Introduction
Asthma is a chronic inflammatory airway disorder with various phenotypes, and obesity increases the risk of developing asthma 1.5 - to 3 - fold [
1‐
3]. The association of asthma and obesity is now considered as a phenotype with its own clinical, biological and functional characteristics [
4]. Obese patients with asthma often have impaired response to the inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) combination, and have worse asthma control with 4- to 6-fold higher risk of being hospitalized compared with non-obese patients with asthma [
5,
6].
Approximately 60% of adult asthma exacerbations (AEs) are triggered by viral infection [
7]. Human rhinovirus (HRV), respiratory syncytial virus (RSV), and influenza virus (IFV) are major causes of AEs [
8]. However, few epidemiologic studies on bacterial infection in AE have been performed, and the potential role of bacterial infection in AE remains controversial. Chronic bacterial colonization is evident in the airway of patients with neutrophilic asthma, with
Haemophilus influenzae (
H. influenzae) being one of the most frequently isolated bacteria [
9,
10]. Previous animal studies have shown that
H. influenzae infection increases T helper 17-associated neutrophilic airway inflammation [
11‐
13]. Bacterial community composition varies with disease features, steroid responses, and inflammatory phenotypes. Neutrophilic asthma is present in a greater proportion of obese than in non-obese patients with asthma [
14,
15].
Bacteria in the lower airways are potential treatment targets, especially in steroid-resistant asthma. The aim of the present study was to investigate the differences in clinical characteristics and isolated pathogens of AEs between obese and non-obese patients and compare their treatment responses.
Materials and methods
Study population
We screened adult patients with AEs who were subjects for microbiological studies in 24 secondary or tertiary medical institutes in the Republic of Korea between January 2015 and December 2018. We included adult patients diagnosed with asthma at least 6 months before AEs regardless of treatment. AE was defined as an acute episode of progressive worsening of asthma symptoms requiring the use of oral/intravenous corticosteroids or more than doubling the dose of maintenance therapy. Of these, we included patients who had Gram staining and culture of sputum or endotracheal aspirates and multiplex reverse-transcription polymerase chain reaction (RT-PCR) for respiratory viruses of nasopharyngeal aspirates or lower respiratory tract specimens. During influenza season, antigen test or RT-PCR for influenza only, instead of RT-PCR for other viruses, was allowed. We excluded patients who had used antibiotics within 4 weeks before the AE episode, who had used 20 mg or more of prednisolone or an equivalent dose of another steroid, and who had used macrolide for more than 4 weeks.
Patients were classified into obese and non-obese groups, and their clinical characteristics, treatment response, and isolated pathogens were compared. Obesity was defined as a body mass index (BMI) ≥ 25.0 kg/m
2 in accordance with the Asia-Pacific criteria of the World Health Organization guidelines [
16].
Informed consents were waived because of the retrospective study design, and the study was approved by the institutional review board of the Ewha Womans University Mokdong hospital (EUMC 2019-06-017).
Assessment
The present study investigated the clinical characteristics and isolated pathogens of AEs and compared them between the obese and non-obese groups. Demographic and clinical information of patients were retrospectively collected from electronic medical records. The following variables were assessed: age, sex, BMI, smoking history, comorbidities, treatment regimen for asthma maintenance therapy at the time of AE, and the level of asthma control within 3 months before the episode of AE. Diagnostic criteria for asthma and evaluation of the level of asthma control followed the GINA guideline 2018 [
17]. Comorbidities were investigated through history taking from the patient or review of past medical history at the time of AE. Comorbidity was defined as a condition that the patient currently has or is currently receiving repeated treatment for, except history of tuberculosis. We also included newly diagnosed comorbidities during AE. Symptoms and severity of AE, duration of corticosteroids use, antibiotics and treatment response were also evaluated.
Microbiological evaluation
Viruses and bacteria confirmed by microbiological evaluation at the time of AE diagnosis were investigated. The specific diagnostic kits for the detection of pathogens were different among institutes. Microbiological studies included the following: sputum or endotracheal aspirates, or bronchoalveolar lavage (BAL) fluid for Gram staining and culture; sputum or endotracheal aspirates, or BAL fluid for RT-PCR and/or serology test for Mycoplasma pneumoniae, Chlamydia pneumoniae (C. pneumoniae), Legionella pneumophila, and Bordetella pertussis; nasopharyngeal aspirates, sputum, endotracheal aspirates, or BAL fluid for multiplex RT-PCR for IFV A and B, RSV, HRV, parainfluenza virus 1 to 4, adenovirus, human coronavirus 229E and OC43, human metapneumovirus, enterovirus, and bocavirus.
Statistical analysis
Pearson chi-square test or Fisher’s exact test was used to compare categorical variables, and Student t-test or Mann-Whitney test was used to compare continuous variables. All tests of significance were two-sided, and differences among groups were considered significant when the p-value was < 0.05. All statistical analyses were performed with SPSS software version 22.0 (IBM Corporation, Armonk, NY, USA).
Discussion
In the present study, we found that bacterial infection was identified in 21.1% of all patients with AE. Obese patients with AE used more systemic corticosteroids and had less C. pneumoniae infection compared with non-obese patients. Bacterial infection, especially C. pneumoniae infection, was associated with longer periods of corticosteroid use in the non-obese group.
Consistent with previous reports, HRV, IFV, and RSV were the most commonly isolated viruses in the present study [
8]. Johnston et al. reported that oseltamivir decreases the frequency and symptom severity of AE in children [
18]. However, the identification of viral pathogens in AE is of limited value in clinical practice because antiviral treatment is limited in many cases except IFV infection. The present study showed a high incidence of typical respiratory pathogens, such as
S. pneumoniae and
Pseudomonas aeruginosa, as well as atypical pathogens such as
C. pneumoniae and
Mycoplasma pneumoniae. Iikura et al. reported that typical pathogens were commonly isolated in Japanese patients with AE [
19]. In addition, upper airway detection of
S. pneumoniae during HRV infection is associated with a prevalence of moderate AE [
20]. In the present study, bacterial infection, especially
C. pneumoniae infection, was associated with longer AE duration and longer periods of corticosteroid use in the non-obese group. Several studies have reported that acute or chronic infection of
C. pneumoniae is associated with severe asthma [
21‐
23]. The present study showed that almost all patients with isolated
C. pneumoniae showed positive IgM test results, which indicates an acute infection. Although the reason for the higher incidence of
Chlamydia infection in non-obese patients is unclear, identification of
C. pneumoniae as an acute infectious pathogen as well as colonization might be important in uncontrolled asthma or AE.
There are few epidemiological studies on bacterial infection in AE. Previous clinical trials excluded patients who had received antibiotics at the time of enrollment, those with smoking history, or those with comorbid chronic obstructive pulmonary disease. These patients are likely to benefit from antibiotics, and, some clinicians use empirical antibiotics during AE in clinical practice. A Cochrane review reported that use of antibiotics in patients with AE was associated with longer symptom-free days, shorter periods of AE and higher peak expiratory flow rate [
24]. Because little is known about the most appropriate empiric antibiotic or duration of its use, epidemiological studies on bacterial infection in AE is needed to prevent inappropriate use or overuse of antibiotics.
Scott et al. have shown that neutrophilic airway inflammation improves with weight loss in women [
15,
25]. In addition, there is increasing evidence that asthma is associated with changes in the airway microbiome, which may be altered in obese patients. A recent study including patients with severe asthma showed that obese patients had significantly abundant all taxa and fewer eosinophils in bronchial brushings compared with non-obese patients [
26]. These results may suggest that obesity or altered microbiome or both is associated with less eosinophilic airway inflammation. Impaired response to corticosteroids in obesity might result from its altered pathogenesis, which is related to chronic low-grade inflammation affecting the adipose tissue but might also be associated with bacterial burden [
27,
28]. Because antibiotics may induce the alteration of microbiome composition and antibiotic resistant pathogens, antibiotics should be used cautiously. A total of 88.9% of patients in the present study were prescribed antibiotics, which was higher than we expected. We could not determine whether the patients who received antibiotics had clear signs, symptoms or laboratory test results suggestive of bacterial infection. Isolated microbial data in AE may guide to appropriate use of antibiotics and prevent overuse of antibiotics.
This study has several limitations. Firstly, because only patients with RT-PCR for viruses and culture for bacteria were included,. relatively small number of patients were included in the present study although we included patients from 24 medical institutes across Republic of Korea. Also, patients with severe symptoms requiring hospitalization or those with old age and underlying disease might be preferentially selected. This might have caused a selection bias that excluded younger patients with increased T helper 2-type allergic inflammation. Second, we did not compare the patients with AE with those with stable asthma or with healthy individuals; therefore, the findings cannot be distinguished from colonization. Therefore, further well-designed prospective comparative studies are warranted. Third, antibiotic susceptibility test results for the isolated bacteria could not be found, so it was not possible to evaluate the impact of the susceptibility test results on treatment outcomes. Fourth, we could not correct for differences among institutions because a large number of medical institutions participated in the study and a large difference in the number of patients registered at each institution. Fifth, we could not perform a trend test which determines the seasonality of viral infections each year. Although viral seasonality in the present study was consistent with the results of other nation-wide study conducted in Korea, it is necessary to collect and investigate data over a longer period of time [
29].
Acknowledgements
We thank Soo-Jung Um (Dong-A University), Tae-Hyung Kim (Hanyang University Guri Hospital), Joo Hun Park (Ajou University), Chin Kook Rhee (Seoul St. Mary’s Hospital), Seung Won Ra (Ulsan University Hospital), Myung Goo Lee (Hallym University Chuncheon Sacred Heart Hospital), Yoon Sung Kang (Dongguk University Ilsan Hospital), Sang Bong Choi (Sanggye Paik Hospital), Kwang Ha Yoo (Konkuk University), Ji-Hyung Lee (CHA Bundang Medical Center), Woo Jin Kim (Kangwon National University), Eung Gu Lee (Bucheon St. Mary’s Hospital), Joon Young Choi (Incheon St. Mary’s Hospital), Yeonhee Park (Daejeon St, Mary’s Hospital), Tai Joon An (Yeouido St. Mary’s Hospital), and Hyonsoo Joo (Uijeongbu St. Mary’s Hospital) for the contribution to data acquisition.
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