American Journal of Respiratory and Critical Care Medicine

In a serologically based prospective study, acute infections with four atypical pathogens were determined in 100 adults hospitalized for acute exacerbation of bronchial asthma, and compared with the corresponding rate in a matched control group. Paired sera were tested using immunofluorescence or enzyme immunoassay methods to establish the serologic diagnosis. In 18 patients (18%), there was evidence of acute infection with Mycoplasma pneumoniae, compared with 3% in the control group (p = 0.0006). In 10 of these patients there was evidence of infection with at least one additional pathogen, a respiratory virus in 7. There was no significant difference between the study groups in the rates of acute infection by Chlamydia pneumoniae (8% in the hospitalized patients versus 6% in the control subjects), Legionella spp. (5 versus 3%, respectively), or Coxiella burnettii (no patients in either group). We conclude that of these four atypical pathogens, only infection with M. pneumoniae is associated with hospitalization for acute exacerbation of bronchial asthma. In most of these M. pneumoniae patients there is evidence of infection with a respiratory virus as well. The pathophysiologic and therapeutic significance of these findings should be tested in further studies specifically designed to address these questions.

The pivotal role of respiratory tract infections (RTI) in inducing acute exacerbations of bronchial asthma (AEBA) in children and adults is well established (15). In most of these episodes the specific infectious etiology is a respiratory virus, usually rhinovirus, coronavirus, or influenza (1, 2, 6).

The atypical pathogens are also recognized as causes of RTI, but their role in AEBA is not clear. Some studies found an association between acute infection with Mycoplasma pneumoniae (Mp) and AEBA (79), but others did not (1012). A similar association between Chlamydophila (Chlamydia) pneumoniae (Cpn) and AEBA was found in two studies (13, 14), but was not confirmed in a later one (15). Recent studies have shown that serologic evidence of chronic infection with Cpn was more frequent in patients with asthma (16), but a trial of roxithromycin for 6 weeks in subjects with asthma and serologic evidence of infection with Cpn leaves the question of the importance of Cpn in asthma unanswered (17, 18).

An in-depth analysis leads to the conclusion that the absence of consistent findings in these studies of atypical pathogens stems from the difference in the age composition of the study populations (adults versus children), the presence or absence of appropriate control groups, and, in particular, the substantial differences in the techniques used to identify specific atypical etiologies for AEBA. There are no reports, to our knowledge, of studies in which an association between Coxiella burnetii and Legionella spp., established members of the atypical pathogen group, and AEBA was investigated.

In light of the above, the primary objective of this study was to assess, by advanced serologic methods, the rate of acute infections with these four atypical pathogens in a group of adult patients hospitalized for AEBA compared with a matched control group. Because infection with one of these atypical pathogens can be associated with infection with an additional respiratory pathogen, a second objective of the study was to test and compare the study groups for infections caused by a group of respiratory viruses and the bacterium Streptococcus pneumoniae.

Patients (Study Group)

The study included patients hospitalized for AEBA over a 12-month period who provided informed consent to participate and met all of the following inclusion criteria: (1) age over 18 years; (2) a past history of typical bronchial asthma; (3) reversibility of at least 15% of the FEV1 value with the patient in stable condition; (4) a smoking history of no more than 10 pack-years; (5) the present hospitalization for a new-onset or exacerbation of dyspnea over the week before admission; (6) negation during the hospitalization of causes of dyspnea other than bronchial asthma; and (7) ruling out of pneumonia by admission chest X-ray.

The control group included patients hospitalized over the same time period in the orthopedic surgery ward who provided informed consent to participate and met all of the following conditions: (1) age over 18 years; (2) hospitalization for trauma or elective surgery; (3) no evidence of febrile illness or RTI over the month before hospitalization and during the period between the two serum samples; and (4) negation of any lung disease. Recruitment of control patients was conducted in parallel with the study group to ensure a similar distribution by seasons of the year.

An acute blood sample was drawn for serologic testing within 48 hours of hospitalization and a second (convalescence phase) sample 3 to 5 weeks later.

The etiologic workup in this study was based, exclusively, on serologic tests. Serologic tests were conducted for 12 pathogens known to cause upper or lower RTI that can be identified by serologic testing. The antibody levels for Mp were determined using three commercial enzyme immunoassay (EIA) kits: SeroMp-IgA, SeroMp-IgG, and SeroMp-IgM (Savyon Diagnostics, Ashdod, Israel). These three kits are an improved version of a previous commercial kit, SeroMp (Savyon Diagnostics), whose sensitivity and specificity were assessed and were found to be very good (19). The sensitivity and specificity of the novel SeroMp-IgA kit (with which 85% of the patients were identified as positive for Mp in the present study) was recently validated and found to have high sensitivity and specificity for the serologic diagnosis of acute Mp infection (20). Acute Mp infection was diagnosed if a significant change (according to the formula in the manufacturer's instructions) in the antibody level was found between the acute and convalescence serum samples. The methods, kits, and criteria used to reach serologic diagnoses of infection with the other 11 pathogens were identical to those described in our previous publication (21), with the lone exception that acute Cpn infection was also diagnosed in the presence of unchanged titers of IgG ⩾ 512 or IgM ⩾ 8.

The results were analyzed using the statistical software Epi Info (Epidemiology Program Office, Center for Disease Control and Prevention, Atlanta, GA). The χ2 test or its equivalent served to compare proportions between groups, and ANOVA was done to compare continuous variables among two or more groups. Statistical significance was set at p < 0.05.

An expanded Patients and Methods section with a full study protocol and a detailed description of the laboratory etiologic workup appears in the online supplement of this article.

One hundred thirteen patients with a working diagnosis of AEBA who were hospitalized during the study period were recruited into the study. All the patients survived the hospitalization and the period between the hospitalization and the follow-up appointment, and all came to the follow-up. Eleven patients for whom there was no FEV1 reversibility test before hospitalization and who did not meet the reversibility criteria at the follow-up visit after discharge were not included in the data analysis. Two patients with a polyclonal antibody reaction to all tested pathogens were also excluded from analyses. Thus, the final data analysis was conducted on the study population of 100 patients hospitalized for AEBA. For all of these patients, without exception, a convalescence serum sample was obtained at a mean of 26.2 ± 4.7 days after the initial serum sample was taken (range, 16–40 days).

One hundred sixty-eight patients were recruited during the study period into the control group. Sixteen reported a febrile illness and/or symptoms of respiratory tract infection in the period between the first serum sample and the scheduled time for the second sample, so they were excluded from the study. Eight patients did not provide convalescence serum sample and were also excluded. The final control group of 100 patients was constituted from the remaining 144 patients so that the distribution by sex, age, and season of the year would match the study group as closely as possible. This matching process was performed before the serologic tests were conducted; these 100 patients comprised the final control group. The mean age (± SD) for the control group was 46.9 ± 14.7 years (range, 19–74), and 34 patients were males. The mean time between the serum samples was 24.8 ± 4.2 days (range, 19–37). There were no significant differences in these parameters between the study and control groups.

Table 1

TABLE 1. Demographic data, baseline fev1, fev1 reversibility, and o2 saturation in stable condition, home oxygen, chronic oral steroid therapy, rate of influenza and pneumococcal vaccination, and chronic comorbidity in the 100 patients with asthma


Variable

Result

Range
Sex, % males36
Mean age, yr ± SD48.1 ± 17.818–78
Baseline FEV1, % of expected*63.4 ± 17.336–99
% baseline FEV1 reversibility, mean ± SD*22.6 ± 6.715–47
Baseline O2 saturation, mean ± SD*96.1 ± 3.582–99
Home oxygen, %3
Chronic oral steroid therapy, %24
Influenza vaccination, %28
Pneumococcal vaccination, %7
Diabetes mellitus, %13
Ischemic heart disease, %3
Left-sided heart failure, %
4

*Baseline FEV1, FEV1 reversibility, and O2 saturation values were determined 6 months before hospitalization, or within 1–2 mo after hospitalization, at room air with the patient in stable condition.

shows the demographic characteristics of the study group and clinical data such as baseline FEV1, FEV1 reversibility, O2 saturation in stable condition, home oxygen use, chronic oral steroid therapy, rates of influenza, and pneumococcal vaccination and chronic comorbidity.

Table 2

TABLE 2. Clinical manifestations of exacerbation, arterial po2, pco2, and ph at admission, rates of admission to intensive care and invasive mechanical ventilation, duration of hospitalization, readmission within 30 d, and recovery to baseline functional condition within 30 d after discharge from the hospital in the 100 patients with asthma


Variable

Result

Range
Abrupt onset of exacerbation, %*22
Feeling of shaking chills, %28
Fever during exacerbation, %54
PO2 at admission, mean ± SD at room air61.7 ± 11.634–92
PCO2 at admission, mean ± SD at room air39.0 ± 11.323–81
pH at admission, mean ± SD7.41 ± 0.087.17–7.52
Admission to intensive care, %26
Invasive ventilation, %7
Mean length of hospital stay, d ± SD3.7 ± 2.81–15
Readmission, %5
Recovery within 30 d, %
94

*Development of all symptoms of exacerbation within less than 12 h.

details clinical and laboratory data relating to the exacerbation that led to hospitalization, the clinical course, and the convalescence phase, including arterial Po2, Pco2 and pH at admission, rates of admission to intensive care, rates of mechanical ventilation, duration of hospitalization, rates of readmission within 30 days of discharge, and recovery to baseline function within 30 days of discharge. All blood cultures from febrile patients in the study group on admission were sterile.

There was serologic evidence of acute infection in 49 of the patients in the study group with at least one of the 12 pathogens tested. This rate was significantly higher than the rate in the control group. Table 3

TABLE 3. Comparison of the frequency distribution of acute infections with the various pathogens between the patients with asthma (n = 100) and the control group (n = 100)


Pathogen

Asthma

Control

p Value
Viral agents, %
Influenza virus type A112 0.01
Influenza virus type B51NS
Parainfluenza virus type 130NS
Parainfluenza virus type 220NS
Parainfluenza virus type 310NS
Adenovirus61NS
Respiratory syncytial virus20NS
One or more of the above304< 0.00001
Bacterial agent, %
Streptococcus pneumoniae33NS
Atypical bacterial agents, %
Legionella spp.53NS
Mycoplasma pneumoniae183 0.0006
Coxiella burnetii00NS
Chlamydia pneumoniae86NS
One or more of the above2610 0.003
No infectious etiologies found
51
85
< 0.00001
shows the rates of acute infection with the various pathogens in the study and control groups and a comparison between them. There were significant differences between the study and control groups in the rates of acute infection with respiratory viruses and atypical bacteria, but not S. pneumoniae. Among the atypical bacteria there was a statistically significant difference between the study groups for acute infection with M. pneumoniae, but not the other three atypical pathogens.

In 13 of the 49 patients with acute infection (27%) there was evidence of infection with more than one pathogen. The distribution of the number of acute infections per patient in the study groups is shown in Table 4

TABLE 4. A comparison of the number of acute infections per patient between the patients with asthma (n = 100) and the control group (n = 100)


Positive serologic results

Asthma

Control

p Value
05185< 0.00001
13713< 0.00001
21020.01
310NS
4
1
0
NS
.

In 8 of the 18 patients with acute M. pneumoniae infection this was the only pathogen, whereas in 10 others (56%) at least one other pathogen was identified. In eight of these patients one other pathogen was found, in one patient two were found, and in one patient three other cause of acute infection were identified. In 7 of the 10 patients the additional pathogen was a respiratory virus, in five an atypical bacterium (C. pneumoniae or Legionella spp.), and in one patient S. pneumoniae.

To identify unique characteristics of the group of patients with asthma with evidence of acute Mp infection, we compared all parameters appearing in Tables 1 and 2 between these 18 patients and the 82 patients with asthma without evidence of acute infection with Mp (non-Mp). No statistically significant differences were found for any of these parameters between these two groups. However, interesting trends were found between the groups in some parameters, even though these differences did not reach statistical significance. This was the case in relation to sex (28% males in the Mp group versus 38% in the non-Mp group), chronic oral steroid therapy (33% versus 22%, respectively), diabetes mellitus (6% versus 15%, respectively), and return to baseline function within 30 days (100% versus 93%). In the Mp group there were three patients on home oxygen therapy, seven patients who underwent invasive ventilation, and five patients who were readmitted to the hospital, compared with none in any of these categories in the non-Mp group. For all other parameters appearing in Tables 1 and 2 the results were very similar for the Mp and non-Mp groups of patients with asthma.

There was not a single case of a fourfold or greater increase in antibody titer for Cpn with any of the three antibody types tested in any of the 200 patients in both study groups. The eight positive results in the study group and the six positive results in the control group were determined by the index of an unchanged titer of IgG ⩾ 512 or IgM ⩾ 8.

There was no epidemic of Mp in Israel during the study period, and the seasonal peaks of influenza were not different from other years.

The medical community has become increasingly aware of the importance of the atypical bacteria over the last five decades. Today this group is considered an important etiologic factor in RTI together with respiratory viruses and classical bacteria. In addition to community-acquired pneumonia, in which these pathogens play an important role (22), they are also important in upper and lower RTI in the community (23) and in acute exacerbation of COPD (21). In light of the association between RTI and AEBA described above, it made sense to evaluate the involvement and contribution of these pathogens to AEBA.

Several methodologic issues relating to our study have to be addressed. The etiologic diagnoses for atypical bacteria in the present study were based entirely on serologic tests. At the planning stage of the study we took into consideration the theoretical possibility that the antibody response upon which the diagnoses were based could be nonspecific. The solution to this problem in this study was the absolute requirement that paired sera be obtained for all patients in both study group together with the very strict diagnostic criteria that were based, except for Cpn, on a significant change in the antibody titer between the paired sera. We preferred serologic testing to isolation of pathogens by culture or identification by PCR from respiratory secretions in light of the difficulty in ascribing a cause–effect relationship between a positive finding by these methods and acute infection. This problem is particularly critical in patients with chronic asthma, because colonization of the lower respiratory tract by Mp and respiratory viruses has been found under stable disease conditions at the same time that serology for acute infection with Mp was negative (24, 25). The only one exception to our absolute requirement for a significant antibody titer change between the paired sera as a diagnostic criterion was for Cpn. In this study, as in previous studies (13, 15), acute infection with Cpn was also diagnosed in the presence of high but unchanged titers. These criteria are somewhat problematic in that an unchanged titer may reflect chronic infection with this pathogen and not necessarily acute infection (26). In any event, we found no difference in the rates of acute Cpn infection between the study and control groups with the criteria that were used, nor would a difference have been found with various criteria based on changing titers.

It would have been appropriate to present sensitivity and specificity data for each of the serologic tests used for the various pathogens in this study. This issue of the sensitivity and specificity of serologic tests for the diagnosis of acute respiratory infections is very problematic. An accepted gold standard is required for each pathogen to determine these characteristics. To date there is no single laboratory test for the pathogens tested in the present study that could be considered as a gold standard for acute infection with that pathogen. Even the most advanced methods, such as PCR, can identify with high sensitivity the presence of a specific pathogen in the respiratory tract, but they cannot negate the possibility that the pathogen is present as a chronic agent rather than the cause of acute infection (24, 25). The absence of precise and reliable sensitivity and specificity data for each of the laboratory tests used in this study posed a serious methodologic challenge for us, because the significance of the study findings is dependent upon these unavailable data. We dealt with this challenge by adopting two strategies. First, we used standard, accepted serologic criteria for the difference between two serum samples as the basis for diagnosing acute infection. The application of these criteria necessitated a large effort to obtain two serum samples from each of the participants in the study. Second, we compared the results of the study group with a control group of patients, matched to the study group by age, sex, and season of the year, who did not have evidence of asthma or RTI. This comparison neutralized, in effect, the issue of the specificity of the results for acute exacerbation of bronchial asthma. An example of this can be seen in the absence of a significant difference between the study and control groups for acute infection with Cpn, Legionella spp., or S. pneumoniae. Taken together, these two strategies significantly reduced the importance of the absence of precise sensitivity and specificity data for the various serologic methods in relation to the significance of the study results.

The serologic tests for Legionella spp. in this study were conducted using an in-house kit. It is important to note that there is no commercial kit on the market with which it is possible to test for all 41 serogroups of Legionella spp. that were tested. Although the use of an in-house kit is problematic, this is a universal problem and not a specific one for the present study. The problem stems, primarily, from the absence of a gold standard against which results of serologic tests can be validated. Cultures of pathogens as well as PCR detection have low sensitivity and cannot be used as a gold standard. The accepted substitute for validations of test results is strict QC/QA procedures together with rigid diagnostic criteria, using paired sera. Both of these conditions were strictly adhered to in this study.

We checked the sera from the study and control groups for seven respiratory viruses and S. pneumoniae with the aim of identifying cases in which AEBA was caused by simultaneous infection with an atypical pathogen and an additional respiratory pathogen. Rhinovirus and coronaviruses are conspicuously absent from the list of viruses tested in this study, despite their dominant position among the viruses that cause AEBA (1, 3). The reason they were not included in this study was the known methodologic difficulty in diagnosing acute infection with these pathogens by serologic methods. This difficulty is also reflected in the absence of a commercial kit that can be used to diagnose infections caused by these viruses. The choice of the seven respiratory viruses that were tested in this study was based on the practical consideration of the availability of a reliable kit for their serologic identification, Our decision to include S. pneumoniae was based on our ability to reliably identify infection with this bacterium with the battery of serologic tests used in the study, as proven in our two previous studies on community-acquired pneumonia (27, 28).

The main and most important finding in this study is that, in comparison with the control group, there was a significantly higher rate of acute infection with Mp in the study group, but not with the other three atypical pathogens. The specific rate of 18% acute Mp infections in this population of adults hospitalized with AEBA that was found in this study is very close to the rate of 21% that was found in a previous study in a similar population (7). In that study, 4 of 20 AEBA patients who were positive for acute Mp infection also had community-acquired pneumonia, an exclusion criterion in our study. Exclusion of the patients with community-acquired pneumonia from the population of the previous study would reduce the positivity rate to 18%, a rate that is surprisingly identical to the present result. The authors of that study state that their use of reliable, sensitive methods is the reason for the high rate of Mp infections found in their study compared with previously published studies. The results of the present study strengthen that contention.

There were no statistically significant differences in any parameter between the 18 patients with asthma with Mp infection and the 82 patients with asthma without Mp infection, although in a few parameters a trend toward a difference was found. We believe that this lack of significant difference between the Mp and non-Mp groups of patients with asthma stems from the relatively small size of the group of patients with Mp among the patients with asthma. In addition, the fact that most of these 18 patients also had evidence of infection with an another respiratory pathogen around the time of the acute episode raises the possibility that the clinical expression of the exacerbation was caused solely or predominantly by the other pathogen, making it impossible to demonstrate unique clinical characteristics among the 18 patients with Mp infection.

The rate of acute infection with Cpn in the present study among patients with AEBA was 8%. This rate was not significantly different from the corresponding rate in the control group. This finding is consistent with the result of a previous study conducted in a similar population and with identical methods. That study also reported no significant difference between the AEBA group and a matched control group (15). The positivity rate for acute Cpn infection in the control group in that study was 5.7%, a rate that is identical to our finding. This rate can be explained as true asymptomatic acute infection in the control group or as a false positive rate because of the diagnostic criterion of a high, but unchanged, titer of specific antibodies that may reflect a chronic, rather than an acute, infection.

Approximately one-quarter of the patients in the study group with evidence of an acute infection had at least one additional pathogen. This phenomenon is well recognized in a broad spectrum of RTI (21, 23, 27, 29, 30), so it is not surprising to find it in the context of AEBA. In 10 of the 13 patients with acute infection with more than one pathogen, one of the pathogens was Mp. These 10 patients represented the majority of the patients who were positive for Mp, and in most cases the additional pathogen was a respiratory virus. This high rate of coinfection with a respiratory virus in patients positive for Mp has been reported previously (8, 9). It is important to note that the rate of patients with evidence for more than one pathogen in general, and the combination of Mp and respiratory viruses in particular in the present study, was affected apparently to a great extent by the absence of rhinovirus and coronavirus from the list of tested viruses. In light of the data showing the dominant role played by these viruses in acute infection among patients with AEBA, it is reasonable to assume that the true number of patients with more than one infection, and in particular those patients with Mp and a respiratory virus, is much higher than the rate identified in this study.

Any attempt to reach therapeutic conclusions for AEBA from the results of this study is problematic. The association between Mp RTI and AEBA is apparently mediated by a TH2 type immunologic reaction. This type of immunologic response can be induced by Mp, but is also a hallmark of the immunologic response in AEBA (31). If this is indeed the basis for the induction of AEBA by Mp RTI, there is no assurance that specific antibiotic therapy for Mp, after the infection has already induced the immunologic response, could stop or reverse that response. Another difficult problem concerning the therapeutic application of the results of this study is that in most patients with AEBA with Mp infection another pathogen was also identified, usually a respiratory virus. If this is the case, one cannot negate the possibility that the Mp infection followed the viral infection so that antibiotic therapy would not change the course of AEBA. However, and despite the two qualifications just discussed, we believe that the findings of the study justify the implementation of prospective, well-controlled trials designed to address the question of the effectiveness of specific antibiotic therapy for Mp during AEBA.

We conclude that of these four atypical pathogens, only infection with M. pneumoniae is associated with hospitalization for acute exacerbation of bronchial asthma. In most of these M. pneumoniae–infected patients there is also evidence of infection with a respiratory virus. The pathophysiologic and therapeutic significance of these findings need to be evaluated in future studies designed specifically to address these issues.

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Correspondence and requests for reprints should be addressed to David Lieberman, M.D., Pulmonary Unit, Soroka Medical Center, Beer-Sheva, Israel 84101. E-mail:

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