependent asthma. Subgroup analysis failed to identify markers predicting responsiveness. High-dose IVIG can also be associated with a significant incidence of serious adverse events.

New treatments for asthma: the role of leukotriene modifier agents.

The three leukotriene (LT) modifiers approved for use in the United States, zileuton, zafirlukast, and montelukast, are the first new class of therapeutic agents to be introduced in 20 years for the treatment of asthma. These agents are referred to as leukotriene modifiers and have clearly demonstrated the ability to ameliorate bronchoconstriction and indices of airway edema and abnormal mucus production as observed in clinical trials. These agents have been shown to improve airflow, reduce the need for an inhaled bronchodilator, and improve nocturnal awakenings and asthma symptom scores appreciably. When combined with inhaled corticosteroid therapy, they may either provide additional improvement in efficacy or permit the reduction of the dose of inhaled corticosteroid necessary for effective therapy. Physicians should be familiar with these agents and consider them for use in their practice, in conjunction with current asthma management guidelines.

New perspectives on use of thymic factors in immune deficiency.

Current knowledge on the role of thymic factors in the immune response is inadequate and remains relatively primitive when compared with present technical possibilities for assessing lymphocyte subsets or cytokine interaction. New studies support the potential importance of thymic factors as regulators of immune interactions. Indirect evidence supports the concept that thymic factors may work at the level of IL-2. The functional identity of cells responsive to thymic factors and the relation of observed effects to cytokine network interactions need to be established. The use of thymic factors in the future will depend on the development of criteria to identify appropriate settings in which to use such factors and the implementation of appropriate measures of immune functional response.

Aminophylline therapy does not improve outcome and increases adverse effects in children hospitalized with acute asthmatic exacerbations.

OBJECTIVE: To evaluate the effects of aminophylline (Am) in children hospitalized with asthma. METHODS: Prospective, randomized, double-blind, placebo-controlled trial. Subjects were children between the ages of 5 and 18 years admitted for asthma exacerbation to either a tertiary care children's hospital or an inner-city general hospital in New York. Exclusion criteria were admission to the intensive care unit, initial theophylline level > 5 micrograms/dL, or the presence of other systemic disorders. All patients received nebulized albuterol therapy and intravenous glucocorticosteroids in standardized doses. Thirty-one patients were randomized to receive either an Am bolus followed by continuous Am infusion or placebo (P) bolus and infusion. The outcome variables were: duration of hospitalization, percent of predicted peak expiratory flow rates recorded at 12-hour intervals, number of albuterol treatments required, and adverse effects. RESULTS: There were no significant differences at study entry in age, sex, race, number of previous hospital admissions, prior medications used, clinical symptom scores, or initial peak flow rates for the two groups. For 26 patients who completed this study, 15 patients in the P group were hospitalized for a mean duration of 2.33 +/- 1.3 days, whereas 11 patients in the Am group required 2.58 +/- 1.5 days. There were no significant differences between the two groups for hospital days, peak flow rates at any time interval, or amount of albuterol therapy required (P > .2). In the Am group, 6 of the 14 patients who entered the study experienced significant adverse effects consisting of nausea, emesis, headache, abdominal pain, and palpitations. Only 1 of 17 patients in the P group had an adverse effect (P < .05). CONCLUSIONS: There is no benefit and considerable risk of adverse effects associated with the use of Am in hospitalized asthmatic children.

Identification of anti-idiotypic antibodies in the sera of ryegrass-allergic and nonallergic individuals.

Anti-idiotypic (Id) antibodies (Abs) are generated in the humoral response to antigen (Ag). Some of these anti-Id Abs are capable of binding to the combining site or paratope of Abs that bind Ag. These Ab2 can competitively inhibit the binding of Ab1 to Ag may trigger an Ab1 response similar to the response induced by Ag. To determine if specific Ab2 that inhibit the binding of IgE Abs to ryegrass (RG)-pollen allergens are present in the sera of RG-allergic (RGA) individuals before the initiation of allergen-specific hyposensitization with RG-pollen extract, we studied sera from five RGA and four nonallergic (NA) subjects in an IgE anti-RG RAST-inhibition assay. Ab2-enriched serum fractions were prepared from these study subjects by exhaustive mixed grass-pollen affinity chromatography to remove IgE and IgG anti-RG Ab1 from whole serum aliquots containing Ab1. Unabsorbed, twice-concentrated sera were diluted to one-time concentrated sera with equal volumes of either Ab2-enriched sera without Ab1 or borate-buffered saline absorbed by mixed grass-pollen affinity chromatography. IgE anti-RG Ab1 was determined by a standard RG RAST assay. We have detected Ab2 in the sera of the RGA patients, which inhibit the binding of autologous and allogeneic IgE anti-RG to RG Ags in solid phase. Parallel RG RAST assays with sera from NA subjects demonstrated no significant inhibition. Ab2-enriched sera from some grass-allergic and some NA subjects inhibited IgE anti-RG binding found in some RGA patients' sera. We conclude that anti-Id Abs, Ab2, specific for IgE anti-RG, Ab1, are present in some RGA patients and NA individuals.

Expression of the major rheumatoid factor cross-reactive idiotype in pediatric patients with systemic lupus erythematosus.

Rheumatoid factor cross-reactive idiotype (RF-CRI) is expressed in high concentrations in the sera of some patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). To determine if RF-CRI is specifically expressed in rheumatic disease or if it is secondary to polyclonal B-cell activation, we examined sera of 23 children with SLE, 16 adolescents with infectious mononucleosis (IM), and age-matched pediatric controls for RF-CRI expression. Concentrations of RF-CRI in serum, determined by an inhibition ELISA, were 24 +/- 17 micrograms/ml (mean +/- SD) in 25 normal children, 31 +/- 17 in 16 young adults with IM, and were significantly increased, 70 +/- 80 micrograms/ml, in the 23 children with SLE (p less than 0.036). Eleven of 23 SLE patients had serum RF-CRI greater than the mean +/- 2 SD for normal children. Ten of 23 SLE sera contained IgM rheumatoid factor (RF) activity. One patient with IM had a borderline elevated RF-CRI level, and 5 IM patients had RF in their sera. The serum IgM concentrations in sera were: SLE (192 +/- 93 mg/dl) and IM (234 +/- 77 mg/dl) sera. These levels were significantly elevated compared to controls (132 +/- 44 mg/dl), p less than 0.031 for SLE and p less than 0.001 for IM, suggesting that polyclonal activation of B cells was present in SLE and IM patient groups. Increased expression of RF-CRI in the SLE patients correlated directly with high titer anti-DNA antibody values (r = 0.3965, p less than 0.05) and RF activity when human IgG (r = 0.5026, p less than 0.05) was used as the RF binding substrate and inversely with serum C3 levels (r = 0.3925, p less than 0.05). RF-CRI expression did not correlate with RF that bound rabbit (r = 0.3123, p greater than 0.05). Increased serum RF-CRI expression is not a result of polyclonal B-cell activation. RF-CRI may be selectively up-regulated in patients with SLE.

The major rheumatoid factor crossreactive idiotype and IgA rheumatoid factor in juvenile rheumatoid arthritis.

One third of patients with juvenile rheumatoid arthritis (JRA) are seronegative for classic or hidden IgM rheumatoid factor (RF) yet express the major RF crossreactive idiotype (RCRI). We studied 60 children with JRA and 57 pediatric controls for IgA RF and RCRI expression to determine whether RCRI is associated with IgA RF in JRA. Twenty-one patients had IgA RF using rabbit or human IgG as substrate. Twenty-seven patients with JRA expressed high concentrations of RCRI in their sera. Only 9 of these had IgA RF. Eleven of the RCRI+ sera contained neither IgA RF nor classic or hidden IgM RF, and IgA RF was found in patients with all JRA onset subtypes. In JRA, RCRI may be expressed on either IgG RF or on parallel set antibodies without RF activity.

Severe chronic EBV infection associated with specific EBV immunodeficiency and an EBNA+ T-cell lymphoma containing linear, EBV DNA.

A patient with severe chronic Epstein-Barr virus (EBV) infection (CEBVI) of 6 years duration developed an EBV+ T-cell lymphoma. To determine whether the development of the T-cell tumor was linked to EBV, we studied this patient's EBV-specific immune response and her T-cell tumor tissue for evidence of EBV infection. Peripheral blood lymphocytes from this patient were systematically studied for immune function and response to EBV. Tumor tissue was examined for EBV genome and for evidence of EBV replication. This patient failed to develop anti-EBV nuclear antigen (EBNA) antibodies and had decreased mitogen responsiveness. Her T-cells showed a broad suppression of both autologous and allogeneic B-cells, which was coincident with clinical hypoimmunoglobulinemia. A selective cytotoxic T-cell defect toward autologous EBV-infected B lymphoblasts, which could not be corrected by the addition of lymphokine-mediated T-cell help, was also documented. A lymph node biopsy taken 5 years after her clinical presentation revealed lymph node architecture completely effaced by a diffuse CD3+, CD4+, Ia+, CR2+ T-cell lymphoma containing EBNA and linear, replicating EBV DNA. Select CEBVI patients with humoral and combined cellular aberrations in the immune response to EBV may be predisposed to the development of EBV+ T-cell tumors.

Burkitt's lymphoma in a patient with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) appear to be at increased risk for development of neoplastic disease. We describe the case of a male teenager with SLE and Burkitt's lymphoma. His presentation was similar to that of an exacerbation of his underlying SLE. We believe this to be the first case of Burkitt's lymphoma in a patient with SLE. The association of SLE and malignancy, with emphasis on lymphoproliferative states, is discussed.

Common variable hypogammaglobulinemia, recurrent Pneumocystis carinii pneumonia on intravenous gamma-globulin therapy, and natural killer deficiency.

A toddler with common variable hypoimmunoglobulinemia (CVH), inflammatory bowel disease, and recurrent Pneumocystis carinii pneumonia (PCP) on intravenous gammaglobulin (IVIG) replacement was evaluated for a combined cellular immunodeficiency. He had a normal number of circulating T-cells, natural killer (NK) cells, T-cell subset percentages, and his peripheral blood mononuclear (PBM)-derived B-cell number was low. PBM mitogen blastogenesis and mixed lymphocyte reaction (MLR) were normal. MLR activated T-cells expressed class I and II MHC antigens, interleukin 2 (IL-2), and B-cell growth factor (IL-5)-related receptors. The patient's T-cells induced control B-cell maturation with pokeweed mitogen (PWM-PC), and did not suppress PWM-PC production by allogeneic PBM. Bone marrow (BM) CD19+ B-cell number varied between 10 and 44% of all PBM, and the BM B-cell-enriched fraction failed to differentiate to PWM-PC with autologous or allogeneic T-cell help. The NK activity assayed using K562 target cells was deficient, 9.2 x 7.7% (6.9-9.2%) pt, control 35.9 x 35.8% (16.3-67.2% +/- 12.8). In the presence of interferon-alpha, 800 U/ml, the patient's NK activity increased to 17.2 x 14.9% (12.6-17.2%), control 35.9 x 51.0% (36.5-72.3% +/- 12.0). The patient's cell-mediated lympholysis of HLA nonidentical, allogeneic stimulators was normal. Maintaining trough serum IgG levels above 500 mg/dl was required to suppress recurrent PCP. This functional NK deficiency may be relevant to the development of recurrent PCP in IVIG-treated CVH patients.

Mucha-Habermann's disease and arthritis: possible association with reactivated Epstein-Barr virus infection.

We present a 12-year-old girl with skin lesions, arthritis and clinical response to tetracycline consistent with Mucha-Habermann's disease. She also showed serological evidence of reactivated Epstein-Barr virus (EBV) infection. We believe this represents the first such association of Mucha-Habermann's disease with EBV infection.

Detection of the major rheumatoid factor cross-reactive idiotype precedes human IgG binding activity in a patient with polyarticular juvenile rheumatoid arthritis.

A patient with polyarthritis and subcutaneous nodules was studied for expression of rheumatoid factors (RF) by numerous techniques for 5 months after presentation. Assays for RF binding human or rabbit IgG in whole sera, assays for hidden RF binding human or rabbit IgG, and assays for expression of the major RF cross-reactive idiotype (RCRI) in whole sera or by pokeweed mitogen induced plasma cells were performed (PWM-PC). In this patient, increased expression of RCRI in sera and among PWM-PC preceded detectable RF binding human IgG, and paralleled hidden RF and RF binding rabbit IgG expression.

Abnormal responses to aspirin of leukocyte oxygenation of arachidonic acid in adults with aspirin intolerance.

The effect of 1 microM and 5 microM aspirin on oxygenation of arachidonic acid in vitro by basophils stimulated with anti-IgE was assessed with basophil-enriched suspensions of mononuclear leukocytes from five patients with asthma and hypertrophic allergic rhinitis and one patient with rhinitis alone who had recent adverse pulmonary reactions to aspirin, four aspirin-tolerant patients with asthma receiving therapy similar to that of the aspirin-sensitive patients, and eight normal subjects who resembled the patients with respect to sex and age. As quantified by the combined application of high-performance liquid chromatography and radioimmunoassays, the generation of the principal products prostaglandin E2 (PGE2) and leukotriene D4 was modified differently by aspirin but not sodium salicylate in the aspirin-sensitive patients. The alterations of PGE2 generation and of the ratio of leukotriene D4 to PGE2 generation by aspirin were much greater for basophil-containing leukocytes of aspirin-sensitive patients than those of the two control groups. Although the basic mechanism and relevance to pulmonary reactions of the observed effects of aspirin were not elucidated, aspirin clearly modifies the leukocyte oxygenation of arachidonic acid differently in aspirin-sensitive patients.