Well, a 30-second teaser without as much as story synopsis doesn't exactly give a huge amount of info to speculate, but judging by limited titbits that we have, I've reached a certain conclusion:
1. If it really takes place during the main quest - and judging by Silverhand's voice and leaks mentioning Pacifica, there is no reason to assume that it doesn't - then I have no idea how are they going to explain V taking a long detour from their search for cure. If it is true, than there are only two outcomes I see on how it can possibly be integrated within the narrative:
a) it's going to be a complete side story, detached from the overall plot;
b) It's going to be woven into it, probably by promising some sort of cure to V's condition.
Case (a) will further screw over any sense of urgency that the game has left. Case (b) would probably end in an awkward "Well, this promising lead to saving yourself that you had right here? Yeah, it ain't happening, tough luck bud", which would render the overall experience meaningless.
2. This apparently being the only expansion means that it has to be really, REALLY good. And considering that it takes them more than two years to release it, it probably should not only have quality, but also quantity. But even if it will be massive and amazing piece of work on it's own, it leaves us with a third problem.
3. Lack of closure, both for V and overall story. For fuck sake, one of the endings has a quite shameless cliffhanger, with others not exactly tying every loose end either. What's with Mr. Blue Eyes, what about Crystal Palace? What are Aldecaldos going to do to help V? This are all questions that are going to be left unanswered, which I personally don't like.
For now, it's just speculations. The DLC might be mind-blowingly amazing, it might answer all my questions and more - or it might be so good in it's own right, that I simply wouldn't care about everything I've listed here. But as of now, I'm rather cautiously optimistic.