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closeQuestion about clinical influenza definitions
Posted by Devon_Brewer on 10 Jun 2008 at 00:00 GMT
This is an excellent study and the authors described it well.
It seems that clinical influenza definition 1 is the strictest/narrowest, definition 2 is the next strictest, and definition 3 is the most liberal. If that is the case, why are the SARs and sensitivities highest for definition 1, second highest for definition 2, and lowest for definition3? It seems as if the results for the clinical definitions have been presented in reverse order. For instance, every secondary case by definition 1 should be secondary case by definition 3, but some cases by definition 3 will not be cases by definition 1.
The authors give a comprehensive and thoughtful discussion of their results and the study's limitations. However, there doesn't seem to be a compelling rationale to push ahead and conduct a larger trial on the basis of these results, especially when it appears there is no increased attention to influencing the one potentially manipulable factor (adherence). Certainly pharmaceutical firms don't pursue larger trials of drugs that demonstrate no glimmer of effect in pilot studies, or at least they might redesign the larger trial to address limitations of the smaller trial. Could the authors (or funding agencies) please explain the rationale for devoting limited public funds to such an expensive venture with a low likelihood of success, given the results of the current study?
RE: Question about clinical influenza definitions
bcowling replied to Devon_Brewer on 16 Jun 2008 at 02:32 GMT
Regarding the definitions of influenza, I think definition 3 (fever plus cough or sore throat) is the least liberal, rather than definition 1, which includes either fever or at least 2 respiratory or systemic symptoms? "For instance, every secondary case by definition 1 should be secondary case by definition 3..." - a counterexample is a subject who had runny nose and headache - this subject meets definition 1 but is not a secondary case by definition 3. The difficulties of finding a sensitive and specific definition of clinical influenza are well-known, and this is why we chose to present a range of alternative clinical definitions as secondary outcomes; our primary outcome measure is laboratory-confirmed influenza.
As a result of the pilot study findings we made a series of changes to our main study, as described in our paper and the accompanying protocol. It is well-known that it is difficult to promote better adherence to these kinds of non-pharmaceutical interventions in community settings [eg refs 7-12 from our paper] - nevertheless we have modified our protocol to try to improve adherence by adding further educational components in the home visits.
I think the analogy of NPIs with novel experimental drugs is slightly unhelpful. Pandemic plans typically reference NPIs as the minimum level of protection, and we would expect surgical face masks to be widely used (and are being stockpiled in massive numbers), however there is very little evidence to support their effectiveness specific to influenza. Our study is one of 8 funded by the US CDC to try to derive solid evidence which can either support or refute the widespread use of these interventions in the event of a pandemic - such major decisions couldn't be based only on our pilot study in 124 households (we note that our pilot results are consistent with fairly large protective effects of NPIs, even given the suboptimal adherence). Given the lives and morbidity at stake in the event of a pandemic, we believe that more money, rather than less, should be spent on determining the effectiveness of the various NPIs proposed in pandemic plans.
RE: RE: Question about clinical influenza definitions
Devon_Brewer replied to bcowling on 20 Jun 2008 at 04:48 GMT
Thank you for your clarification about the clinical definitions. I misread an "or" as an "and" in the first definition and didn't think it through the rest of the definitions carefully.
I'm still not sure the enthusiasm for the large scale trials is fully justified. You note that these interventions have been implemented on a broad scale in the past and that massive stockpiling has already been done, both despite a lack of supporting evidence. So it seems the main rationale for evaluating the effectiveness of these interventions is whether to recommend the use of these particular NPIs that have already been deployed for potential use. This isn't a trivial matter, but it also doesn't seem to be more of a priority than other means of responding to (or studying) influenza epidemics, especially those strategies that do not involve already-deployed resources. Indeed, one possible conclusion from your results is that our understanding of the fundamental epidemiology is incomplete; that is, precisely who transmits to whom, when, where, and how. Surprisingly, these are essentially matters of speculation, and until there is solid empirical evidence on the details of transmission in the community, developing effective interventions may be hit-or-miss.
If there are pilot studies on these NPIs from the other 7 sites, it would be wiser to combine results across studies meta-analytically first for a useful and more cost-effective estimate of impact.
How are the results consistent with "fairly large protective effects of NPIs"? Given the small sample, the confidence intervals are wide, so it could also be said that the results are just as consistent with fairly large harmful effects.
RE: RE: RE: Question about clinical influenza definitions
bcowling replied to Devon_Brewer on 08 Jul 2008 at 02:53 GMT
I think a very important point has been made - our understanding of the epidemiology of influenza (and other respiratory viruses) remains incomplete. Our study allows us the opportunity to add to our understanding of household transmission, while other studies planned in HK and elsewhere (including the other NPI studies) may be able to fill in further gaps in knowledge.
A complicating factor with conducting meta-analyses of the 8 CDC-funded studies is the differing study designs from site to site, but this is not insurmountable with modelling techniques available. Logistical problems affected pilot studies in 2007 in the US centres, but results from their 2008 studies should be available soon.
Our pilot results are consistent with harmful effects - this is not implausible, for example lack of careful disposal of face masks could actually increase risk of transmission, via contaminating hands and then surfaces.