Sunday Clark

Human recombinant granulocyte-macrophage colony-stimulating factor increases cell-to-cell adhesion and surface expression of adhesion-promoting surface glycoproteins on mature granulocytes.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to inhibit migration of mature granulocytes and to enhance their antibody-dependent cellular cytotoxicity. We found that human recombinant GM-CSF also enhanced granulocyte-granulocyte adhesion and increased by two- to threefold the surface expression of Mo1 and LeuM5 (P150, 95), two members of a family of leukocyte adhesion molecules (Leu-CAM). Increased Mo1 surface expression occurred within 15 min at 37 degrees C and was maximal at the migration inhibitory concentration of 500 pM. One-half maximal rise in the expression of Mo1 on the cell surface occurred at 5 pM. The chemotactic peptide f-Met-Leu-Phe produced a comparable rise in surface Mo1 with one-half maximal expression occurring at 7 nM. Both GM-CSF and f-Met-Leu-Phe produced optimal granulocyte-granulocyte adhesion at 500 pM and 100 nM, respectively. This adhesion-promoting effect induced by either stimulus was inhibited by a mouse monoclonal antibody directed against Mo1 antigen. These data indicate that GM-CSF promotes cell-to-cell adhesion, presumably through enhanced expression of leukocyte adhesion molecules. This mechanism may explain, in part, the known effects of GM-CSF on the function of mature granulocytes.

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) shortens the period of neutropenia after autologous bone marrow transplantation in a primate model.

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hematopoietic reconstitution after autologous bone marrow transplantation was evaluated in a primate model. Animals were given a continuous intravenous infusion of recombinant human GM-CSF for several days both before and after transplantation or only after the transplant procedure. Marrow ablation was accomplished by total body irradiation. In both groups of animals, the neutrophil count reached 1,000/mm3 by 8-9 d posttransplant compared with an interval of 17 and 24 d for two concurrent controls. After withdrawal of GM-CSF, neutrophil counts fell to values comparable to those observed in untreated controls. Accelerated recovery of platelet production was also observed in four of the five animals. Two additional animals were initially given GM-CSF several weeks posttransplantation because of inadequate engraftment. Prompt and sustained increases in neutrophil and platelet counts were observed. We conclude that GM-CSF may be useful in accelerating bone marrow reconstitution.

Human recombinant granulocyte-macrophage colony stimulating factor and interleukin 3 have overlapping but distinct hematopoietic activities.

The hematopoietic stimulatory activities of human recombinant IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF) were directly compared using highly enriched human bone marrow progenitor target cells. IL-3 supported a larger number of erythroid and megakaryocytic progenitor cells than did GM-CSF, while GM-CSF supported more myeloid progenitors. IL-3 directly stimulated the division and migration of primitive erythroid burst forming units, while GM-CSF merely sustained their net survival in culture without promoting division and expansion. IL-3 promoted the formation of larger numbers of multipotential granulocyte-erythroid-macrophage-megakaryocyte colony forming unit--derived colonies than did GM-CSF. These data indicate that human IL-3 and GM-CSF have overlapping but distinct hematopoietic activities, and suggest a potential role for the clinical application of combined IL-3/GM-CSF therapy.

Multicenter study of patients with angiotensin- converting enzyme inhibitor-induced angioedema who present to the emergency department

BACKGROUND Recent data are lacking about the number of patients with angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema who present to the emergency department (ED). Current management of the condition and clinical outcomes also are not known. OBJECTIVE To describe the clinical epidemiology of ACEI-induced angioedema in patients who present to the ED. METHODS We performed a medical record review of ACEI-induced angioedema in patients who presented to 5 EDs in the Emergency Medicine Network. A structured data abstraction form was used to collect each patients demographic factors, medical history, and details about the angioedema that prompted the ED visit. The medical record review also focused on treatment provided in the ED and subsequent need for hospitalization. RESULTS We identified a total of 220 patients with ACEI-induced angioedema. The frequency of ACEI-induced angioedema among all patients with angioedema who presented to the ED was 30% (95% confidence interval, 26%-34%). The annual rate of visits for ACEI-induced angioedema was 0.7 per 10,000 ED visits. The most frequent presenting signs were shortness of breath, lip and tongue swelling, and laryngeal edema. Most patients (58%) were sent home directly from the ED, whereas 12% were regular inpatient admissions, 11% were admitted to the intensive care unit, and 18% were admitted under observation status (<24 hours). Pharyngeal swelling and respiratory distress were independent predictors of hospital admission and longer length of stay. CONCLUSION ACEI-induced angioedema accounted for almost one-third of angioedema treated in the ED, although it remains a rare ED presentation. A subgroup of these patients still needs inpatient hospitalization for management of upper airway angioedema.

Stimulation of human hematopoietic colony formation by recombinant gibbon multi-colony-stimulating factor or interleukin 3

Recently, the gene for a novel mammalian hematopoietic growth factor homologous to murine interleukin 3 was isolated from a gibbon T cell line and expressed in monkey COS cells. The factor, termed multi-colony stimulating factor (multi-CSF) or interleukin 3, is stimulatory to human target cells. We investigated the range of enriched human bone marrow and fetal liver hematopoietic progenitors responsive to multi-CSF; compared the colony types observed with those obtained in the presence of recombinant granulocyte-macrophage CSF (GM-CSF); and analyzed the effects on colony formation of combining multi-CSF with GM-CSF or granulocyte-CSF (G-CSF). The results show that multi-CSF acts as a multipoietin. Alone it stimulates the formation of colonies derived from granulocyte, macrophage, eosinophil, and megakaryocyte progenitors. In combination with erythropoietin it supports the development of both erythroid and mixed colonies. Furthermore, the data show that multi-CSF is a more potent stimulus of erythroid progenitors than GM-CSF. In combination with G-CSF multi-CSF substantially increases granulocyte colony number over the number obtained with each factor alone. We conclude that multi-CSF may prove to have important therapeutic potential in vivo as a stimulus for hematopoiesis.

Prospective Multicenter Study of the Viral Etiology of Bronchiolitis in the Emergency Department

Abstract Objectives:  To determine the viral etiology of bronchiolitis and clinical characteristics of children age < 2 years presenting to the emergency department (ED) with bronchiolitis. Methods:  The authors conducted a 14‐center prospective cohort study during 2005–2006 of ED patients age < 2 years with bronchiolitis. The study was conducted in 10 states as part of the Emergency Medicine Network. Researchers collected nasopharyngeal aspirates and conducted structured interviews, medical record reviews, and 2‐week follow‐up telephone calls. Samples were tested using reverse transcription polymerase chain reaction for respiratory syncytial virus (RSV), rhinovirus (RV), human metapneumovirus (hMPV), and influenza viruses (Flu). Results:  Testing of 277 samples revealed 176 (64%) positive for RSV, 44 (16%) for RV, 26 (9%) for hMPV, 17 (6%) for Flu A, and none for Flu B. When children were categorized as RSV only, RV only, RV and RSV, and all others (hMPV, Flu, no identified virus), children with RV only were more likely to be African American (19, 62, 14, and 40%, respectively; p < 0.001) and have a history of wheezing (23, 52, 21, and 15%, respectively; p = 0.01). In multivariate models, children with RV were more likely to receive corticosteroids (odds ratio [OR] 3.5; 95% confidence interval [CI] = 1.5 to 8.15). The duration of illness may be shorter for children with RV (Days 8, 3, 6, and 8; p = 0.07). Conclusions:  In this multicenter study, RSV was the most frequent cause of bronchiolitis (64%). RV was present in 16%, and these children have a distinct profile in terms of demographics, medical history, and ED treatment.

National study of US emergency department visits for acute allergic reactions, 1993 to 2004

BACKGROUND The clinical epidemiology of acute allergic reactions in the emergency department (ED) is uncertain. OBJECTIVES To characterize ED visits for acute allergic reactions and to evaluate national trends in ED management. METHODS The National Hospital Ambulatory Medical Care Survey was used to identify a nationally representative sample of ED visits between 1993 and 2004. Cases with a diagnosis of acute allergic reaction were identified by International Classification of Diseases, Ninth Revision (ICD-9) codes (9950, 9951, 9952, 9953, 9956). RESULTS A total of 12.4 million allergy-related ED visits occurred from 1993 to 2004, representing 1.0% (95% confidence interval, 0.93%-1.10%) of all ED visits or 1.03 million ED visits per year. The number of allergy-related ED visits remained relatively stable, averaging 3.8 per 1,000 US population per year (95% confidence interval, 3.4-4.1; P for trend = .39). Although 63% of all visits were coded as urgent, only 4% required hospitalization. Anaphylaxis coding was rare (1%). ED staff prescribed medications in 87% of visits, especially histamine, blockers (62%; P for trend = .29). Increases were noted from 1993 to 2004 for corticosteroids (22% to 50%; P < .001), histamine2 blockers (7% to 18%; P < .001), and inhaled beta-agonists (2% to 6%; P = .008). Epinephrine use was infrequent and declining (19% to 7%; P = .04). CONCLUSION Between 1993 and 2004, significant variability has occurred in ED management of acute allergic reactions.

Regional variation in epinephrine autoinjector prescriptions in Australia: more evidence for the vitamin D-anaphylaxis hypothesis.

BACKGROUND There is little information on the regional distribution of anaphylaxis in Australia. OBJECTIVE To examine the influence of latitude (a marker of sunlight/vitamin D status) as a contributor to anaphylaxis in Australia, with a focus on children from birth to the age of 4 years. METHODS Epinephrine autoinjector (EpiPen) prescriptions (2006-2007) in 59 statistical divisions and anaphylaxis hospital admission rates (2002-2007) in 10 regions were used as surrogate markers of anaphylaxis. RESULTS EpiPen prescription rates (per 100,000 population per year) were higher in children from birth to the age of 4 years (mean, 951) than in the overall population (mean, 324). In an unadjusted model of children from birth to the age of 4 years, decreasing absolute latitude was associated with a decrease in EpiPen prescription rates, such that rates were higher in southern compared with northern regions of Australia (beta, -44.4; 95% confidence interval, -57.0 to -31.8; P < .001). Adjusting for age, sex, ethnicity, indexes of affluence, education, or access to medical care (general, specialist allergy, or pediatric) did not attenuate the finding (beta, -51.9; 95% confidence interval, -71.0 to -32.9; P < .001). Although statistical power was limited, anaphylaxis admission rates (most prominent in children aged 0-4 years) showed a similar south-north gradient, such that admission rates were higher in southern compared with northern regions of Australia. CONCLUSIONS EpiPen prescription rates and anaphylaxis admissions are more common in southern regions of Australia. These data provide additional support for a possible role of vitamin D in the pathogenesis of anaphylaxis.

Anaphylaxis in the community: Learning from the survivors

BACKGROUND Most studies of anaphylaxis in the community focus on persons at risk who might, or might not, have experienced anaphylaxis. OBJECTIVE We sought to focus on survivors of anaphylaxis in the community and their experiences in using, or not using, an epinephrine autoinjector for first-aid treatment. METHODS An e-mail survey was conducted. Responses were anonymous and could not be traced to any person or location. Anaphylaxis was defined as the most severe sudden-onset allergic reaction ever experienced by the participants or a person for whom they were responsible (eg, a child). There were 17 core multiple-choice questions for all participants, with 16 additional questions for users who injected epinephrine either into themselves or someone else, and 1 additional question for nonusers. RESULTS Of the 1885 participants, 500 (27%) were epinephrine users, and 1385 (73%) were nonusers. The groups were similar with regard to multisystem organ involvement (82% vs 78%, P = .07) and many other aspects of anaphylaxis; however, epinephrine users were more likely (all P < .05) to report respiratory or shock symptoms; to report peanut, fish, or insect sting triggers; to be asthmatic; and to have taken or been given asthma medication on the day of the episode. Epinephrine users reported problems in deciding whether to give the injection, repeat the dose, and/or go to an emergency department. Nonusers reported not injecting epinephrine for various reasons, including use of an H(1)-antihistamine (38%), no prescription for epinephrine (28%), and/or a mild anaphylaxis episode (13%). CONCLUSIONS In a unique population composed of 1885 survivors of anaphylaxis in the community, users of epinephrine autoinjectors for first-aid treatment were outnumbered by nonusers. The insights reported by epinephrine users and the reasons why nonusers did not inject epinephrine are documented.

Multicenter Study of Repeat Epinephrine Treatments for Food-Related Anaphylaxis

OBJECTIVE: We sought to establish the frequency of receiving >1 dose of epinephrine in children who present to the emergency department (ED) with food-related anaphylaxis. PATIENTS AND METHODS: We performed a medical chart review at Boston hospitals of all children presenting to the ED for food-related acute allergic reactions between January 1, 2001, and December 31, 2006. We focused on causative foods, clinical presentations, and emergency treatments. RESULTS: Through random sampling and appropriate weighting, the 605 reviewed cases represented a study cohort of 1255 patients. These patients had a median age of 5.8 years (95% confidence interval [CI]: 5.3–6.3), and the cohort was 62% male. A variety of foods provoked the allergic reactions, including peanuts (23%), tree nuts (18%), and milk (15%). Approximately half (52% [95% CI: 48–57]) of the children met diagnostic criteria for food-related anaphylaxis. Among those with anaphylaxis, 31% received 1 dose and 3% received >1 dose of epinephrine before their arrival to the ED. In the ED, patients with anaphylaxis received antihistamines (59%), corticosteroids (57%), epinephrine (20%). Over the course of their reaction, 44% of patients with food-related anaphylaxis received epinephrine, and among this subset of patients, 12% (95% CI: 9–14) received >1 dose. Risk factors for repeat epinephrine use included older age and transfer from an outside hospital. Most patients (88%) were discharged from the hospital. On ED discharge, 43% were prescribed self-injectable epinephrine, and only 22% were referred to an allergist. CONCLUSIONS: Among children with food-related anaphylaxis who received epinephrine, 12% received a second dose. Results of this study support the recommendation that children at risk for food-related anaphylaxis carry 2 doses of epinephrine.