Prospective observational study of chronic rhinosinusitis: environmental triggers and antibiotic implications.

BACKGROUND: A prolonged course of antibiotic therapy is often initiated for chronic rhinosinusitis (CRS) based on symptomatology. We examined differences in clinical manifestations and underlying conditions in patients with symptoms typical for CRS. CT scan abnormality of the sinuses was the gold standard for diagnosis of CRS. METHODS: We performed a prospective observational study of 125 adults with classic symptoms of CRS undergoing nasal endoscopy and sinus CT. RESULTS: The patients were classified into 2 groups: (1) those with radiographic evidence of sinusitis by CT (Sx + CT) (75) and (2) those with normal CT scans of the sinus (Sx - CT) (50). Decreased smell was significantly more common in Sx + CT than in Sx - CT patients, (P = .003). Paradoxically, headache, facial pain, and sleep disturbance occurred significantly more frequently in patients with Sx - CT than in patients with Sx + CT (P < .05). The absence of mucopurulence on endoscopy proved to be highly specific for Sx - CT patients (100%). On the other hand, sensitivity was low; only 24% of Sx + CT patients demonstrated mucopurulence by endoscopy. Improvement in response to antibiotics was similar between both CRS categories. CONCLUSIONS: Most symptoms considered to be typical for CRS proved to be nonspecific. Interestingly, symptoms that were more severe were significantly more likely to occur in younger patients who were Sx - CT. The efficacy of antibiotic therapy was uncertain. We suggest that objective evidence of mucopurulence assessed by endoscopy or CT should be obtained if antibiotics are to be given for prolonged duration. We recommend a moratorium for the widespread practice of a prolonged course of empiric antibiotics in patients with presumed CRS.

Experimental rhinovirus infection increases human tissue kallikrein activation in allergic subjects.

BACKGROUND: Rhinovirus infection is a major cause of asthma exacerbations. While rhinovirus infection is known to generate kinins in the upper respiratory track, little is known about the effect of rhinovirus on kinin generation in the lower airway. We previously identified human tissue kallikrein (hTK) as the principal lung kininogenase during allergic airway inflammation. In this report we investigate the effect of experimental rhinovirus infection on hTK activity in the airways of atopic subjects with and without asthma. METHODS: Eight atopic subjects, 4 with asthma, underwent bronchoscopy with lavage. At least 1 month later, subjects were inoculated with rhinovirus, then underwent repeat bronchoscopy with lavage 4 and 18 days later. hTK mRNA was measured in nasal scrape samples by quantitative real-time PCR. hTK activity (chromogenic substrate assay) and IL-8 levels (ELISA) were assessed in the bronchoalveolar lavage fluid. RESULTS: At day 4 after rhinovirus inoculation, nasal hTK mRNA was modestly increased in both the rhinitis (1.7-fold) and asthmatic (2.1-fold) groups. A doubling or greater increase in hTK activity after rhinovirus infection was observed in all 4 asthmatic subjects (mean 19-fold increase) but only in 1 of 4 atopic subjects without asthma (mean 2-fold increase). Rhinovirus infection also increased the IL-8 protein level in bronchoalveolar lavage fluid, which correlated with hTK activity (R = 0.82). CONCLUSION: Experimental rhinovirus infection in allergic asthmatic subjects is accompanied by increased lower airway hTK activation, which parallels the appearance of IL-8. Rhinovirus-induced hTK activation may contribute to airway inflammation and asthmatic exacerbations.

Treatment of naturally acquired common colds with zinc: a structured review.

BACKGROUND: Over the past 20 years, the use of zinc as an over-the-counter alternative therapy for the common cold has vastly grown in popularity. Recent reports of potentially permanent anosmia caused by intranasal zinc therapy warrant careful analysis of the therapeutic effects of zinc. METHODS: A search of the Medline database (including articles published during 1966-2006) for studies of zinc and the common cold produced 105 published reports. Fourteen were randomized, placebo-controlled studies that examined the effect of zinc lozenges, nasal sprays, or nasal gels on naturally acquired common colds. Eleven features of experimental design affecting signal quality, chance, bias, and blinding were used to evaluate the 14 placebo-controlled studies. These criteria were validated case definition, quantifiable hypothesis, sample size calculation, randomized assignment, double blinding, proof of blinding, measurement of compliance, measurement of dropout rate, analysis by intent to treat, description of methods of analysis, and measurements of probability. Equal weight was given to each criterion, because failure to meet any one could potentially invalidate the findings of a clinical trial. RESULTS: Four studies met all 11 criteria. Three of these studies reported no therapeutic effect from zinc lozenge or nasal spray. One study reported positive results from zinc nasal gel. Of the remaining 10 studies, 6 reported a positive effect and 4 reported no effect. Intent-to-treat analysis was the most common criterion not met. CONCLUSIONS: This structured review suggests that the therapeutic effectiveness of zinc lozenges has yet to be established. One well-designed study did report a positive effect of zinc nasal gel.

Influenza, Winter Olympiad, 2002.

Prospective surveillance for influenza was performed during the 2002 Salt Lake City Winter Olympics. Oseltamivir was administered to patients with influenza like illness and confirmed influenza, while their close contacts were given oseltamivir prophylactically. Influenza A/B was diagnosed in 36 of 188 patients, including 13 athletes. Prompt management limited the spread of this outbreak.

Dispersal of Staphylococcus aureus into the air associated with a rhinovirus infection.

OBJECTIVE: To determine whether healthy adult nasal carriers of Staphylococcus aureus can disperse S. aureus into the air after rhinovirus infection. DESIGN: We investigated the "cloud" phenomenon among adult nasal carriers of S. aureus experimentally infected with a rhinovirus. Eleven volunteers were studied for 16 days in an airtight chamber wearing street clothes, sterile garb, or sterile garb plus surgical mask; rhinovirus inoculation occurred on day 2. Daily quantitative air, nasal, and skin cultures for S. aureus; cold symptom assessment; and nasal rhinovirus cultures were performed. SETTING: Wake Forest University School of Medicine, Winston-Salem, North Carolina. PARTICIPANTS: Wake Forest University undergraduate or graduate students who had persistent nasal carriage of S. aureus for 4 or 8 weeks. RESULTS: After rhinovirus inoculation, dispersal of S. aureus into the air increased 2-fold with peak increases up to 34-fold. Independent predictors of S. aureus dispersal included the time period after rhinovirus infection and wearing street clothes (P < .05). Wearing barrier garb but not a mask decreased dispersal of S. aureus into the air (P < .05). CONCLUSION: Virus-induced dispersal of S. aureus into the air may have an important role in the transmission of S. aureus and other bacteria.

Treatment of the common cold with echinacea: a structured review.

BACKGROUND: Echinacea is a herbal preparation that is frequently used to treat the common cold. Spending on echinacea in the United States has risen to >300 million dollars annually. METHODS: A total of 322 articles related to echinacea and colds, including 9 placebo-controlled clinical trials, were identified using the Medline and PubMed databases. Eleven features of experimental design that affect the accuracy of the measurement of features of interest, the probability of a chance relationship, bias, and blinding were used to evaluate the 9 placebo-controlled studies. The criteria were validated case definition, quantifiable hypothesis, sample-size calculation, randomized assignment, double blinding, proof of blinding, measurement of compliance, measurement of drop-out rate, analysis by intention to treat, description of the methods of analysis, and measurement of probability. Equal weight was given to each criterion, since failure to meet any one of them could potentially invalidate the findings of a clinical trial. RESULTS: Of the 9 studies, 2 met all 11 criteria. The results of both studies were judged to be negative by the people who performed the studies. Of the remaining 7 studies, 6 were judged to have positive results, and 1 was judged to have negative results. The criterion most commonly not met was proof of blinding. CONCLUSIONS: This structured review suggests that the possible therapeutic effectiveness of echinacea in the treatment of colds has not been established.

Acute community-acquired bacterial sinusitis: continuing challenges and current management.

Acute sinusitis is one of the most common infections seen in general clinical practice. The most common cause of acute sinusitis is viral; however, many patients receive a prescription for an antibiotic. Such injudicious prescribing habits have a major impact on health care costs, contribute to the increasing prevalence of drug-resistant strains of common respiratory pathogens, and reflect many of the challenges in differentiating viral and bacterial disease. Sinus puncture and culture of the aspirate, the diagnostic reference standard in the research setting, are not appropriate for routine clinical practice. However, certain clinical signs and symptoms that do not improve or that worsen after 7-10 days are currently accepted criteria for diagnosis of bacterial sinusitis. Accurate diagnosis can select patients who would benefit most from antimicrobial use. Antimicrobial agents should be selected on the basis of local resistance patterns, and their spectrum of activity should cover the common bacterial pathogens, including resistant strains.

Airborne dispersal as a novel transmission route of coagulase-negative staphylococci: interaction between coagulase-negative staphylococci and rhinovirus infection.

OBJECTIVE: To investigate whether rhinovirus infection leads to increased airborne dispersal of coagulase-negative staphylococci (CoNS). DESIGN: Prospective nonrandomized intervention trial. SETTING: Wake Forest University School of Medicine, Winston-Salem, North Carolina. PARTICIPANTS: Twelve nasal Staphylococcus aureus-CoNS carriers among 685 students screened for S. aureus nasal carriage. INTERVENTIONS: Participants were studied for airborne dispersal of CoNS in a chamber under three conditions (street clothes, sterile gown with a mask, and sterile gown without a mask). After 2 days of pre-exposure measurements, volunteers were inoculated with a rhinovirus and observed for 14 days. Daily quantitative nasal and skin cultures for CoNS and nasal cultures for rhinovirus were performed. In addition, assessment of cold symptoms was performed daily, mucous samples were collected, and serum titers before and after rhinovirus inoculation were obtained. Sneezing, coughing, and talking events were recorded during chamber sessions. RESULTS: All participants had at least one nasal wash positive for rhinovirus and 10 developed a symptomatic cold. Postexposure, there was a twofold increase in airborne CoNS (P = .0004), peaking at day 12. CoNS dispersal was reduced by wearing a gown (57% reduction, P < .0001), but not a mask (P = .7). Nasal and skin CoNS colonization increased after rhinovirus infection (P < .05). CONCLUSIONS: We believe this is the first demonstration that a viral pathogen in the upper airways can increase airborne dispersal of CoNS in nasal S. aureus carriers. Gowns, gloves, and caps had a protective effect, whereas wearing a mask did not further reduce airborne spread.

Viral titers in nasal lining fluid compared to viral titers in nasal washes during experimental rhinovirus infection.

BACKGROUND: The concentration of rhinovirus in nasal wash specimens from infected volunteers peaks at 48-72 h after inoculation. The volume of expelled nasal fluid peaks at the same time, raising the question of whether the viral concentration in nasal wash reflects viral replication in nasal cells or merely the production of an increased volume of nasal fluid during a cold. OBJECTIVES: To determine the amount of rhinovirus in nasal lining fluid during colds before the nasal fluid has been diluted in a nasal wash. STUDY DESIGN: Rhinovirus titers were determined in nasal wash specimens collected daily for five days from 14 subjects with type16 rhinovirus infection. The urea concentration in nasal lining fluid equals that in blood. By determining the urea concentration in a nasal wash and comparing it to the urea concentration in blood from the same subject, it was possible to determine the amount of dilution of the nasal lining fluid. The dilution factor (reciprocal of the dilution) was then used to calculate the viral concentration in undiluted nasal lining fluid. RESULTS: The dilution factor in 70 nasal washes varied from 5 to 64. The viral GMTs (+S.E.) in nasal washes were 1.79 (+0.3) TCID(50)/ml at 24 h, 3.11 (+0.15) at 48 h, and 2.61 (+0.3) at 72 h. The viral GMTs in nasal lining fluid, based on urea adjusted values, paralleled those in nasal washes but were approximately one log higher. Virus concentrations returned to near baseline values by day 5. CONCLUSIONS: The temporal pattern of rhinovirus shedding observed in nasal wash specimens, with a peak in virus concentration at 48-72 h after infection, is a true indication of virus production in nasal cells and not an artifact of the increased amount of nasal fluid produced during the early phase of a cold.

Acute community-acquired bacterial sinusitis: the value of antimicrobial treatment and the natural history.

Two areas of investigation were reviewed: (1) placebo-controlled trials of antimicrobial treatment involving patients with a clinical diagnosis of acute community-acquired bacterial sinusitis (ACABS) for whom pre- and posttherapy sinus aspirate cultures were not performed, and (2) uncontrolled trials of antimicrobial treatment involving patients with ACABS for whom pre- and posttherapy sinus aspirate cultures were performed. The clinical diagnostic criteria in the controlled trials were not correlated with sinus aspirate culture results and, thus, were of questionable validity. Most of the populations probably included patients with viral rhinosinusitis. In 10 uncontrolled studies, the posttreatment, weighted, pooled mean bacterial resolution rate (+/- standard error) at 7-10 days, based on sinus aspirate culture results, was 91%+/-10%. In 9 controlled trials, the weighted pooled mean rate of clinical improvement (+/- standard deviation) at 7-14 days for placebo recipients was 52%+/-18%. In 1 controlled trial in which diagnosis was based on duration of unimproved illness, 57% of placebo recipients and 85.5% of treated patients were healthy or had improved by day 10. Additional studies of ACABS are needed.

Phase II, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray 2-percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers.

Human rhinovirus (HRV) infections are usually self-limited but may be associated with serious consequences, particularly in those with asthma and chronic respiratory disease. Effective antiviral agents are needed for preventing and treating HRV illnesses. Ruprintrivir (Agouron Pharmaceuticals, Inc., San Diego, Calif.) selectively inhibits HRV 3C protease and shows potent, broad-spectrum anti-HRV activity in vitro. We conducted three double-blind, placebo-controlled clinical trials in 202 healthy volunteers to assess the activity of ruprintrivir in experimental HRV infection. Subjects were randomized to receive intranasal ruprintrivir (8 mg) or placebo sprays as prophylaxis (two or five times daily [2x/day or 5x/day] for 5 days) starting 6 h before infection or as treatment (5x/day for 4 days) starting 24 h after infection. Ruprintrivir prophylaxis reduced the proportion of subjects with positive viral cultures (for 5x/day dosing groups, 44% for ruprintrivir treatment group versus 70% for placebo treatment group [P=0.03]; for 2x/day dosing groups, 60% for ruprintrivir group versus 92% for placebo group [P=0.004]) and viral titers but did not decrease the frequency of colds. Ruprintrivir treatment reduced the mean total daily symptom score (2.2 for ruprintrivir treatment group and 3.3 for the placebo treatment group [P=0.014]) by 33%. Secondary endpoints, including viral titers, individual symptom scores, and nasal discharge weights, were also reduced by ruprintrivir treatment. Overall, ruprintrivir was well tolerated; blood-tinged mucus and nasal passage irritation were the most common adverse effects reported. Pharmacokinetic analysis of plasma and nasal ruprintrivir concentrations revealed intranasal drug residence with minimal systemic absorption. Results from these studies in experimental rhinoviral infection support continued investigation of intranasal ruprintrivir in the setting of natural HRV infection.

Experimental rhinovirus challenges in adults with mild asthma: response to infection in relation to IgE.

BACKGROUND: Although most children and young adults with asthma are atopic, exacerbations of asthma are frequently associated with viral respiratory tract infections, especially those caused by rhinovirus (HRV). OBJECTIVE: Young atopic adults with mild asthma were evaluated before and during an experimental HRV infection to test the hypothesis that airway inflammation before virus inoculation may be a risk factor for an adverse response to HRV. METHODS: Experimental HRV infections were evaluated in 16 allergic volunteers with mild asthma and 9 nonatopic control patients (age, 18 to 30 years). Before virus inoculation, each participant was screened with tests for lung function, prick skin tests for sensitization to common aeroallergens, measurements of total serum IgE, and serum neutralizing antibody to rhinovirus-16 (the serotype used for inoculation). The response to infection was monitored for 21 days by using symptom diary cards, tests for lung function, and markers of airway inflammation in nasal washes, blood, and expired air. RESULTS: During the infection, asthmatic patients had cumulative upper and lower respiratory tract symptom scores that were significantly greater over the course of 21 days than scores from the control patients. At baseline, the asthmatic patients also had increased sensitivity to methacholine and significantly lower values for FEV(1) (percent predicted) than the control patients (geometric mean and intraquartile values: 87% [79% to 91%] for the asthmatic patients and 101% [90% to 104%] for the control patients, P <.03). Among the patients with mild asthma, 6 had levels of total serum IgE that were substantially elevated (range, 371 to 820 IU/mL) compared with 10 who had lower levels (range, 29 to 124 IU/mL). Those with high levels of IgE had significantly greater lower respiratory tract symptom scores during the initial 4 days of the infection than the low IgE group. They also had higher total blood eosinophil counts at baseline, increased eosinophil cationic protein in their nasal washes (>200 ng/mL), and augmented levels of expired nitric oxide at baseline and during peak cold symptoms. In contrast, levels of soluble intracellular adhesion molecule-1 in nasal wash supernatants from the asthmatic patients with high IgE were diminished, both at baseline and during the infection. CONCLUSIONS: The reduced lung function and increased markers of inflammation observed before virus inoculation in the asthmatic patients who had high levels of total serum IgE may be risk factors for an adverse response to infections with HRV.

Symptom severity patterns in experimental common colds and their usefulness in timing onset of illness in natural colds.

Mean total symptom severity scores for subjects with experimental rhinovirus colds peak 48 h after viral inoculation. Also, total symptom scores for natural rhinovirus and nonrhinovirus colds peaked on day 2 of illness in a long-term, noncompensated epidemiology study. In contrast, the mean total symptom scores for compensated patients receiving placebo in natural cold treatment trials peaked on day 1. Comparisons by day indicated that scores for symptoms reported as occurring on day 1 in the natural cold treatment trials corresponded with experimental cold scores for symptoms reported 48 h after viral inoculation. Comparisons of frequency and cumulative distribution scores for the 2 groups indicated that natural colds in the treatment trials were of longer duration than reported. A mean total symptom severity score of

Combined antiviral-antimediator treatment for the common cold.

A randomized, controlled, double-masked clinical trial was conducted with a combination antiviral-antimediator treatment for experimental rhinovirus colds. In all, 150 healthy men and women (aged 18-51 years) were randomly assigned to 1 of 3 groups: intranasal interferon (IFN)-alpha2b (6 x 10(6) U every 12 h x 3) plus oral chlorpheniramine (12 mg extended release) and ibuprofen (400 mg) every 12 h for 4.5 days (n=59 subjects); intranasal placebo plus oral chlorpheniramine and ibuprofen (n=61 subjects); or intranasal and oral placebos (n=30 subjects). Treatment was started 24 h after intranasal viral challenge. During the 4.5 days of treatment with IFN-alpha2b, chlorpheniramine, and ibuprofen, the daily mean total symptom score was reduced by 33%-73%, compared with placebo. Treatment reduced the severity of rhinorrhea, sneezing, nasal obstruction, sore throat, cough, and headache and reduced nasal mucus production, nasal tissue use, and virus concentrations in nasal secretions. IFN-alpha2b added to the effectiveness of chlorpheniramine and ibuprofen and was well tolerated.

Clinical significance and pathogenesis of viral respiratory infections.

Viral respiratory tract infections, also known as colds, are the most common infection in humans. The majority of these infections are caused by rhinoviruses. Rhinovirus deposition in the nose or the eye initiates infection. The virus attaches to the host cell intercellular adhesion molecule-1 (ICAM-1) receptors in the back of the throat. Subsequent viral replication triggers the release of inflammatory mediators and activation of neurogenic pathways, which lead to symptoms. Symptoms occur within 10 to 16 hours after virus entry into the nose and peak on days 2 to 3 of infection. Symptom duration is typically 1 week, although 25% of cases last longer. Understanding the chronology of these events is important in the timing of treatment. Because of the rapidity of symptom onset, early treatment is the key to reducing viral replication and illness. Also, early treatment may reduce the risk of transmission.

Viral respiratory infection therapy: historical perspectives and current trials.

Attempts to relieve the misery of the common cold have been made since long before current understanding of its viral origin. Although current symptomatic therapies provide some relief, any effective treatment must incorporate an antiviral to address the infection. Symptom production is related not only to viral cytopathic effect but also to the early activation of several inflammatory pathways. Antiviral treatment alone may not be able to prevent these events. Combining an antiviral with selected therapeutic agents that block these inflammatory pathways has been shown to improve the effectiveness of cold treatment. Early diagnosis and initiation of treatment combined with regular dosing until symptoms subside appears to be the most effective treatment strategy to maximize therapeutic outcomes. This strategy reduces viral shedding in nasal fluid, provides treatment for the period of maximum symptom burden, and may reduce the frequency and severity of the sinus disease that accompanies colds.