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Rackemann described the 'intrinsic asthma' population over 50 years ago as a unique subgroup that was characterized by onset of progressive loss of lung function beginning later in life, possibly after a respiratory infection. It has also been associated with a female predominance, aspirin-sensitive bronchospasm, and nasal polyposis. While the aetiology is not understood, we propose that persistent respiratory infections play a central role in the development of intrinsic asthma.

The suitability of employing AIR Inhaled Insulin (AIR Insulin; AIR is a registered trademark of Alkermes) during acute upper respiratory tract infection (URI) has not been determined. Twenty-one healthy, non-diabetic subjects were enrolled in a single-sequence, two-period, euglycemic clamp study. Subjects received a single 12 U-equivalent dose of AIR Insulin before rhinovirus (RV16) inoculation and during symptomatic infection. Spirometry was used to evaluate pulmonary safety. AIR Insulin exposure (the area under the immunoreactive insulin (IRI) concentration vs time curve from time zero until the IRI concentrations returned to the predose baseline value (AUC(0-t'))) and glucodynamic response (total amount of glucose infused (G(tot))) were comparable before and during RV infection (AUC(0-t') 46,300 vs 52,600 pmol min/l, P=0.21; G(tot) 61,800 vs 68,700 mg, P=0.42, respectively). Variability of pharmacokinetic and pharmacodynamic parameters did not change during URI; either did the number or intensity of adverse events. No significant change in forced expiratory volume or forced vital capacity was observed following AIR Insulin administration or during URI. The AIR Insulin system provides similar pharmacokinetic and glucodynamic responses under conditions of an experimentally induced RV infection and is regarded as suitable for use in diabetic patients during URIs.

Respiratory infections are common causes of increased asthma for patients of all ages. Current evidence indicates that viral, and not bacterial, infections are the most important respiratory illnesses which increase the severity of asthma. Of the respiratory viral infections associated with increased asthma, rhinoviruses, i.e. the cause of common colds, have proven to be the virus most often found in association with increased asthma severity. Although the association between rhinovirus infections and asthma is most dramatically illustrated in children, asthma patients of all ages can be affected and the attacks of asthma can be severe. Studies to establish the mechanisms by which rhinoviruses enhance asthma severity have begun to focus on how this virus promotes allergic inflammation. We have found that experimental rhinovirus infections enhance airway responsiveness and, perhaps most importantly, the likelihood that a late allergic reaction will occur to an antigen challenge. Furthermore, using bronchoscopy and segmental antigen challenge, we have found that rhinovirus infections promote mast cell release of histamine and the recruitment of eosinophils to the airways. These data support the concept that rhinovirus infections act to promote allergic inflammation and by this mechanism increase both the likelihood of asthma occurring and the severity of wheezing.

Parainfluenza type 1 (Sendai) virus infection in young rats induces airway growth abnormalities associated with persistent pulmonary dysfunction and hyperresponsiveness. The objectives of this study were to compare virus-susceptible brown Norway (BN) rats and virus-resistant F344 rats and to determine which of several virus-induced structural abnormalities, including bronchiolar hypoplasia, alveolar dysplasia, bronchiolar mural fibrosis, and increases in bronchiolar mast cells, were associated with virus-induced increases in pulmonary resistance and hyperresponsiveness to methacholine. We also determined whether bronchiolar mural thickening and fibrosis may be caused by increased bronchiolar expression of cytokines such as TGF-beta 1 into airways. BN rats infected with virus developed increases in respiratory resistance and hyperresponsiveness that persisted for 28 to 65 d after inoculation. Functional abnormalities were most strongly associated with bronchiolar mural thickening and fibrosis as well as with recruitment of inflammatory cells, including macrophages, mast cells, lymphocytes, and eosinophils, into the bronchiolar wall. F344 rats were resistant to significant virus-induced alterations in bronchiolar airway wall thickness and mast cell increases as well as to pulmonary function abnormalities. BN rats had increase pulmonary mRNA levels of TGF-beta 1 at 10 and 14 d after viral inoculation as compared with F344 rats. BN rats also had greater numbers of bronchiolar macrophages expressing TGF-beta 1 protein that were localized in bronchiolar walls at 10, 14, and 30 d after inoculation. We conclude that recruitment and persistence of airway inflammatory cells and airway wall fibrosis may be important alterations induced by viral lower respiratory disease during early life that can lead to long-term airway dysfunction and hyperresponsiveness. Virus-induced airway fibrosis may be mediated in part by increased TGF-beta 1 gene expression by bronchiolar macrophages in genetically susceptible individuals.

Viral respiratory infections can increase asthma symptoms in many patients. Although the mechanisms of these effects are not fully established, there is evidence that respiratory viruses can promote some components of allergic inflammation. In this regard, there is evidence that rhinovirus respiratory infections can lead to the development of late allergic reactions to inhaled allergen. This change in response to inhaled allergen supports the possibility that some respiratory infection will promote bronchial inflammation and may be a factor for increased wheezing with respiratory infection.

Viruses provoke symptoms of wheezing in many patients with asthma. Furthermore, there is evidence that viruses increase airway responsiveness in non-asthma patients. The mechanisms involved in these reactions are not clearly established, but evidence suggests that the ability of viruses to promote this bronchial responsiveness may be related to an upregulation of the allergic inflammatory reaction. This would explain why patients may be more prone to have a late asthmatic reaction.

Airway responsiveness is increased during respiratory virus infections, both in subjects with asthma and without underlying pulmonary disease. Furthermore, the airway hyperresponsiveness is altered for a prolonged period of time, weeks or months after the viral illness has subsided. This article reviews the possible mechanisms of virus-associated airway hyperresponsiveness, including the complex interplay of IgE-dependent reactions, changes in autonomic nervous system function and inflammation, epithelial damage, effects of viruses on the cellular immune response, and enhanced late-phase response.

Bacterial pneumonia remains a major health threat, with particular risk for infants in developing countries. The effective design of strategies that minimize the morbidity and mortality from pneumonia requires an awareness of the host defense mechanisms that function to prevent respiratory infections. In this review the normal immune host defenses and the abnormalities in this process that promote the development of lower respiratory bacterial infections will be briefly reviewed. A brief discussion will focus on a complication of respiratory infections, asthma, which can follow viral illness and also be a significant problem for children.

The effects of RVIs on airway reactivity are multiple but do not necessarily include direct changes in the intrinsic contractile properties of airway smooth muscle. Rather, respiratory viruses influence bronchial smooth muscle function through a variety of other mechanisms: production of virus-specific IgE antibodies, epithelial injury, polymorphonuclear-dependent inflammation, and enhanced mediator release. Thus, a common pathway to airway hyper-reactivity during respiratory viral illnesses is an overall enhancement of factors that cause or lead to inflammation. When the airways become the target of enhanced inflammation, bronchial reactivity and obstruction are accentuated. Although many questions remain to be answered, future studies to evaluate the biology of respiratory virus effects on mechanisms of allergic sensitization and airway responsiveness promise to provide a greater understanding of the pathogenesis of asthma.

The parainfluenza 3 (P-3)-infected guinea pig was examined as a model for virus-provoked airway hyperreactivity by measuring changes in airway overflow pressure in response to intravenously (iv) administered histamine. In vitro responses of lung parenchymal strips to several contractile substances were also measured. All studies were conducted 4 days after nasal insufflation with P-3 or P-3 growth medium (control). Increases in airway overflow pressure caused by histamine were enhanced by P-3 infection, and the dose required to produce a standard level of response was decreased (i.e., there was an increase in sensitivity to histamine). Enhancement of in vivo histamine responses caused by P-3 was prevented both by cutting the vagus nerves in the midcervical region and by iv administered hexamethonium, 5 mg/kg. The enhancement was not blocked by 1 mg/kg of atropine given iv, but was blocked by a larger dose 5 mg/kg. The larger dose of atropine significantly antagonized responses to histamine in the P-3-infected state. Increases in airway overflow pressure produced by electrical stimulation of the left vagus and nicotine (1 and 10 mg/kg given iv), both studied after bilateral vagotomy and propranolol, 1 mg/kg given iv, were also enhanced by P-3 infection. Atropine, 1 mg/kg given iv blocked the P-3-induced enhancement of responses to vagus stimulation. Propranolol, 1 mg/kg, and phentolamine, 3 mg/kg, given together iv, produced a doubling of the airway overflow pressure only in P-3-infected animals. Propranolol alone or other receptor antagonists did not produce as marked a change in either group of animals.(ABSTRACT TRUNCATED AT 250 WORDS)

From this review, it is apparent that the effects of respiratory viral infection on airway reactivity are multiple. Although virus-associated changes are many, we have at present no evidence to show that respiratory viruses cause intrinsic abnormalities in airway smooth muscle function. Rather, respiratory viruses influence bronchial smooth muscle function through a variety of other means: epithelial injury, PMN-dependent inflammation, and greater mediator release. These observations suggest that a common pathway to development of airway hyperreactivity during respiratory viral illnesses is to enhance those factors which participate in the inflammatory response. When the target of this enhanced inflammatory response becomes the airway, greater bronchial reactivity and obstruction result. Although many questions remain to be answered, we feel that future studies to evaluate the biology of respiratory virus effects on mechanisms of airway responsiveness will lead to a greater understanding of asthma pathogenesis.

The pathogenesis of both allergic diseases and asthma remains an unsolved mystery. Of considerable interest, and perhaps insight, into this problem are clinical observations that viral illnesses play an important role in the allergic diathesis. Conclusive evidence to establish a relationship linking viral illnesses to clinical allergy has yet to be established. Nonetheless, recent observations in this arena are intriguing to scientist and clinician alike. The following discussion reviews recent investigations that evaluate the relationship between viral illnesses and development of allergic disease and asthma.

A number of important mechanisms have been identified by which viruses can provoke asthma. From the data available, there does not appear to be one single mechanism available to explain virus-induced asthma. The relationship between viral URIs and asthma is complex and involves many organ systems: airway epithelium, autonomic nervous system control, and the immediate hypersensitivity system. Identifying the effects of respiratory viruses on airway function remains an important undertaking as we try to better understand and control this precipitant of asthma.

Although viral upper respiratory infections (URIs) provoke wheezing in many asthma patients, the effect of these illnesses on the airway response to inhaled antigen is not established. The following study evaluated the effect of an experimental rhinovirus (RV) illness on airway reactivity and response to antigen in 10 adult ragweed allergic rhinitis patients. Preinfection studies included measurements of airway reactivity to histamine and ragweed antigen. Furthermore, the patients were also evaluated for late asthmatic reactions (LARs) to antigen (a 15% decrease in forced expiratory volume of the first second approximately 6 h after antigen challenge). 1 mo after baseline studies, the patients were intranasally inoculated with live RV16. All 10 patients were infected as evidenced by rhinovirus recovery in nasal washings and respiratory symptoms. Baseline FEV1 values were stable throughout the study. During the acute RV illness, there was a significant increase in airway reactivity to both histamine and ragweed antigen (P = 0.019 and 0.014, respectively). Before RV inoculation, only 1 of the 10 subjects had an LAR after antigen challenge. However, during the acute RV illness, 8 of 10 patients had an LAR (P less than 0.0085 compared with baseline); the development of LARs was independent of changes in airway reactivity and the intensity of the immediate response to antigen. Therefore, we found that not only does a RV respiratory tract illness enhance airway reactivity, but it also predisposes the allergic patient to develop LARs, which may be an important factor in virus-induced bronchial hyperresponsiveness.

Isoproterenol inhibits zymosan-stimulated release of lysosomal enzymes from granulocytes. Using this as an in vitro cell model to study beta-adrenergic response, granulocyte reaction to isoproterenol was examined in asthma. There was a significantly decreased response to isoproterenol (10(-7) to 10(+-5) M) in patients with mild asthma who had not taken bronchodilators for 2 weeks before study and also in patients with severe asthma requiring bronchodilators and corticosteroids. During respiratory infections that provoked an attack of asthma, the granulocyte response to isoproterenol was further decreased. The change in granulocyte response to isoproterenol may reflect a similar change in beta-adrenergic tone of the airways and provide one explanation for asthma during colds.

A clear relationship between viral upper respiratory infections and exacerbations of asthma has been established in numerous clinical studies. However, a unifying concept to explain how respiratory viruses bring about these changes has not been established unless it is the ability of viral illnesses to promote the inflammatory process. These changes in inflammation potentially encompass several organ systems: airway epithelium, the autonomic nervous system, and immediate hypersensitivity reactions. Thus, enhanced airway reactivity in viral respiratory infections represents a complex orchestration of many factors and functions to create the end result of bronchial hyperresponsiveness. Insight into precisely how the respiratory virus initiates these changes should provide valuable and new information into the pathogenesis of asthma. Therefore, not only is virus-induced asthma an important clinical problem, but it may also serve as a window to mechanisms of airway hyperreactivity and asthma.