Cassie and Len Calabrese’s Covid-19 Corner: Issue #15

Amidst the COVID-19 craziness, do not forget about influenza vaccination

As flu season quickly approaches we want to take a moment to highlight the importance of getting this years’ (and every years’) flu shot – a thought that may currently be on the back burner for patients and even some health care workers given everything going on in the world right now. This year, while battling the ongoing COVID-19 pandemic, in the coming months we will also be battling flu season. While we have some hope that the severity of the 2020-2021 influenza season will be less severe than previous years (with universal masking and social distancing already in place, decreased air travel, fewer crowds, etc), now it is more important than ever to maximize uptake of seasonal influenza vaccine, and the reasons for this are many. Firstly, influenza cases this season are not only going to complicate the clinical picture when a patient presents with “flu-like” symptoms, as they will need to be simultaneously evaluated for COVID-19 infection, but influenza cases will further burden an already burdened healthcare system. Even during years when the seasonal influenza vaccine has had low effectiveness, it still has a powerful impact in terms of reduction in the number of cases, hospitalizations, and death due to influenza. The benefits of the seasonal influenza vaccine extend beyond the reduced number of cases and include off-target benefits such as decreased cardiovascular mortality (, amongst others. Second, vaccination of healthcare workers is of the utmost importance this season, both to protect our patients and to keep ourselves healthy so we can continue to care for our patients. We encourage you to read an excellent piece in Healio Infectious Disease ( that reminds us of all the reasons to get vaccinated. We appreciate the part about staying home when sick with flu or flu-like symptoms, as this is something that historically we as healthcare providers do poorly, mostly out of a sense of duty. One retrospective study of Canadian health care workers found that over 90% of the healthcare workers who reported having a respiratory illness during flu season admitted to working at least one day during that illness (Cowman K, et al. Am J Infect Control. 2019;doi:10.1016/j.ajic.2018.02.004). While it is our duty to stay home while sick, there is still the possibility of influenza transmission during the pre-symptomatic period, and vaccination is the best mode of prevention.

The rheumatology community has a duty to educate our patients about the importance of seasonal influenza vaccine both for our patients and their families, but we also have a duty to ensure that our workplace vaccine coverage is near 100%, to protect our patients, our families and ourselves. It has been shown that workplaces with flu vaccine mandates have the highest uptake/coverage rates. While this sounds severe, there is the option for a healthcare worker to apply for exemption, however, there are VERY few reasons to not get a flu shot – in fact, there is only one true contraindication, and this is if you have experienced an allergic reaction to a previous flu vaccine. Despite this, poor vaccine uptake is fueled by numerous excuses and fears, and that is why it is so important for us as healthcare providers to take a few minutes each visit to listen to our patients’ reasons for not wanting flu vaccine, have a discussion about their concerns, and educate them. One of the most common reasons that patients do not get yearly flu shots (aside from “it gives me the flu”) is egg allergy. ACIP recommendations state that persons with any egg allergy history (including anaphylaxis) can receive any flu shot formulation safely. If a patient has a history of anaphylaxis to eggs, they can still receive any flu shot formulation as long as administered by a health care provider who knows how to manage allergic reactions. For the upcoming

flu season, the recommendations have been updated to remove this latter recommendation if eggless vaccines are given (e.g. Flublok or recombinant vaccine). The most effective method of increasing vaccine uptake is for a patient to hear the recommendation from their health care provider. While our days are already so busy, this only takes a couple of minutes and the impact is priceless.

Len’s Comments from the COVID- 19 literature

In September we saw the number of publications on COVID-19 surpass 60,000 articles, so it’s a guarantee that none of us are in control of this literature and I already see signs on the horizon that ‘favorite’ paradigms are being lobbied for regarding pathogenesis, transmission, and treatment. I say beware! Remain skeptical and let the data speak for themselves. I will comment on two areas of interest, which I would classify as a known unknown and finally one unknown unknown (thank you, Donald Rumsfeld).

Known unknown – Treatment of hyperinflammatory Act 3 of COVID-19

It is now clear that despite nearly 400 different drugs being tested in over 3200 trials registered in that the big winner thus far is glucocorticoids. How ironic this seems to me given how old-school and low cost they are, combined with even more recent disappointing news about anti-IL-6 this past week ( ). I am not saying that all the other targeted therapies are not or will not be demonstrated to be effective but only now that they must be proven to be more effective than glucocorticoids or perhaps enhance the effect of glucocorticoids.

A meta-analysis of glucocorticoid therapy for COVID-19 accrued across 7 trials was published in JAMA this past week ( that clearly demonstrated that glucocorticoids given to patients with serious (i.e. hypoxic) COVID-19 infection reduced mortality at 28 days with a summary odds ratio of 0.66 and achieving statistical significance. Of note was that lower dose regimens (6 mg of dexamethasone or 200 mg of hydrocortisone for varying time periods) appeared to be more effective than higher dose regimes. As we have previously commented on the RECOVERY dexamethasone trial, this rigorous analysis is reassuring and strongly suggests that glucocorticoids are now standard of care for COVID-19 patients who are deteriorating from a respiratory perspective. Lastly, remember that data from the COVID-19 Rheumatology Global Alliance ( ) and other sources have consistently demonstrated that being on glucocorticoids at baseline ( i.e. at time of infection) at doses of 10 mg of prednisone daily or so is not only not protective but associated with increased disease burden and mortality. Our interpretation of these data, as many others have done a well, is that early in the course of COVID-19 infection activation of innate immunity (ACT 1) and sequential engagement of adaptive immunity (ACT 2, perhaps commencing as early as day 5) is critical to limit the progression of the disease and avoid ACT 3 with its progressive inflammatory complications (see Figure 1). Thus, too much immunosuppression early is counterproductive to building an effective integrated defense against COVID-19 but delayed application of immunosuppression with moderate doses of glucocorticoids appears to be beneficial. Over the next several months we will critically appraise the data as it rolls out on the therapies under investigation with which we are most familiar and interested in. We are increasingly wary of the litany of positive low quality, non-randomized studies that seem to routinely show a benefit but somehow flounder in trials of more rigid design. Stay tuned.

Unknown unknown – What about methotrexate?

All of us are aware by now that both the ACR and EULAR guidelines suggest that when a rheumatic disease patient has a high-risk COVID exposure or has documentation of infection that we stop DMARDs and targeted therapies. Each guideline also has some wording that is like with a ‘wink, wink’ to discuss possibly continuing anti-IL-6 if they are on it. I understand why this exception was crafted but now, with mounting negative data, anti-IL-6 therapy has lost some of its luster but many trials are still underway. The rationale of the overall recommendation here is that when faced with an early infection we are trying to maximize our integrated host defenses to limit the progression of the disease. Among the defenses, our immune system deploys to defend us there is no doubt that an early interferon response is critical for success. We have previously discussed there is mounting evidence that in COVID-19 interferon deployment is limited by viral-mediated defenses. A recent study this past week has actually identified a specific gene that is a key player in this viral countermeasure to our immune response ( ). When the virus breaches the innate defense network we then rely on the development of a humoral response as well as a cell-mediated response. In most individuals, our immune response is efficient and effective and leads to resolution of the infection. Thinking about this for a moment, ask yourself what do we know about our drugs and their capacity to suppress antibody response to T cell-dependent antigens? (COVID-19 gene products like the spike protein and others are T cell-dependent). Drawing upon lessons from vaccines in rheumatologic disorders, we know that most of our targeted therapies and targeted synthetic therapies have little effect on flu vaccine (a relevant comparator in many ways) but we also know that rituximab and methotrexate palpably inhibit such responses. We also have learned the underlying mechanism for this methotrexate inhibitory capacity acting via BAFF signaling and finally, we know that if we hold merely two doses of methotrexate after flu vaccination it significantly enhances the humoral response

to the vaccine. This is standard of care in our Rheumatology-Infectious Disease clinic, by the way. Thus, of all the drugs we can hold (as per both sets of COVID-19 recommendations) methotrexate makes the most sense. For how long is unknown but we believe that until the infection has turned the corner, two to three weeks depending on the individual circumstances, makes the most sense for now. Curiously no study to date has demonstrated clearly that being on methotrexate at the onset of infection is a poor prognostic marker for disease progression but the data are small and imperfect. I have been informed that the COVID-19 Rheumatology Global Alliance is well into the next phase of data analysis on over 6000 patients and we eagerly await their findings as they may shed important light on this question.

I will close with a question for you. What will we know and what will we do when the first COVID-19 vaccine is approved, which we believe will be sooner rather than later (An election day surprise)? If our patients are even eligible for Tier 1 vaccine, which they should be, will you hold methotrexate? Let us know.

Shout out with any questions or comments @LCalabreseDO calabrc@ccf.orf @CCalabreseDO

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