APPROXIMATELY 12 million people are diagnosed with asthma in the United States alone . While there is no consensus on a definition, asthma can be described as a syndrome characterized physiologically by hyperreactive airways and clinically by cough, shortness of breath, and wheezing. Etiological causes of asthma inflammation and abnormal physiology continue to be defined and redefined. At the heart of this debate for many years has been the role that infectious agents may play in the pathogenesis or exacerbation of asthma. This review will discuss the in vitro, epidemiologic, and clinical studies that have examined the possible protective and harmful roles of infectious diseases in the pathogenesis of asthma. The potential dual role of antibiotics as anti-infective and anti-inflammatory agents for the treatment of asthma will also be discussed.
Can Infectious Diseases Play a Protective Role in the Pathogenesis of Asthma?
In vitro studies
Asthma is associated with a persistent atopic state characterized by a predominantly T helper (Th)-2 lymphocyte mediated immune system. During the first six months of life, there is usually a change from a predominantly Th-2 immune response, developed in utero, to a Th-1 response. Some children do not experience this Th-1 shift and have an expansion and maturation of Th-2 memory cells. This result has been shown to increase the likelihood of a persistent atopic state and the development of asthma in predisposed children [2,3]. It has been argued that exposure to certain infections early in life may stimulate this switch by activating the anti-infection, Th-1 immune response. Thus, it is theorized that certain infections early in life may actually prevent the subsequent development of asthma later in life.
These theories are supported by numerous epidemiologic studies. It is well known that the prevalence of asthma and other atopic diseases are higher in developed countries . The prevalence rates of asthma has increased dramatically in the United States during the last 30 years while at the same time the incidence of childhood infections are thought to be decreasing [5–7]. It has been shown that in areas where tuberculosis (a disease marked by a vigorous Th-1 response) is endemic, asthma rates are some of the lowest in the world . On a smaller level, it has been observed that young siblings of large families have a lower incidence of atopy . In a recent investigation, 1,314 German children born in 1990 were followed from birth till age 7 years to investigate the development of asthma . Children who experienced more than two episodes of runny nose during the first year of life were less likely to have a diagnosis of asthma by age 7 years. Likewise, a herpes type infection before the age of 3 years was also associated with a lower diagnosis of asthma. On the other hand, persistent lower respiratory tract infections showed a positive association with the development of wheeze at 7 years.
Case series/Clinical studies
Small case series also support the theory that certain childhood respiratory infections may play a protective role in later development of asthma and atopy . It has been observed that exposure to certain infections can result in long-term asthma remissions . Exposure to Mycobacterium tuberculosis prior to age 12 has been shown to lower IgE levels and lower the incidence of asthma, rhinitis, and eczema when compared with those that had not been exposed . However, many of the children in this study had been vaccinated with the BCG vaccine and none of the children had documented tuberculosis. Vaccination soon after birth did not appear to prevent the later development of atopy. A recent study of over 2,500 school children in Hong Kong who had received the BCG vaccine also showed no significant relationship between asthma and positive tuberculin response . In addition, case reports have documented improvement in asthma signs and symptoms after hepatitis A virus infections, measles, chickenpox, herpes zoster, and tuberculosis . In summary, it appears from epidemiologic studies and small case series that certain infections early in life but not others may offer a protective effect to the subsequent development of asthma.
What is the Role of Infectious Diseases in the Pathogenesis of Asthma?
It is well established that infections can precipitate asthma exacerbations. At the same time, it is debated that certain infections, namely virus and atypical bacteria, may also be involved in the pathogenesis of asthma.
Asthma is characterized by hyperreactive airways and impaired development of the pro-inflammatory Th-1 cytokine response with a shifted response towards a Th-2 cytokine response . Clinical signs and symptoms of asthma include cough, shortness of breath, and wheeze. As a root cause of these abnormalities, chronic airway inflammation and the newer concept of airway remodeling are areas of intense interest. The ability of viruses and atypical organisms, namely C pneumoniae and M pneumoniae to elicit these pathological changes has been intensely researched.
In vitro studies
For many years, viruses have been reported to cause wheezing exacerbations in children and adults and several studies have investigated the pathogenesis underlying these clinical observations [16,17]. Viral infections usually affect the bronchial epithelium by causing epithelial damage, epithelial denudation, and/or mucosal infiltration with lymphocytes and eosinophilia. In animal studies after infection with influenza virus, the desquamated airway epithelium has been shown to have an increased contractile response and increased hyper-responsiveness to certain neuropeptides . The mechanism is thought to involve many of the pathologic responses present in asthmatics, including an increase in cholinergic tone, changes in airway nitric oxide secretion, and induction of pro-inflammatory cytokines [19,20]. Release of the cytokine interleukin- (IL-) 8 has been shown to occur within 1 day of infection of epithelial cell lines with rhinovirus  and respiratory syncytial virus . The vascular and airway epithelium can be stimulated by viral induction of these cytokines allowing increase adhesion proteins resulting in inflammatory cell infiltration. Overall, the loss of epithelial integrity can result in increased susceptibility to irritants along with neural pathway activation leading to bronchoconstriction .
Production of virus-specific Immunoglobulin-E and the development of late allergic responses have also been postulated as mechanisms of viral-induced bronchospasm . Immune responses to viral infection in early childhood that involves IgE or eosinophilic responses have been shown to be predictive of persistent wheezing symptoms in children up to age 6 . In vitro data has shown that the immune responses to viruses have similarities to that of an allergen response. Interferon gamma secretion from natural killer cells and CD8+ T cells occurs in response to viral infection results in lyses of infected cells through eosinophil superoxide and basophil histamine release [23,25].
Chlamydia and Mycoplasma have been shown to impair the Th-1 response similar to the manner described in the pathogenesis of asthma . A vigorous Th-1 response is required to eradicate these atypical infections, while a predominant Th-2 response can lead to persistence of the infection. Although not proven with asthma, a Th-2 immune response to Chlamydia has been shown to lead to chronic inflammatory damage such as pelvic inflammatory diseases . C. pneumoniae also elicits similar pathophysiological mechanisms in humans as virus infections, including ciliary dysfunction, epithelial damage, and generation of pro-inflammatory cytokines . Thus, C. pneumoniae infections evoke many of the inflammatory and pathological changes seen with asthma. However, although the current body of evidence suggests that C. pneumoniae may be implicated in the pathogenesis of asthma, further studies are required.
Case reports have detailed many examples of viral-induced pulmonary inflammatory states include the decreased sensitivity to steroids after viral infections , and increased airway hyperresponsiveness to methacholine challenge after rhinovirus infections . It has also been demonstrated that children infected with respiratory syncytial virus infections are prone to recurrent episodes of wheeze after they recover [30,31].
Mycoplasma pneumoniae is a common cause of respiratory infections, especially in young adults . The presence of M. pneumoniae in the upper and lower airways of patients with asthma has been demonstrated using serology, immunofluorescent staining, and polymerase chain reaction (PCR). During the 1970s, serological detection of M. pneumoniae was observed in over 40% of children hospitalized with asthma attacks and in 32% of asthmatic children during recurrent episodes of wheezing [33,34]. In a later study, infection with M. pneumoniae, detected by immunofluorescent staining of throat swabs, was significantly associated with acute asthma exacerbations in 25% of patients with asthma (pediatric and adult) compared with 5.7% for matched, non-asthmatic controls . Investigations using PCR technology have shown mixed results. Freymuth et al. investigated the presence of M. pneumoniae in 132 nasal aspirates from 75 children hospitalized with severe asthmatic attacks. M. pneumoniae was detected in 2.2% of aspirates. In another study of 108 children aged 9–11 years followed over 292 episodes of asthma exacerbations, M. pneumoniae was found in very few cases (0.7%) . Contrasting these studies, Kraft et al. investigated the presence of M. pneumoniae in the lower airways of 18 adults with chronic, stable asthma and 11 non-asthmatic controls . Patients were evaluated for M. pneumoniae in bronchoalveolar lavage by PCR and enzyme-linked immunoassay (EIA) and with serologic measurement. M. pneumoniae was detected by PCR in 56% of the asthmatic patients and in 9% of the controls. In this study, serologic and culture measurements for M. pneumoniae were negative in all patients. Recently, these findings were supported by another study that demonstrated a higher percentage of atypical organisms (primarily M pneumoniae) in the lungs of chronic asthmatics than healthy controls . Thus, an association has been reported between M. pneumoniae and asthma. However, results have not been consistent. The role of M. pneumoniae in the pathogenesis of asthma will require further delineation.
Eight case reports, 13 case series, and 18 epidemiologic studies representing over 4,000 cases and controls have investigated the association of C. pneumoniae with asthma as outlined in a recent, excellent review article . Of the 18 epidemiologic studies, 15 showed a significant association between asthma and C. pneumoniae. An association was detected regardless of PCR testing (n = 2 studies), fluorescent antigen testing (n = 1), C. pneumoniae specific secretory IgA antibody testing (n = 1), specific serum IgE (n = 2), IgA (n = 4), or other antibodies (n = 7). More recently, serologic testing for C. pneumoniae was investigated with adult patients who first became symptomatic with asthma after an acute respiratory illness . Serum samples from 68 patients with onset of asthma associated with an infection were compared to 36 patients with atopic or exercise-induced asthma, 16 non-asthmatic patients with acute bronchitis, and 44 non-asthmatic controls. Serologic markers for C. pneumoniae were more prevalent in patients with acute bronchitis and with asthma that first became symptomatic after a respiratory infection. In another recent study, high titers of serologic antibodies, detected by microimmunofluorescence, were related to markers of severe asthma, including use of high-dose inhaled steroids and decreased FEV1 .
The use of antibiotics due to anti-infective effects.
Tetracyclines, the macrolides, and the newer quinonlones have in vitro activity against atypical organisms such as C. pneumoniae and M. pneumoniae [41,42]. These organisms are usually not easily eradicated. Treatment of respiratory infections due to these atypical organisms often require prolonged courses (2–3 weeks). Even with prolonged therapy of up to 3 weeks, C. pneumoniae may still persist. Thus, any study assessing the use of antibiotics for the eradication of presumed atypical organisms in asthmatics should require prolonged therapy .
Four case reports have reported on the use of antibiotics (primarily macrolides) in four asthmatic patients infected with C. pneumoniae [27,43,44]. Three of four patients improved on long-term antibiotic therapy while the patient who did not improve received a 7-day course of erythromycin therapy. Three open-label studies have studied the use of tetracyclines or macrolides for the treatment of patients with asthma and evidence of current or previous infection with C. pneumoniae. In a prospective, open label study, 118 children admitted to an emergency department for wheezing and 41 age- and sex-matched controls were assessed for evidence of C. pneumoniae by culture or serology . C. pneumoniae was isolated from 13 children and two controls. Twelve of the 13 children were treated with macrolides with documented eradication of the organism. Nine of these children (75%) had a marked improvement in their asthma after eradication of the organism. Another open-label trial investigated forty-six patients with moderate to moderately severe, stable, chronic asthma treated with oral doxycycline, azithromycin, or erythromycin for 4 weeks . Asthma symptoms disappeared in four patients with C. pneumoniae respiratory tract infections, and, of the remaining 42 seroreactive patients, 50% had either complete remission or major clinical improvement. Another case series reported similar improvements in three steroid-dependent patients seropositive for C. pneumoniae treated with clarithromycin or azithromycin over extended periods . Most recently, a multicenter, randomized, double-blind, 6-week trial of placebo versus roxithromycin, a 14-membered macrolide not available in the United States, was conducted in 232 patients with asthma and serological evidence of C. pneumoniae infection . At the end of the study period, patients treated with roxithromycin had a significant increase in evening peak expiratory flow rate versus placebo. This effect did not persist at 3 months follow-up period. However, this study could be critiqued for its short duration of antibiotic therapy.
Efficacy of antibiotics due to an anti-inflammatory effect.
There has been interest regarding the efficacy of certain antibiotics against asthma unrelated to their antimicrobial effect. Spector et al. reported a double-blind, crossover trial comparing troleandomycin to placebo in 74 severe, corticosteroid-dependent asthmatic and bronchitic patients . Fifty subjects (67%) experienced marked improvement in their sputum production, pulmonary function measurements, need for bronchodilators, and subjective evaluations. Although the effects of troleandomycin were originally attributed to corticosteroid inhibition, the immunomodulatory properties of antibiotics has emerged as another possible mechanism of effect .
The non-antibacterial, immunomodulatory effects of antibiotics have been described mostly with macrolide antibiotics. Ex vivo and in vitro evidence supports enhanced immunologic function in association with macrolide treatment. Clinically, this effect was first noted in Japanese patients with diffuse panbronchiolitis (DPB), a chronic, non-infectious inflammatory disease of the airways . Since the initiation of low-dose macrolide therapy, the 10-year survival for DPB has increased from less than 10% to greater than 90% .
Laboratory and animal models also support these clinical observations of anti-inflammatory effects of macrolides. Macrolides have been shown to decrease neutrophil oxidant burst capacity, neutrophil chemotaxis, pro-inflammatory cytokine concentrations, reactive oxygen species, and mucus secretion [53–56]. It is hypothesized that the high intracellular accumulation of macrolides may alter the cell function causing these immunomodulatory effects.
Clinical trials investigating macrolide anti-inflammatory effects and asthma have generally not explored the role of the atypical organisms. Case reports and abstracts have described asthmatic patients weaned from corticosteroids after initiation of troleandomycin and clarithromycin and decreased mucus production after initiation of erythromycin [57–59]. Other small-scale studies have shown decreased bronchial hyperresponsiveness in patients given low-dose erythromycin for 10 weeks, decreased corticosteroid requirements in children given troleandomycin for 12 weeks and 1 year, and in adults given clarithromycin for 6 weeks [60–63]. A small study showed improvement in pulmonary function and quality of life scores including decreased social concerns and chest discomfort in 15 steroid-dependent asthmatics given 6 weeks of clarithromycin .
Overall, an increasing amount of literature has commented on the benefits of antibiotic therapy for the treatment of asthma. Whether this effect is due to an antibacterial effect on atypical organisms, the nonantibacterial, immunomodulatory effects of these antibiotics, or a combination of the two remains to be determined. Future randomized, placebo-controlled trials will help to answer these questions.
Virus and acute asthma exacerbations
Besides playing a potential role in pathogenesis of chronic asthma, respiratory viruses and atypical organisms are known to precipitate acute asthmatic exacerbations. In the early 1970s, several studies documented the association of acute viral illness with asthma exacerbation in children and adults [16,17]. More recently, in a prospective study of schoolchildren in the United Kingdom with a history of wheeze, common viral genomes were found by PCR in 85% of subjects with asthmatic exacerbations manifested by decreased peak flows or increased wheezing . Another large study of young children in France also showed a high incidence of rhinovirus and respiratory syncytial virus in children with acute asthma exacerbations . To add further complexity, the degree of airway responsiveness in infants may also be related to lung function at birth . Although distinctive features of viral infections may occur, the presentation of an asthmatic exacerbation caused by a virus is usually more dependent on the age and the immunocompetence of the patient than on the specific virus . The association of viral infections with asthma exacerbation can be demonstrated in adults but does not appear to be as strong [17,66]. In an emergency room study of adult asthmatics, 55% of acute asthma exacerbations were associated with infections by viruses, including rhinovirus, coronaviruses, and influenza .
Asthma is a heterogeneous disease, and thus, any study investigating the cause of asthma is confounded by a host of variables. Studies in twins have shown a disparity in asthma predilection. These differences, along with the rapid increase in asthma prevalence suggest that factors other than genetic predisposition may be at work. Reports have indicated that change in diet, increased allergen exposure, and changes in living conditions are causative factors towards the development of asthma [68,69]. From an epidemiologic viewpoint it had been noted that there seems to be a negative correlation between family size and atopic disease. Rural environments, especially with farm animals near the residence, and the presence of a dog in the house seem to protect against asthma . A German study reported a much higher incidence of atopy and hay fever in East Germany compared to West Germany . The authors postulated that the smaller family size, improved living conditions, and the decreased incidence of infectious diseases seen in the West may have been explanatory. Ball et al. recently examined the effect of siblings along with the attendance at day-care facilities as asthmatic risks . They found that the presence of one or more older siblings at home protected against the development of asthma, as did attendance at day care before age 6 months. Children that had higher exposure rates to other children at home or at day care were more likely to have frequent attacks of wheeze at age 2. However, these children were less likely to have frequent wheezing from ages 6 through 13. Another study showed that attendance at day care placed children at increased risk for recurrent wheezing and asthma in children less than 5 years of age. Children 5–14 years of age were found to have a decreased frequency of asthma if they previously had attended day care .
In summary, it has been well documented that the genesis, exacerbation, and persistence of asthma can be associated with infectious agents. The etiology is likely complex and multifactorial involving immune system maturation, epithelial damage, and cytokine and antibody responses. There seems to be a protective effect of certain early childhood infections against later atopy and asthma while infection later in life may be harmful and lead to the development of asthma. Issues such as the timing of infection, the offending microbe, and the environment in which infection is occurring will need to be further addressed. The antiinflammatory effects of certain antimicrobials are well documented and it is hoped that these agents can have an impact on chronic asthma. The questions of the extent these antibiotics may have on the treatment of early wheeze in children, or what effect the elimination of chronic carrier states with atypical organisms may have on asthma control still need to be answered. How best to utilize the anti-inflammatory effects of certain antibiotics in the treatment of chronic asthma still needs to be determined.
It is well established that many chronic diseases are thought to have an association with infectious agents. The role of infectious disease in asthma is well documented but very complex. By defining the role of infection both directly on the airway epithelium, and indirectly on the host’s immune response makes infection a key consideration when defining the asthma syndrome. More data in the future regarding the presence of various organisms and the effect on treatment will help shed further light on the question.
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