Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%).

BACKGROUND AND OBJECTIVES: A new intravenous immunoglobulin (IGIV) process has been developed that integrates efficient inactivation of enveloped virus, using caprylate, with immunoglobulin G (IgG) purification and caprylate removal by column chromatography. Two clinical studies were conducted to compare the pharmacokinetics of the new product, IGIV-C, 10% (Gamunex, 10%), formulated with glycine, with the licensed solvent-detergent (SD)-treated intravenous immunoglobulin IGIV-SD, 10% (Gamimune N, 10%), formulated with glycine, and IGIV-C, 5%, formulated with 10% maltose. MATERIALS AND METHODS: Both studies were randomized, multicentre crossover trials of 18 and 20 (respectively) adult patients with primary humoral immune deficiency in which patients received one IGIV product for three consecutive periods (3-4 weeks) before crossing over to the other product. Pharmacokinetic parameters were determined after the third infusion of each product. RESULTS: IGIV-C, 10% was bioequivalent to IGIV-SD, 10%, with half-lives (t1/2) of 35 and 34 days, respectively. IGIV-C, 5%, was bioequivalent to IGIV-C, 10%, with t1/2 of 35 and 36 days, respectively. The products had comparable safety profiles. CONCLUSIONS: The pharmacokinetic profiles observed in these trials indicate that IGIV-C, 10% may replace, and be administered in a manner similar to, IGIV-SD, 10%.

Urinary histamine metabolite elevations during experimental influenza infection.

BACKGROUND: Although histamine is hypothesized to mediate symptoms induced by viral upper respiratory infections, elevations of this mediator have not been observed in nasal lavage fluids recovered from patients with viral upper respiratory infections. OBJECTIVE: The purpose of this study was to use a novel method to determine whether histamine is released during experimental influenza A infection. METHODS: Healthy adults (n = 15) were cloistered and inoculated intranasally with influenza A virus, and monitored for infection and illness. Daily morning void urines were collected and assayed for histamine and its metabolites by gas chromatography-mass spectrometry. Total histamine was calculated for each urine specimen by summing the assayed values of histamine and its metabolites. RESULTS: All subjects were infected and developed illness. ANOVA documented a significant effect of study day (viral infection) on urinary levels of total histamine (P < 0.02). Pairwise analysis showed a significant elevation 2 days after inoculation. CONCLUSIONS: These results provide the first direct evidence that histamine is released in vivo during infection with a virus that causes cold/flu symptoms.

Long-term safety and efficacy of a chlorofluorocarbon-free beclomethasone dipropionate extrafine aerosol.

BACKGROUND: Beclomethasone dipropionate (BDP) extrafine aerosol, a newly developed pressurized metered dose inhaler (pMDI) with a hydrofluoroalkane-134a (HFA) propellant (HFA-BDP; Qvar, 3M Pharmaceuticals, St. Paul, MN), has been shown to be effective in controlling asthma symptoms at approximately half the daily dose of chlorofluorocarbon (CFC)-BDP. OBJECTIVE: This study evaluated the long-term efficacy and safety of switching patients with asthma maintained on a stable dose of CFC-BDP pMDI to therapy with HFA-BDP pMDI at approximately half their previous daily dose of CFC-BDP. METHODS: This was an open-label, randomized, parallel-group multicenter trial. Patients with at least a 6-month history of asthma whose symptoms were controlled on CFC-BDP, 400 to 1600 microg daily, during a 2-week run-in period were randomized in a 1:3 ratio to CFC-BDP at the same daily dose or HFA-BDP at approximately half the daily dose of CFC-BDP for 12 months. RESULTS: A total of 473 patients were randomized: 354 to HFA-BDP, 119 to CFC-BDP. There were no statistically significant differences between groups in mean change from baseline in morning (AM) peak expiratory flow rate or forced expiratory volume in one second throughout the study. There were no consistent differences between treatment groups in individual asthma symptoms or daily beta2-agonist use during the study. There was an increase in the percentage of symptom-free days between baseline and month 12 in the HFA-BDP group (11.5%) and the CFC-BDP group (4.6%). No statistically significant differences in serum osteocalcin levels or adverse events were seen during the study or in AM plasma cortisol levels at month 12. CONCLUSIONS: Asthma control was maintained in patients switched from a stable dose of CFC-BDP (400 to 1600 microg daily) to HFA-BDP at approximately half the CFC-BDP dose (200 to 800 microg daily), and was maintained over the next 12 months. HFA-BDP demonstrated a similar safety profile to CFC-BDP; there were no differences between the agents with regard to systemic effects.

Effect of experimental influenza A infection on systemic immune and inflammatory parameters in allergic and nonallergic adult subjects.

BACKGROUND: The economic impact and medical complication rate of viral upper respiratory infections are well documented, but many of the physiologic, inflammatory, and immune responses to respiratory viruses have only recently been investigated. A previous study demonstrated differential systemic immune and inflammatory responses in allergic rhinitis (AR) and nonallergic rhinitis (NAR) subjects during experimental infection with rhinovirus-39. OBJECTIVE: The purpose of this study was to compare selected systemic immune and inflammatory responses to experimental influenza A virus (FLU) challenge in seronegative AR and NAR subjects. METHODS: Peripheral blood was obtained at baseline (study day 0) and 3, 6, 18, and 31 days after intranasal FLU challenge and assayed for leukocyte histamine release, serum immunoglobulins, and plasma histamine. RESULTS: All subjects were infected, as manifested by viral shedding in nasal secretions and/or seroconversion. FLU infection induced decreases in spontaneous leukocyte histamine release and increases in anti-immunoglobulin E-induced leukocyte histamine release, which were evident at least 1 month after infection, but caused no significant changes in serum immunoglobulins or plasma histamine. There were no differences between AR and NAR subjects for any of the study parameters. CONCLUSIONS: The results show that intranasal challenge with FLU induces changes in leukocyte histamine release, but not other systemic immune and inflammatory responses.

Combination of inhaled corticosteroids plus other medications in the management of moderate to severe persistent asthma.

Severe persistent asthma accounts for a small percentage, probably less than 5% of all patients with asthma, but is responsible for the major portion of health care costs associated with the illness. According to the National Institutes of Health (National Asthma Education and Prevention Program) guidelines for the management of asthma, patients with severe asthma should be treated with high dosages of inhaled corticosteroids. These inhaled corticosteroids can be given in conjunction with a brief course of oral or parenteral systemic steroids, but it is best to decrease or eliminate systemic corticosteroid therapy whenever possible to prevent the side effects of long-term oral prednisone therapy. If inhaled corticosteroids do not control the asthma, then one or perhaps two, and even three, other long-term control medications can be added to the therapy regimen. Current guidelines recommend adding a long-acting beta 2-agonist such as salmeterol to the inhaled corticosteroid. Recent evidence suggests that leukotriene receptor antagonists can also be used in conjunction with inhaled steroids. Theophylline is also recommended as another controller agent to be considered. Unfortunately, no studies have comparatively evaluated all of these different classes of agents, even in moderate asthma, in head-to-head trials. This manuscript will review the current literature and provide the author's perspective on the combination of these medications in the pharmacologic management of moderate to severe persistent asthma.

Abnormal middle ear pressures during experimental influenza A virus infection--role of Eustachian tube function.

INTRODUCTION: Experimental infection of adults with influenza A virus, rhinovirus or RSV causes abnormal ME pressure in some, but not all subjects. The hypothesis tested in this study is that the response variability is caused by constitutional differences in the functioning of the Eustachian tube. METHODS: 18 adult subjects were experimentally infected with influenza A virus. On five occasions before virus exposure, middle ear pressure (by tympanometry) and Eustachian tube function (by sonotubometry) were recorded bilaterally. Tests were repeated on days 1 through 8 and 10 after infection. Individual ears were classified with respect to the number of pre-exposure, positive sonotubometric testings and the middle ear pressure response to infection was compared between ears with Eustachian tube openings at all pre-infection test sessions (GR-A) and those with at least one negative test (GR-B). RESULTS: Pre-exposure, 19, six, four, four, one and two ears had tubal openings on five, four, three, two, one and zero sessions, respectively. For that period, GR-A had significantly lesser average intra-ear and intra-group middle ear pressure variances compared to GR-B, but there were no between-group differences in the average middle ear pressure or in the number of observations of abnormal middle ear pressure. After virus exposure, middle ear pressure variances and the number of abnormal observations increased and the average pressure decreased in both groups, but the effects were more pronounced for GR-B ears. CONCLUSIONS: These results support the hypothesis that pre-existing good Eustachian tube function reduces the otological complications of viral upper respiratory tract infection.

Diagnostic assessment of otitis media.

Accurate diagnosis of OM is important but often difficult. To enhance the likelihood of accurate diagnosis, pneumatic otoscopy is the preferred method of examination generally available to clinicians. Findings by pneumatic otoscopy should be coupled with the presence or absence of symptoms and signs to delineate a diagnosis of AOM or OME. Tympanometry can be a useful adjunct in the clinical assessment of middle ear effusion. Audiometry is particularly important for patients with recurrent or chronic middle ear disease.

Therapeutic approaches to allergic rhinitis: treating the child.

Allergic rhinitis is currently the most common of all chronic diseases in children. However, children frequently lack the ability to verbalize their symptoms, with the result that the condition may go undiagnosed and untreated. Unfortunately, untreated allergic rhinitis not only detrimentally affects children's physical and psychosocial well-being, quality of life, and capacity to function and learn, but it is also associated with and may contribute to potentially serious sequelae, including asthma, sinusitis, and otitis media. Because children may not accurately describe their symptoms, the classic signs of allergic rhinitis in the pediatric population, including the allergic shiner, the allergic crease, and the allergic salute, are particularly important in enabling the clinician to recognize those children who may have this condition; other significant signs include mouth breathing, snoring, chronic cough, and continual throat clearing. The options for treating allergic rhinitis in the child are the same as those for the adult, and the clinician can expect the same level of efficacy. Environmental control for allergen avoidance is an important goal, but the clinician must prescribe it within the context of the family's lifestyle to obtain compliance. Complete avoidance of inhalant allergens is not always feasible, and medications are necessary. Oral antihistamines remain the mainstay of initial treatment for allergies. Given evidence of the significant deleterious effects of the sedating antihistamines on learning, the clinician should prescribe nonsedating second-generation agents whenever possible. Decongestants may be needed. Intranasal corticosteroids are a most effective option, and these agents lack the systemic side effects associated with orally administered steroids. In persistent disease, allergen immunotherapy injections may be considered. In all cases, the clinician should consider issues that are likely to influence compliance in the pediatric population.

Rhinitis and asthma connection: management of coexisting upper airway allergic diseases and asthma.

Asthma is a chronic inflammatory disease of the lower airways. Epidemiologic surveys and clinical reports have documented that allergic rhinitis coexists with asthma in many patients. Provocative bronchial challenge with allergens responsible for allergic rhinitis in susceptible asthma patients can elicit asthma, and these responses have been linked to bronchial airway hyperreactivity. Provocative bronchial methacholine challenge in allergic rhinitis patients will demonstrate increased airway responsiveness to the bronchial challenge in 30% of those allergic rhinitis patients who had no past history of asthma. These data suggest that subclinical asthma may be present in certain patients with allergic rhinitis. The focus of the National Heart, Lung, and Blood Institute (NHLBI) guidelines for the pharmacologic treatment of asthma focuses on medications to relieve the symptoms of asthma, i.e., bronchodilators and anti-inflammatory agents (i.e., inhaled corticosteroids, cromolyn, and leukotriene modifiers) to control asthma. Avoidance of allergens such as house dust mite are also recommended. Although not emphasized in these NHLBI guidelines, recent studies have observed that treatments, including intranasal steroid, cromolyn, antihistamines, and decongestants, which provide relief of nasal symptoms in patients with both allergic rhinitis and asthma, will also improve the pulmonary symptoms of allergic asthma. This article will review the recent literature.

Delayed separation of the umbilical cord and partial deficiency of sialyl lewis X antigen.

A 5-week-old male infant presented with failure of separation of the umbilical cord. He was evaluated for the presence of integrin and selectin ligand leukocyte adhesion molecules on his neutrophils and monocytes. Integrin molecules appeared to be normally expressed, but expression of sialyl Lewis X (sLe(x)) was decreased. The expression of sLe(x) gradually increased, and the umbilical cord separated at 10 weeks of age. Further study revealed decreased numbers of sLe(x)-positive neutrophils with a lower mean fluorescence intensity on neutrophils from cord blood compared to neutrophils in adult peripheral blood. This study indicates that this patient had an uncommonly low level of sLe(x) expression and infers that adequate expression may be required for the inflammatory reaction needed for umbilical cord separation.

Diminished IL-10 production in subjects with allergy after infection with influenza A virus.

BACKGROUND: Recent studies have documented a link between respiratory viral infections and the expression of asthma and other allergic disorders. Results from other studies have suggested that diminished production of IL-10, an anti-inflammatory cytokine, may contribute to the pathophysiologic features of these diseases. OBJECTIVE: The objective of this study was to determine whether diminished IL-10 production and TH2 cytokine skewing occur in allergic, as compared with nonallergic, subjects after experimental infection with the influenza A virus. METHODS: PBMCs were isolated from 11 subjects with allergy and 14 subjects with no allergy before and after influenza A infection and stimulated with either mitogen (PHA) or antigen (influenza A). Supernatants were assayed for IL-10, IL-4, and IFN-gamma by ELISA. RESULTS: PBMC IL-10 production was significantly diminished in subjects with allergy, as compared with subjects with no allergy, after experimental infection with influenza A virus. However, significant TH2 skewing and enhanced airway symptoms were not observed in these same subjects. CONCLUSIONS: These data provide further support that subjects with allergy have an intrinsic inability to upregulate IL-10 production in response to inflammatory stimuli and extend this observation to include respiratory viral infections. Future studies in this area could lead to a better understanding of the pathogenesis of asthma and other allergic disorders

Body odor in dermatologic diagnosis.

Patients with an unpleasant body odor often consult dermatologists. A dermatologist needs to become familiar with the occurrence and significance of medically related odors. Although body odor may be essentially physiological, and problems with body mal-odor are paid little attention, they can cause many personal troubles and may induce a variety of psychosocial disturbances. Body odor in general is an indicator of individual care and hygiene, or results from eating garlic, onion, spicy foods, curry, or drinking alcohol; however, in some instances it can be pathologic. It is a well-known clinical fact that many diseases (both of internal and cutaneous origin), several syndromes, and some intoxications cause characteristic, peculiar, and identifiable odors. Their identification can provide diagnostic clues, guide the laboratory evaluation, and help in the choice of immediate and appropriate therapy. Thus, olfactory evaluation can be an important part of clinical examination and olfactory diagnosis is still valid in recognizing certain diseases. This report reviews the physiological and pathologic body odors and the importance of olfactory diagnosis in dermatology.

Intranasal budesonide aqueous pump spray (Rhinocort Aqua) for the treatment of seasonal allergic rhinitis. Rhinocort Aqua Study Group.

To determine the relative efficacy, compare the incidence of adverse events, and ascertain the systemic glucocorticoid effect of the nasal application of several doses of budesonide, 406 patients with seasonal ragweed-induced allergic rhinitis were randomized in a double-blind, parallel group design to receive intranasal budesonide aqueous pump spray (Rhinocort Aqua) 32 micrograms, 64 micrograms, 128 micrograms, 256 micrograms, or placebo once daily for 4 weeks. A total of 231 adults and 175 children participated in the study conducted at 14 centers in two geographic regions, the Midwest and the Northeast United States, during the 1994 ragweed season. Pollen counts were collected at each site by the Rotorod method. The primary efficacy parameter was the change from baseline nasal index score (NIS) for the overall study population--defined as the sum of scores for nasal congestion, runny nose, and sneezing. The study was powered only to evaluate the overall study population for statistical significance. Significant differences in NIS were observed in each active treatment group compared with placebo (p < or = 0.003). Compared with placebo, budesonide aqueous spray significantly reduced individual symptoms of runny nose and sneezing at all doses (p < or = 0.008), and nasal congestion and nasal itching at all doses except 64 micrograms (p < or = 0.022). In the Midwest pollen belt where the 1994 ragweed season was representative of a typical pollen season, it was possible to establish a dose-response relationship for comparison of budesonide aqueous spray 256 micrograms versus 32 micrograms (p = 0.017). The incidence of adverse events was similar between budesonide aqueous-treated and placebo-treated patients. Importantly, there was no effect of budesonide aqueous spray on basal or ACTH-stimulated plasma cortisol levels in either adults or children at the end of 4 weeks of treatment. Intranasal budesonide aqueous pump spray, administered once daily, was efficacious and was generally well tolerated in both adults and children with seasonal allergic rhinitis.

Increased interleukin-6 levels in nasal lavage samples following experimental influenza A virus infection.

Interleukin-6 (IL-6) is a pleotropic cytokine implicated in the pathogenesis of local inflammation during viral upper respiratory infections. This study determined if experimental influenza A virus infection causes local IL-6 production. Seventeen healthy, adult subjects were intranasally inoculated, by course drops, with a safety-tested strain of influenza A/Kawasaki/86 (H1N1) virus. Nasal lavage samples were collected, symptoms were recorded, and expelled nasal secretions were weighed once before and then daily for 8 days after the virus inoculation. Lavage samples were submitted for virus culture and were examined for IL-6 and IL-4 by enzyme-linked immunosorbent assay. The IL-6, but not IL-4, levels were significantly increased in the nasal lavage samples of the 12 subjects who shed virus but not in those of the 5 subjects who did not shed virus. Moreover, the elevations in IL-6 levels were related temporally to the development of nasal symptoms and secretions but not to systemic symptoms. These results suggest a role for locally produced IL-6 in the pathogenesis and expressed symptomatology of influenza A virus infection.

Sinusitis: bench to bedside. Current findings, future directions.

Sinusitis, an inflammatory disease of the sinus, is one of the most commonly reported diseases in the United States, affecting an estimated 14% of the population. The prevalence of sinusitis is rising. Between 1990 and 1992, persons with sinusitis reported approximately 73 million restricted activity days-an increase from the 50 million restricted activity days reported between 1986 and 1988. Because critical questions remain unanswered about its cause, pathophysiology, and optimal treatment, sinusitis continues to generate significant health care costs and affects the quality of life of a large segment of the U.S. population. To identify critical directions for research on sinus disease, the American Academy of Allergy, Asthma and Immunology and the American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc., convened a meeting in January 1996 in collaboration with the National Institutes of Allergy and Infectious Disease. This document summarizes the proceedings of that meeting and presents what is intended to be the background for future investigation of the many unanswered questions related to sinusitis.

Sinusitis: bench to bedside. Current findings, future directions.

Sinusitis, an inflammatory disease of the sinus, is one of the most commonly reported diseases in the United States, affecting an estimated 14% of the population. The prevalence of sinusitis is rising. Between 1990 and 1992, persons with sinusitis reported approximately 73 million restricted activity days--an increase from the 50 million restricted activity days reported between 1986 and 1988. Because critical questions remain unanswered about its cause, pathophysiology, and optimal treatment, sinusitis continues to generate significant health care costs and affects the quality of life of a large segment of the U.S. population. To identify critical directions for research on sinus disease, the American Academy of Allergy, Asthma and Immunology and the American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc., convened a meeting in January 1996 in collaboration with the National Institutes of Allergy and Infectious Disease. This document summarizes the proceedings of that meeting and presents what is intended to be the background for future investigation of the many unanswered questions related to sinusitis.

Otitis media and its relation to allergic rhinitis.

Otitis media is a multifactorial illness that is the most common childhood disease that requires physician care, and its resultant health care costs are high. The established role of infection in the pathogenesis of otitis media has promoted aggressive antimicrobial therapy with specific antibiotic protocols for acute otitis and prophylactic antibiotic regimens for chronic or recurrent acute otitis media. Even though these antibiotic regimens have been widely used, there has not been a decreased incidence of otitis media and its complications. The possibility that allergy contributes to chronic or recurrent otitis media especially in children older than 3 years has been debated for years. If a causal relationship between allergic respiratory diseases and middle ear disease were to be established, then one would anticipate that anti-allergic therapy would reduce the morbidity and health care costs associated with otitis media.

Treatment strategies designed to minimize medical complications of allergic rhinitis.

Perennial and seasonal allergic rhinitis affect many million Americans and account for close to $2 billion annually in medical costs and lost productivity. The symptoms of allergic rhinitis, including sneezing, rhinorrhea, nasal congestion, and pruritus are, at best, very annoying and may be quite debilitating in some patients, causing irritability, insomnia, and fatigue. Moreover, allergic rhinitis is often not self-limiting and can contribute to serious medical complications such as sinusitis and otitis. Aggressive medical management of allergic rhinitis is important in the therapy for chronic sinusitis and otitis media and may prevent progression to more serious disease. Accurate diagnosis and initiation of environmental control measures to reduce exposure to causative factors should accompany initiation of pharmacotherapy. Antihistamines form the cornerstone of pharmacologic therapy, and use of the newer nonsedating antihistamines such as loratadine, terfenadine, and astemizole is not associated with the sedation produced by the classic antihistamines. Both loratadine and terfenadine are available in combination with a decongestant. Topical intranasal corticosteroids are another important component of pharmacologic management of allergic rhinitis. Allergen immunotherapy (hyposensitization) is used in those patients not adequately managed with pharmacotherapy. The relative safety and convenient dosing schedule of the newer medications should be accompanied by enhanced patient compliance and, hence, better control of allergic symptoms, halting progression of allergic rhinitis to serious medical complications.

Treatment of allergic rhinitis: effect on occupation productivity and work force costs.

Allergic rhinitis, one of the most common chronic illnesses, can have a negative impact on occupational productivity in the work-place. Allergic rhinitis affects over 13 million workers (6.15 million men and 6.11 million women) of the United States work force. Work place productivity can be reduced in the several ways: (1) Employee works at suboptimal efficiency because of the disease or its treatment; (2) employee takes a sick day away from work because of allergic rhinitis or its complications; (3) employee takes time off from work to care for or transport a child or dependent who needs care for allergic rhinitis or its complications, and (4) worker takes time off because of a work-related injury related to the disease or the medication used to treat the illness. Although nonsedating antihistamines and intranasal anti-inflammatory medications have been developed as effective therapies and are available as prescription drugs, many workers (50%) indicate that they manage their allergic rhinitis with over-the-counter medications. Most of these over-the-counter medicines contain sedating antihistamines which are known to alter cognitive and motor function. To determine whether the medications used by 3394 members of a health maintenance organization were associated with incident work-related injury, they were compared to two control groups selected from the membership and matched for age, gender, and Standard Industrial Classification Code of their employer. Medication use was determined from pharmacy data. The injuries included 496 fractures on dislocations, 2728 open, crushing, or superficial injuries, 176 burns, and 63 internal injuries. The risk of injury was statistically significantly elevated among users of sedating antihistamines. Utilizing demographic data the annual cost of last productivity to employers and society as the result of allergic rhinitis and its therapy with the over-the-counter sedating antihistamines is estimated to be greater than $4 billion.