Chlamydia pneumoniae and Childhood Asthma

Abstract

Asthma is the most common chronic disease in childhood and it is a major global health problem. Asthma is characterized by chronic airway inflammation and the pathogenetic mechanisms leading to asthma are likely to be diverse, and influenced by multiple genetic polymorphisms as well as environmental factors, including respiratory tract infections. Chlamydia pneumoniae is a human pathogen belonging to the Chlamydiae family. Since its recognition in 1989, C. pneumoniae has been extensively studied for its role as a widespread respiratory pathogen and its potential consequences in both children and adults. Its ability to evade the human immune system, biphasic development cycle, and capacity to spread throughout the host has made it a suspect in many chronic inflammatory diseases, including asthma. Chlamydia pneumonia is of particular interest among the various infections associated with new-onset asthma, asthma severity, and treatment resistance.

1. Introduction

Since its recognition in 1989, Chlamydia pneumoniae has been extensively studied for its role as a widespread respiratory pathogen and its potential consequences for both children and adults. Its ability to evade the human immune system, biphasic development cycle, and capacity to spread throughout the host has made it a suspect in many chronic inflammatory diseases, including asthma.

Asthma is the most common chronic disease in childhood [1] and it is a major global health problem, affecting an estimated 300 million people of all ages worldwide [2].

Asthma is characterized by chronic airway inflammation. The pathogenetic mechanisms leading to asthma are likely to be diverse and influenced by multiple genetic polymorphisms as well as environmental factors, including respiratory tract infections. Chlamydia pneumonia is of particular interest among the various infections associated with new-onset asthma, asthma severity, and treatment resistance. This chapter aims to provide an overview of the association between Chlamydia pneumonia and childhood asthma and to summarize the most recent evidence on this topic.

1.1 Asthma

Asthma is an umbrella term for heterogeneous diseases with similar clinical manifestations, but different underlying pathophysiological mechanisms and prognoses. The Global Initiative for Asthma (GINA) defines asthma as “the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory airflow limitation” [1]. These symptoms can be triggered by respiratory irritants, exercise, respiratory infections, and exposure to allergens in susceptible individuals.

Asthma symptoms and airflow limitation may resolve with or without treatment, and patients may remain asymptomatic for weeks or months. While many patients with classic asthma symptoms respond well to conventional treatments, some do not. These cases may be related to different underlying mechanisms.

1.2 Asthma phenotypes

Asthma phenotypes define clinically observable characteristics and are classified according to different elements (e.g., the age of onset, triggers, comorbidities, etc.). Besides, asthma endotypes define the underlying biological mechanisms making the clinical characteristics. Detailing the differences in the phenotypes and pathological or molecular characteristics of the content of the inflammation are trying to be explained by genotypes [3, 4, 5].

In order to achieve a more personalized medicine, especially for those with severe, treatment-resistant asthma, it seems future research will target classifying phenotypes based on endotypes (pathophysiological mechanisms) and the biomarkers associated with them. Additionally, exploring the etiology and mechanisms of the disease would help to more accurately predict the persistence of childhood asthma and its prognosis.

Several key elements, such as the age of onset, triggering factors, characteristics of symptoms, and biomarkers, have been taken into consideration when determining phenotypes of asthma [6].

Phenotypes by age of onset: This group consists of patients who were diagnosed with asthma at the age of 12 or older, with no definite upper age limit [7]. Typically, this group consists of adults, particularly women, who exhibit asthma that requires high doses of inhaled corticosteroids or is relatively resistant to corticosteroids [8].

Phenotypes by biomarkers: Asthma phenotyping can be conducted on biomarkers found in bronchial biopsy specimens, induced sputum, and peripheral blood, such as eosinophils and neutrophils (and the associated cytokines) that are involved in the Th-2 and non-Th-2 pathways, respectively [5, 9, 10].

A. Type 2 asthma can be further divided into two subtypes: allergic asthma and eosinophilic asthma [11]. (a) Allergic asthma is typically seen in children and is characterized by a history of eczema, allergic rhinitis, or food-drug allergies. This phenotype usually responds well to inhaled corticosteroids. (b) Eosinophilic asthma is identified when a patient’s blood eosinophil count is >150/μl, and the eosinophil rate is higher than 2% in the sputum. Features of this phenotype include high eosinophil count, increased asthma severity, late-onset, and steroid resistance.

B. Non-Type 2 asthma refers to a group of patients who do not exhibit biomarkers of type-2 inflammation, such as epidermal prick test-compatible allergic comorbidities or eosinophils in blood/sputum. Their airway inflammation is either neutrophilic or paucigranulocytic (with few inflammatory cells). This non-allergic asthma group does not respond well to inhaled corticosteroid treatment. Neutrophil-derived inflammation, which may be associated with disorganized airway microbiota, appears to be linked to the most severe forms of asthma, typically seen in very young children and teenagers [12].

Asthma severity and asthma control were often used interchangeably. Today, asthma severity is evaluated retrospectively and defined as a condition where high doses and/or multiple medications are required to control the disease. Uncontrolled/difficult asthma is now considered a condition where symptoms persist despite treatment, and patients experience frequent exacerbations or attacks [2, 6, 13, 14].

2. Asthma treatment

The goal of asthma treatment is to achieve daily symptom relief, reduce the risk of future exacerbations, and keep medication use within safe limits in terms of side effects. Asthma treatments fall into three categories: controller drugs (such as inhaled corticosteroids and leukotriene antagonists), symptom-relief/rescue medications (such as fast-acting bronchodilators and inhaled/systemic corticosteroids), and additional therapies (such as long-acting inhaled anticholinergics, low-dose corticosteroids, biologic agents, and immunotherapy) that are utilized when the patient’s symptoms remain unchanged despite the use of high-dose controller drugs in settings where the risk factors are controlled [6]. The role of macrolides in the treatment of asthma has been a topic of interest for decades. The use of these medications will be discussed in more detail later in this chapter.

2.1 Childhood asthma

Asthma is the most common chronic disease in children, with a current prevalence ranging from 6–9% [15]. Preschool-aged children are particularly susceptible to symptoms similar to those of asthma, such as acute bronchiolitis and wheezing, making it crucial to predict if they will eventually develop asthma. Follow-up studies have revealed that remission of the disease is possible during adolescence, with rates varying from 15 to 64% [16]. Individuals with a milder onset and lower allergic susceptibility have a higher probability of remission [6].

Allergic asthma is the most common phenotype in childhood and is characterized by a history of atopic dermatitis, allergic rhinitis, food allergies, and IgE mediation. Eosinophilic infiltration marks airway inflammation in these patients. Nonallergic asthma is the second most common phenotype, which is marked by neutrophilic inflammation and lacks an atopic component [17].

Research suggests that multiple genetic and environmental factors interact to influence clinical manifestation, bronchial hyperresponsiveness, and the presence of atopy. It is now acknowledged that asthma has an integral relationship with the immune system. Atopy and asthma are related, although it is not a direct correlation since not all atopic people develop asthma, and not all asthmatics have detectable allergic sensitivity. Increased levels of IgE, the release of allergens from mast cells, the growth of eosinophils in the lungs, inflammation in the airways, and an imbalance of Th1 and Th2 responses indicate that a dysregulated immune system contributes to the development of asthma.

2.2 Asthma and hygiene hypothesis

Epidemiological studies have provided evidence for a rise in asthma and allergic illnesses in industrialized countries over recent decades, leading to the development of the “hygiene hypothesis.” This hypothesis proposes that a lack of early childhood exposure to infectious agents, symbiotic microorganisms (e.g., probiotics), and parasites increases susceptibility to allergic diseases by altering the immune system. Evidence suggests that populations with greater exposure to infectious agents, such as in developing countries or families with more children, have a lower prevalence of allergic diseases. It is thought that decreased exposure to the microbial environment in more developed countries results in an immune system that is more likely to elicit allergic responses, rather than the protective immune responses that exposure to these organisms could elicit.

However, recent studies have suggested that the hygiene hypothesis may not be applicable to asthma, but instead, asthma may be connected to infections experienced during the life cycle [18, 19, 20]. The immune response generated from these infections is dependent on the route, duration, dose, and a person’s genetic makeup [21].

2.3 The microbiome of the airway

Recent studies have suggested that the “microbiome of the respiratory tract” may play a role in the development of asthma [22]. This is supported by two studies that revealed notable variations between the quantity and variety of microbial populations in healthy individuals and asthmatics [23, 24]. Microbiomes, also known as microbial flora, are generally not considered to be a threat to human health since they are usually present in the lungs and other small environments in the body. However, as our understanding of these organisms and their effects on diseases such as atopy and asthma increases, their impact should be taken into account.

Research into the microbiome of the gut has established that the airways also contain a typical flora, with varying numbers, diversity, and distribution of prokaryotic species. Early research into this new field has suggested that various types of bacteria that are present in increased numbers in asthmatic airways may be contributing to the chronic airway inflammation and hyperreactivity that characterize asthma. A study with a relatively small sample size found that treatment with clarithromycin improved patients with increased bacterial populations and diversity [23].

Moreover, the microbial populations of the gastrointestinal tract are also being studied, and early antibiotic exposure has been linked to the development of atopy and asthma by altering the gastrointestinal tract flora [25, 26, 27]. The significance of these differences is yet to be fully determined.

2.4 Asthma and infection

For more than 20 years, researchers have been investigating whether asthma is an infectious disease, but a definitive answer has yet to be found [28]. Investigating the origins of asthma is challenging because it is difficult to collect samples from the lungs of children. It is now believed that a combination of genetic mutations and environmental conditions is responsible for the various pathways of asthma, making it a syndrome with a typical clinical presentation but with a myriad of potential pathogenic mechanisms.

Recent research suggests that the prolonged presence of certain microorganisms in the bronchi may be linked to the development of asthma. Acute viral infections are well-known triggers of asthma exacerbations in both adults and children. In contrast, little is known about the role of chronic infections in the pathogenesis of the disease itself.

Asthma can be caused by a variety of factors, including atopy, respiratory infections, genetic predisposition, and a Th2-biased immune response. Polymorphisms in host defense genes can also influence the host’s innate immune response. The effect of infectious agents on asthma can vary depending on the type of asthma, such as childhood- or adult-onset, atopic or nonatopic, and neutrophilic, eosinophilic, or paucigranulocytic leukocyte airway predominance.

Numerous studies suggest that early-life lower respiratory tract infections, especially those caused by viruses such as Rhinoviruses (RV) and Respiratory Syncytial Virus (RSV), are linked to an increased risk of school-age asthma [29]. Additionally, atypical bacteria, such as Mycoplasma pneumoniae and C. pneumoniae, may also contribute to persistent infections and be involved in the development of asthma [30, 31, 32, 33]. Of particular interest is the role of C. pneumoniae, an obligate intracellular respiratory pathogen, in both asthma severity and treatment resistance [34].

3. C. pneumoniae: a pathogen causing more than pneumoniae

C. pneumoniae is a widespread cause of infection, with an estimated seroprevalence of over 50% among adults in many countries [35, 36, 37]. However, the prevalence is relatively low in children under 5 to 10 years old (7–8%), but it sharply increases to 40–55% in those aged 20 and continues to increase gradually, reaching 70–80% in the elderly [38, 39].

In 1989, Grayston identified C. pneumoniae as a novel species based on its distinct morphology, DNA sequence, and associated clinical disease spectrum within the Chlamydiae family [40]. Subsequently, C. pneumoniae has been linked to 6–22% of upper and lower respiratory tract infections, including pharyngitis, laryngitis, sinusitis, bronchitis, and pneumonia, in both children and adults [41, 42, 43]. This obligatory intracellular pathogen has been associated with an extensive range of conditions, such as cardiovascular disease, Alzheimer’s disease, arthritis, lung cancer, diabetes, and asthma [44].

3.1 Biology and developmental cycle

C. pneumoniae is a human pathogen belonging to the Chlamydiae family. Its developmental cycle is complex and involves alternating between an infectious, extracellular elementary body, and a noninfectious, intracellular reticulate body. These two forms exist in a membrane-bound compartment called an inclusion, located inside a mucosal cell. After multiple replications, the reticulate body returns to the elementary body form and is released from the host cell, enabling it to infect nearby cells. This life cycle plays a crucial role in the molecular pathogenesis of chronic chlamydial infections.

To inject effector molecules into host cells, Chlamydia spp. utilizes a type III secretion system (T3SS). This T3SS produces a unique family of proteins known as inclusion membrane proteins (Incs). Incs are essential for the intracellular survival of Chlamydia spp. as they recruit host proteins to the inclusion, hijack the endocytic-lysosomal pathway, and help maintain the structural integrity of the inclusion. Additionally, Incs can enhance virulence by interfering with host antimicrobial pathways, promoting resistance to apoptosis, or constructing novel complexes with unique functions [45, 46].

Although studies of C. trachomatis have contributed significantly to our understanding of chlamydial infection and metabolism in humans, not all of these findings apply to C. pneumoniae. Significant differences in transcription, metabolism, and morphology exist between C. pneumoniae and other chlamydial species.

Research has shown that C. pneumoniae can modulate host cell apoptosis to evade detection by the host’s immune system by interfering with tumor necrosis factor-alpha (TNF-alpha) and various signaling pathways [47]. This trait of the microorganism suggests that if the host cell can survive after the expulsion of extracellular vesicles, it could enable further reinfection and the maintenance of chronic, asymptomatic disease. The ability of C. pneumoniae to spread from the lungs to distant body parts and persist in those tissues for an extended period is essential to the development of the infection [48].

Persistence of Chlamydia Infection: Chlamydia infection is caused by the direct effects of chlamydial proteins, as well as mechanisms that utilize the host cell’s machinery. When exposed to stressful conditions, Chlamydiae cease production of infectious extracellular bodies (EBs) and instead form viable but noninfectious forms characterized by a continued synthesis of unprocessed 16S rRNA and genomic replication [47]. These persistent forms can remain in the host for a prolonged period and are often associated with enlarged and malformed RBs, which can return to the normal developmental cycle when the inducing factor is removed [44]. In vitro, experiments have shown that several factors, including exposure to interferon-gamma (IFN) or antibiotics (such as penicillin and amoxicillin) and nutrient deprivation, can trigger the formation of persistent forms.

4. Asthma and C. pneumoniae

In the early 1990s, Hahn and colleagues were the first to suggest a possible link between C. pneumoniae and asthma when they observed a connection between Ig levels, wheezing, and adult-onset asthma [49]. To further investigate this association, they followed 10 patients who had acute C. pneumonia infection and de novo wheezing for 10 years, collecting clinical and microbiological data [50]. Among the 10 patients, one had pneumonia, while the other nine had bronchitis. Of the nine with bronchitis, four improved without treatment, while the remaining five developed chronic asthma during follow-up.

The investigation of the association between C. pneumoniae and asthma is impeded by the lack of standardized, sensitive, and specific detection methods for the pathogen. Nucleic acid amplification tests (NAATs), such as real-time PCR assays, offer accurate and efficient means of diagnosing acute C. pneumoniae infections [51]. However, the microimmunofluorescent antibody test is the most sensitive and specific serologic test for acute infection [40], despite its technical challenges and subjective interpretation. C. pneumoniae culturing is difficult and should be performed in cell culture. Additionally, there are practical and ethical obstacles to sampling the lower respiratory tract in representative populations of asthma patients and control subjects. Clinical research serological testing methods are limited by the high prevalence of antibodies to C. pneumoniae in the general population and the short duration of the initial antibody response (3–5 years), indicating that chronic infection and reinfection are common [52]. Serological methods cannot distinguish between acute, chronic, or reactivated prior infections. Therefore, new molecular diagnostic methods, such as PCR, have been developed to detect the pathogen’s DNA. Although PCR testing can detect uncultivable organisms, it cannot differentiate between viable and nonviable organisms when used in antibiotic treatment studies [53]. However, reverse transcriptase-PCR can identify metabolic activity by detecting messenger RNA and may overcome this limitation [54].

Several studies using serological diagnostic techniques have linked C. pneumoniae to stable asthma in both adults and children. The studies used heat-shock proteins (HSPs) of C. pneumoniae, which are overproduced in persistent infections and associated with hypersensitivity and immunopathology [55]. Significant differences in the prevalence of antibodies to these HSPs were observed [56, 57, 58]. Falck et al. found that persistently increased levels of C. pneumoniae IgA antibodies were associated with pronounced symptoms of chronic respiratory tract disease [56]. A recent study concluded that asthmatics with IgA and IgG against C. pneumoniae have more severe disease with increased airway obstruction, higher doses of ICS, more signs of air trapping, and less type-2 inflammation [59].

A dose-response relationship between C. pneumoniae HSP60 IgA antibodies and pulmonary function has also been observed, with an inverse association seen between IgG antibodies to C. pneumoniae and percent-predicted FEV1 in asthmatics with elevated IgG and/or IgA levels. These elevated levels of IgA antibodies have also been associated with a higher daytime asthma symptom score and the need for high-dose inhaled corticosteroids. In general, higher C. pneumoniae antibody titers appear to be linked to several asthma severity markers [60].

A study involving 332 asthmatic patients discovered a significant correlation between asthma and elevated levels of IgG antibodies to C. pneumoniae, with the strongest correlation being observed in non-atopic longstanding asthma [58]. However, a population-based study conducted in Italy found a significant correlation between C. pneumoniae seropositivity and atopy among young adults [59].

Regarding children with reactive airway disease, Emre et al. discovered a correlation between C. pneumoniae infection and wheezing, with 85.7% of the 14 wheezing asthmatic patients testing positive for C. pneumoniae [61]. Immunoblotting detected anti-C. pneumoniae IgE, while anti-C. pneumoniae IgG and IgM were not detected by microimmunofluorescence. This suggests that the production of specific IgE may be a mechanism underlying reactive airway disease in some patients with C. pneumoniae infection. A subsequent study of asthmatic children found C. pneumoniae-specific IgE antibodies even in the absence of acute airway infection (negative PCR), suggesting that C. pneumoniae can stimulate allergic responses [61].

Studies comparing the T helper responses in C. pneumoniae-infected peripheral blood mononuclear cells (PBMC) of asthmatic patients to those of non-asthmatic control subjects revealed that C. pneumoniae infection can induce allergic responses in asthmatic PBMC, as indicated by an increase in the production of Th2-type cytokines (such as IL-4) and induction of IgE responses [62]. Recent studies with similar findings have suggested that C. pneumoniae infection may trigger IgE-specific responses in both asthmatic children and adult asthma patients [63, 64].

Research has indicated that C. pneumoniae infections can lead to the development of organism-specific IgE chemical mediators, which can cause airway inflammation and consequent wheezing. Furthermore, CP-specific IgE has been linked to severe persistent asthma, indicating that persistent infection may be causing asthma symptoms. Therefore, treating the underlying C. pneumoniae infection may help to lessen or even abolish symptoms [65].

Teig et al. conducted a study involving 38 children with stable chronic lung disease and 42 healthy controls. They found that 24% of the children with lung disease tested positive for C. pneumoniae using PCR, while none of the controls tested positive [66]. In a similar study, Cunningham et al. detected C. pneumoniae DNA in nasal specimens from 28% of stable asthmatic children, and the PCR result remained positive for a few months [67]. Biscione et al. utilized reverse transcriptase PCR to detect RNA of the major outer membrane protein (MOMP) from C. pneumoniae, which is only created during productive infection. This method was found to distinguish colonization from productive infection. They reported an increase in the detection of this organism in asthmatic patients compared to nonatopic spouses of asthmatic patients who served as controls [68].

There is evidence that C. pneumoniae infection may be related to asthma exacerbations. Acute asthma exacerbations are a common cause of hospitalization and visits to the Emergency Department (ED) in children, and they account for a significant proportion of asthma-related issues. Respiratory infections have been strongly linked to exacerbations, making them potential targets for treatment. Evidence suggests that C. pneumoniae is associated with asthma attacks, particularly in cases of severe attacks in children [69, 70]. Furthermore, atypical bacterial infections have been shown to cause attacks that are associated with persistent symptoms and a slower rate of recovery after 3 weeks [71].

Mounting evidence suggests that C. pneumoniae could play a role in the pathogenesis of asthma. Components of C. pneumoniae, such as transcription factors, have been found to activate components in bronchial tissue, leading to increased cytokine release and airway remodeling [72]. Furthermore, studies have shown that patients with C. pneumoniae-specific antibodies are more likely to experience severe airway inflammation than those without [73]. These findings suggest that C. pneumoniae reactivation could be a potential trigger for neutrophilic airway inflammation in people with asthma.

C. pneumonia infections might be worsening asthma. Webley found that 33% of asthma patients had C. pneumonia present in their bronchoalveolar lavage (BAL) samples by culture, and 67% were PCR-positive [74]. In a study of a heterogeneous group of children with asthma and recurrent bronchial obstructions, Schmidt et al. reported a 52% PCR-positivity rate for C. pneumonia in bronchoalveolar lavage specimens [75]. This suggests that C. pneumonia infections are more common in asthmatic patients than previously thought. It is worth considering whether C. pneumonia infection or colonization has a worsening effect on chronic respiratory diseases, as these invasive procedures such as bronchoscopy are only performed in treatment-resistant patients.

C. pneumoniae infection has been linked to an increase in the number and longevity of immune and inflammatory cells, which can lead to a reduced response to steroid treatment and increase the likelihood of treatment resistance [76].

A subpopulation of 5–25% of asthmatics, typically those with more severe disease and uncontrolled symptoms despite high doses of steroids, are labeled as having severe, steroid-resistant asthma. Respiratory infections are being implicated in the pathogenesis of severe, steroid-resistant asthma, and neutrophil-dominated endotypes of disease. Neutrophilic asthma is found to be associated with increased bacterial burden and interleukin 8 levels [34]. It has been suggested that neutrophilic asthma is less responsive than eosinophilic asthma to anti-inflammatory therapies, including corticosteroids. A study of children with asthma found that those who were PCR-positive for C. pneumoniae had higher concentrations of IL-8 and neutrophils in their bronchoalveolar lavage fluid than those who were PCR-positive for C. trachomatis or mycoplasma organisms but PCR-negative for C. pneumoniae [34]. This suggests that undiagnosed C. pneumoniae infections in children may contribute to inadequately controlled asthma by inducing IL-8.

Several studies have suggested that chronic C. pneumoniae infection is associated with a decline in respiratory function and more severe disease in both children and adults [68, 77, 78], and these associations are supported by biologically plausible mechanisms [79]. Cigarette smoke exposure is a known risk factor for steroid resistance in asthma [80]. Similarly, C. pneumoniae (CP) is known to induce ciliostasis of the pulmonary bronchial epithelium [81] and can infect alveolar macrophages and lung monocytes, resulting in increased production of TNF-, IL-1, IL-6, and IL-8, as well as human bronchial smooth muscle cells, leading to the production of IL-6 and basic fibroblast growth factor (with potential effects on bronchial hyperreactivity and lung remodeling) and chronic infection exposes tissues to cHSP60 and LPS, which have been linked to increased inflammation and asthma [82].

Numerous clinical studies have found associations between C. pneumoniae infection and the onset of childhood asthma. However, the relationship between C. pneumoniae infection and late-onset asthma in adult studies has yielded contradictory findings. A cross-sectional study conducted on patients with severe, late-onset, nonatopic asthma showed intriguing results suggesting a possible link between C. pneumoniae infection and fixed airway obstruction in adults [83].

A case-control study conducted in Italy found that children aged 2–14 years who presented to the pediatric emergency department with an acute episode of wheezing had a significantly higher incidence (15.5%) of acute C. pneumoniae infection compared to healthy controls [83]. Follow-up revealed that those who were not treated with antibiotics were more likely to experience recurrent wheezing than those without the infection. A study conducted in Japan also demonstrated similar findings, with higher CP-IgM levels present in hospitalized wheezing infants than in controls and a higher incidence of asthma in those with C. pneumoniae infection than in those without [84]. A larger follow-up study conducted 2 years later revealed that C. pneumoniae infection, a family history of allergic diseases, the number of eosinophils, and the serum IgE concentration at the initial examination were risk factors for asthma progression [85].

The use of mouse models has enabled researchers to determine the mechanisms by which Chlamydia respiratory infections in early life may be associated with the emergence and increased severity of allergic airway disease (AAD) later in life. Infections at all ages (neonatal, infant, and adult) were found to induce inflammation. However, it was observed that chlamydial infection during early life, but not in adulthood, was associated with the development of asthmatic characteristics in allergen-induced AAD. In particular, neonatal and infant infections were found to result in mixed type 1/type 2 immunity with increased levels of interleukin-13 (IL-13) and interferon (IFN), which, in turn, was associated with increased mucus-secreting cells and airway hyperreactivity (AHR) in AAD later in life, when compared to age-matched uninfected controls [86, 87]. Jupelli et al. later confirmed the effects of infant infection on the structure and function of the respiratory system [88]. Interestingly, it was found that infant infection increased the number of airway eosinophils [84, 85, 89]. Further investigation revealed that inflammation and AHR can lead to steroid resistance [75].

5. Macrolides in asthma treatment

Macrolides, such as clarithromycin and azithromycin, have been extensively studied for decades as a potential treatment for asthma. Although the results of clinical trials have been controversial, they are now included in severe adult asthma treatment guidelines as an additive agent due to their antibacterial, antiviral, anti-inflammatory, and immunomodulatory features [90, 91, 92]. The anti-inflammatory effects of macrolides may be particularly beneficial for patients with type 2 inflammation, while the antibiotic and antiviral effects may prevent respiratory infections in patients with neutrophilic inflammation [93].

Macrolides have been found to be effective in treating both eosinophilic and non-eosinophilic asthma phenotypes as adjunctive therapy in severe asthma [91, 94].

It is well-known that severe asthma can present with different phenotypes, such as increased concentrations of eosinophils or neutrophils and IL-8 in the airways. Patients with neutrophilic asthma have been shown to respond better to macrolide therapy and this type of asthma is thought to be more associated with bacterial pathogens and IL-8 [95]. Infection-mediated asthma is particularly related to neutrophilic, steroid-resistant asthma, leading many studies to focus on atypical bacterial infections in asthma and the effectiveness of macrolide treatment [96].

Two randomized, double-blind, placebo-controlled studies have reported contrasting results. Kraft and colleagues reported that clarithromycin treatment substantially increased FEV1 in asthmatic patients with PCR evidence of C. pneumoniae or M. pneumoniae infection in upper or lower airway samples [97]. However, the study conducted by Sutherland and colleagues did not support these findings [98]. The contrasting results can be attributed to the difficulty of accurately diagnosing atypical bacterial infections, as reported in a related meta-analysis [99].

6. Conclusion

Asthma is a heterogeneous disease that presents with similar clinical manifestations, is characterized by airway inflammation, and is likely to have different mechanisms of pathogenesis. Research suggests that multiple genetic and environmental factors, including respiratory pathogens and airway microbiome, interact to influence clinical manifestation, bronchial hyperresponsiveness, and the presence of atopy.

In addition to the role of viral infections in early life, many clinical and animal studies support the role of Chlamydia related respiratory infections in the development of asthma. Furthermore, Chlamydia pneumonia has been linked to severe and steroid-resistant asthma.