Infectious triggers of pediatric asthma

Infectious triggers of pediatric asthma

James E. Gern, MDa,*, Robert F. Lemanske, Jr., MDa,b

aDepartment of Pediatrics, University of Wisconsin Medical School, Madison, WI 53792, USAbDepartment of Medicine, University of Wisconsin Medical School, Madison, WI 53792, USA

Respiratory infections can cause wheezing illnesses in children of all ages and

also can influence the causation and disease activity of asthma. For years it has been

recognized that respiratory syncytial virus (RSV) infections often produce the first

episode of wheezing in children who go on to develop chronic asthma. More re-

cently, it has been proposed that repeated infections with other common childhood

viral pathogens might help the immune system develop in such a way as to prevent

the onset of allergic diseases and possibly asthma. In addition to the effects of viral

infections, infections with certain intracellular pathogens, such as Chlamydia and

Mycoplasma, may cause acute and chronic wheezing in some individuals, whereas

common cold and acute sinus infections can trigger acute symptoms of asthma. In

this article, the epidemiologic, mechanistic, and treatment implications of the

association between respiratory infections and asthma are discussed.

Epidemiology

Can infections cause asthma?

Asthma is a multifactorial disease that is likely to be the result of interactions

between a genetically determined predisposition to allergic diseases and envi-

ronmental factors that serve to enhance allergic inflammation and target inflam-

mation to the lower airway (Fig. 1). Genetic factors may include regulation of

cytokines that control the generation of IgE and eosinophilic inflammation, along

with polymorphisms in genes that regulate airway tone (eg, b-adrenergicreceptors) and repair mechanisms for acute injuries. Recent epidemiologic studies

suggest that environmental factors, and especially exposures in early infancy,

0031-3955/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S0031-3955(03)00040-3

This work was supported by NIH Grants AI34891, HL56396, 1RO1HL61879, and P01HL070831.

* Corresponding author. University of Wisconsin Hospital, 600 Highland Avenue, K4/918,

Madison, WI 53792–9988.

E-mail address: [email protected] (J.E. Gern).

Pediatr Clin N Am 50 (2003) 555–575

may play a major role in the development of the immune system. In this regard,

exposure to microbial products, allergens, stress, and perhaps even certain

infections may help the immune system to mature so that allergies are less likely

to occur. If allergy is present, severe lower respiratory infections (eg, RSV

bronchiolitis, and perhaps chronic infections with Mycoplasma, Chlamydia, and

Adenovirus) may damage the lungs or target allergic inflammatory responses to

the lower airway and thus promote the development of asthma.

Respiratory syncytial virus, lower respiratory illness, and bronchiolitis

Infection with RSV is the most common cause of bronchiolitis, which parallels

many of the features of childhood asthma [1]. From 1980 to 1996, rates of

hospitalization of infants with bronchiolitis increased substantially [2]; from this

report among others, RSV was found to cause about 70% of these episodes,

whereas Parainfluenza, Influenza, and Metapneumoviruses are less frequent

causes of wheezing. Although nearly all children are infected with RSV by

age 2 years [3], and only a subset of these infections cause wheezing, it is clear

that there are specific host risk factors that may predispose a child to lower

respiratory manifestations of infection. Some of the identified risk factors for

wheezing with respiratory infections in infancy include young age, small lung

size, passive exposure to smoke, and virus-induced immune responses [3,4].

Fig. 1. Role of viral infections in the pathogenesis of asthma. LRI = lower respiratory infection;

RSV = respiratory syncytial virus; PIV = parainfluenzavirus.

J.E. Gern, R.F. Lemanske, Jr. / Pediatr Clin N Am 50 (2003) 555–575556

Recently, additional insight into these areas has been provided by the results of

an 11-year prospective study involving 880 children who were enrolled at birth,

followed for the development of lower respiratory tract illnesses in the first

3 years of life and then evaluated for the presence or absence of physician-

diagnosed asthma or a history of current wheezing at ages 6 and 11 years [5].

Respiratory syncytial virus bronchiolitis increased the risk for both frequent

episodes of wheezing (> 3/year) and infrequent episodes of wheezing (< 3/year);

however, the risk decreased gradually with age and was not significant by age

13 years [6]. A decrease in the frequency of wheezing with increasing age

following documented RSV infections has been observed by other investigators

as well [7,8]. These data suggest that, although RSV infections contribute

substantially to the expression of the asthmatic phenotype, other cofactors (eg,

genetic, environmental, developmental) also seem to contribute, either in the

initial expression or the modification of the phenotype over time.

From a number of epidemiologic observations, it seems that other viral

infections during infancy and early childhood that have a predisposition for

lower airway involvement (eg, Parainfluenza, Influenza A) can also be associated

with chronic lower respiratory tract symptoms including asthma. [5,9–11].

Prospective measurements of lung function before the infection demonstrated

that children with reduced levels of lung function in infancy seem to be at

increased risk for the development of chronic lower respiratory tract sequelae

following viral infections. [5]. Whether this defect is alone responsible for these

developments is presently unknown. Further, the ability of one virus (ie, RSV) to

be more likely responsible for these outcomes (because of either virus- or host-

specific factors) has also not been well defined [8]. Indeed, recent data indicate

that bronchiolitis induced by viruses other than RSV may be associated with an

even greater risk for childhood asthma [12].

Chronic respiratory infections and asthma

It has been proposed that chronic viral and bacterial infections cause some

cases of recurrent wheezing and asthma. Organisms that have been implicated in

this process include Adenovirus [13], Chlamydia pneumoniae [14], and Myco-

plasma pneumoniae [15,16].

Historically, the first potential association between asthma and C. pneumoniae

was reported in 1991 in a study in which 9 of 19 wheezing adult asthmatic

patients were found to have serologic evidence of current or recent infection

with this organism [17]. Further, in school-aged children with asthma, titers of

C. pneumoniae–specific secretory IgA antibodies were greater in persons who

reported four or more exacerbations in the study than in those who reported only

one. Although there was no evidence linking acute Chlamydia infection and acute

exacerbations of asthma, these findings suggest that chronic infection with

Chlamydia was more common in children with higher rates of exacerbations.

Chronic chlamydial infection may possibly promote ongoing airway inflam-

mation that increases susceptibility to other exacerbating stimuli such as viruses,

allergens, or both.

J.E. Gern, R.F. Lemanske, Jr. / Pediatr Clin N Am 50 (2003) 555–575 557

Thus far the most comprehensive evaluation of the role of both Chlamydia and

Mycloplasma infections in chronic asthma was recently reported by Martin et al

[15]. This group of investigators evaluated 55 adult patients with chronic asthma

(percent of predicted forced expiratory volume at 1 second [FEV1] = 69.3 ± 2.1%)

and 11 controls for infection with Mycoplasma, Chlamydia, and viruses. Fifty-six

percent of the asthmatic patients had a positive polymerase chain reaction (PCR)

assay for Mycoplasma (n = 25) or Chlamydia (n = 7), which were mainly found in

lavage fluid or biopsy samples. Only 1 of 11 control subjects had a positive PCR

for Mycoplasma. Cultures for both organisms were negative in all patients,

and serologic confirmation correlated poorly with PCR results. Although these

intriguing findings suggest that these organisms may play a role in the patho-

physiology of asthma in some patients, the specificity of these findings to asthma

and the phenotypic and genotypic characteristics of the at-risk patient need

further delineation.

There have been several attempts to test the role of chronic infection in

patients with asthma through therapeutic trials of antibiotics. Although some of

these studies have had promising results [18], the data are difficult to interpret

because of the difficulty in eradicating Chlamydia and Mycoplasma infection,

nonblinded study designs, and the fact that many of the macrolide antibiotics

have anti-inflammatory effects in addition to serving as antimicrobials [19].

One additional mechanism implicated in the pathogenesis of chronic

asthmatic symptoms is latent Adenovirus infection [13]. A latent infection

occurs when a virus incorporates itself into the host cell DNA and continues to

express viral genes periodically. Respiratory disease caused by adenoviruses

can be followed by latent infection that persists for many years [20]. A

Slovenic study demonstrated that 94% of children with steroid-resistant asthma

had detectable Adenovirus antigens, compared with 0% of controls [21]. In

adults both with and without asthma, as many as 50% of the individuals tested

showed evidence of adenoviral infection [15]. Although these preliminary

results are intriguing, additional studies are needed to establish the causality

and the specificity of these observations to asthma pathogenesis and to define

the immunoinflammatory mechanisms contributing to these associations in

adult and pediatric patients.

Infections and acute exacerbations of asthma

Viral respiratory infections

The relationship between viral infections and wheezing illnesses in older

children and adults has been clarified by the advent of sensitive diagnostic tests,

based on PCR, for picornaviruses such as Rhinovirus (RV). With the devel-

opment of these more sensitive diagnostic tools, information linking common

cold infections with exacerbations of asthma has come from a number of sources.

Prospective studies of persons with asthma have demonstrated that up to 85% of

exacerbations of asthma in children and nearly half of such episodes in adults are

caused by viral infections [22]. Although many respiratory viruses can provoke


acute asthma symptoms, RV is most often detected, especially during the spring

and fall RV seasons. In fact, the spring and fall peaks in hospitalizations caused

by asthma closely coincide with patterns of RV isolation within the community

[23]. Influenza and RSV are somewhat more likely to trigger acute asthma

symptoms in the wintertime but seem to account for a smaller fraction of asthma

flares. Furthermore, RV infections are frequently detected in children over the age

of 2 years who present to emergency departments with acute wheezing [24,25]

and in adults account for approximately one half of asthma-related acute care

visits [26]. Together, these studies provide evidence of a strong relationship

between viral infections, particularly those caused by RV, and acute exacerbations

of asthma.

Individuals with asthma do not necessarily have more colds, and neither the

severity nor duration of virus-induced upper respiratory symptoms is enhanced

by respiratory allergies or asthma [27,28]. In contrast to findings in the upper

airway, a prospective study of colds in couples consisting of one asthmatic and

one nonasthmatic individual demonstrated that colds cause greater duration and

severity of lower respiratory symptoms in persons with asthma [28]. These

findings suggest that there are fundamental differences in the lower airway effects

of respiratory viral infections related to asthma.

Although viral infections alone can promote lower airway symptoms, there is

evidence that viral infections may exert synergistic effects with other known

triggers for asthma. For example, the effects of colds on asthma may be amplified

by exposure to allergens [29] and possibly by exposure to greater levels of air

pollutants [30].

In addition to provoking asthma, RV infections can also increase lower airway

obstruction in individuals with other chronic airway diseases (eg, chronic

obstructive lung disease, cystic fibrosis) [31,32], and in infants [33] and elderly

persons [34]. Thus, common cold viruses that produce relatively mild illnesses in

most people can cause severe pulmonary problems in selected individuals.

Bacterial sinusitis

The nature of the association between asthma and sinusitis in children has

been the subject of debate for many years. Much of the difficulty in defining this

relationship results from the uncertainties in making the clinical diagnosis of

sinusitis, because the signs and symptoms of sinusitis in children overlap with

many common childhood respiratory disorders, including the common cold,

allergic rhinitis, and asthma.

Asthma and sinusitis are frequent comorbidities in children [35], and clinical

signs and symptoms compatible with sinusitis often occur during acute exacer-

bations of asthma, raising the possibility that bacterial sinusitis causes increased

lower respiratory symptoms. This hypothesis was the subject of a study

conducted by Rachelefsky and colleagues [36], who prospectively identified

48 children ages 4 to 13 years who had daily coughing and wheezing for at least

3 months, abnormal sinus radiographs (more than 6 mm maxillary sinus mucosal

edema on the Water’s view), and evidence of airway obstruction on pulmonary


function tests (decreased FEV1 and decreased forced expiratory flow in the

midexpiratory phase [FEF25%–75%]). These children were treated with 2 to

5 weeks of antibiotics, and 9 of the children with persistent symptoms and

radiographic evidence of sinusitis were subsequently referred to an otolaryngol-

ogist for antral lavage. Posttreatment evaluation revealed substantial improve-

ment in upper and lower respiratory symptoms, reduced use of bronchodilators,

and improved radiographic appearance of the sinuses. Although this study did not

include a control group, the findings suggest that children with chronic lower

respiratory symptoms that are refractory to usual asthma therapy may be at

increased risk of having concomitant bacterial sinusitis and that this infection

may contribute to the production of both upper and lower respiratory symptoms.

Two additional studies have expanded on these findings by correlating

respiratory symptoms, findings on sinus radiographs, and results of sinus aspirate

cultures in children with asthma and clinical evidence of sinusitis. Friedman and

colleagues [37] evaluated eight children with abnormal maxillary sinus radio-

graphs (opacification of at least one maxillary sinus) and acute asthma that was

unresponsive to bronchodilator therapy. Cultures of the sinus aspirate were

positive in five of these patients, and each patient improved after 2 weeks of

combined antibiotic and asthma therapy, including short courses of oral cortico-

steroid in four individuals. Goldenhersh et al [38] evaluated 12 children with

respiratory allergy and chronic sinusitis, including 9 asthmatic children between

the ages of 3 and 9 years who had nasal congestion or cough of more than

30 days’ duration, and abnormal sinus radiographs (8 of the 9 children had

opacification of at least one maxillary sinus). Pathogens, most commonly

Moraxella catarrhalis, were cultured from aspirates from 7 of the 9 asthmatic

subjects. Together, these studies suggest that children with asthma, chronic or

bronchodilator-resistant cough or wheeze, and chronic nasal congestion should be

evaluated for sinusitis, and that under these conditions, a sinus radiograph

revealing complete opacification of a maxillary sinus is usually indicative of

bacterial sinusitis. These studies also suggest that the combination of nasal lavage

and antibiotic therapy improves upper airway symptoms and may improve

asthma control as well. Finally, the limited data available regarding culture of

sinus content in children with asthma indicate that the microbiology of sinusitis is

similar in children with or without asthma [37–40].

Several mechanisms have been proposed to explain how infections of the

paranasal sinuses could cause bronchospasm and exacerbate asthma [41–43]. It

has been suggested that chronic aspiration of the contents of inflamed sinuses

could aggravate asthma [43,44]. Another hypothesis is that there are reflexes that

connect upper and lower respiratory function, although significant sinobronchial

reflexes are difficult to demonstrate in humans [45,46]. It has also been suggested

that pharyngobronchial reflexes can be triggered by postnasal drip of neutrophils

and inflammatory mediators to provoke acute lower airway symptoms [47,48].

There is clinical evidence that most patients with sinusitis develop a hyper-

responsiveness of the upper airway and that this upper airway hyperresponsive-

ness is often accompanied by bronchial hyperresponsiveness [47]. Furthermore,


treatment of the chronic sinusitis with antibiotics and nasal corticosteroids can

improve both upper and lower airway hyperresponsiveness. These findings

suggest that postnasal drip associated with sinusitis might trigger upper airway

hyperresponsiveness and subsequently affect the lower airway through a pha-

ryngeal-pulmonary reflex. This hypothesis is consistent with reports that dem-

onstrate that treatment with intranasal corticosteroids can reduce the likelihood of

acute exacerbations of asthma [49].

Finally, some data indicate that chronic sinusitis and asthma may both be mani-

festations of a generalized inflammatory disorder of the respiratory mucosa, thus

explaining their frequent coexistence. Although there are few published studies

involving children, it is clear that the mucosal inflammation associated with

chronic sinusitis in adults resembles that of asthma. The mucosa in chronic sinus-

itis is infiltrated by eosinophils, mast cells, and T cells [50], and mucosal eosino-

philia is particularly striking in patients with asthma [51]. Other features of asthma,

such as mucosal thickening, epithelial cell damage, and increased histamine and

leukotriene levels are also found in chronic sinusitis, suggesting that common

pathogenic mechanisms underlie these two frequently associated disorders.

Can certain infections reduce the risk of developing allergies and asthma?

It has been suggested that some viral or bacterial infections might actually

protect against the subsequent development of allergies and asthma. This contro-

versial theory, termed the hygiene hypothesis, was first suggested by David

Strachan [52], who noted that the risk of developing allergies and asthma is

inversely related to the number of children in the family, an observation that has

been duplicated in a number of subsequent studies [53,54]. This finding has led to

speculation that infectious diseases, which are more likely to be transmitted in large

families, could modulate the development of the immune system in a manner to

reduce the chances of developing allergies. This hypothesis suggests that the

immune system is immature at birth; in support of this concept, experimental

evidence shows that Th1-like interferon (IFN) responses are depressed in cells from

umbilical cord blood [55]. According to the theory, each infection would provide a

stimulus for the development or activation of Th1-like immune responses. This

repetitive stimulation would lead to the development of balanced Th1-like and

Th2-like cytokine responses and, as a result, to a low risk of developing allergies. In

the absence of exposure to infectious diseases in infancy, the immune system is

skewed toward Th2-like responses, and on exposure to environmental allergens,

the risk of allergic sensitization would be increased.

During the past decade, a number of epidemiologic variables have been

evaluated in relation to the hygiene hypothesis. Presently, the evidence most

strongly supports a reduction in the incidence of allergic sensitization in

individuals from large families, particularly the youngest in the family (birth-

order effect), and in those living in a less affluent environment [56]. These

relationships are stronger for allergic sensitization than for asthma [57,58].

Whether the effects of being in a large family result from increased exposure


to infectious diseases has been evaluated in two types of studies. First, the

influence of specific infections has been related to the subsequent development of

atopic diseases. Some of the first studies suggested that infections with specific

pathogens such as measles [59] or Mycobacteria [60] were associated with lower

rates of allergen sensitization and asthma; however, these results have not been

verified in more recent studies [61,62]. There is better evidence that repeated

exposure to infectious diseases during early infancy in settings such as day care

centers may reduce the risk of allergen sensitization [63,64].

The route of infection may be important in determining long-term effects on

allergies and asthma. For example, RSV bronchiolitis seems to be a risk factor for

the development of asthma but in most studies does not promote allergic

sensitization. In contrast, infections acquired by oro-fecal transmission (eg,

hepatitis A), are associated with lower rates of allergy and asthma [65]. These

findings suggest that foodborne and fecal-oral rather than respiratory tract

transmission of infection may be a more likely determinant of the risk of allergic

sensitization during childhood.

Other epidemiologic and biologic factors that have been considered to

influence the development of allergic sensitization or asthma include early

exposure to a farming lifestyle [66,67], alterations in bacterial flora of the gut

[68], and increased antibiotic usage [69]. Furthermore, it has recently been

demonstrated that high levels of exposure to endotoxin in the home, as occurs in

farmhouses and homes with furred pets, is associated with reduced rates of

allergy and an enhanced number of IFN-producing cells in peripheral blood

[70,71]. Collectively, these studies suggest that exposure to microbes, in addition

to infections per se, may affect immune development to reduce the risk of atopy

and asthma. This concept has led to efforts to use oral administration of probiotics

(live cultures of Lactobacillus) to try to reduce the incidence of atopic diseases,

and early results look promising [72,73].

In summary, the effects of infections on the incidence of allergic disorders and

asthma are complex and are likely to depend on the specific pathogen, route of

infection or exposure, cumulative number of infections, and the age of the child

and stage of immunologic development. One other factor to consider is the

genetic makeup of the child, because polymorphisms in genes related to either the

innate or adaptive immune systems could strongly influence the immune

response to microbial products or infections and, potentially, the incidence of

allergies and asthma [74].

Mechanisms of virus-induced wheezing and asthma

Respiratory symptoms are likely to be the result of two factors: destruction of

normal airway tissue because of the direct effects of the virus, and pro-

inflammatory immune responses to the infection. For viruses such as RV, which

infect relatively few cells in the airway, the proinflammatory response may be the

primary mechanism for airway symptoms and lower airway dysfunction [75].


The various components of the immune response, both antiviral and proinflam-

matory, are reviewed in the following sections.

Inflammation

Epithelial cells

The epithelial cell serves as the host cell for viral replication and also helps to

initiate antiviral responses. Damage to the epithelial cells can disturb airway

physiology through a number of different pathways. For example, epithelial

edema and shedding together with mucus production can cause airway obstruc-

tion and wheezing. Virus-induced epithelial damage can also increase the

permeability of the mucosal layer [76,77], perhaps facilitating allergen contact

with immune cells and leaving neural elements exposed.

The processes associated with viral replication trigger both innate and adaptive

immune responses within the epithelial cell. Virus attachment to cell surface

receptors may initiate some immune responses. For example, RSV infection

activates signaling pathways in airway epithelial cells through the surface

molecule toll-like receptor 4 (TLR-4) [78]. There is also evidence of receptor-

independent pathways for virus activation of epithelial cells, such as the

generation of oxidative stress [79].

Replication of viral RNA can also stimulate antiviral responses in epithelial

cells. Double-stranded RNA (dsRNA) that is synthesized in virus-infected cells

can bind to cell surface receptors and also directly activates intracellular enzymes,

such as the dsRNA-dependent protein kinase (PKR) and 2–5 oligoadenylate

synthase, which are important components of the innate antiviral immune

response [80]. Through this mechanism, viral replication induces innate antiviral

activity through the generation of nitric oxide, activation of RNase L, and

inhibition of protein synthesis within infected cells. In addition, dsRNA gen-

erated during viral infections promotes the activation of chemokine genes such

as interleukin (IL)-8 and RANTES (Regulated by Activation, Normal T cell

Expressed and Secreted), which recruit inflammatory cells into the airway [81].

Thus, host cell recognition of dsRNA is an important pathway for the initiation of

multiple and antiviral and proinflammatory pathways within the cell.

Granulocytes and mononuclear cells

During natural infection, the initial inoculum that transmits the illness is

assumed to be quite small; however, viral titers in respiratory secretions can attain

106 infectious units/mL, even after dilution by nasal lavage [82]. At this point, it

is likely that mononuclear cells are activated by these high titers of virus. As a

result, monocytes, macrophages, and, presumably, dendritic cells secrete proin-

flammatory cytokines such as IL-1, IL-8, tumor necrosis factor-alpha (TNF-a),IL-10, and IFN-a [83–85]. These cytokines activate other cells in the envir-

onment and are potent inducers of adhesion molecules. Together with chemo-

kines generated by epithelial cells, this response provides a potent stimulus for

inflammatory cell recruitment.


Acute respiratory viral infections are often accompanied by neutrophilia in

airway secretions, and products of neutrophil activation are probably involved in

obstructing the airway and causing lower airway symptoms [86,87]. Of particular

interest is evidence that activated neutrophils, through the release of the potent

secretagogue elastase, can increase goblet cell secretion of mucus [88]. In

addition, changes in IL-8 levels in nasal secretions have been related to res-

piratory symptoms and virus-induced increases in airway hyperresponsiveness

[89,90]. These findings suggest that neutrophils and neutrophil activation

products contribute to airway obstruction and symptoms during viral infections

and exacerbations of asthma.

Lymphocytes are recruited into the upper and lower airways during the early

stages of a viral respiratory infection, and it is assumed that innate and adaptive

immune responses serve to limit the extent of infection and to clear virus-infected

epithelial cells. This process is consistent with reports of severe viral lower

respiratory infections in immunocompromised patients [91].

For RSV, the G (attachment) and F (fusion) proteins are the major surface

glycoproteins against which neutralizing antibody is directed. In both murine [92]

and human [93] in vitro experiments, it has been noted that the G protein elicits a

predominant Th2 immune response, whereas the F protein and infectious RSV pro-

duce a predominant Th1 response. This property of the G protein has led to

speculation that this may be a mechanism by which RSV promotes allergen

sensitization. In murine models, RSV infections are associated with the devel-

opment of airway hyperresponsiveness [94] and an augmented allergic airway

response [95]. Some [96], but not all [97], investigators have demonstrated that

these alterations are related to increased production of the Th2-like cytokine IL-13

in the airway.

These and other animal models of respiratory viral infection suggest that

cellular immune responses and patterns of cytokine production may be related to

the outcome of respiratory infections. This same concept has been tested in a

limited number of studies involving humans. For example, reduced peripheral

blood mononuclear cell production of IFN-g both during and months following

RSV infection has been observed in only those children who develop subsequent

asthma [98]. In contrast, concentrations of IFN-g in upper airway secretions are

increased during episodes of viral-induced wheezing compared with upper

respiratory infections [99].

Additional information has been obtained by evaluating immune responses in

volunteers inoculated with a strain of RV. In these studies, strong IFN-g responsesto virus in blood mononuclear cells were associated with reduced viral shedding

[100]. In addition, stronger Th1-like response in sputum cells (higher IFNg/IL-5mRNA ratio) during induced colds was associated with milder cold symptoms and

also with more rapid clearance of the virus [82]. There is evidence that production

of IFN-g in response to viruses may be impaired in asthma [101]. Together, these

experimental findings suggest that the impaired cellular immune responses to

respiratory viruses, and reduced IFN-g production in particular, could promote

more severe clinical manifestations of viral respiratory infections in asthma.


Effects of allergy

Several studies have addressed the possibility that allergic individuals may

have impaired antiviral responses and, as a result, develop more severe mani-

festations of viral respiratory infections, particularly in relationship to airway

obstruction and wheezing. In infants, several studies have evaluated whether

allergy, atopic dermatitis, or a family history of allergy increase the risk of acute

bronchiolitis during RSV epidemics [102–106]; however, these studies have

yielded conflicting results. In addition, it seems unlikely that infections with RSV

in infancy cause allergy [6,106], although this possibility, too, is a matter of

controversy [107].

Despite these uncertainties, more convincing evidence implicates respiratory

allergy as a risk factor for wheezing with common cold infections later in

childhood. In studies conducted in an emergency department, risk factors for

developing acute wheezing episodes were ascertained [25,108]. Individual risk

factors for developing wheezing included detection of a respiratory virus, most

commonly RV, positive allergen-specific IgE as detected by radioallergosorbent

testing (RAST), and evidence of eosinophilic inflammation. Viral infections and

allergic inflammation synergistically enhanced the risk of wheezing [25].

Furthermore, other studies have shown that experimental inoculation with RV

is more likely to increase airway responsiveness in allergic individuals than in

non-allergic individuals [109]. Finally, the risk of hospitalization among virus-

infected individuals is increased in patients who are both sensitized and exposed

to respiratory allergens [29]. Considered together, these findings provide strong

evidence that individuals with either respiratory allergies or eosinophilic airway

inflammation have an increased risk for wheezing with viral infections.

Viral infections may interact with allergic inflammation to promote airway

dysfunction through several mechanisms [110]. First, it has been suggested that

viruses capable of infecting lower airway epithelium may lead to enhanced

absorption of aeroallergens across the airway wall predisposing to subsequent

sensitization [111,112]. Second, viral infections may lead to mast cell mediator

release within the airway, resulting in the development of bronchospasm and

the ingress of eosinophils [113–118]. Third, airway resident and inflammatory

cell generation of various cytokines (TNF-1b, IL-1-, IL-1b IL-6) [119–122],

chemokines (macrophage inflammatory protein [MIP]-1a, RANTES, monocyte

chemotactic protein [MCP]-1, IL-8) [123,124], leukotrienes [99], and adhesion

molecules (intercellular adhesion molecule-1 [ICAM-1]) [119] may further

increase the ongoing inflammatory response.

Studies have been performed using bronchoscopy and experimental viral

inoculation to try to understand RV-induced inflammation in the lower airway

and interactions with allergen-induced inflammation. These studies have dem-

onstrated that RV infections can enhance lower airway histamine responses and

eosinophil recruitment in response to allergen challenge [125,126]. In addition,

during a RV infection, study subjects had enhanced immediate responses to

allergen and were more likely to have a late asthmatic response after allergen


challenge [127]. These findings suggest that RV can enhance both the immediate

and the late-phase response to allergen.

How do common cold infections disturb lower airway physiology?

Rhinovirus has traditionally been considered to be an upper airway pathogen

because of its association with common cold symptoms and the observation that

RV replicates best at 33� to 35�C, which approximates temperatures in the upper

airway. There is evidence to indicate that lower airway temperatures may also be

conducive to RV replication. Lower airway temperatures have been directly

mapped using a bronchoscope equipped with a thermister [128]. During quiet

breathing of air at room temperature, airway temperatures are generally lower

than 35�C down to the level of fourth generation bronchi. Moreover, RV seems to

replicate equally well in cultured epithelial cells derived from either upper or

lower airway epithelium [129]. Finally, although RV has been difficult to culture

from the lower airway, it has been detected in lower airway cells and secretions

both by reverse transcription polymerase chain reaction (RT-PCR) and in situ

hybridization of mucosal biopsies after experimental inoculation [130,131].

These findings establish that RV can replicate in the lower airway epithelium

at temperatures found in the large airway of the lung. This concept is further

supported by evidence that RV infections can produce lower airway inflam-

mation, including increased neutrophils in bronchial lavage fluid [132], influx of

T cells and eosinophils into lower airway epithelium [133], and enhanced

epithelial expression of ICAM-1 [134].

Remaining challenges include determining how much virus is present in the

lower airway and establishing whether viral replication in the lower airway is a

sufficient stimulus to provoke exacerbations of asthma. Alternate mechanisms to

explain the link between colds and increased asthma include virus-induced

systemic immune activation, the existence of reflex bronchospasm triggered by

upper airway inflammation, and the aspiration of inflammatory cells and

mediators that are generated in the upper airway [135].

Effects of viral infections on airway hyperresponsiveness

Information derived from animal models, as well as clinical studies of natural

or experimentally induced viral infections, indicate that viruses can enhance

airway hyperresponsiveness, which is one of the key features of asthma [136].

Clinical studies have generally shown that viral infections cause mild increases in

airway responsiveness during the time of peak cold symptoms and that these

changes can sometimes last for several weeks. A heightened sensitivity to inhaled

irritants and greater maximum bronchoconstriction in response to these stimuli

have been observed. The mechanism of virus-induced airway responsiveness is

likely to be multifactorial, and contributing factors are likely to include impair-

ment in the inactivation of tachykinins, virus effects on nitric oxide production,

and virus-induced changes in neural control of the airway [137].


Treatment

Wheezing infants

One of the biggest challenges in treating infants who present with wheezing is to

try to differentiate RSV bronchiolitis from wheezing that is caused by early-onset

asthma. This differentiation is important, because bronchodilators produce at best

only modest short-term improvements in clinical features of mild or moderately

severe bronchiolitis and do not affect the rate or duration of hospitalization [138].

Given the high costs and uncertain benefit of this therapy, bronchodilators are not

recommended for routine management of first-time wheezers.

A meta-analysis of studies involving therapy of bronchiolitis with either oral

or parenteral corticosteroids concluded that this approach produced modest

benefits [139]. Of 12 relevant publications, 6 met the selection criteria and had

relevant data available. Corticosteroid therapy (prednisone, prednisolone, methyl-

prednisone, hydrocortisone, dexamethasone given orally, intramuscularly, or

intravenously in dose ranges of 0.6 to 6.3 mg/kg/day of prednisone equivalents)

was associated with a statistically significant reduction in clinical symptom

scores and length of hospital stay (0.4 day difference). The analysis suggested

that corticosteroid treatment might have its greatest effects in more severe cases,

and that clinical benefits are noticeable in the first 24 hours.

Several placebo-controlled trials [140–149] have addressed the question as to

whether corticosteroid treatment can prevent respiratory sequelae after RSV

bronchiolitis [8]. Seven of 10 of these trials did not show any long-term effects

(follow-up time from 6 months to 5 years) on postbronchiolitic wheezing, the

development of various wheezing phenotypes (transient, persistent, or late onset),

or a subsequent diagnosis of asthma. In the three trials that did show some

benefit, the positive effects observed were mainly over shorter time intervals

following infection.

Because elevated levels of leukotrienes have been reported in respiratory tract

secretions of infants who develop recurrent wheezing following RSV bronchiol-

itis [150,151], the effect of a leukotriene receptor antagonist in modulating these

developments recently has been evaluated. In a prospective, placebo-controlled

trial, a 28-day treatment course of montelukast significantly reduced lower

respiratory tract symptoms in infants who were hospitalized for RSV bronchiol-

itis [152]. These preliminary observations suggest a potential role of this class of

compounds in improving short-term symptom control and also in preventing

long-term lower respiratory tract sequelae.

Role of oral and inhaled corticosteroids in acute exacerbations of asthma

Numerous studies have been conducted to assess the role of systemic cortico-

steroid therapy in acute episodes of asthma in children and adults, and it is assumed

that many of these episodes are caused by viral respiratory infections. A meta-

analysis of these studies supports the early use of systemic corticosteroids in acute


exacerbations based on a reduction in the admission rate for asthma and prevention

of relapse in the outpatient treatment of exacerbations [153]. As a reflection of such

information, the most recent National Heart, Lung, and Blood Institute guidelines

for the diagnosis and management of asthma recommend the addition of cortico-

steroids for asthma exacerbations unresponsive to bronchodilators [154].

Children who experience frequent exacerbations of asthma may receive

several short courses of systemic corticosteroids during each viral season. The

potential toxicity of repeated courses of oral corticosteroids is a significant

clinical concern and has prompted studies to determine whether high doses of an

inhaled corticosteriod might be just as effective with a lower potential for side

effects. Standard treatment doses of inhaled corticosteroid do not seem to prevent

virus-induced exacerbations of asthma [155]. In contrast, treatment of at-risk

children with early signs of viral upper respiratory infection with high doses of

inhaled corticosteroid (eg, 800 to 3200 mg budesonide per day) may help prevent

acute asthma attacks [156,157]. In addition, some [158], but not all [159], studies

suggest that high-dose inhaled corticosteroids compare favorably with systemic

preparations for the treatment of acute asthma in children who present to an

emergency department. Collectively, these studies suggest that inhaled cortico-

steroids can be useful in preventing asthma symptoms induced by viral infections

under some conditions. Although they provide useful information, all these

studies are limited by small numbers of patients and do not delineate features

predictive of patients who would be expected to respond to a given therapy. In

addition, the ideal drug, dosage, delivery system, and duration of therapy remain

unclear. Improved delivery of a potent drug to the lower airway may be

associated with a more favorable clinical response.

Antiviral strategies and future directions

Influenza vaccine has been used for years as a means of preventing virus-

induced exacerbations of asthma in the winter. For RSV and RV, which are more

frequently associated with wheezing illnesses, there are still no proven and cost-

effective antiviral strategies. Several antiviral agents are in development, and a

number of antirhinovirus compounds have been tested in clinical trials. These

compounds include molecules such as soluble ICAM and capsid-binding agents

(eg, pleconaril), which either hinder RV binding to cellular receptors or inhibit

uncoating of the virus to release RNA inside the cell [160–163], and inhibitors of

RV 3C protease [164]. Whether these antiviral agents can prevent asthma

exacerbations if given at the first sign of a cold has not yet been tested.

The other potential therapeutic approach for respiratory viral infections would

be to inhibit specific proinflammatory immune responses induced by the virus.

Although glucocorticoid therapy can be effective in this regard, future studies

will determine whether more focused inhibition of specific components of virus-

induced inflammation, such as proinflammatory cytokines (eg, IL-8) or mediators

(leukotrienes, bradykinin), will be able to provide safe and effective relief from

virus-induced wheezing and asthma.


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Infectious triggers of pediatric asthma