Kiki’s Comments                                                                                                        June 2020

                        TWiV 621: An Era of COVID-19 Poppycock

            Key Points:

*hydroxychloroquine and chloroquine appears to decrease survival and increase ventricular arrhythmias in COVID-19 patients—this is NOT a recommended treatment for COVID-19

*late stage bacteremia being noticed that is not just nosocomial-associated 

*increase in second trimester miscarriages associated with COVID-19

*pediatric multi-inflammatory syndrome is still rare, but several times higher than normal in association with CoV-2 exposure; good response to treatment

*CDC says that about half of the serology tests are questionable; two tests are necessary to have higher certainty of results

*do not hyper-dose on any therapeutic, particularly those that do not have a proven benefit (vitamin D); some proposed therapeutics have detrimental effects

*first transmission of COVID-19 into the US occurred in January-February 2020 from Wuhan, China to Washington

*dispersion factor (K) is important for determining the epidemiology of COVID-19

*neutrophil-lymphocyte ratio is an important clinical factor in patients for tracking disease progression of COVID-19

            Clinical Update with Daniel: The Good, The Bad, and The Ugly

*good: sheltering in place and measures that were employed in the New York area were effective at limiting the spread and decreasing the number of cases and deaths

*test-based paradigm returns: society is returning to a test-based paradigm with employers and the general community requesting PCR testing and serology testing and requiring a negative to go to work. This makes some individuals hesitant to get tested because they are worried about having freedoms restricted in the case of a positive test.

*silent spreaders: as people are being tested for surgery, a number of people without symptoms are testing positive for COVID-19—this is creating an infection control issue. So far 10-15% of people being screened for surgeries are coming back positive, which is a little higher than what we have been expecting given serology testing results. 

*late stage issue: we are seeing really prolonged PCR positivity, some up to or more than two months post infection, and late stage symptoms that are occurring for 6-8 weeks, including low-to-high grade fevers. There is a late stage chronic diarrhea that is being noticed now, as well, that is being noted by gastroenterologists. There is also a trend of individuals who are sick, improve, and then appear to become sick again.

*late stage bacteremia: we are seeing people that never came to the hospital presenting in bacteremia occurring fatally at week 3-4 that have a positive serology test and some who were PCR positive while in hospital.

*second trimester miscarriages: this may be due to thrombotic issues, but we are seeing an association with increased second trimester miscarriages and positive COVID-19 PCR tests or serology

*pediatric multi-inflammatory syndrome: we are still noticing a rise in these conditions associated with COVID-19—this is still rare, just several times higher than we would normally see. Median age is 10 years, but we have seen it in people up to 20 years of age. These kids tend to have fevers. More than half get a skin rash and a swelling of lymph nodes in the neck, and many end up with conjunctivitis (red eyes, red and cracked lips). A minority have respiratory symptoms. Many have nausea, diarrhea, stomach pain. A majority have some sort of heart symptom involved, usually left ventricular involvement. There appears to be an acute response to therapy (right now a pooled IgG and/or steroids); if untreated, we are worried about long-term impacts.

*serology testing: CDC came out with a result saying that about half of the results of serology tests are questionable. Due to this the CDC is recommending orthogonal testing.

n.b. orthogonal testing is a repeated test, i.e. if you have two positive tests the predictive value is in the high 80s (good) rather than one test which has lower predictive value

*at home COVID-19 tests: there are websites that will provide swab tests that can be sent to your home to improve access to testing.

n.b. do NOT use tests to imply that you or others are immune—we do not know about reinfection risks

*medical management from door-to-door: we are still using risk stratification when people come in where we look at the neutrophil-lymphocyte ratio, respiratory rate, oxygen saturations, procalcitonin, C-reactive protein, and D-dimer. We are still seeing the same early pattern where the first week is viral and the second week we see the potential serge (remdesivir has been a little positive here in patients that are requiring some oxygen, but not much, i.e. not high flow or ventilator patients). 

            Questions for Daniel:

*Will: what is your opinion on vitamin D and COVID-19? First off, do not run out and start hyper-dosing on anything, including vitamin D, as we do not have results that would support that yet. We will speak on this as more results come in.

*Mona: what do you think of proning and why hasn’t this been used from the onset? Proning has been around for decades, 30-40 years. One of the pieces of advice given from China early in the pandemic was to start ventilating patients early, which may have been not great. Once we started waiting before intubating patients, we noticed higher mortality rates in patients on ventilators compared to those that were not intubated early, and started trying other things, including proning. Once there was some note of benefit from proning, starting with The Irish Patient, we very quickly started adopting this practice, which had particularly rapid beneficial feedback.

*Brynn: what is your advice about sending children back to school in the Fall, particularly for children that already have respiratory issues? The biggest predictor for severe COVID-19 is age, particularly over 50 years of age. If you are making this decision for your children and there is a .1-.2 percent chance of severe COVID-19 for your child, 2 in 1000, it may be a difficult choice. This is a low proportion, but we are getting more information about the Kawasaki-like syndromes and other symptoms in children. It will be decision that every parent will have to make based on the risk, but there are definitely things schools can do to reduce that risk. We have not found asthma to be an issue, whereas COPD has been a predictor of severe COVID-19. 

*Steve: T cell count is low in severely affected patients of COVID-19—is this a new development or finding? No, this is something we have seen and have been talking about for a while (at least two months—April 2020). We found early in COVID-19 that neutrophils would go up, but B and T cells have been going quite low. This neutrophil-lymphocyte ratio is part of how we have been tracking people and disease progression.


*Lancet Adenovirus Type 5: these are usually E1 deleted, E3 inactivated viruses currently being looked at for a vaccine in Wuhan, China. This vaccine is going into the next phase of trials.

n.b. we probably would take the chimp vaccine over adenovirus type 5 because of potential cross-reactivity, while some of us are hoping for the mRNA vaccine

*Lancet Hydroxychloroquine or Chloroquine: aggregated information from many hospitals in many countries and looked at the different treatments given and combinations. Found that hydroxychloroquine and chloroquine had no benefit, but was associated with decreased survival and increased risk of ventricular arrhythmias.

*Remdesivir double-blind and controlled clinical trial: median recovery time in hospital (time-to-recovery) was significantly shortened, indicating that there is a clinical benefit of administering remdesivir early in the disease course. On the other hand, the US ran out of much of the remdesivir supply (late April 2020), so this treatment will depend on access. 

*MMWR coronavirus-19 spread: there is evidence from four different sources indicating presence of limited community transmission in early February or late January in the US from an early transmission. This transmission was a traveler from Wuhan who traveled to Washington State. 

*Bioarchive multi-school study at the University of Michigan: BSL-3 study of approved drugs for immune assistance and have found a couple promising drugs like Lactoferrin. The technique of infecting cells in culture and analyzing them with fluorescent probes for subtleties in cytopathic probes is interesting and could be effective for determining drugs (high content drug screening). 

*Science Superspreaders: This depends on reproductive rate (R0) and dispersion factor (K). The lower the K the more the disease comes from small numbers of people. K depends on how much the disease clusters. For SARS-1, the K was 0.16, MERS was 0.25, CoV-2 is estimated at 0.1, meaning for COVID-19 80% of cases lead to only 10% of the spread. If the 10% of people or situations that cause the larger portions of the spread could be identified, it could help with policy and control.By Kiki Warren (