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Abstract Rationale Exposure to particulates from burning biomass is an increasing global health issue. Burning biomass, including wood smoke, is associated with increased lower respiratory infections. Objectives To determine whether acute exposure to wood smoke modifies nasal inflammatory responses to influenza. Methods Healthy young adults (n = 39) were randomized to a 2-hour controlled chamber exposure to wood smoke, where exposure levels were controlled to particulate number (wood smoke particles [WSP]; 500 μg/cm3) or filtered air, followed by nasal inoculation with a vaccine dose of live attenuated influenza virus (LAIV). Nasal lavage was performed before exposure (Day 0) and on Days 1 and 2 after exposure. Nasal lavage fluid cells were analyzed for inflammatory gene expression profiles, and cell-free fluid was assayed for cytokines. Measurements and Main Results Only IP-10 protein levels were affected, suppressed, by WSP exposure in aggregate analysis. Subsequent analysis indicated an exposure × sex interaction, prompting additional analyses of WSP- and LAIV-induced changes in males and females. Inflammation-related gene expression profiles differed between the sexes, at baseline (males greater than females), after LAIV inoculation (females greater than males), and after WSP exposure (increase in males and decrease in females), demonstrating that WSP- and LAIV-induced changes in antiviral defense responses in the nasal mucosa occur in a sex-specific manner. Conclusions WSP exposure resulted in minimal modification of LAIV-induced responses in aggregate analysis. In contrast, analyzing WSP-induced modification of LAIV responses in the sexes separately unmasked sex-specific differences in response to exposure. These data highlight the need for additional studies to understand sex-specific pollutant-induced effects. Clinical trial registered with www.clinicaltrials.gov (NCT02183753).

Abstract Rationale The mechanisms that underlie the pathogenesis of chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD) are not clear. Objectives To first evaluate the inflammatory profiles of CRSsNP and CRSwNP tissues and then to investigate whether clinical differences observed between CRSwNP and AERD are in part secondary to differences in inflammatory mediator expression within nasal polyp (NP) tissues. Methods Expression levels of numerous inflammatory mediators were determined by quantitative real-time polymerase chain reaction, ELISA, and multiplex immunoassay. Measurements and Main Results CRSwNP NP had increased levels of type 2 mediators, including IL-5 (P < 0.001), IL-13 (P < 0.001), eotaxin-2 (P  < 0.001), and monocyte chemoattractant protein (MCP)-4 (P < 0.01), compared with sinonasal tissue from subjects with CRSsNP and control subjects. Expression of IFN-γ messenger RNA or protein was low and not different among the chronic rhinosinusitis subtypes examined. Compared with CRSwNP, AERD NP had elevated protein levels of eosinophil cationic protein (ECP) (P < 0.001), granulocyte–macrophage colony–stimulating factor (GM-CSF) (P < 0.01), and MCP-1 (P = 0.01), as well as decreased gene expression of tissue plasminogen activator (tPA) (P = 0.02). Despite the higher eosinophilia in AERD, there was no associated increase in type 2 mediator protein levels observed. Conclusions CRSwNP was characterized by a predominant type 2 inflammatory environment, whereas CRSsNP did not reflect a classic type 1 milieu, as has been suggested previously. AERD can be distinguished from CRSwNP by elevated ECP levels, but this enhanced eosinophilia is not associated with elevations in traditional type 2 inflammatory mediators associated with eosinophil proliferation and recruitment. However, other factors, including GM-CSF, MCP-1, and tPA, may be important contributors to AERD pathogenesis.

Background. Serum antibody to the hemagglutinin (HA) of influenza viruses is a correlate and predictor of immunity to influenza in humans; the relative values of other correlates are uncertain. Methods. Serum and nasal secretions (NS) were collected in fall and spring of 2009—2011 from healthy adults who were monitored for acute respiratory illness (ARI). Serum samples were tested for hemagglutination-inhibition (HAI) antibody increase and secretions for virus if ill; enrollment sera were also tested for neuraminidase-inhibiting (NI) antibody and NS for neutralizing (neut), NI, immunoglobulin A (IgA), and immunoglobulin G (IgG) anti-HA antibody. Results. Serum anti-HA and anti-neuraminidase (NA) antibody titers to 2009(H1N1) pandemic influenza virus (pH1N1) correlated with titers in NS (including IgA and IgG antibody). Increasing anti-HA and anti-NA titers in serum and NS tests all correlated with reducing infection and infection-associated illness. Multivariate analyses indicated serum HAI and NI each independently predicted immunity to infection and infection-associated illness. Only serum NI independently predicted reduced illness among infected subjects. Conclusions. Increasing anti-HA and NA antibody in serum and secretions correlated with reducing pH1N1 influenza virus infection and illness in healthy young adults. Both anti-HA and anti-NA antibody are independent predictors of immunity to influenza; ensuring induction of both by vaccination is desirable.

Background Exposure to diesel exhaust causes inflammatory responses. Previous controlled exposure studies at a concentration of 300 μg/m 3 of diesel exhaust particles mainly lasted for 1 h. We prolonged the exposure period and investigated how quickly diesel exhaust can induce respiratory and systemic effects. Methods Eighteen healthy volunteers were exposed twice to diluted diesel exhaust (PM 1 ~300 μg/m 3 ) and twice to filtered air (PM 1 ~2 μg/m 3 ) for 3 h, seated, in a chamber with a double-blind set-up. Immediately before and after exposure, we performed a medical examination, spirometry, rhinometry, nasal lavage and blood sampling. Nasal lavage and blood samples were collected again 20 h post-exposure. Symptom scores and peak expiratory flow (PEF) were assessed before exposure, and at 15, 75, and 135 min of exposure. Results Self-rated throat irritation was higher during diesel exhaust than filtered air exposure. Clinical signs of irritation in the upper airways were also significantly more common after diesel exhaust exposure (odds ratio=3.2, p<0.01). PEF increased during filtered air, but decreased during diesel exhaust exposure, with a statistically significant difference at 75 min (+4 L/min vs. -10 L/min, p=0.005). Monocyte and total leukocyte counts in peripheral blood were higher after exposure to diesel exhaust than filtered air 20 h post-exposure, and a trend (p=0.07) towards increased serum IL-6 concentrations was also observed 20 h post-exposure. Conclusions Diesel exhaust induced acute adverse effects such as symptoms and signs of irritation, decreased PEF, inflammatory markers in healthy volunteers. The effects were first seen at 75 min of exposure.

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

Background. The nonstructural protein NS1 of influenza virus counteracts the interferon-mediated immune response of the host. By deleting the open reading frame of NS1, we have generated a novel type of influenza vaccine. We studied the safety and immunogenicity of an influenza strain lacking the NS1 gene (ΔNS1-H1N1) in healthy volunteers. Methods. Healthy seronegative adult volunteers were randomized to receive either a single intranasal dose of the ΔNS1-H1N1 A/New Caledonia vaccine at 1 of 5 dose levels (6.4, 6.7, 7.0, 7.4, and 7.7 log10 median tissue culture infective dose) (n= 36 recipients) or placebo (n= 12 recipients). Results. Intranasal vaccination with the replication-deficient ΔNS1-H1N1 vaccine was well tolerated. Rhinitis like symptoms and headache were the most common adverse events identified during the 28-day observation period. Adverse events were similarly distributed between the treatment and placebo groups. Vaccine-specific local and serum antibodies were induced in a dose-dependent manner. In the highest dose group, vaccine-specific antibodies were detected in 10 of 12 volunteers. Importantly, the vaccine also induced neutralizing antibodies against heterologous drift variants. Conclusions. We show that vaccination with an influenza virus strain lacking the viral interferon antagonist NS1 induces statistically significant levels of strain-specific and cross-neutralizing antibodies despite the highly attenuated replication-deficient phenotype. Further studies are warranted to determine whether these results translate into protection from influenza virus infection. Trial registration. ClinicalTrials.gov identifier: NCT00724997.

Inhalation of tobacco smoke has been linked to increased risk of viral infection, such as influenza. Inhalation of electronic-cigarette (e-cigarette) aerosol has also recently been linked to immune suppression within the respiratory tract, specifically the nasal mucosa. We propose that changes in the nasal mucosal immune response modify antiviral host-defense responses in e-cigarette users. Nonsmokers, cigarette smokers, and e-cigarette users were inoculated with live-attenuated influenza virus (LAIV) to safely examine the innate immune response to influenza infection. Before and after LAIV inoculation, we collected nasal epithelial-lining fluid, nasal lavage fluid, nasal-scrape biopsy specimens, urine, and blood. Endpoints examined include cytokines and chemokines, influenza-specific IgA, immune-gene expression, and markers of viral load. Statistical analysis included primary comparisons of cigarette and e-cigarette groups with nonsmokers, as well as secondary analysis of demographic factors as potential modifiers. Markers of viral load did not differ among the three groups. Nasal-lavage-fluid anti-LAIV IgA levels increased in nonsmokers after LAIV inoculation but did not increase in e-cigarette users and cigarette smokers. LAIV-induced gene-expression changes in nasal biopsy specimens differed in cigarette smokers and e-cigarette users as compared with nonsmokers, with a greater number of genes changed in e-cigarette users, mostly resulting in decreased expression. The top downregulated genes in cigarette smokers were SMPD3, NOS2A, and KLRB1, and the top downregulated genes in e-cigarette users were MR1, NT5E, and HRAS. Similarly, LAIV-induced cytokine levels in nasal epithelial-lining fluid differed among the three groups, including decreased antiviral host-defense mediators (IFNγ, IL6, and IL12p40). We also detected that sex interacted with tobacco-product exposure to modify LAIV-induced immune-gene expression. Our results demonstrate that e-cigarette use altered nasal LAIV-induced immune responses, including gene expression, cytokine and chemokine release, and LAIV-specific IgA levels. Together, these data suggest that e-cigarette use induces changes in the nasal mucosa that are consistent with the potential for altered respiratory antiviral host-defense function. Clinical trial registered with www.clinicaltrials.gov (NCT 02019745).

Nasal lavage is an ancient practice that still has a fundamental role in the management of sinonasal conditions. The history related to these devices is extensive and remarkable. By reviewing it, it is hoped that a broader view can be achieved on what is currently possible with nasal lavage and how advances may be made in the future. A careful review of different sources, such as ancient manuscripts, registered patents and scientific papers, was conducted to achieve a thorough examination of the history related to nasal rinsing devices. Nasal lavage has evolved significantly since first considered for medical use and has always played a central role in the treatment of patients with sinonasal conditions. Further innovation is still necessary to surmount the shortcomings of current nasal lavage systems.

Either placebo or a preparation of chemically defined extracts from Echinacea angustifolia root was administered to 399 volunteers before or after inoculation with rhinovirus. These rigorously controlled studies found no evidence that echinacea is effective in treating or preventing the common cold. These rigorously controlled studies found no evidence that echinacea is effective in treating or preventing the common cold. The common cold is a benign and self-limited illness most commonly caused by the rhinoviruses. Although the importance of the common cold derives primarily from its frequency and from the enormous socioeconomic impact it has, it is clear that the common cold in general and rhinovirus infection in particular are associated with significant medical consequences. 1 – 8 There are no specific antiviral treatments for rhinovirus infection. Perhaps because of the lack of specific therapies, concern about the risks relative to the benefits of treatments for symptoms, and the relatively benign nature of the common cold, there is wide interest in the . . .

Background The common cold, the most prevalent contagious viral disease in humans still lacks a safe and effective antiviral treatment. Iota-Carrageenan is broadly active against respiratory viruses in-vitro and has an excellent safety profile. This study investigated the efficacy and safety of an Iota-Carrageenan nasal spray in patients with common cold symptoms. Methods In a randomized, double-blind, placebo-controlled exploratory trial, 35 human subjects suffering from early symptoms of common cold received Iota-Carrageenan (0.12%) in a saline solution three times daily for 4 days, compared to placebo. Results Administration of Iota-Carrageenan nasal spray reduced the symptoms of common cold (p = 0.046) and the viral load in nasal lavages (p = 0.009) in patients with early symptoms of common cold. Pro-inflammatory mediators FGF-2, Fractalkine, GRO, G-CSF, IL-8, IL-1α, IP-10, IL-10, and IFN-α2 were reduced in the Iota-Carrageenan group. Conclusions Iota-Carrageenan nasal spray appears to be a promising treatment for safe and effective treatment of early symptoms of common cold. Larger trials are indicated to confirm the results.