Viral Initially Allergy and Asthma

Widodo Judarwanto. Children Allergy Center Jakarta Indonesia.

Viral respiratory tract infections are important respiratory pathogens implicated in allergy exacerbations such as asthma, dermatitis, allergy gastrointestinal  and other manifestation. The etiology and morbidity associated with allergy and asthma are thought to stem from both genetic factors and potentially modifiable environmental factors, such as viral infections. Although it is unclear whether respiratory viral infections initially allergy and  asthma, observational studies have demonstrated a high rate of allergy and asthma in children with a history of severe viral lower respiratory tract infections during infancy, and viruses are associated with the majority of asthma exacerbations among both children and adults.

Introduction

The possible role of viral infections in the inception of asthma has been the matter of considerable debate. Older data suggested that viral respiratory infections occurring during early life could alter the lungs and the immune system, thus starting the process leading to allergic sensitization and persistent bronchial responsiveness. More recent studies suggest that infants who wheeze belong to two distinct groups, which at present can only be differentiated by the evolution of their illness. Most of these infants have a transitory tendency to wheeze during viral infections, and their lung function shortly after birth is significantly lower than that of infants who will not wheeze during similar infections. Most of these children become symptom-free during the preschool years, and their condition is not associated with higher serum IgE levels. A smaller group of children who wheeze as infants will still have wheezing episodes during the early school years. The factors that determine which infants will become persistent wheezers are not well understood, but viral infections per se are likely to play a minor role, if any. Early sensitization to aeroallergens in subjects genetically predisposed to having high serum IgE levels seems to be the main risk factor for this condition.

Viruses are recognized to be the major cause of respiratory infections. Clinical and experimental evidence also supports an important role for viruses in the pathogenesis of lower airway disease and asthma exacerbation. In prospective epidemiological studies, 80% of asthma exacerbations in school-aged children and half of all asthma exacerbations in adults have been associated with viral upper respiratory infections. Human rhinovirus (HRV) has been implicated as the principal virus associated with asthma exacerbation. In our studies on respiratory viruses, we have observed two clinical patterns of presentation. The viruses can either be a precipitating factor of respiratory illness characterized by a typical clinical onset, or can induce an atypical clinical onset such as haemoptysis, pleuritis, spontaneous pneumothorax and asthmatic syndrome. Thus the observed clinicoradiological and functional features during atypical viral respiratory infection may be correlated to the long-term biological effects induced by previous and concurrent infections.

The impact of respiratory viral infection on wheezing illnesses and asthma exacerbations

Patients at risk of asthma, or with existing asthma, viral respiratory tract infections can have a profound effect on the expression of disease or loss of control. New evidence has shown that wheezing episodes early in life due to human rhinoviruses are a major risk factor for the later diagnosis of asthma at age 6 years. For those with existing asthma, exacerbations are a major cause of morbidity, can need acute care, and can, albeit rarely, result in death.

Viral respiratory tract infections, predominantly those caused by human rhinoviruses, are associated with asthma exacerbations. Respiratory viral infections profoundly influence the disease activity of wheezing illnesses and asthma in early childhood. Viral bronchiolitis shares many features with asthma and a subset of children develop recurrent wheezing after their initial illness. Recently mechanisms for virus-induced exacerbations of childhood asthma are beginning to be focused on and defined. Viruses cause systemic immune activation and also produce local inflammation. These factors are likely to affect airway pathogenesis leading to airway narrowing, an increase in mucus production, and eventually bronchospasm, and airway obstruction. These new insights related to the pathogenesis and disease activity are likely to provide new targets for the therapy and prevention of early asthma in childhood.

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.

There is also evidence that deficiencies in antiviral activity and the integrity of the airway epithelial barrier could make individuals with asthma more likely to have severe viral respiratory infections of the lower airway, and thus increase the risk of exacerbation. In view of the effect of respiratory viruses on many aspects of asthma, efforts to understand the mechanisms and risk factors by which these airway infections cause changes in airway pathophysiology are a first step towards improved treatment.

Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract disease in infants and children worldwide and the most common cause of childhood hospitalization in high-income countries. In industrialized countries, the rates of RSV hospitalization have been increasing, and, likewise, an increase in atopic disease has been reported.

In prospective cohort studies, RSV bronchiolitis during infancy or in the first 3 years of life has been found to be an important risk factor for the development of subsequent wheezing and asthma in the ensuing 7 to 11 years, and a causal relation between RSV hospitalization and subsequent hypersensitive airways has been suggested. However, it has also been suggested that a family history of atopy may dispose infants to develop more serious RSV lower respiratory tract infections (LRIs), and studies have shown that a parental history of asthma, especially on the maternal side, increases the risk of developing LRI in early life. It is still unclear, however, whether RSV LRI is causal in the development of subsequent recurrent wheezing and asthma or whether severe RSV LRI occurs on the background of an atopic predisposition and/or hypersensitive airways. The present study examined whether atopic disposition, wheezing, and atopic disorders were determinants for subsequent RSV hospitalization.

Mechanism

The role of respiratory viral infection in the development of asthma remains unclear. A number of factors play crucial roles, including the type of virus, the severity of the disease, the time of the infection, and, most important, the host predisposition. On the other hand, there is little doubt that a strong association exists between viral respiratory infections and induction of wheezing illnesses and asthma exacerbations. The underlying mechanisms, although not fully clarified, are likely to be multifactorial, involving inflammation of the bronchial mucosa, which interacts under certain circumstances with allergic inflammation. In addition, repetitive infections play an important role in perpetuating inflammation and airway hyperresponsiveness, especially in the presence of atopy, leading from childhood asthma to a more persistent asthma phenotype.

The mechanisms by which Viral respiratory tract infections trigger inflammatory responses in the lower airway are poorly understood, in particular their ability to infect the lower airway. Bronchial inflammatory cell (lymphocyte and eosinophil) recruitment has been demonstrated. IL-8 is a potent proinflammatory chemokine that is chemotactic for neutrophils, lymphocytes, eosinophils, and monocytes and may be important in the pathogenesis of virus-induced asthma. Increased levels of IL-8 have been found in nasal samples in natural and experimental rhinovirus infections. In these studies we therefore examine the ability of rhinovirus to infect a transformed lower airway epithelial cell line (A549) and to induce IL-8 protein release and mRNA induction. We observed that rhinovirus type 9 is able to undergo full viral replication in A549 cells, and peak viral titers were found 24 h after inoculation. Rhinovirus infection induced a dose- and time-dependent IL-8 release up to 5 days after infection and an increase in IL-8 mRNA expression that was maximal between 3 and 24 h after infection. UV inactivation of the virus completely inhibited replication, but only reduced IL-8 protein production and mRNA induction by half, while prevention of virus-receptor binding completely inhibited virus-induced IL-8 release, suggesting that part of the observed effects was due to viral replication and part was due to virus-receptor binding. These studies demonstrate that rhinoviruses are capable of infecting a pulmonary epithelial cell line and inducing IL-8 release. These findings may be important in understanding the pathogenesis of rhinovirus-induced asthma exacerbations.

Acute viral infection results in increased airway responsiveness to inhaled methacholine and pulmonary neutrophilic and eosinophilic inflammation. This response is associated with predominant production of Th-1-type cytokines in peribronchial lymph node cells in vitro. Mice sensitized to ovalbumin via the airways after RSV infection developed increased airway responsiveness to methacholine and pulmonary eosinophilic and neutrophilic inflammation, associated with the predominant production of Th-2-type cytokines. Treatment of the mice with anti-IL-5 antibody abolished airway hyperresponsiveness and eosinophilic but not neutrophilic inflammation in both acutely infected mice and mice sensitized after infection.

To address the role of IL-11 in viral airways dysfunction, we determined whether infectious agents that exacerbate asthma stimulate stromal cell IL-11 production, determined whether IL-11 could be detected at sites of viral infection and evaluated the effects of IL-11 on airway physiology. Respiratory syncytial virus (RSV), parainfluenza virus type 3 (PIV3), and rhinovirus (RV) 14 were potent stimulators while cytomegalovirus and adenovirus only weakly stimulated and herpes simplex virus type 2 and bacteria did not stimulate IL-11 elaboration. IL-11 was not detected or barely detected in nasal aspirates from children without, but was detected in aspirates from children with viral upper respiratory tract infections. The levels of IL-11 were highest in patients with clinically detectable wheezing. IL-11 also caused nonspecific airways hyperresponsiveness in BALB/c mice. These studies demonstrate that three major causes of viral-induced asthma, RSV, RV, and PIV, in contrast to other viruses and bacteria, share the ability to induce stromal cell IL-11 production. They also demonstrate that IL-11 can be detected in vivo during viral respiratory infections, that the presence of IL-11 correlates with clinical bronchospasm and that IL-11 is a potent inducer of airways hyperresponsiveness. IL-11 may be an important mediator in viral airways disorders.

Prevention

Respiratory viral infections are very important triggers of asthma exacerbation. Recent epidemiologic studies support the hypothesis that they are associated with 80 to 85% of acute attacks of asthma in children. The respiratory syncytial and parainfluenza viruses are predominantly detected in infants, while rhinovirus and mycoplasma are the commonest in children. In practice for anallergy and  asthmatic child, it is necessary: 1. to vaccinate against influenza; 2. resume or increase the inhaled antiinflammatory therapeutics in moderate to severe asthma, before the viral epidemic season; 3. teach the child and his family on the attitude to have during an upper respiratory infection and when to visit a physician.

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