Who Needs a Corona?
Authors: Kevin L. Winthrop
Journal: Arthritis & Rheumatology (2020)

While the Western world now takes on a viral pandemic, the news cycle and constant reminders to wash your hands and avoid touching your face might drive anyone to reach in the fridge for a beer. It is “Corona time,” but unfortunately it is the virus of which we speak. At the time of this writing (early/mid-March 2020), there are many more questions than answers. It is clear that the virus is at least as transmissible as influenza, and it is likely that there is little or no preexisting immunity within the world's population. Accordingly, it has the capacity to spread easily and has shown the ability to inflict severe harm, particularly among older adults and those with preexisting conditions. Most of our clinical information comes from early reports of the virus's impact in China and Italy and the cluster of cases within the state of Washington. The latter has made it clear that the virus has been in the US since January, and has been transmitted in the general population in Washington (and likely other locales in the US) since that time. While our incidence count continues to climb each day, our true incidence in the US is undoubtedly much higher than identified, simply due to our lack of testing. Sometimes it feels better not to know? As of March 11, the US has 647 confirmed cases, among which 25 (3.9%) have died. One day later as I edit this manuscript prior to submission, we now have 938 cases, among which 29 (3.1%) have died. To date we have tested just over 8,500 persons 1, and testing has focused only on individuals who are severely ill or have had contact (or potential contact) with those who have COVID-19. The Republic of Korea, in contrast, has tested >200,000 individuals 1, 2, many of whom presumably are asymptomatic or have little likelihood of having the disease. The more widespread “screening,” however, has allowed the Republic of Korea to more accurately describe the burden of COVID-19, as well as to take nationwide public health actions geared toward mitigating the spread of virus from cases to others. While the Centers for Disease Control and Prevention (CDC) and public health authorities have worked double-time to develop guidance, recommendations, and protocols for physicians and the public, the lack of test kits has hampered early efforts of containment. CDC should not be held accountable for the mass production of test kits (not what CDC does), but rather the US regulators and offices of emergency preparedness at the federal level should be partnering with industry and others (e.g., global health foundations) to rapidly manufacture and validate test kits for use. I suspect this will occur before this article is published, but the delay has meant the US incidence has remained low (because we are not testing) and the public's understanding of personal risk is frankly unknown and informed more by the 24-hour news cycle than it is by data. So what should rheumatologists and their patients know and consider during these times of “social distancing”? I've addressed the most common questions that I receive hourly. The mortality of this virus ranges according to country, which reflects differential patterns in testing and identifying those with disease. While mortality is high in countries like the US and Italy, individuals with minimal or no symptoms have not been tested. In the Republic of Korea, where testing has been much more widespread, the observed mortality is 0.7% 3. This doesn't sound too bad, although when compared to the usual influenza mortality of 0.1% 4, one can quickly do the math and conclude that COVID-19 has the capacity to cause thousands of deaths in the US if it becomes widespread. Currently influenza causes an estimated 30,000–60,000 deaths each year in the US 4—all the more reason to take extraordinary efforts to contain COVID-19. Reports suggest that the elderly with comorbid heart and lung conditions are at highest risk of morbidity and mortality, and although many news headlines insist the “elderly and immunocompromised” are at higher risk, there are absolutely no data commenting on the outcomes of COVID-19 infections in those with autoimmune inflammatory diseases, those receiving immunosuppressive agents, or those with other immunodeficiencies. To date it is unclear if rheumatology patients are at higher risk due to their diseases or their therapies; however, many patients are likely at increased risk due to their age and comorbidities, including smoking- or autoimmune-related lung disease and cardiovascular disease. Despite US universities releasing students home without student cases or evidence of campus transmission (as a college tuition paying parent, I thought these actions were premature!), there is very little evidence of severe outcomes in children and younger individuals. There have been no deaths reported in those under age 30 from the Republic of Korea or under age 50 from Japan 5. In China, a recent cohort study identified a number of comorbidities (hypertension, diabetes, chronic obstructive pulmonary disease, others) to be common in hospitalized patients with COVID-19, but in a multivariate model advanced age was the primary risk factor for mortality among cases 6. Perhaps most disturbing was the finding of prolonged viral shedding among survivors, up to 37 days (median 20 days), raising the prospect of contagiousness even after disease recovery. A registry has been established to collect case reports of rheumatology patients with COVID-19. Rheumatologists are encouraged to report cases at http://rheum-covid.org. Currently unknown. Clinical trials are now enrolling to test both remdesivir (an RNA polymerase inhibitor that failed in Ebola trials) 7, 8 and the HIV drugs lopinavir/ritonavir (clinical trial no. ChiCTR2000029308). Other compounds have shown in vitro activity, e.g., hydroxychloroquine (5 times more active in vitro than chloroquine) 9. There is speculation that baricitinib and other drugs that block AAK1 might inhibit viral entry into pulmonary alveolar cells and potentially decrease the risk of infection. However, given the ability of JAK inhibitors to diminish signaling associated with innate antiviral defenses (e.g., type 1 and 2 interferons), the ethics of such a trial are tricky. At this time, though, other immunomodulators are also being hypothesized as potentially useful in decreasing virus-associated inflammation and morbidity. There are case reports from China describing the use of anti–interleukin-6 therapy against the virus, and Regeneron recently announced that they will evaluate sarilumab as a therapy for COVID-19 10. In fact, on March 10, Chinese medical authorities released updated guidelines for the treatment of COVID-19 that include the use of tocilizumab, and a clinical trial evaluating its use has been started there. Maybe and maybe not. In case series to date, it appears that much of the morbidity of this virus is related to immune activation, inflammation, and sepsis. The contribution of secondary bacterial infection to COVID-19–related mortality is unknown. As indicated above, there are at least several biologic agents known to increase the risk of serious bacterial and opportunistic infections that may actually have a role in limiting the inflammation related to this virus. While I would speculate that most biologics and small molecules would increase the risk of secondary bacterial infection in those with COVID-19, it is at least theoretically possible that rheumatology patients with COVID-19 might have better outcomes with some biologics as compared to infected individuals not receiving antiinflammatory treatment. This might be akin to the finding that while anti–tumor necrosis factor (anti-TNF) therapies increase the risk of infection development while patients are hospitalized, it turns out that for those already having an infection at the time of hospitalization, receiving such biologic therapy at the time of infection development appeared protective (lower risk of sepsis and death) compared to those who were receiving nonbiologic DMARDs at the time of their infection 11. Interestingly, the main risk factors for sepsis and death in this specific anti-TNF analysis were age and cardiovascular disease—the very same risk factors described in the analyses of COVID-19 deaths. Regardless, it is obviously best to avoid being a subject in such a study. As indicated above, I don't know. There are potential benefits (antiinflammatory) and potential risks (likely increased risk of secondary bacterial infection). The risk could vary between therapeutic classes. For now, in a case of proven or suspected COVID-19 infection, I would stick with the guidance and standard of care for any serious infection and interrupt DMARD treatment temporarily, until clinical improvement against the virus has occurred. This advice could very well change in the next month, as case series of such patients with such exposures will undoubtedly be published. We don't know, and why hasn't this study been done yet? (“current evidence suggests hours to days,” says the CDC web site 12.) My advice—go outside and take a walk (13). Spend time increasing your fitness and meeting friends (who are not sick) in outdoor places where transmission should be less common. Listen to the advice coming from public health agencies (e.g., state health department or CDC), particularly if you are of advanced age with diabetes or chronic lung or heart disease. I don't know. While there is reason to speculate that the outbreak will subside in the summer months (like influenza season wanes), there is no guarantee that COVID-19 will disappear as did SARS, and transmission could potentially occur year-round (as for influenza). The silver lining (albeit small one) with COVID-19 is that influenza season should be shortened as individuals and businesses take extra precautions that will likely diminish influenza transmission—although at the time of this writing we are seeing an increase in influenza A cases locally in Oregon, likely due to increased testing 14. Other than this, I see few silver linings to this epidemic—only enormous and overwhelming amounts of work for health care systems, tremendous anxiety and disruption, and many thousands of deaths that otherwise would not have occurred. This is the likely scenario, making therapeutic and vaccine development of the utmost importance, as social distancing can only go so far. Finally, epidemics such as these remind our leaders that public health agencies and health care systems need to be funded and equipped for such events (despite their infrequency). CDC's budget should not be going down annually (as it recently has) 15. And one more plea to whomever is in charge of this thing: please, please do not cancel March Madness! Addendum. As of April 12, 2020, there were 555,371 cases of COVID-19 infection in the US, and 22,056 deaths ( 16). Dr. Winthrop drafted the article, revised it critically for important intellectual content, and approved the final version to be published.