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1 Centre of Pulmonary Medicine and Rehabilitation, S. Raffaele Hospital, Tosinvest Sanità, Rome, Italy. 2 Dept of Respiratory Medicine, Queen's Medical Centre, Nottingham, 3 The Respiratory Centre, Queen Alexandra Hospital, Portsmouth, and 4 Dept of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London, UK
We thank D.L. Hahn for his interest in our study 1 and for commenting upon the interesting issues he raised relating to the study and its interpretation, particularly regarding the presence of acute infection, reactivation, colonisation or chronic infection. These are important issues and informed debate about them is to be welcomed.
D.L. Hahn comments that, in the introduction, we stated that Chlamydophila pneumoniae serology could not differentiate acute from other infections. In fact, we stated that serology cannot reliably differentiate between past and present infection, or acute and chronic infection. We acknowledge that there are published proposed serological criteria for acute primary infection using the microimmunofluorescence (MIF) test 2. However, these authors stated that "standardized definitions for ‘acute infection’ and ‘past exposure’ are proposed", and that "these standards should be applied in future investigations and periodically modified as indicated". Although certainly the best advice available to date, we believe that these excellent recommendations are certainly not the last word in C. pneumoniae diagnosis, which remains a very much still evolving field.
As D.L. Hahn states, we also implied that C. pneumoniae serology may be (not "was") nonspecific, i.e. cross-reactive with other Chlamydia species 1. We stand by this comment, as there is data indicating this may be the case 3. We do not wish to imply that all or even most C. pneumoniae serology is nonspecific, and we believe that most well-performed MIF testing is indeed specific. However, we do believe that more objective, more specific tests are needed to complement MIF in the serodiagnosis of C. pneumoniae infection. Thankfully, the number of such available tests is increasing and they are being used in ongoing studies of C. pneumoniae in asthma 4. We hope that further studies such as these will improve our diagnostic accuracy in due course. We agree with D.L. Hahn that specificity can be improved by parallel measurement of other Chlamydia species and other unrelated organisms, as Hahn et al. 5 and Wark et al. 6 have previously carried out. Such methodological rigour is to be encouraged.
D.L. Hahn states that serial MIF testing using acknowledged criteria 2 would have established whether the positive (PCR) detections we reported 1 were related to acute infection or not. Regrettably, serial blood sampling was not part of our study design, as the original design was conceived to investigate rhinovirus infections 7, for which serology is impractical. The decision to use these samples to investigate the presence of C. pneumoniae was only taken once the rhinovirus study was completed. We agree that such serial serological testing would have been desirable and would have added to the evidence, but believe that "established" is too strong a word. The debate regarding C. pneumoniae diagnostic methods will certainly continue until clearly accepted gold standard tests are available. Until such time, the data available can only be interpreted in an unbiased manner, and we strongly support D.L. Hahn's call for future research to include a combination of sensitive nucleic acid detection, serial serological testing and appropriate control groups to address the issue of exactly what type of C. pneumoniae infection is associated with asthma and whether it plays a role in disease pathogenesis.
We thank D.L. Hahn for commenting upon our discussion of whether the PCR detections that we reported were related to acute infection, reactivation, colonisation or chronic infection 1. We entirely agree that it is unlikely that a 22% cumulative incidence rate over 3 months was caused by acute exogenous infections because, as D.L. Hahn states, the annual nonepidemic C. pneumoniae acute infection rate in the adult population is reported to be <2% 8. To our knowledge, our study was not conducted during a community epidemic of C. pneumoniae infection 1. We are unable to be certain whether any positive detections were associated with an acute respiratory illness, as these samples were taken every 2 weeks, irrespective of the presence or absence of symptoms. This design was adopted to allow us to investigate the frequency of infections independent of bias due to symptom severity, which would have been introduced by studying reported illness episodes 1, 7.
We do not believe that our study was able to reliably determine whether these detections were reactivation, colonisation or chronic infections. However, as stated in the discussion, positive detections were all of a duration <28 days, except one detection of duration <42 days and two detections in which duration could not be defined 1. The fact that we detected what we believe to be very low bacterial loads, and the short durations of positivity, argue against both acute primary infection and chronic infection. Further studies will be needed, but the working assumption is that these detections relate to colonisation with bacterial loads close to the detection limit of the PCR assay, or to short-term reactivation.
We also agree with D.L. Hahn that our results do not permit us to conclude whether the increased detections relate to atopic status or asthmatic status, as the study design compared atopic asthmatic cases with nonatopic controls. It would clearly be desirable to perform a study including three populations (atopic asthmatic, atopic nonasthmatic and normal nonatopic subjects), in order to answer this question; however, our spouse-pair design, adopted to control for exposure to infectious agents as closely as possible 7, did not allow this.
Finally, we support D.L. Hahn's conclusion that uncertainty about the exact type of infection should not delay performance of clinical trials to establish whether asthma is treatable with antichlamydial antimicrobials. These studies should be high-quality, randomised, placebo-controlled studies, and should be supported by further studies on the relationships between Chlamydophila pneumoniae detection and asthma pathogenesis, to help define which populations are most likely to benefit. We believe such studies should initially be focused on populations that are least well served by currently available asthma treatments, namely, acute asthma exacerbations, new onset adult asthma and severe asthma. It is encouraging to note that, in the context of acute exacerbations, where evidence for a role for Chlamydophila pneumoniae infection is increasing 6, 4 and where concerns about the induction of antimicrobial resistance to antibiotic therapy would be less worrisome as therapy would be short term, just such a high-quality, randomised, placebo-controlled study is already underway 4.
REFERENCES
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