Joshua L. Kennedy

Pathogenesis of rhinovirus infection.

Since its discovery in 1956, rhinovirus (RV) has been recognized as the most important virus producing the common cold syndrome. Despite its ubiquity, little is known concerning the pathogenesis of RV infections, and some of the research in this area has led to contradictions regarding the molecular and cellular mechanisms of RV-induced illness. In this article, we discuss the pathogenesis of this virus as it relates to RV-induced illness in the upper and lower airway, an issue of considerable interest in view of the minimal cytopathology associated with RV infection. We endeavor to explain why many infected individuals exhibit minimal symptoms or remain asymptomatic, while others, especially those with asthma, may have severe, even life-threatening, complications (sequelae). Finally, we discuss the immune responses to RV in the normal and asthmatic host focusing on RV infection and epithelial barrier integrity and maintenance as well as the impact of the innate and adaptive immune responses to RV on epithelial function.

Galactose-α-1,3-galactose and Delayed Anaphylaxis, Angioedema, and Urticaria in Children

BACKGROUND AND OBJECTIVE: Despite a thorough history and comprehensive testing, many children who present with recurrent symptoms consistent with allergic reactions elude diagnosis. Recent research has identified a novel cause for “idiopathic” allergic reactions; immunoglobulin E (IgE) antibody specific for the carbohydrate galactose-α-1,3-galactose (α-Gal) has been associated with delayed urticaria and anaphylaxis that occurs 3 to 6 hours after eating beef, pork, or lamb. We sought to determine whether IgE antibody to α-Gal was present in sera of pediatric patients who reported idiopathic anaphylaxis or urticaria. METHODS: Patients aged 4 to 17 were enrolled in an institutional review board–approved protocol at the University of Virginia and private practice allergy offices in Lynchburg, VA. Sera was obtained and analyzed by ImmunoCAP for total IgE and specific IgE to α-Gal, beef, pork, cat epithelium and dander, Fel d 1, dog dander, and milk. RESULTS: Forty-five pediatric patients were identified who had both clinical histories supporting delayed anaphylaxis or urticaria to mammalian meat and IgE antibody specific for α-Gal. In addition, most of these cases had a history of tick bites within the past year, which itched and persisted. CONCLUSIONS: A novel form of anaphylaxis and urticaria that occurs 3 to 6 hours after eating mammalian meat is not uncommon among children in our area. Identification of these cases may not be straightforward and diagnosis is best confirmed by specific testing, which should certainly be considered for children living in the area where the Lone Star tick is common.

Comparison of Viral Load in Individuals with and without Asthma during Infections with Rhinovirus

RATIONALE Most virus-induced attacks of asthma are caused by rhinoviruses (RVs). OBJECTIVES To determine whether people with asthma are susceptible to an increased viral load during RV infection. METHODS Seventy-four children (4-18 yr old) were enrolled; 28 with wheezing, 32 with acute rhinitis, and 14 without respiratory tract symptoms. Nasal washes were evaluated using quantitative polymerase chain reaction for RV to judge viral load along with gene sequencing to identify strains of RV. Soluble intercellular adhesion molecule-1, IFN-λ1, and eosinophil cationic protein in nasal washes, along with blood eosinophil counts and total and allergen-specific IgE in sera, were also evaluated. Similar assessments were done in 24 young adults (16 with asthma, 8 without) who participated in an experimental challenge with RV (serotype 16). MEASUREMENTS AND MAIN RESULTS Fifty-seven percent of wheezing children and 56% with acute rhinitis had nasal washes testing positive for RV. The geometric mean of viral loads by quantitative polymerase chain reaction in washes from wheezing children was 2.8-fold lower, but did not differ significantly from children with rhinitis (7,718 and 21,612 copies of viral RNA per microliter nasal wash, respectively; P = 0.48). The odds for wheezing were increased if children who tested positive for RV were sensitized to one or more allergens (odds ratio, 3.9; P = 0.02). Similarly, neither peak nor cumulative viral loads differed significantly in washes from adults with asthma compared with those without asthma during the experimental RV challenge. CONCLUSIONS During acute symptoms, children infected with RV enrolled for wheezing or acute rhinitis had similar viral loads in their nasal washes, as did adults with and without asthma infected with RV-16 experimentally.

The role of allergy in severe asthma

The classification of asthma to identify forms which have different contributing causes is useful for all cases in which the disease requires regular treatment, but it is essential for the management of severe asthma. Many forms of the disease can occur, and complex mixtures are not uncommon; here we artificially separated the cases into four groups: (i) inhalant allergy, (ii) fungal sensitization with or without colonization (including ABPA); (iii) severe sinusitis with or without aspirin‐exacerbated respiratory disease (AERD), and (iv) non‐inflammatory cases, including those associated with severe obesity and vocal cord dysfunction (VCD). The reason for focusing on these groups is because they illustrate how much the specific management depends upon correct classification. Inhalant allergy can present as chronically severe asthma. However, severe attacks of asthma requiring hospital admission can occur in cases which are generally only mild or moderate. The best recognized and probably the most common cause of these acute episodes is acute infection with a rhinovirus. Recent evidence suggests that high titre IgE, particularly to dust mite, correlates to exacerbations of asthma related to rhinovirus infection. Although it is well recognized that the fungus Aspergillus can colonize the lungs and cause severe disease, it is less well recognized that those cases may not have full criteria for diagnosis of ABPA or may involve other fungi. Identifying fungal cases is important, because treatment with imidazole antifungals can provide significant benefit. Taken together, specific treatment using allergen avoidance, immunotherapy, anti‐IgE, or antifungal treatment is an important part of the successful management of severe asthma, and each of these requires correctly identifying specific sensitization.

Chronic sinusitis pathophysiology: the role of allergy.

Background Chronic hyperplastic eosinophilic sinusitis (CHES) is an inflammatory disease characterized by eosinophil infiltration of sinus tissue that can present with and without nasal polyps (NPs). Aeroallergen sensitization in CHES occurs regularly, but the causality between allergen sensitivity, exposure, and disease is unclear. Methods Allergen is unlikely to directly enter healthy sinuses either by diffusion or ciliary flow, and, even this is more problematic given the loss of patency of the ostia of diseased sinuses. Inflammation and tissue eosinophilia can develop secondary to allergen exposure in the nares, with systemic humoral recirculation of allergic cells including eosinophils, Th2 lymphocytes, and eosinophil precursors that are nonspecifically recruited back to the diseased sinuses. Results The possibility of an allergic reaction to peptides derived from bacteria (i.e., Staphylococcus or superantigens) or fungi that colonize the diseased sinus also provides a plausible allergic mechanism. Conclusion Treatments of this disease include agents directed at allergic mediators such as leukotriene modifiers and corticosteroids, although this does not necessarily signify that an IgE-dependent mechanism can be ascribed. However, more recently, omalizumab has shown promise, including in patients without obvious aeroallergen sensitization. Although many aspects of the role of allergy in CHES remain a mystery, the mechanisms that are being elucidated allow for improved understanding of this disease, which ultimately will lead to better treatments for our patients who live daily with this disease.

Chronic rhinosinusitis and antibiotics: the good, the bad, and the ugly.

Background Despite the recognition that bacteria are universally present in the sinuses of patients with chronic rhinosinusitis (CRS) no compelling role for a primary infectious etiology of CRS has been elucidated. CRS is a constellation of inflammatory diseases that typically involve either noneosinophilic or eosinophilic processes, distinct conditions that must be treated individually. Methods The bacteria that are present in the sinuses may be innocuous bystanders but alternatively may contribute to the presence and severity of the disease through their ability to influence immune responses, function as immune adjuvants, provide antigens or superantigens that contribute to adaptive immune activation, or in forming the basis for the frequent acute superinfections. However, those bacteria that do contribute to the persistence and severity of CRS primarily reside in biofilms, and, as such, are not capable of being eradicated with antibiotics at the doses at which they can be used, even when local irrigation is considered. Results Biofilms create an inhospitable environment for antibiotic potency by down-regulating the metabolic activity of their “core” bacteria, decreasing the oxygen concentration, and altering the pH at the core of the biofilm. Conclusion Ultimately, if topical antibiotics are considered, they should be primarily focused on treating acute exacerbations and choices of antibiotics should optimally be based on endoscopic culture. This should be done with the recognition that while under certain circumstances antibiotics can ameliorate the severity of CRS, even if bacterial eradication were possible, this would not eliminate the underlying primary pathogenic mechanism or the natural history of these conditions.

The past, present, and future of monoclonal antibodies to IL-5 and eosinophilic asthma: a review

Asthma is a heterogeneous syndrome that might be better described as a constellation of phenotypes or endotypes, each with distinct cellular and molecular mechanisms, rather than as a singular disease. One of these phenotypes is eosinophilic asthma. As the development of eosinophilic inflammation is categorically dependent on the biological activity of Interleukin (IL)-5, IL-5 antagonism became an obvious target for therapy in this phenotype. Early trials of monoclonal antibodies targeting the biological activity of IL-5, including reslizumab, mepolizumab, and benralizumab, were performed on asthmatics with no concern for evidence of eosinophilia. These trials were largely unsuccessful. However, during these trials, researchers recognized the need to quantify eosinophilia in asthma subjects in order to identify those asthmatics in whom these medications would be more likely to improve symptoms and lung function. Using biomarkers, such as sputum and blood eosinophilia, recent studies of these medications have shown improvements in blood and sputum eosinophilia, forced expiratory volume in 1 second, and quality of life assessments as well as reducing occurrences of exacerbations. Moving forward, better and less invasive biomarkers of eosinophilia are necessary to ensure that the correct patients are chosen to receive these medications to receive maximal benefit.

Rhinovirus and Asthma: a Storied History of Incompatibility

The human rhinovirus (HRV) is commonly associated with loss of asthma symptom control requiring escalation of care and emergency room visits in many patients. While the association is clear, the mechanisms behind HRV-induced asthma exacerbations remain uncertain. Immune dysregulation via aberrant immune responses, both deficient and exaggerated, have been proposed as mechanisms for HRV-induced exacerbations of asthma. Epithelium-derived innate immune cytokines that bias Th2 responses, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), have also been implicated as a means to bridge allergic conditions with asthma exacerbations. In this review, we discuss the literature supporting these positions. We also discuss new and emerging biotherapeutics that may target virus-induced exacerbations of asthma.

Infection with human rhinovirus 16 promotes enhanced IgE responsiveness in basophils of atopic asthmatics

Rhinovirus and IgE act in concert to promote asthma exacerbations. While basophils are the principal cell type in the blood that is activated by IgE, their role in virus‐induced asthma episodes remains elusive.

Aspirin-Exacerbated Respiratory Disease: Prevalence, Diagnosis, Treatment, and Considerations for the Future:

Aspirin-exacerbated respiratory disease (AERD) is a late onset condition characterized by the Samter triad (aspirin sensitivity [as well as sensitivity to any nonselective cyclooxygenase inhibitor], nasal polyps, asthma) and additional features, including eosinophilic chronic rhinosinusitis, hypereosinophilia, anosmia, frequent absence of atopy, and, intolerance to ingestion of red wine and other alcoholic beverages. The diagnosis is rare, and, because of this, it is also often missed by physicians. However, it is highly overexpressed in patients with severe asthma (and severe chronic rhinosinusitis with nasal polyps), which makes its recognition essential. For this review, we considered mechanisms involved in the pathogenesis of this disease and discussed the clinical symptoms of AERD. We also discussed the role of aspirin desensitization in the treatment of AERD. Also, we considered medications (e.g, leukotriene modifiers) and surgical interventions that have a role in the treatment of AERD.