Mycoplasma pneumoniaepneumonia revisited within the German Competence Network for Community-acquired pneumonia (CAPNETZ)

Mycoplasma pneumoniae as an important pathogen of community-acquired pneumonia (CAP) is only rarely diagnosed in routine practice. This is explained by the many limitations of paired serology which still is the applied diagnostic tool in most cases. In several epidemiologic studies of CAP, largely relying on paired serology, Mycoplasma pneumoniae was identified in 5–15% of cases, resulting in a second or third rank pathogen causing CAP in most series [1, 2]. Together with Legionella spp. and Chlamydophila pneumoniae, these three pathogens are usually addressed as "atypical bacterial pathogens", and considered as prominent targets for broad spectrum antimicrobial treatment including atypical coverage [3].

This approach is questionable for several reasons. First, it may discourage clinical services to include microbial investigations in their diagnostic work-up and thereby promote the decline of any effort to design targeted antimicrobial treatment. Second, relying on paired serology for the diagnosis of MPP necessarily misses acute deaths from pneumonia, and may thereby provide misleading clinical descriptions of the disease and underestimate the prognostic implications of this pathogen. Finally, lumping together all three atypical pathogens throughout all pneumonia severities at admission may heavily bias the potential prognostic implications of the pathogens included in this group, and thereby lead to recommendations of initial empiric antimicrobial treatment implying frank overtreatment.

The main findings of our study, based on very strict diagnostic criteria in a large population of patients with CAP, can be summarized as follows: 1) Mycoplasma pneumoniae is an important pathogen causing CAP 2) patients with MPP are characterized by a quite specific clinical pattern, including younger age, absent or limited co-morbidity, limited inflammatory response, and usually presented with a mild to moderate pneumonia; 3) as a consequence, the majority of patients were treated as outpatients, hospitalized patients had a shorter length of stay, and mortality was minimal; 4) patients with Mycoplasma pneumonia treated as outpatients had even milder pneumonia than those hospitalized; 5) although there was a trend for patients with Mycoplasma pneumonia receiving antimicrobial drugs active against atypical bacterial pathogens more frequently than those with other or unknown etiologies, the rate of discordant treatment remained high.

This study is unique for the strict criteria for the diagnosis of Mycoplasma pneumonia and the large number of patients identified by this diagnostic approach. It is also unique for offering an identical extensive microbiological workup for hospitalized as well as outpatients. The incidence of Mycoplasma pneumoniae pneumonia was 6.7%, which is at the lower range of previous figures reported in recent large etiologic studies.

Previous series of patients with CAP due to Mycoplasma pneumoniae have largely relied on serologic testing, either using paired serum samples or including IgM and/or acute IgG or IgA [9‐14]. When designing our study it was decided – due to feasibility – to collect only one acute phase serum sample. This might be considered as a limitation of our study.

When considering our study patients with M.pneumoniae pneumonia we felt safe to designate patients with a positive PCR result from respiratory samples as a proven case of M.pneumoniae infection. Due to the fact that in many cases acute phase sera were available and serological tests had been performed, we then had a closer look at our serological test results to answer the question whether patients with a positive IgM for M.pneumoniae in their acute phase serum might be considered as proven cases of M.pneumoniae infection as well. In fact, the detection of specific IgM antibodies is generally accepted as an indication of a recent infection. Two aspects persuaded us to follow this hypothesis:

(i) IgM antibodies to M.pneumoniae are only very rarely detected in the sera of healthy subjects. When evaluating the Virotech kit used in our study in blood donors and orthopaedic patients only 2 out of 602 patient samples were IgM positive (0.3%), whereas IgA and IgG antibodies were detected in a significant number of healthy persons [[15], C. Lück, personal communication].

(ii) Patients with a positive PCR result had very similar demographic and clinical characteristics if compared to patients with IgM antibodies only. Especially if looking at the initial CRB65 score, the proportion of patients requiring mechanical ventilation and the outcome (Table 3), we assumed it might be justified to regard PCR as well as IgM only positive patients as an entity if discussing clinical characteristics and management.

We used a commercially available test that uses specific Mycoplasma pneumoniae proteins as antigens. Therefore, a high specificity might be assumed and was demonstrated in a recent publication [15]. The detection of Mycoplasma pneumoniae DNA has a high positive predictive value. Albeit a persistence of Mycoplasma pneumoniae DNA after infection or within the incubation time has been reported it is generally accepted that such events are very rare (<0,5%) [16, 17].

In one third of our MPP patients we found concordant positive PCR and positive IgM test results. The IgM EIA used showed a moderate sensitivity in sera collected in the acute phase [15]. Thus, it seems reasonable to assume that some of the PCR positive patients might not yet have developed IgM antibodies. On the other hand, PCR might have resulted false-negative due to the detection limit of the PCR detection as well as the rapid elimination of Mycoplasma pneumoniae after the initiation of antimicrobial treatment. In this context it should be noted that 27% of our patients received antibiotic agents at the time of inclusion into our study. The affection of antimicrobial treatment on clinical presentation and PCR or IgM responses in CAP caused by M.pneumoniae has never been studied to our knowledge. Therefore, we ignore the true effect of this confounder.

Despite our different and strict diagnostic approach based exclusively on real-time PCR in respiratory samples and acute phase IgM, our data confirm previous findings of MPP being associated with several peculiar clinical characteristics. Apart from Chlamydophila pneumoniae, Mycoplasma pneumoniae is the only bacterial respiratory pathogen clearly occurring more frequently in younger adults. In a large study on the etiology of CAP, Mycoplasma pneumoniae was the only age-associated pathogen [18]. It appears that it usually occurs before the forth decade. In this age class, it has been shown that Mycoplasma pneumoniae can result as the most frequent pathogen even prior to Streptococcus pneumoniae [9, 19]. Probably as a consequence, patients with Mycoplasma pneumoniae have considerably fewer co-morbidities. The only concomitant disease occurring with a frequency of more than 10% in our MPP population was COPD.

Another important feature of MPP is its usually less severe presentation, both in terms of clinical CRB-65 severity scores as well as inflammatory response. None of the severe complications of Mycoplasma pneumoniae reported in the literature could be observed in our series [2], although it cannot be definitely excluded that we missed single cases with severe Mycoplasma pneumonia. In accordance with the regularly mild presentation of MPP, and in line with several previous reports, more than half of our patients were treated as outpatients, hospitalized patients had a shorter length of hospitalization, and mortality was very low [10‐14]. Moreover, those treated as outpatients were even younger and presented with a milder pneumonia than those hospitalized (with 99% having CRB-65 scores of less than 2).

Our findings may have significant implications for future recommendations of empiric antimicrobial treatment in patients with CAP, particularly with respect to the need for covering atypical pathogens. If we consider Legionella spp., Mycoplasma pneumoniae and Chlamydophila pneumoniae as the three atypical bacterial pathogens treatable by antibacterial agents, it appears that only Legionella spp. are associated with a relevant mortality. In a recent series from our group, we could show that Legionella spp. was found with equal frequency in both ambulatory and hospitalized patients. However, severity was low and mortality was zero in ambulatory patients [5]. As a result, and in line with a recent meta-analysis of outcomes in non-severe CAP, atypical coverage does not seem to be relevant in terms of prevention of mortality in outpatients with CAP [20]. Following the definition of CAP used in our study we would advocate that in Germany as well as in other countries with comparable epidemiological settings a dual treatment with coverage of atypical pathogens as empirical standard therapy is not indicated for patients with mild CAP. However, antibiotic pneumococcal coverage continues to be the main demand in the treatment of this patient group.

Only recently, in a large study across four important world regions, Arnold et al. found a lower mortality in hospitalized patients receiving atypical coverage. As a result, and referring to several other studies with similar findings, they strongly recommended such coverage in all hospitalized patients [3, 21, 22]. In their study, the global incidence of Legionella spp. was 5%, of Chlamydophila pneumoniae 7%, and of Mycoplasma pneumoniae 12%. However, the rate of patients discharged alive at 14 and 30 days was not different but appeared only significantly different when the total number of patients discharged alive was considered, hinting at non-pneumonia-related reasons for different outcomes. Several other reports also do not support the conclusion of Arnold et al. [20, 23‐25]. Taking into account these reports and the present data, increased mortality in hospitalized patients with CAP is almost exclusively related to cases with moderate to severe pneumonia caused by Legionella spp. Another concern relates to mixed infections. In our series, the rate of mixed infections was low (n = 20), with no associated mortality. Most co-infections were caused by pneumococci and Legionella spp. which may be detected using routine diagnostic methods according to current ATS/IDSA recommendations [26]. Thus, a strategy of active search for patients with Legionella spp. or, in cases of more severe pneumonia, also for patients with Mycoplasma pneumoniae and Chlamydophila pneumoniae should obviate the need of regular atypical coverage in all hospitalized patients.