Click here to listen to a recording of Dr. DiRocco's presentation.
Patients staying for three days or more who were not known to be colonized with either bacterium were eligible for enrollment. All patients were tested for colonization within two days of admission by surveillance culture. Patients admitted to intervention ICUs were subject to universal gloving until the results of the admitting surveillance cultures were established. If colonization was detected, patients were thereafter assigned to full contact precautions. If not, they were assigned to usual care. In control ICUs, surveillance cultures were sent but the results were not reported to the providers; detection of VRE/MRSA colonization was left to whatever the local procedure happened to be.
The primary outcome was the ICU-level incidence of new events of colonization/infection (no attempt was made to differentiate for the purposes of the study) with MRSA or VRE per 1000 ICU patient-days at risk. There was no significant difference in the primary outcome between control and intervention ICUs.
Dr. McCabe made a number of interesting points about this study. First the rates of adherence to all levels of precaution documented in the internationally famous research institutions where the study was conducted are abysmal. Given that the Hawthorne effect was presumably operative in this unblinded study, the real rates are probably worse. Second, because the intervention used an outside reference lab for surveillance cultures, leading to very long median times to detection of MRSA and VRE, it fell short of what is practically possible in most community hospitals (including ours). Finally, on a related note, not much attention is given to describing "usual practice." In our hospital, "usual practice" is actually more comprehensive than the "intervention" trialled here. For a brief discussion of cluster-randomization, see our other blog.
Dr. Badran: Early vs. Late ART in Suspected TB .
Click here to listen to a recording of the presentation.
Dr. Badran presented an unblinded, randomized trial comparing early (i.e. < 2 weeks) initiation of ART in HIV infected patients with CD4+ T-cell counts less than 250 per cubic mm, compared to later initiation of therapy (8-12 weeks). The study was motivated by ambivalence in current expert opinion: on the one hand, there's concern that early initiation may increase the risk of interactions between antituberculous and antiretroviral drugs and may precipitate IRIS; on the other hand, later initiation of ART has been shown to correlate with worse HIV-related outcomes.
The primary endpoint was survival to 48 weeks without a previously undiagnosed AIDS-defnining illness. The investigators also monitored rates of TB-associated IRIS, which were confirmed by a blinded reviewer. No significant difference in the primary outcome was observed. The rate of TB-associated IRIS was higher in the early-initiation group, although this was not correlated with a higher incidence of adverse outcomes, at least during the follow-up period.
The authors interpreted their results as indicating that early initiation of ART is desirable and should be widely implemented.
Dr. McCabe pointed out that this is an instance of a bizarre surrogate endpoint, since anything from oral candidiasis to death qualified as an instance of the primary endpoint. However, as he pointed out, the point of treating AIDS is to prevent death, not candidiasis. The incentive to generalize one's surrogate endpoint is that it massively lowers the statistical power required to detect it; but in this case, it also massively dilutes the study's ability to tell us what we want to know, which is whether early ART kills people, not whether it makes them get thrush.
A final interesting point has to do with one of the study's methodological choices. The investigators included subjects who had both confirmed TB and suspected TB. Their rationale was that "in clinical practice, the decision to start or delay ART must often be made before there is a definitive diagnosis of tuberculosis." To use some jargon, they were conducting a "strategy study" to evaluate the approach empirically, rather than an "efficacy study" which would have been designed to scientifically evaluate the mechanics of cause and effect.
The problem with this, however, is that no individual patient actually has a chance of having tuberculosis between zero and infinity. All of them actually either have tuberculosis or do not have it. What we want to know as clinicians is not whether ART is good or bad for somebody who may or may not have TB, but how it effects people who actually do have it. The inclusion of people who didn't have it in the first place undoubtedly dilutes any malign effects early ART may have had on those who did.
Dr. Chow: Looking at the Recent Outbreak of E. Coli-Related HUS in Germany
Click here to listen to a recording of the presentation.
Dr. Chow presented an article which used three epidemiological methods to retrospectively analyze the recent outbreak of Escherichia coli serotype O104:H4 in Germany, which caused a disproportionate number of cases of hemolytic-uremic syndrome. While the epidemic was initially attributed to Spanish producers of cucumbers and tomatoes (causing significant temporary damage to the Spanish economy) the investigators were able to trace the microbe to a single sprout producer in Lower Saxony.
Dr. McCabe pointed out that this was a very alarming development in the world of medical microbiology. The organism responsible was not of the serotype normally associated with HUS, it was enteroaggregative rather than enterohaemorrhagic, and it manifested extended spectrum beta-lactamase resistance. Further outbreaks of this or similar organisms could represent a major threat to public health.
In this paper, the authors used the epidemiological data they collected to produce both a case-control and a cohort study. Both are types of observational study, as opposed to experimental studies. Both allow the investigator to determine the strength of association between an exposure (or risk factor) and an outcome; however, there are important differences in how they're conducted and in what, exactly, they allow one to say, which need to be well-understood by anybody reading them. If you need further convincing that this is important, you might check out these two articles, which illustrate the frankly terrifying extent of misunderstandings in the peer-reviewed literature. A brief explanation of case-control and cohort studies, and a recording of the explanation we gave at journal club, are available on the chiefs' notes blog.
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