Reply to Hagdu and to Moss et al.

To the Editor— In his letter, Hadgu [1] states that the resurgence in chlamydia cases in British Columbia is a result of switching laboratory tests to nucleic acid amplification tests (NAATs) and argues that NAATs suffer from poor specificity and that, therefore, the results published in our article [2] may not be valid Hadgu, among others [3–5], has previously raised methodological concerns regarding the evaluation of NAATs, suggesting that discrepant analysis may have overestimated NAAT sensitivity and specificity. Although this debate between laboratory investigators and statisticians remains unresolved [6], we do not believe that this bias significantly impacts our interpretation of the results First, during the 14 years of the chlamydia control program in British Columbia, a variety of laboratory tests were used sequentially, including cell culture, direct fluorescent antigen detection, EIA, and NAAT. Yet, as shown in figure 4 in our article, the relative risk of Chlamydia trachomatis reinfection steadily increased between 1989 and 2003, at the rate of 4.6% per year, despite the introduction of new diagnostic modalities at different times. Second, one would have to assume that NAATs have differing false-positive rates in individuals with and without a prior positive test, to account for the observation that reinfection rates have increased since the mid-1990s. However, it is not clear that a compelling biological basis exists to support this assumption. Additionally, the 2 distinct trends observed in first infection and reinfection rates cannot be solely attributed to sensitivity/specificity differences of a specific diagnostic test, since the same laboratory testing technique was used to identify all cases during any time interval. Third, Hadgu suggests that NAATs are, for a variety of reasons, poorly suited for the evaluation of reinfection status, in part because of the possibility of residual DNA from a previous infection remaining in the host. However, we noted that, whether 1-, 3- or 6-month intervals between 2 positive laboratory tests were used to define reinfection, virtually identical relative risks of reinfection were obtained. The effect of residual DNA from prior infection, if real, should have significantly increased the relative risk when a shorter, rather than longer, interval was used. Lastly, although neither US Centers for Disease Control and Prevention (CDC) nor Canadian guidelines specifically recommend (or advise against) NAATs as part of a national chlamydia control program, “the majority of CDC consultants believe that non-NAATs are substantially less sensitive than NAATs when used on urine specimens” [7]. For these reasons, we conclude that the increasing reinfection rates observed with a population-based chlamydia control program are more likely to reflect changes in population-level immunity than nonspecificity in NAATs

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