SARS-CoV-2 & Back to School.

August 20, 2020August 20, 2020 / Kellie / Leave a comment

It has been a few weeks since our last post on the blog. It seems that COVID-19 has shown us it is here to stay for the time being. Local legislators, public health officials, and politicians are trying to navigate how to safely return to a somewhat normal life while keeping infection rates low. One of the biggest questions that has come up is whether or not we can safely return children to schools without risking a further spread of COVID-19.

While some schools have reopened and faced infection among their staff and students, other areas are still deciding whether students will stay remote or return to school in a hybrid learning format. A few weeks ago a photo from a Georgia High School was brought to the attention of the media. The video showed crowded hallways and many high schoolers not wearing a mask. It has been reported that in this school, there have been a handful of positive cases reported. Schools in Mississippi, Tennessee, Indiana, and North Carolina have all reportedly opened and noted positive cases causing the schools to close or students to quarantine. (Read the New York Mag article here.)

Worldwide…

According to the John Hopkins’ Dashboard there are now more than 20 million cases worldwide. Based on a 5 day average of new cases, numbers are rising in India, Colombia, and Peru. There have been over 780,000 deaths globally.

Source: https://coronavirus.jhu.edu/data/new-cases

In the United States…

As of Wednesday afternoon, there have been 5,460,429 positive cases. According to the CDC website, there were about 40,000 new cases reported in the last 24 hours. This number has decreased over the last few days, along with the number of positive testing samples. The national average of tests that were positive decreased from 8.7% (reported by the CDC on July 25th) to 7.0% as of the data reported by the CDC on the week ending August 8th. As of August 8th, the South East (11.5%) and South Central (12.6%) regions continued to have the highest percentages of specimens testing positive for SARS-CoV-2. If you look closely at the chart below, you can see the rise in the grey and red lines, which represent the pediatric population and percent positivity of tests.

Source: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/08072020/public-health-lab.html

In Children…

The AAP released its data on Children and COVID-19 for the last three weeks. What was notable from this data reported was that children accounted for about 9% of all COVID cases in the US for a total of 406,109 total child COVID-19 cases as of the data on 8/13. What was most alarming was the 40% increase in COVID cases from 7/16-7/30 for a total of 97,078 new child cases reported. From 7/9-8/6 there were 179,990 new cases reported in children (200,184 to 380,174) which was a 90% increase over that 4 week period. Despite this increase, children were only reported as 0.5-4.6% of all COVID hospitalizations and 0-0.4% of all COVID deaths.

https://downloads.aap.org/AAP/PDF/AAP%20and%20CHA%20-%20Children%20and%20COVID-19%20State%20Data%20Report%208.13.20%20FINAL%20v2.pdf

So we know that disease is less severe in children, however, about 1 month following COVID-19 exposure was the initial presentation of MIS-C which we summarized here & here. So although symptoms of COVID-19 may not be as severe, we have yet to see the spike in MIS-C cases following this rapid increase in pediatric COVID-19 cases.

I am not sure about my other colleagues in pediatrics, but I have had many friends ask about safely sending their children back to school. It is a difficult question to answer as I am not a parent who has to balance child care needs with my work schedule. This question is one that is even stumping many experts in the field. The AAP released their updated guidance on the matter on Wednesday.

We may not have the best answer to this question, but we do have some data that can help guide our management. Earlier studies may have given us false reassurance that children were not as affected by COVID-19, however more recent studies have discussed transmission of SARS-CoV-2 among pediatric patients and demonstrated this may not be the case.

Up first, South Korea’s Contact-Tracing Program…

An early release article titled “Contact Tracing during Coronavirus Disease Outbreak, South Korea, 2020” in Emerging Infectious Diseases described the data collected from the robust contact tracing program that was utilized in South Korea during the pandemic.¹ The program identified 59,073 contacts of 5,706 index patients. (Index patients were defined as the first laboratory confirmed case or first documented case in a cluster.) They then grouped index patients by age and noted how many positive cases came from these index patients. A “case” was defined as a contact with symptom onset after that of a confirmed COVID-19 index patient. Patients were monitored for an average of 9.9 days after infection was confirmed.

Overall, a total of 11.8% of household contacts of index patients had COVID-19 (95% CI 11.2%-12.4%)
For children age 0-9, there were 29 index patients and 237 contacts were traced, while for children age 10-19 there were 124 index patients and 457 contacts were traced. These numbers were lower than the remaining age groups.
In household contacts of patients age 10-19 years of age, 18.6% of contacts had COVID-19 (95% CI 14.0%-24.0%)
For most age groups COVID-19 detection was significantly higher in household contacts than non household contacts.
Children aged 0-9 had a lower number of positive household contacts- reported at 3 positive of 57 contacts, for 5.3% positive with a 95% CI (1.3-13.7).

So what does this tell us? Children aged 10-19 had the highest positivity rate among their household contacts, while non household contacts for children ages 0-9 years old had positivity slightly lower than the entire contact tracing program. However, the authors remind us in their conclusions that this data was collected in the middle of school closures, so the detection rates may be altered, but this information should most definitely be considered as schools begin to reopen.

On to Switzerland and COVID-19 in Families…

A brief released titled “COVID-19 in Children and the Dynamics of Infection in Families” in Pediatrics described patients under 16 years old with SARS-CoV-2 infection from March 10 – April 10, 2020 in Geneva University Hospital’s Surveillance Network.² This study identified a total of 4310 patients with SARS-CoV-2 Infection, 40 patients (0.9%) were under 16 years old.

The median age of the study patients was 11.1 years old
The most commonly reported symptoms for the cohort were cough, fever, nasal discharge, and headache.
The study evaluated familial clusters and looked at 111 household contacts (HHCs) of the study children
- 39 mothers, 32 fathers, 23 pediatric siblings, 8 adult siblings, and 7 grandparents were evaluated.
- In the 39 study cases, 31 Adult HHCs (79%) were suspected or confirmed with COVID-19 prior to the study child suggesting that children may be mainly infected in familial clusters
- Children developed symptoms first in only 8% of households (3/39)
- In the households, adult HHCs developed symptoms about 85% of the time vs only 43% of pediatric HHCs (p< .001)

This study was similar with previous data that showed children as index cases in <10% of familial clusters of SARS-CoV-2.

Source: : Posfay-Barbe KM, Wagner N, Gauthey M,
et al. COVID-19 in Children and the Dynamics of
Infection in Families. Pediatrics. 2020;146(2):
e20201576

Next, age related NP SARS-CoV-2 Levels in Chicago…

A Research Letter titled “Age-Related Differences in Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Levels in Patients With Mild to Moderate Coronavirus Disease 2019 (COVID-19)” was published in JAMA Pediatrics on July 30th.³ This letter presented the data collected between March 23 and April 27, 2020 on SARS-CoV-2 reverse transcriptase-polymerase chain reaction (PCR) swabs in individuals ages 1 month to 65 years that presented to various testing centers in Chicago, IL. This letter described the PCR amplification cycle threshold (CT) of the samples collected and analyzed. Click on the link for more detailed information but a CT is the number of cycles it takes for a signal to cross the fluorescent threshold, and this has been shown to be inversely proportional to the amount of target nucleic acid in the sample, ie less cycle thresholds = more nucleic acid). It had been previously reported that patients with severe infection had lower CT values, so 7 children who required supplemental oxygen were excluded from this analysis. In addition 7 asymptomatic patients, 29 patients with unknown duration of symptoms, and 19 patients with symptom onset one week prior to collection were excluded.

The final cohort for analysis included 145 patients grouped by age: <5 years old (n=46), 5 to 17 years old (n=51), and 18 years to 65 years (n=48)
The median CT value for ages 5-17 was 11.1 [interquartile range 6.3-15.7] and the median CT value for ages 18-65 was 11.0 [IQR 6.9-17.5]
For children under 5 years old there was a significantly lower median CT value from the other two groups at 6.5 [IQR 4.8-12.0].
- This indicates that children have equivalent or more viral nucleic acid in their upper respiratory tract compared to older children and adults.
- These observed values demonstrate an approximate 10-fold to 100-fold greater amount of SARS-CoV-2 in the upper respiratory tract of young children
- When including the patients with unknown duration of symptoms the statistical difference between the groups was similar.

Source: Heald-Sargent T, Muller WJ, Zheng X, Rippe J, Patel AB, Kociolek LK. Age-Related Differences in Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Levels in Patients With Mild to Moderate Coronavirus Disease 2019 (COVID-19). *JAMA Pediatr.* Published online July 30, 2020. doi:10.1001/jamapediatrics.2020.3651

So what does all this data tell us?….

We know from previous data that children overall have less severe disease and lower hospitalization and mortality rates due to COVID-19. What we can see from the limited data presented here is that although less likely to be the first infected case in the household children are still likely to spread SARS-CoV-2 infections to their household contacts, especially those aged 10-19. The data also shows that there may be more SARS-CoV-2 in the upper respiratory tracts of younger children under 5 years old. So school aged children are capable of spreading SARS-CoV-2 based on what we see here. As we begin to see schools open here in the United States, we will have more data on our pediatric cases and transmission. For now, the jury still remains out on the safest approach for Schools in the setting of SARS-CoV-2.

Here are a few more recommended readings:

Lee B and Raszka WV. COVID-19 Transmission and Children: The Child Is Not to Blame. Pediatrics. 2020;146(2):e2020004879

Kelvin AA, Halperin S. COVID-19 in children: the link in the transmission chain. The Lancet Infectious Diseases. 2020;20(6):633-634. doi:10.1016/s1473-3099(20)30236-x

P.S…. In our high schoolers we already know vaping is bad. Mix vaping and COVID-19 infections? Even worse. https://www.cnn.com/2020/07/13/health/young-adults-smoking-risk-coronavirus-wellness/index.html

Thanks for reading along and stay safe! As always, you can contact us here.

Resources:

TREATMENT.

July 6, 2020August 25, 2021 / Kellie / Leave a comment

Throughout the globe, there are now more than 10 million confirmed cases of COVID-19. Worldwide there have been more than 500,000 deaths. According to the most recent WHO situation report there were over 200,000 newly confirmed cases in the last day, with the Americas reporting over 120,000 of those. Outside of the US, Brazil and India reported over 100,000 new cases in the last 7 days.

In the US, the last time we posted we were down to about 20,000 new confirmed cases a day. Over the last week, our confirmed cases have continued to increase with 4 days in a row of over 50,000 confirmed cases. There have been 126,576 total deaths. Many southern states have seen an increase in positive confirmed cases as they begin to reopen businesses. Some will argue that the uptick in cases is due to more testing, but when looking at the overall percentage of positive tests, we can see that we are seeing more positive cases, not because of “testing” but because there is more COVID in the community. According to the CDC, the overall percentage of respiratory samples testing positive for SARS-CoV-2 increased from 6.5% to now 8.7% positivity in the most recent reported week . This increase in positive tests was driven primarily by increases in 7 regions. The South East and South West/Coast regions reported 10%-15% of specimens positive for SARS-CoV-2. The South Central Surveillance region reported >15% of cases positive. Meanwhile, New England, the Midwest, and the Mid-atlantic regions had a decrease in percent positive specimens.

Source: The New York Times | Johns Hopkins University

Source: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html

According to the VPS dashboard, there have been 832 confirmed COVID-19 patients in those sites that reported to the dashboard. There have been 35 confirmed deaths. Our last post described the findings of the CAKE study and we reported on MIS-C here and here.

Treatment of patients presenting with COVID-19 has continued to be a topic of much debate and deliberation. Studies and literature on the efficacy of treatment options continue to surface daily. I recently cared for a patient for whom Remdesivir was a topic of discussion, so today I wanted to briefly discuss some of the treatment options for COVID-19 patients that we have not yet addressed here.

First up, Remdesivir

Remdesivir is a viral RNA-dependent RNA polymerase inhibitor. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Remdesivir achieves it’s antiviral effects by inhibiting viral nucleic acid synthesis. ¹ The use of Remdesivir is primarily for Ebola infection, however it demonstrated poor efficacy in a phase III clinical trial for Ebola. Both in vitro and in vivo studies using animal models Remdesivir demonstrated activity against MERS-CoV and SARS-CoV which are both structurally similar to SARS-CoV-2.

This figure below demonstrates the life cycle of SARS-CoV-2 and the mechanism of action of Remdesivir and how it inhibits RNA genome replication.

At the end of May, a preliminary report and results of the Adaptive Covid-19 Treatment Trial (ACTT-1) was released.¹ The enrollment of the ACTT-1 took place from February to April of 2020 at 60 different trial sites in the United States, Europe, Asia, and Mexico. The study was a double blind, randomized, placebo-controlled trial of IV remdesivir in adult hospitalized with Covid-19 and evidence of lower respiratory tract involvement. The treated group was treated with 10 days of Remdesivir, 200mg on day 1 with 100mg daily for 9 additional day.

The inclusion criteria per the study protocol were as follows: Laboratory-confirmed SARS-CoV-2 infection as determined by PCR < 72 hours prior to randomization. At least one of the following radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR evidence of rales/crackles on exam AND SpO2 <94% on RA or requiring mechanical ventilation and/or supplemental oxygen. All patients were over 18.

1,107 patients were assessed for eligibility and 1,063 underwent randomization
- 541 patients were assigned to received Remdesivir and 522 were assigned to received the placebo.
- In their initial analysis, data for 538 patients in the Remdesivir group and 521 in the control group were included
- Overall, those who received Remdesivir had a shorter time to recovery than patients in the placebo group (median: 11 days vs 15 days; Recovery rate ratio 1.32; 95% confidence interval, 1.12 to 1.55; P<0.001)
- Recovery rate ratio was also evaluated for baseline ordinal score
  - For the 127 patients not receiving Oxygen, Recovery Rate Ratio 1.38 (0.94-2.03)
  - For the 421 patients were receiving Oxygen, Recovery Rate Ratio 1.47 (1.17-1.84)
  - For the 197 patients High Flow or Non-Invasive Ventilation, Recovery Rate Ratio 1.20 (0.79-1.81)
  - For the 272 patients receiving mechanical ventilation or ECMO, Recovery Rate Ratio 0.95 (0.64-1.42)
- Secondary outcomes evaluated were odds of improvement and mortality
  - In the group receiving Remdesivir, the Odds Ratio for Improvement at 15 days was 1.50, 95% CI 1.18-1.91, p=0.001.
  - Overall mortality was numerically lower in the Remdesivir group, but the difference was not significant.

So overall, this study showed that Remdesivir showed a benefit for recovery overall, and showed the most benefit for recovery in patients who were receiving oxygen therapy. This is a large group studied, and the authors compare their results with those from a randomized trial in China. (here is the link for that article.)

COVID-19 has challenged our need for urgent treatment modalities, with little evidence to support the efficacy of said treatments. A study published in June of 2020, described the efficacy of remdesivir in rhesus macaques infected with SARS-CoV-2.² This study looked at two groups of six rhesus macaques who were inoculated with SARS-CoV-2. Twelve hours post inoculation one group was treated with 10 mg/kg IV Remdesivir while the other group was treated with an equal volume of a vehicle solution. Treatment was continued 12 hours after the first dose and then every 24 hours after with a dose of 5 mg/kg. They monitored serum concentrations of remdesivir and its downstream metabolite.

In the group treated with Remdesivir:
- The clinical score (based on pre-established scoring sheet) was significantly lower twelve hours following treatment and remained lower throughout the study
- X-Rays taken on days 0, 1, 3, 5 and 7 post inoculation showed significantly less severe pulmonary infiltrates in the treated group (See image below, treated group on top row, vehicle solution group bottom row)
- On days 1,3,7 post inoculation viral loads from a bronchoalveolar lavage (BAL) were reduced in the remdesivir treated group, but the difference was not statistically significant. However, in the treated group the infectious titer in the BAL was 100-fold lower when compared to the control group. This difference was not noted in nose, throat, or rectal swabs.
- On post-mortem examinations of lung tissue it was noted that the remdesivir treated group had a lower mean of viral RNA when compared to the control group. The treated group also had significantly less lung area grossly affected with lesions.
- It appeared on histological exam that the Remdesivir had an obvious effect on the treatment of the lung lesions. (Images available on Page 6 of PDF linked)

Image 1: Source: Williamson, B. N. et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature https://doi.org/10.1038/s41586-020-2423-5 (2020)

There are many other literature reviews of Remdesivir available. Here are some of the other articles I found interesting: 1, 2, 3, 4.

Now onto, Dexamethasone…

Remdesivir had been discussed for a few months since the beginning of COVID thanks to it’s use in Ebola and MERS. Dexamethasone and corticosteroids are communly utilized in SARS, MERS, and other pneumonias in past and current practice. On June 22 the preliminary report of the Effect of Dexamethasone in Hospitalized Patients with COVID-19 was published pre-print. In this preprint article was the preliminary data from the RECOVERY trial (Randomised Evaluation of COVID-19 therapy). The RECOVERY trial is a “randomized, controlled, open label, adaptive, platform trial” which compared many treatment modalities in hospitalized COVID-19. At the beginning of COVID-19, steroids were not recommended or contraindicated.

The RECOVERY trial was conducted at 176 National Health Service hospital organizations in the United Kingdom. Hospitalized patients with suspected or laboratory confirmed SARS-CoV-2 infection were included and written informed consent was obtained by all patients or a legal representative. Eligible and consented patients were assigned in a ratio of 2:1 to either the standard care group or standard care plus dexamethasone group. The dexamethasone group was to receive 6mg dexamethasone IV or enteral daily for up to 10 days. If dexamethasone was unavailable or the physician believed it to be contraindicated the patient was excluded from the randomized comparison.

Of the 11,320 patients randomized between March 19th and June 8th, 9,355 were eligible to receive Dexamethasone.
Of those eligible 2,104 were randomized to Dexamethasone treatment and 4,321 were randomized to usual care.
- The mean age of those in the study was 66 years old and the majority were male. Half of the patients had a pre-existing comorbidity and 82% had laboratory confirmed SARS-CoV-2 infection with 9% still having tests pending. 16% of the patients required mechanical ventilation or ECMO while over half required oxygen only.
- The primary outcome in this trial was 28 day mortality.
  - 454 of 2014 (21.6%) patients in the dexamethasone group had mortality at 28 days vs 1065 of the 4321 (24.6%) patients in the usual care group, Rate Ratio 0.83, 95% CI 0.74-0.92, P<0.001.
  - A subgroup analysis showed that there was the greatest benefit was among the patients that were receiving invasive mechanical ventilation. 28 day Mortality was reduced by 35% in patients that were mechanically ventilated and by 20% in patients receiving oxygen, both of which were statistically significant.
  - Patients who had longer duration of symptoms (symptoms more than 7 days) had a greater mortality benefit.
- The dexamethasone group had a shorter length of hospitalization when compared to the standard care group.
- The risk of progressing to invasive mechanical ventilation was lower in the group that received dexamethasone.

So overall, both Remdesivir and Dexamethasone have shown benefit in recovery and decreased mortality from infection with SARS-CoV-2. It appears that Remdesivir may be more benifical in the early stages of treatment while Dexamethasone appears to show its greatest benefit in those presenting with a longer course of symptoms prior to hospitalization.

Again, this information is adult based and our knowledge of Acute SARS-CoV-2 infection in pediatric patients in not entirely understood. Treatment modalities will continue to be a discussion as the virus finds new zones of increased replication in the US. Stay tuned for more information on Pediatric Presentations of COVID-19 later this week.

As always, you can contact me here!

References
1. Beigel J, Tomashek K, Dodd L, Mehta A, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of Covid-19 — preliminary report. N Engl J Med. 2020. https://doi.org/10.1056/NEJMoa2007764.
2. Williamson, B. N. et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature https://doi.org/10.1038/s41586-020-2423-5 (2020)
3. Horby, Peter, et al. “Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report.” 2020, doi:10.1101/2020.06.22.20137273.

COVID IN THE PEDS ICU

June 11, 2020July 6, 2020 / Kellie / 1 Comment

Over the past two weeks, COVID took a back seat in the media to another public health crisis: Racial Inequalities and Disparities in the United States. (See this JAMA Article here on COVID-19 and Racial Disparities.) So that those important issues could be addressed, I only updated small parts of the website as to not deter attention from an equally important discussion and focus in the public health arena…..

Over the past week, we are beginning to see more MIS-C patients in our hospital, so I wanted to focus on the recent literature on MIS-C and COVID-19 in the Peds ICU that was released this week.

First, let’s dive into the recent numbers and projections of COVID-19. (Skip the numbers to go to straight to the literature by clicking here). According to the John Hopkins Dashboard, as of this afternoon, there are 7.4 million confirmed COVID-19 cases in the world with 2 million of those in the United States. The US reports 113,341 deaths due to COVID-19. At the beginning of this week, the US saw a lower number of deaths at about 400 new deaths reported on June 7th, and 500 deaths on June 8th.. However over the last two days of reporting we have seen 1,000 and 900 new deaths reported due to COVID-19.

In Wisconsin, we are down to about 200 to 300 new cases of COVID-19 reported daily and we are in the single digits to low teens for newly reported deaths, this number seems to have dropped off over the last week of May. See the DHS dashboard here.

It is difficult to anticipate how the reopening of states will see affect the number of fatalities from COVID-19, but we may see the case numbers increase following the demonstrations and state reopenings over the next week. See a link here for where states are in their new case trends. But, as we have learned over the last few weeks as pediatricians we are just starting to see the effects of COVID-19 in children. (Read our summaries here: PIMSTS #1, PIMSTS #2)

According to the VPS database, there have been 619 COVID-19 patients in the PICUs reporting to the database with 80% of those being under 18 years old. There were 32 confirmed deaths and 11,000 patients tested. A recent addition to the database was a diagnosis of MIS-C, and based on the 165 patients who had this data reported, 68 (41%) fit criteria for MIS-C/PIMS-TS.

Earlier this week, Pediatrics pre-published an article titled “Pediatric Critical Care and COVID19.”¹

What was released was the data from the CAKE study. The CAKE study (Critical Coronavirus And Kids Epidemiologic) was a small case series of 17 children under 19 with severe or critical infection from COVID-19. The countries that collaborated were in Chile, Colombia, Italy, Spain, and USA. 6 patients were from Europe, 4 patients from North America, and 7 patients from South America.

They noted that 65% of patients were male with a median age of 4 years old and 14 did NOT have a known COVID exposure. Fever was the symptom most commonly found at admission, and the median time to presentation was about 3 days following symptom onset.

In looking at the break down by region reporting, patients in Europe and North America more commonly reported GI symptoms and patients in North and South America presented with a cough. It was also notable that patients in Europe reported a COVID-19 exposure when compared to the Americas.

On admission, 50% of the patients had a leukocytosis and 76% had an elevated CRP. Elevated procalcitonin and D-dimer were also noted in a little over one-third of patients on presentation.
8 of the 17 patients (47%) required mechanical ventilation and 9 of the 17 patients (53%) required vasoactive infusions.
All but 2 patients were treated with Antibiotics and over half received corticosteroids.
- 4 of the 17 patients (24%) received Remdesivir, all in North America
- 7 of the 17 patients (41%) were treated with Tocilizumab (Europe and North America)
- 8 of the 17 patients (47%) were treated with Hydroxychloroquine
The most common diagnosis was Pneumonia (76% of patients)
- ARDs was reported in 8 of the patients with 3 of those meeting criteria for Severe ARDS
- 3 patients suffered cardiac arrest.
For outcomes: only 1 patient, a 3yo F in South America died.
The median ICU length of stay was 5.5 days.

I found this article to be extremely informative and it was quite interesting to see the different presentations throughout the different parts of the world. I highly recommend taking a look at the break down of patient presentations, treatments, and outcomes in the supplemental tables of the article.

This week we also saw publication of a larger case series regarding PIMS-TS or MIS-C here in the US. On June 8th JAMA published:

“Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2” ²

This article describes a case series of 58 children in 8 hospitals in England between the end of March and middle of May of 2020. They compared the clinical and laboratory findings of these 58 children with those who presented with Kawasaki Disease, Kawasaki Disease shock syndrome, and toxic shock syndrome between 2002 and 2019. They included any patients who met the UK, CDC, or WHO definition for PIMS-TS without requiring proof of exposure to COVID. (See Table 1 in the article for the differences in Definitions)

The patients that met inclusion criteria had a median age of 9 years old. 33 of the 58 (57%) were female and 40 of the 58 (69%) were black or asian. In this group, comorbidities were not common and only present in 7 children.
Presenting symptoms were persistent fever (>38 °C for >72 hours was an inclusion criteria), GI symptoms (vomiting, diarrhea, abdominal pain), conjunctival injection, and erythematous rash.
29 of the 58 patients were classified as developing shock and the same number of patients required admission to the Peds ICU
- Of those that developed shock, the median age of presentation was similar to the entire cohort: 10.5 years old. 55% were male. 48% were Black, 20% were Asian, and 20% were white.
- Presenting symptoms were similar in this group with again over half presenting with GI symptoms.
- 18 of the 29 patients (62%) who developed shock also had evidence of left ventricular dysfunction on echo and 19 (66%) had an elevation in troponin.
  - Of the 11 patients who had a BNP measured, all 11 were elevated.
  - Of these patients, 4 patients developed arrhythmias
- 11 of the 29 patients with shock also developed an acute Kidney injury
- Patients who developed shock has higher CRP and neutrophil counts, as well as lower albumin and lymphocyte counts.
- 27 of the 29 patients required inotropic support, 23 of the 29 patients with shock required intubation, and 3 patients required ECMO. 1 patient in the shock group died.
- IVIG and Steroids were the most commonly utilized therapy options for the 29 patients presenting with shock.

In comparing the cohort of PIMS-TS in this cohort with patients with Kawasaki Disease, Kawasaki Shock Syndrome, or toxic shock syndrome, it was noted that those with PIMS-TS tend to be older, show more signs of inflammation, and have higher markers of cardiac injury. The Figure on page E9 shows a great visual representation of the comparison of these groups.

Again, we are still learning more about how COVID-19 affects children, and each study published continues to supplement the little knowledge we have. Please feel free to contact here if you have any recommendations on articles or posts you would like to see summarized.

I also want to share a few quick articles on COVID-19 that are important to stay informed!

The AAP recently released interim guidance for life support of COVID-19 confirmed or suspected neonates or children. Find that article here.³
Testing continues to be one of the best ways to identify cases. However, we still can’t say for certain what every test result means for the virus. One article from the New England Journal of Medicine discusses False Negatives.⁴ Another piece from The New York Times is an op-ed which discusses COVID-19 Antibody testing.
With the states opening up, we still have questions about the spread of the virus. Read this blog post written by biologist Erin Bromage and featured in the New York Times back in May.

Resources
1. González-Dambrauskas S, Vásquez-Hoyos P, Camporesi A, et al. Pediatric critical care and COVID19. Pediatrics. 2020; doi: 10.1542/peds.2020-1766
2. Whittaker E, Bamford A, Kenny J, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA. Published online June 08, 2020. doi:10.1001/jama.2020.10369
3. Topjian A, Aziz K, Kamath-Rayne BD, et al. Interim Guidance for Basic and Advanced Life Support in Children and Neonates With Suspected or Confirmed COVID-19. Pediatrics. April 2020. doi:10.1542/peds.2020-1405.
4. Woloshin S, Patel N, Kesselheim AS. False Negative Tests for SARS-CoV-2 Infection — Challenges and Implications. New England Journal of Medicine. May 2020. doi:10.1056/nejmp2015897.

#PIMSTS

May 19, 2020July 6, 2020 / Kellie / 3 Comments

At the beginning of last week I posted a brief review of the literature that had been published about the association between COVID-19 and Pediatric Multi-System Inflammatory Syndrome. We knew that more information would be coming and you would be kept up to date with that. As promised, here is your update.

This syndrome has caused such a stir in the pediatric community that it has received a couple different titles. One is “Pediatric Inflammatory Multisystem Syndrome Temporally related to SARS-CoV-2” which even has its own hashtag on twitter: #PIMSTS.

The CDC has also given it a different name: Multi Inflammatory Syndrome in Children aka MIS-C.

This link will bring you to all content on Twitter that is related to this inflammatory syndrome we are seeing.

CDC has the following case definition for MIS-C:¹

An individual aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem organ involvement (> 2 of the following systems: cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological)
- Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
- Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin
AND No alternative plausible diagnoses
AND Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms

They also report that some patients may meet full or partial criteria for Kawasaki disease but should be reported if they meet the case definition for MIS-C. They also report that MIS-C should be considered in any pediatric death with evidence of SARS-CoV-2 infection.

The CDC held a webinar on May 19th which hosted speakers that addressed the UK and New York experience with PIMS-TS. They also addressed the use of immunomodulators in adults presenting with hyper inflammatory syndromes from COVID-19.

Dr. Michael Levin from the UK described that they had seen 38 cases from 8 hospitals since the end of March. The cases described seemed to have followed the peak of SARS-CoV2 cases by about a month. The median age was 11 years old and most patients were previously healthy with the only comorbidities reported being asthma and epilepsy. The usual presenting symptoms were prolonged fevers, sore throat, headache, abdominal pain, rash, and conjunctivitis. 75% of patients presented with shock with 70% requiring inotropic support. Their work up was significant for elevated CRP, increased neutrophil counts, lymphopenia, and increased D-dimer. The Royal College of Pediatrics and Child Health released their guidance at the end of April.
In New York, there have been 43 cases reported to the New York State Health Department. 33 of these patients presented to Cohen Children’s Hospital from April 17th-May 13th. Dr. James Schneider reported the findings of these patients during this webinar. The median age was 8.6 years and again most were previously healthy with only a handful having a history of reactive airway disease or obesity. All patients had fever for a median of 4 days (IQR 3-5) prior to presentation. Half of the patients presented with neurocognitive symptoms or respiratory symptoms. Almost all of the patients had GI symptoms. About three-quarters of patients presented in shock and over half of the patients met criteria for complete Kawasaki Disease. Admission to the PICU was required in almost 80% of patients with average length of stay being 4 days. Patients had normal white counts, lymphopenia, mild hyponatremia and mild elevations in liver enzymes on their workup. CRP levels were significantly elevated with a median level of 206 mg/L. D-Dimer, fibrinogen, BNP, troponin, and procalcitonin were all reportedly elevated as well. The majority of patients (73%) were SARS-CoV-2 PCR negative and IgG positive. Only 18% were positive for both PCR and IgG. 70% of patients were reported to have acute kidney injuries and liver injury was present in 20%. Half of the patients required respiratory support with 18% undergoing mechanical ventilation. Half of the patients had coronary artery abnormalities and myocardial dysfunction was present in 58%. 100% of the patients were treated with IVIG, 70% with steroids, and 88% with aspirin. There were 0 mortalities reported in this population and 82% of the patients have been discharged.
Dr. Vincent C. Marconi reported similar findings of a hyper-inflammatory state in the adult literature. However, most adults will tend to have more respiratory illness when comparing to children presenting with the hyper-inflammatory presentation. He reviewed the clinical course of an adult patient who underwent treatment for a hyperinflammatory state. He explained the pathophysiology of the inflammatory processes reviewed data on immunomodulatory therapies including: IL-6 blockade, IL-1 blockade, GM-CSF blockade , JAK Blockade , and TNF blockade. His slides were very informative and can be found at the webinar link above.

Since my last post, there have been a few more articles published that I wanted to update you on.

First, Evelina London released their clinical guidance for PIMSTS. Quick reminder, they reported 8 cases of this syndrome, and it was summarized in our initial post (linked at the top of this page). This page is very useful in workup and clinical management of these patients.

The literature….

One study comes from the Bergamo province in Italy. It was published in the Lancet on May 13th and you can find it linked here. The report describes the difference in clinical findings of patients with Kawasaki syndrome pre and post the COVID-19 epidemic. They included patients who were diagnosed with Kawasaki-like disease at their center from 2015-2020 and divided the patients into two groups: those who presented with symptoms prior to the epidemic (Jan 1, 2015-Feb 17, 2020) and those who presented after (Feb 18 and April 20, 2020).² Group 1, the pre-epidemic group, had a total of 19 patients over about a 5 year time period. Those in group 2, the post-epidemic group, included 10 patients over a 2 month time period. The incidence for group 2 was 10 per month versus 0.3 per month in group 1, this p value was <0.00001.

Those ten patients in Group 2 presented between the dates of March 17 and April 14, 2020.

They ranged from 2 years to 16 years old.
The group was split down the middle, half presenting with complete Kawasaki and half presenting with incomplete Kawasaki.
6 patients also presented with diarrhea and 4 patients had meningeal signs.
5 patients met criteria for Macrophage Activation Syndrome
5 patients met criteria for Kawasaki Disease shock syndrome.
Half of the patients had a chest x-ray consistent with pneumonia.
6 patients had abnormal echocardiograms including 2 with aneurysms greater than 4mm, 5 with ejection fractions less than 50%, 4 with mitral valve regurgitation, and 4 with pericardial effusions.
Only 2 patients had a nasal swab positive for SARS-CoV-2 but 8 patients had serologies positive for SARS-CoV-2 IgG, with 3 of those 8 with positive IgM serologies.
All patients had negative blood cultures.

The article describes the lab findings of each of the 10 patients in group 2 including in Table 1. The article also compares the two groups side by side.

When comparing the patients presenting with Kawasaki like disease before and after the SARS-CoV-2 epidemic…

The group presenting after the epidemic was significantly older with a mean age of 7.5 years (SD 3.5) vs a mean age of 3 years (SD 2.5) in the pre-epidemic group. (p 0.0035)
There were differences noted on CBC analysis as well. The post-epidemic group had significantly lower white cell counts, lymphocytes, and platelets with higher neutrophils when compared to the group pre-epidemic.
Ferritin was significantly higher in the post-epidemic group with a mean of 1176 ng/mL (SD 1032) vs 187 ng/mL (SD 89) in the pre-epidemic group, p 0.011.
There was no significant difference between ESR, Hemoglobin, Albumin, liver enzymes, fibrinogen, D-dimers or CPK.
Significantly more patients in the post-epidemic group has Kobayashi score>5

Yes, there are clinical differences between the two groups, but what is intriguing as well is that the incidence of Kawasaki-like disease incidence increased by 30-fold.

Source: Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. *The Lancet*. 2020. doi:10.1016/s0140-6736(20)31103-x.

As you can see by the chart demonstrated above, the increase of incidence in the Kawasaki Disease-like syndrome appeared around 3 weeks following the drop off of the peak of the peds emergency visits during the epidemic.

The other recently published article was released by the AHA this past week for pre-publication. This is titled: Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic and can be found at this link. This study collected data retrospectively over a 2 month period (March 22-April 30, 2020) in pediatric intensive care units in 14 centers throughout France and Switzerland.³ They included patients admitted to the pediatric intensive care unit who had fever >38.5, cardiogenic shock or acute left ventricular dysfunction, with an inflammatory state.

35 patients ages 0-16 with a median age of 10 years old met inclusion criteria.
None of the patients had underlying cardiac disease, and the most common comorbidities reported were obesity or asthma.
31 of the 35 patients had confirmed SARS-Cov-2 infection
- NP-PCR was positive in 12 patients
- Fecal PCR was positive in 2 patients
- Antibody assays were positive in 30 patients
- 13 patients had recent contact with family members displaying viral symptoms.
All children presented with fever and generalized weakness or fatigue.
- GI symptoms were present in 80% of patients
  - 2 patients underwent surgical intervention for possible appendicitis, that were ultimately diagnosed as mesenteric adenitis.
- Classic signs of Kawasaki disease were frequently reported, however no patients met diagnostic criteria for Kawasaki disease
- The median delay between onset of clinical symptoms and symptoms of heart failure was 6 days. (IQR 4.5-6 days)
- 29/35 patients were admitted to the pediatric ICU initially. The 6 patients who were admitted to the pediatric ward deteriorated within the first 24 hours of admission and required transfer to the ICU.
- Lab findings: All patients had evidence of inflammation with an elevated CRP and D-dimer and 13 patients had elevated Interleukin 6 levels. Mild to moderate troponin elevation and BNP elevation was present in all patients.
- ECHO Findings: All patients had and ejection fraction less than 50% on echo, with 10/35 patients having EFs less than 30%. 31/35 had left ventricular hypokinesis and 6 patients had dilation of the coronary arteries.
- Treatment/Management: 10 patients required VA ECMO for cardiogenic shock with a median ECMO duration of 4.5 days (IQR 3-6). 28/35 patients required inotropic support and 25 patients received IVIG. 12 patients received steroids and 3 received interleukin 1 receptor antagonist.
- Outcomes: At the time of this article hitting the press 28 patients had favorable clinical evolution and 7 of the 35 were either still hospitalized or had residual left ventricular dysfunction. The median ICU stay was 7 days (IQR 3.7 to 10 days) . There were no reported deaths in the 35 patients.

Source: Belhadjer Z, Méot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. *Circulation*. 2020. doi:10.1161/circulationaha.120.048360
Red text indicates signs or symptoms consistent with
Kawasaki disease. In black, signs that are rare in Kawasaki disease. Percentages are those
present in the present series of patients.

As we have said before, information is being released daily about PIMSTS and MIS-C. There are general guidelines being published by each institution and we can expect to see more data over the next few weeks.

Here are some links to helpful inforgraphics: Don’t Forget the Bubbles gif, AHA infographic, Adapted RCPCH by Daniel Gooding, RN

Another published literature source which has links to the two ongoing clinical studies as well: Kawasaki-like disease: emerging complication during the COVID-19 pandemic by Russell M Viner, Elizabeth Whittaker

We will continue to keep you updated as more information becomes available and published. Please feel free to contact us here if you have an article we should feature or discuss!

References

PEDIATRIC MULTI-SYSTEM INFLAMMATORY SYNDROME.

May 11, 2020July 6, 2020 / Kellie / 4 Comments

It has been 108 days since the first case of COVID-19 was confirmed in the US. We have heard of the devastating effects the virus has had on adults for months. However, over the last week, media attention has shifted to focusing on pediatric patients and the late effects COVID-19 seems to be causing. For months, we have reported that children seemed to be relatively protected from the severe ARDS presentation the adult world was seeing, but reports of cases of a hyperinflammatory shock state, similar to Kawasaki disease or toxic shock syndrome, has been reported in multiple children throughout the globe.

Before we dive in, let’s take a look at our current numbers… (Don’t care about the numbers and just want to see the summary?? Click here to jump ahead)

4.1 MILLION...

confirmed cases globally with the US reporting the highest number of confirmed cases at 1.3 million cases according to John Hopkins dashboard. (p.s. for those of you who haven’t looked at this dashboard there is a new US Map area I highly suggest looking at).

The US had 79,699 confirmed deaths, which puts the Case Fatality Rate in the US at about 6%. Worldwide, daily cases have leveled off, but not necessarily decreased, with over 75k cases confirmed daily over the last week, and confirmed cases in countries such as France, Brazil, Iran, and Belgium are on the rise. In the US, daily cases continue to be reported at 25-30k new cases daily, which appears to be slightly down from the past few weeks.

Available on https://coronavirus.jhu.edu/data/new-cases

In the state of Wisconsin, we have about 300 new cases reported daily with a total cumulative number of cases at 10.2k. In looking at the DHS website, last week we had a steady number of deaths, slightly up from the week prior at about 10 to 15 deaths per day. 70% of deaths are in patients over 70 years old and our Case Fatality Rate in WI is around 4%, lower than the national average.

In peds ICUs reporting to the VPS dashboard we can see that there have been 25 confirmed deaths in 404 COVID-19 positive patients, with the majority of cases and deaths still reported in New York and New Jersey.

So yes, our curve seems to have flattened… BUT our cases continue to rise with more testing and as states start to open back up, we will continue to have more information and data regarding COVID-19 and may see another surge of cases in the near future. Including, the pediatric presentations.

PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME.

Over the past weeks, there have been reports surfacing of a hyperinflammatory syndrome in pediatric patients following exposure to COVID-19. The syndrome appears to resemble Toxic Shock Syndrome or Kawasaki Disease in its presentation.

On April 7th, Hospital Pediatrics released a pre-publication case report describing a 6 month old, fully immunized female who presented with signs and symptoms of Kawasaki Disease with concurrent COVID-19 infection. This was the first reported case in the medical literature that I can find. This patient initially presented with fever, fussiness, and poor appetite and progressed to a erythematous, blotchy, non-pruritic rash, with limbic sparing conjunctivitis, dry cracked lips, no lymphadenopathy, and some mild tachypnea with accessory muscle use. On Day 5 of fever, the patient received 2g/kg of intravenous immunoglobulin (IVIG) and high dose aspirin according to Kawasaki treatment guidelines. Her ECHO revealed no evidence of coronary dilation, aneurysm, effusion, and normal valve and ventricle function.

About 1 month later, on May 4th New York Health Officials began to issue alerts describing a presentation, similar to that described in the previous case report. They reported that as of May 6th, 64 patients had presented with a multi-system inflammatory syndrome associated with COVID-19 in the state of New York. They describe that the syndrome had features which overlap with Kawasaki Disease and Toxic Shock Syndrome. They report that inflammatory markers may be elevated as well as symptoms of fever, abdominal pain, and rash. They also report that myocarditis has also been observed in presentations of their patients. The most alarming presentation is that some patients had developed cardiogenic and vasogenic shock. According to multiple new sources, there have been deaths reported in at least 3 pediatric patients from this presentation. They report that most patients have tested positive for SARS-COV2 or corresponding antibodies. See the full advisory report here. (Some other reads: 1, 2, 3.) These case reports have not yet been released for publication in medical journals that I could find.

On the same day of the NY state health report, The Lancet, release a correspondence from South Thames Retrieval Service in London, UK. They reported that during a 10 day period in mid April, they noted a cluster of eight children who presented with hyper-inflammatory states, again with presentations similar to Kawasaki Disease or toxic shock syndrome. They reported that of the 8 cases, all children were previously healthy with 5 being male, and 6 children of Afro-Caribbean descent. Half of the children had known family exposure to COVID-19. The children ranged in age from 4 years old to 14 years old. All children were reported to have fevers >39 degrees celsius, with the majority reporting rashes and abdominal pain along with peripheral edema and generalized anxiety pain. All patients were reported to progress to a warm, vasoplegic shock, which required hemodynamic support volume resuscitation, norepinephrine, and milrinone. 7 required mechanical ventilation for cardiovascular support, NOT for respiratory support. (2 of these are reported as non-invasive). One patient required ECMO, and this patient did not survive. 6 of 8 echocardiograms reported ventricular dysfunction (both right sided, left sided, and bilateral). Only two patients were reported to be SARS-CoV2 positive, with three patients noted to have parental exposure. One of the positive tests was reported post-mortem. All children were treated with IVIG, ceftriaxone and clindamycin, and 6 of the 8 children were treated with aspirin. See the full chart below for more information.

Source: Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. *The Lancet*. 2020. doi:10.1016/s0140-6736(20)31094-1.

So the information is limited, but alarming for the Peds ICU world. Of note, after this publication was brought to press, another London Children’s hospital reported over 20 patients with a similar presentation. As more information comes to the medical literature world we plan to keep you updated. There is a webinar out of London regarding this information that is very helpful and highly recommended for learning purposes. Please contact me directly for more information. (The link is not available for press release, so would like to only share with those in the medical community treating these patients.)

See this press release from Paediatric Intensive Care Society here.

See our literature review page for a few more links and updated information!

Resources:

Jones VG, Mills M, Suarez D, et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020; doi: 10.1542/hpeds.2020-0123
Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. The Lancet. 2020. doi:10.1016/s0140-6736(20)31094-1.

COVID-19 VACCINE DEVELOPMENT.

May 4, 2020May 7, 2020 / Kellie / Leave a comment

All the important information summarzied here courtesy of MCW Peds Resident:
Dr. Swathi Prasad.

Since its outbreak in the end of 2019 and spread to pandemic status by early 2020, SARS-CoV-2, the causal coronavirus of COVID-19, has infected more than 3.4 million individuals worldwide (as of 5/2 per the Hopkins COVID-19 tracker). Initial responses included public health measures, but now the focus has begun to shift to therapeutic interventions and prevention via vaccine development. While previous timelines for vaccines have been close to 10 years from inception through all trials and assessments by regulatory agencies and eventual mass manufacturing and distribution, the Ebola pandemic cut this timeline in half, and companies are hoping to reduce the time needed for a COVID-19 vaccine to one year. Below is a summary of some vaccine basics, some of the more advanced trials, and a myriad of sources as the landscape of vaccine development continues to change.

A quick disclaimer: Even as I write this article, the world continues to be updated with both more information about COVID-19 as well as information from the ongoing trials. One of the most comprehensive and updated resources continues to be the “World Health Organization’s landscape of COVID-19 candidate vaccines” with list here (updated as of 04/30/20), which can also be found by googling “WHO draft landscape of COVID-19 candidate vaccines”.

Coronavirus is…

…a betacoronavirus (described as such by the “crown” of spikes or surface glycoproteins under electron microscope), with genomic sequencing similar to that of 2003’s SARS virus. This RNA genome appears to encode in particular for a spike protein (S protein) that allows it attack our bodies by attaching to the angiotensin-converting enzyme 2 (ACE2) receptor, leading to uptake into our cells. With a significant number of severe infections and mortality rate, health experts around the globe recognize the need for focus not only on therapeutics but also on vaccines for this new virus.

Vaccines are…

…important, and in this blog, we shouldn’t have to explain why. Vaccine technology over the last decade has led to the development of RNA and DNA candidates, vector vaccines, protein vaccines, and a few other mechanisms or platforms (see below). As of now, we know that SARS-CoV-1 and MERS-CoV vaccines showed that the S protein on the surface of the virus is an ideal target for a vaccine by allowing antibodies to target this pike and interfere with binding to ACE2 receptors (see Figure 1), neutralizing the virus, making this a potential starting point for some of the current vaccine developers.

Why do we think a vaccine might work for COVID-19?

SARS-CoV-2 doesn’t appear to be “formidable” – it changes slowly which is important in developing a vaccine that will be universally impactful, and vaccines against related coronaviruses causing SARS and MERS have worked well in animal models. For example, the SARS-CoV-1 vaccine model did show protection in animal models challenged with that virus, but also some complications including eosinophilic infiltration in the lungs, liver damage in ferrets. However, studies as development persisted all correlated vaccination with greater survival, reduced virus titers, and/or less morbidity compared with unvaccinated animals. While vaccine researchers continue to work towards a vaccine, they acknowledge the risks associated with them, thus leading to very strictly defined and closely regulated trials before anything will be distributed to the public.

But there are still a few unknowns about the coronavirus that will also impact vaccine development…

The four human coronaviruses that cause minor colds don’t trigger long-lasting immunity, leading to a consideration of whether there is a waning antibody response. As a whole, we are still trying to figure out what re-infections look like, and their time frame, which requires more testing. For now, vaccine developers will need to take the potential for waning humoral immunity in months or years into consideration, especially as countries consider how to wean down restrictions on physical distancing.

Other important factors include our knowledge of the worse impact this infection has on older individuals, in particular due to this segment of the population responding less well to vaccines. While they may benefit if vaccination prevents transmission in younger adults, the need for more antigen or adjuvants for vaccinations for this population should be considered.

So, what’s out there right now? (as of April 23, 2020)

Recommended reads:
- The COVID-19 vaccine development landscape, on Nature (April 9, 2020)
- Covid-19 Vaccine Frontrunners, on The Scientist (updated April 23, 2020)
- COVID-19 Vaccine Candidates, on AssayGenie (last updated date unknown)

Current vaccine proposed mechanisms
(The following table was adapted from Table 1 of a status report published in Immunity. )

Platform	Target and Mechanism	Existing, Licensed Human Vaccines Using the Same Platform	Advantages	Disadvantages	Current COVID-19 vaccine in progress at the clinical evaluation level?
RNA vaccine (additional source)	Targets the S protein Introduces an mRNA sequence coded for a specific antigen (the S protein) to teach the immune system to recognize and fight it	No	Faster to produce Cheaper to produce Safer to patient, and when being handled due to no infectious virus presence Generally show good tolerance by healthy individuals	Safety issues with reactogenicity have been reported – the mRNA strand can elicit unintended reactions Delivery is challenging as mRNA is quickly broken down.	Yes 1. Moderna
DNA vaccine (additional source)	Targets the S protein Introduces plasmid containing DNA sequence encoding an antigen (the S protein) to stimulate B- and T-cell responses	No	No infectious virus needs to be handled Easy scale up Low production costs High heat stability Tested in humans for SARS-CoV-1, rapid production possible DNA and mRNA offer flexibility in terms of antigen manipulation and potential for speed	Vaccine needs specific delivery devices to reach good immunogenicity	Yes 1. Inovio Pharmaceuticals
Inactivated Virus (additional source)	Targets the whole virion Bacteria or virus are grown in culture, then inactivated with heat/chemicals, purified to vaccine components only, and then administered via injection.	Yes – polio, hep A	Proven and straight forward process used for several licensed humanVaccines, and thus existing infrastructure can be used Has been tested in humans for SARS-CoV-1, adjuvants can be used to increase immunogenicity (see below)	Large amounts of infectious virus need to be handled (could be mitigated by using an attenuated seed virus). Antigen and/or epitope integrity needs to be confirmed. Requires multiple doses (first dose “primes”, the next confer protection), and antibody titers can wane over time with a mostly humoral response.	Yes 1. Beijing Institute of Biological Products/Wuhan Institute of Biological Products 2. Sinovac
Non-replicating viral vector (additional source)	Targets the S protein Use an inactivated or killed viral vector (such as adenovirus) to express proteins of the virus to be recognized by the immune response and create a response	Yes – VSV	No infectious virus needs to be handled Excellent preclinical and clinical data for many emerging viruses, including MERS-CoV Viral vectors offer high level of protein expression, long term stability, induce strong immune responses	Vector immunity might negatively affect vaccine effectiveness (depending on the vector chosen).	Yes 1. University of Oxford 2. CanSino and Beijing Institute of Biotechnology
Recombinant protein vaccines (additional source)	Targets the S protein Virus-like particles (often those from the outer shell of a virus) are used to prompt an immune response, but ar non-infectious as they do not contain genetic material.	Yes – influenza, HPV, HBV	No infectious virus needs to be handled, adjuvants can be used to increase immunogenicity. Already licensed vaccines are based on recombinant proteins, and so could take advantage of existing large-scale production capacity	Global production capacity might be limited Antigen and/or epitope integrity needs to be confirmed. Yields need to be high enough.
Live attenuated vaccines (additional source)	Targets the whole virion Derived from wild or disease-causing viruses (or bacteria), weakened in a lab by epeat culturing, and then dosed in tiny amounts to the body to stimulate an immune response.	Yes – MMR, varicella	Straightforward process usedfor several licensed humanvaccines, existing infrastructurecan be used. Often confer immunity with one dose.	Creating infectious clones for attenuated coronavirus vaccine seeds takes time because of large genome size. Safety testing will need to be extensive.
Adjuvants (source)	Improve immune response and increase efficacy of vaccines which may have weak immunogenicity		Could enhance immunogenicity and make lower doses viable, enabling vaccination of more people without compromising protection		Multiple developers have indicated plans to develop adjuvanted vaccines against COVID to us with vaccines developed by others

Why do we need to consider so many platforms?

We assume that protection will come from the activation of and presence of neutralizing antibodies against the viral spike S protein, preventing uptake by human ACE2 recptor, though some propose that instead a T cell response may be a better correlate based on some existing monkey studies. Diverse platforms, not all of which are the basis for licensed vaccines, may allow for increased speed of development and manufacture, and may be better suited for specific population subtypes.

Ok, fine. But I’m really here for an update on who has ACTUALLY got a vaccine going.

Recommended reading, updated 4/23: COVID-19 Vaccine Frontrunners via The Scientist

Moderna, CanSino, and the first human trials (source)

Moderna’s experimental vaccine first came to fame when the first US citizen received their mRNA vaccine on 3/16 in the first US launch of a clinical trial against COVID-19. (On this same date, China’s CanSino vaccine trial began their own trial.) These were the first two to go to human trials. This happened relatively quickly – Chinese researchers first publicized the full RNA sequence on 1/10/20, and less than ten weeks later, a vaccine was administered to volunteers in the Kaiser Permanente Washington Health Research Institute trial. Moderna’s vaccine is made of lipid nanoparticles containing mRNA that will direct cells to produce the spike protein previously described to train the body into an immune response.. Linked here is a link to their timeline and work, as well as FAQ. Notably, it was not tested in animals before going to human testing. It is currently in the phase I, open-label, dose ranging clinical trial stage with testing in males and non-pregnant females.

CanSino’s vaccine uses a non-replicating version of Adenovirus-5 (another common-cold-causer) as a vector to carry in the gene for the coronavirus spike protein. Possible limitations described have been that existing immunity may lead to a response against the vector itself, preventing the spike protein from even being delivered. Previous trials of an Ad5 based vaccine (against HIV, by Merck) also led to harm, but a 2017 Chinese produced Ebola vaccine showed a good safety profile, thus reducing concern for now. CanSino is now in phase I and phase II of clinical trials.

Sinovac (1)

As of 4/23/20, scientists in Sinovac Biotech reported that one of the vaccines in development had protected a rhesus macacques from infection by new coronavirus. The vaccine itself is a chemically inactivated version of the whole virus particles added to an immune booster called alum (the same strategy used for a SARS vaccine previously developed), and was introduced to eight monkeys; three weeks later, the monkeys had SARS-CoV-2 introduced via tubes down the tracheas. Seven days after virus introduction, it was undetectable in pharynx or lungs. The control animals showed high levels of viral RNA in several body parts and severe pneumonia.

Feedback thus far has been mixed. Some experts are in favor of this “old school” method, which would be appropriate to make and distribute in lower-middle-income countries. Others are concerned that this number is too small for statistically significant results (and that the method of introduction of virus does not reflect the process of human infection). Most notably, the monkeys don’t seem to develop the full range of severity of symptoms seen in humans.

Phase I clinical trials were started recently in Shanghai with plans for high and low doses and a placebo to be given to an equal distribution of 144 volunteers. Sinovac has their own information here.

Inovio Pharmaceuticals (1, 2)

Inovio seems to have already been working on a DNA platform, and leveraged this to create their own COVID-19 vaccine candidate. After mice and guinea pigs mounted immune esponses against the virus, they moved to monkeys. Now in Phase I trial in Pennsylvania and Kansas City, the plan is for a two dose vaccine four weeks apart after preclinical animal model testing with encouraging immune response data (per company).

University of Oxford (1, 2, 3)

Within the last few days, Oxford began their own Phase I/II trial using the same adenovirus (non-replicating) vector from chimpanzees used to target MERS in Saudi Arabia. As of 4/27, new updates were reported that six rhesus macaque monkeys dosed with the vaccine last month and then exposed to heavy virus quantities were healthy more than 28 days later. This particular trial is prioritizing recruitment of healthcare workers given higher likelihood of exposure, and now with their vaccine results from monkeys as well as previous trials (including one from 2019 against an earlier coronavirus) have allowed this team to hope to test 6,000 people by end of May, and potential have their vaccine ready by the end of October with emergency approval.

Beijing Institute of Biological Products (1)

Based out of WuHan, this company has also been working on phase I/II clinical trials for an inactivated COVID-19 vaccine. Less information was easily found on this product from more objective sources, but the clinical trial information page itself is notable for its proceeding after studies in monkeys, mice, rabbits, and guinea pigs supported its movement to testing in humans, and for its inclusion criteria of healthy subjects from age 6 upwards.

Who is funding all of these efforts?

For one, the Coalition for Epidemic Preparedness Innovations (CEPI), a nonprofit set up to coordinate R+D for vaccines against emerging infectious diseases. They have been investing in manufacturing facilities, as well as staging clinical trials for eight total groups in the hopes that they can compress the overall timeline. Their goal? To push six of eight products into safety studies, with the hope that three will be worthy of full-scale trials. So far, they have nearly $30 million invested.

Another source of funds has been the Biomedical Advanced Research and Development Authority (BARDA), part of the HHS, which has sponsored in particular the Johnson&Johnson Janssen division, Moderna’s efforts, and Sanofi’s new recombinant vaccine candidate.

How long will we have to wait?

We’ve all heard Dr. Anthony Fauci predict that a vaccine may take over a year and up to two years (optimistically) to get to the public, especially if we stick to the regulations in place for safety purposes (animal models, testing toxicity and safety, phase I/II/III trials), but also as we try and figure out what manufacturing may look like. With no previous coronaviruses, we’re not only creating the vaccine but production platforms, vectors, distribution networks in parallel in the hopes of cutting down on time to giving this out to the general population. Some companies hope to launch efficacy trials by the end of 2020, to determine by the beginning of 2021 whether a vaccine works. China’s companies think they may be able to move things up sooner.

All companies and experts acknowledge that the vaccines might be too late for the first wave of this pandemic, but might be useful for additional waves, or in a post-pandemic scenario as the virus continues to circulate. Viruses keep coming, and other viruses will have their own waves this coming fall. Development even during this pandemic will be important to our management of future outbreak infectious diseases.

Thank you Dr. Swathi Prasad for this great summary!

Where did we find all this info? See our sources with their links below!

WHAT ABOUT HYDROXYCHLOROQUINE?…

April 21, 2020July 6, 2020 / Kellie / 3 Comments

First, the new numbers…

As of this morning, the John Hopkins map reports worldwide we have now 2.5 million confirmed cases with 174,336 deaths. Looking at the total daily cases worldwide the numbers seem to have somewhat stabilized with a total of anywhere from 70k to 90k cases reported each day worldwide. The highest numbers of confirmed cases were on 4/12 with 99.1k and following that 4/16 with 96.4k. Most recently on 4/20 there were 70.2k new confirmed cases of COVID-19. The US reporting 25k-30k new cases each day.

The WHO situation reports lag a day or two behind the
John Hopkins map, but I still find it to be a reliable source as far as reporting new deaths by country. The situation reports from the last few days show us that globally there are anywhere from 5k to 6k deaths reported daily, with the US report 1.7k to 2k deaths per day.

In Wisconsin, according to the DHS, we have a total of 4,499 confirmed cases as of 4/20 with 230 deaths. The case fatality rate (CFR) is currently 5.1%, which seems to be comparable to the US CFR of 5.37%. The ages of confirmed COVID-19 patients seem to follow a symmetric distribution with 20% of patients ranging in the 50-59 age range. 28% of patients require hospitalization, with the majority of those being over 60. 7% of patients in Wisconsin with COVID-19 require ICU care, again the majority of these patients being over 60 years old

Peds ICU data on the VPS website shows us that there have been 237 positive COVID 19 patients with 11 confirmed deaths in pediatric ICUs reporting to the dashboard. 40% of these patients reported are over 18 years old. The highest rate of cases continues with the national trends of NY with 88 cases and NJ with 32 cases.

So we are still seeing more COVID-19 cases, and can expect to see more cases as our testing capabilities expand and potentially as stay at home orders are lifted or violated… so let’s recap the treatment option that has been the topic of much debate and discussion..

Hydroxychloroquine

What exactly is it?

Hydroxychloroquine is a less toxic derivative of chloroquine. These drugs belong to a class of drugs called 4-aminoquinolones. Both chloroquine and hydroxychloroquine have been approved for the treatment of malaria. They are also utilized in autoimmune illnesses such as lupus and rheumatoid arthritis. The origin of chloroquine can date back to as early as the 1630’s where the powdered bark of a tree was utilized to treat malaria and called quinine. Flash forward about 300 years to 1944 and the chemical synthesis of quinine and related compounds were achieved. One of these, Chloroquine, was approved for FDA use in the treatment of malaria a few years later. Hydroxychloroquine, a less toxic derivative, followed about five years after. Throughout the last half of the 1900s many randomized trials were conducted about the effects of chloroquine and hydroxychloroquine. Studies throughout the years had shown that these drugs have strong evidence that these drugs have strong immunomodulatory capacity, promoting their use in autoimmune disorders such as lupus and rheumatoid arthritis. (1)

How does it work?

In general, the effects of chloroquine and hydroxychloroquine have been studied in healthy individuals. Chloroquine is administered as a phosphate salt while hydroxychloroquine is administered as a sulfate. Both drugs have a large distribution in blood, long half-lives (40-60 days), and renal clearance plays a major role in their bioavailability.

There are many various mechanisms of action which explain the therapeutic effects of hydroxychloroquine and chloroquine based on in vitro studies. The three main effects are thought to be:

Inhibition of lysosomal activity
- Lysosomes function in cells to reduce cellular substances, aid in antigen processing and promote immune activation
- Studies have shown that in vitro chloroquine can destabilize lysosomal membranes inside cells. By inhibiting lysosomal activity, the function of lymphocytes may be inhibited.
- Another proposed mechanism is that the anti-inflammatory effects of hydroxychloroquine are due to the disruption of antigen presentation. By increasing the pH of the endosomal compartments it is suggested that autophagosomes and lysosomes may not be able to fully mature and the MHC class II-mediated presentation on antigens to CD4+ T cells is disrupted, therefore immune activation is unable to occur properly. See the figure below.
Inhibition of signaling pathways
- By altering endosome pH there is interference with toll-like receptor (TLR) action
- By binding to nucleic acids directly it is likely that TLR9 signaling is inhibited at the intracellular level via TLR-ligand interactions.
- It is likely that the inhibition of TLR processing and binding are the central mechanisms of action for these drugs.
Reduction of anti-inflammatory cytokines
- Studies have shown that in-vitro have shown that hydroxychloroquine and chloroquine decrease the production of anti-inflammatory cytokines such as IL-1, IL-6, and TNF. This is likely via inhibition of TLR pathways mentioned in the last bullet.

But why the discussion about using it for COVID treatment?

For decades, there have been studies regarding the drug’s efficacy against certain viruses such as dengue, HIV, ebola, and even influenza. As previously mentioned the thought behind the use is that it interferes with viral entry into cells and viral replication by altering the pH of organelles such as lysosomes and endosomes. In addition, it was thought to interfere with the glycoslyation of cellular receptors of SARS-CoV. (2) Some clinical studies in prior years demonstrated chloroquine was effective at reducing viral loads of HIV in asymptomatic patients, but results against viruses such as dengue and chikungunya were not conclusive.

COVID-19 first emerged in China in December of 2019. Within months, as the disease progressed many studies regarding treatment came forward, starting to first emerge in February. One study out of China looked at the in-vitro effects of chloroquine on the cytotoxicity, virus yield, and infection rates of 2019-nCoV. The study infected cells with nCoV and evaluated efficacy based on viral copy numbers via PCR and confirmed with immunofluorescence at 48h. The study showed that chloroquine potentially blocked virus infection at low-micromolar concentration and showed a high selectivity index. This study also demonstrated that chloroquine functioned at entry and post-entry stages of the virus in the cells studied. The study suggested that also due to its immune-modulating activity in-vivo the drug may have more efficacy. (3)

Shortly following this, China began to study the efficacy of chloroquine in COVID-19 patients. 20 clinical studies were launched initially. (4) The first study to report efficacy was out of China and reported that more than 100 patients with COVID-19 infection had an improvement in their in pneumonia exacerbation, lung imaging findings, promoting conversion to negative viral testing, and shortening the disease course. (5) However, this data has not yet been published, so the exact information is not yet available. This particular report did not note any adverse effects of chloroquine.

Further in vitro studies continued to compare the efficacy of hydroxychloroquine and chloroquine and demonstrated that hydroxychloroquine had superiority to chloroquine with doses recommended of hydroxychloroquine sulfate 400 mg twice daily on the first day, then 200 mg twice daily for the next 4 days. (6)

The first nonrandomized trial was completed in France at the beginning of March. Confirmed COVID-19 patients over 12 years old were placed in a single-arm trial which treated patients with 600mg of hydroxychloroquine daily and tested their nasopharyngeal viral load. The primary endpoint was virological clearance at 6 days post study inclusion. This study enrolled a total of 42 patients, with 26 in the treatment arm and 16 as control. 6 patients were lost to follow-up, three of those due to transfer to ICU. In their group 17% of patients were asymptomatic, 61% presented with Upper Respiratory Tract Infection Symptoms, and 22% of patients had Lower Respiratory Tract Symptoms. They noted a significant difference in viral load at 6 days post inclusion as 70% of the patients treated with hydroxychloroquine were virologically cured compared to 12.5% in the control group (p=0.001) When azithromycin was added in as a treatment modality, 100% of hydroxychloroquine patients were PCR negative. Without azithromycin, only 57.1% of hydroxychloroquine treated patients were negative and 12.5% of control group patients cleared, p<0.001. In addition, the drug appeared to be more effective in symptomatic patients vs those who were asymptomatic, p<0.05. (7) This study did not include patients in the intensive care units and did not report any adverse effects noted in their patients.

Shortly following, a pre-print study released demonstrated the results of a randomized clinical trial in China looking at hydroxychloroquine efficacy in COVID-19. In February, this study looked at 62 patients with confirmed SARS-CoV-2 via PCR. Their inclusion criteria were patients over 18, with mild disease as defined by a SaO2/SPO2 ratio >93% or PaO2/FiO2 ration >300, and had a CT demonstrating pneumonia. They excluded severe and critical illness, renal failure patients, arrhythmias, and retinopathy (the last three all potential side effects of hydroxychloroquine). They randomized 62 patients into a treatment and control group. The treatment group received 400 mg a day of hydroxychloroquine treatment. The data demonstrated that the treated group recovered from their elevated temperatures quicker, 2.2 (SD 0.4) days to recovery in the treated group vs 3.2 (SD 1.3) in the control group, p=0.0008. In addition, cough remission time was reduced in the treated group, 2.0 days (SD 0.2) in the treated group and 3.1 days (SD 1.5), p=0.0016. CT findings of pneumonia improved as well on day 6 in 80.6% of the treated group vs 54.8% of the control group. This study did report mild adverse effects in two patients: one with a rash and one with a headache. 4 patients in the untreated group went on to develop severe illness, while 0 patients in the treatment group progressed. (8)

There is SO much more information out there on hydroxychloroquine in COVID-19, I did my best to recap the most relevant literature. There are many ongoing clinical trials that can be searched at clinicaltrials.gov. Based on SCCM’s Surviving Sepsis Guidelines for COVID-19, they agree that there is insufficient evidence to make a recommendation on the use of chloroquine or hydroxychloroquine in critically ill adults. (9) If you recall, the data presented above did not study its efficacy in critically ill adults.

In addition, the FDA has not yet approved hydroxychloroquine as a treatment option for COVID-19, but they encourage participation in randomized clinical trials that may produce evidence regarding the efficacy of these drugs. They also have issued an Emergency Use Authorization to authorize the use of chloroquine and hydroxychloroquine in patients who are hospitalized and for whom a clinical trial is not available.

So, for now, the consensus on the use of this treatment modality is split, while some countries recommend the use of hydroxychloroquine in the treatment of COVID patients, other countries continue to recommend caution as the adverse effects have not yet been studied or documented thoroughly.

As we receive more clinical trial data or treatment recommendations from SCCM, the FDA, or CDC I will update. For now, I hope this helps understand hydroxychloroquine a little better.

The studies are all cited and linked below along with two more similar studies not mentioned above!

Stay Safe Everyone!
Kellie

One report published in early April looked at a potential new mechanism of action of hydroxychloroquine against SARS-CoV-2.

This study looked at optimizing dosing of hydroxychloroquine.

References
1. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Reviews Rheumatology. 2020;16(3):155-166. doi:10.1038/s41584-020-0372-x.
2. Dyall J, Gross R, Kindrachuk J, et al. Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies. Drugs. 2017;77(18):1935-1966. doi:10.1007/s40265-017-0830-1.
3. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research. 2020;30(3):269-271. doi:10.1038/s41422-020-0282-0.
4. Philippe Colson , Jean-Marc Rolain , Jean-Christophe Lagier ,
Philippe Brouqui , Didier Raoult , Chloroquine and hydroxychloroquine as available weapons to fight COVID-19, International Journal of Antimicrobial Agents (2020), doi:https://doi.org/10.1016/j.ijantimicag.2020.105932
5. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioScience Trends. 2020;14(1):72-73. doi:10.5582/bst.2020.01047.
6. Alia E, Grant-Kels JM, Does Hydroxychloroquine Combat COVID-19?
A Timeline of Evidence Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/j.jaad.2020.04.031
7. Philippe Gautret ,Jean-Christophe Lagier ,Philippe Parola ,Van Thuan Hoang ,Line Meddeb ,Morgane Mailhe ,Barbara Doudier ,Johan Courjon ,Val ́erie Giordanengo ,Vera Esteves Vieira ,Herv ́e Tissot Dupont ,St ́ephane Honor ́e ,Philippe Colson ,Eric Chabri`ere ,Bernard La Scola ,Jean-Marc Rolain ,Philippe Brouqui ,Didier Raoult , Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of anopen-label non-randomized clinical trial,International Journal of Antimicrobial Agents(2020), doi:https://doi.org/10.1016/j.ijantimicag.2020.105949
8. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. 2020. doi:10.1101/2020.03.22.20040758.
9. SCCM: COVID-19 Guidelines. Society of Critical Care Medicine (SCCM). https://www.sccm.org/SurvivingSepsisCampaign/Guidelines/COVID-19. Accessed March 20, 2020.

4.14.20

April 14, 2020July 6, 2020 / Kellie / Leave a comment

So what has been happening over the last couple of weeks?….

COVID-19 continues to take its toll on the health systems and economy of the entire world. New York City is the center of the pandemic in the US and since our last update the Unites States has surpassed Italy and Spain in its total deaths due to the COVID-19. As of this evening, according to John Hopkin’s dashboard found here there are a total of 1,979,477 confirmed cases of COVID-19 throughout the entire globe. With these confirmed cases, there have been 126,539 deaths. The countries with the highest death rates are as follows:

United States: 25,981 deaths with New York State accounting for over 10,000 of those deaths.
Italy: 21,067 deaths
Spain: 18,255 deaths.

*According to the World Health Organization Situation Reports from April 11-14th, Italy and Spain have continued to report 400-600 new deaths every day. *

From April 14, 2020 World Health Organization Situation Report. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200414-sitrep-85-covid-19.pdf?sfvrsn=7b8629bb_4

In the US, we continue to see about 30,000 new cases reported to the CDC every day, although this number seems to have plateaued while our death toll continues to rise with a little under 2,000 deaths a day reported to the WHO. Over 100,000 patients remain hospitalized while 48,000 individuals have recovered.

In Wisconsin, we have a total of 3,555 COVID-19 cases with anywhere from 120-180 new cases reported daily according to the Wisconsin Health Department site. The hospitalization rate in the state of Wisconsin is reported to be about 30% which appears to be higher than the national average of 16% according to John Hopkins data. We have a total of 170 deaths with 100 of those in the city of Milwaukee.

How are we with our hospital capabilities in the state?

I found this dashboard tonight which is fantastic at creating a visual for where we are with our bed capacity in the state and ICU hospitalizations. (Data as of the morning of April 14th… )

For the state: We are 77% of our bed capacity with 2,637 of the state’s 11,278 beds available. There are 277 patients with COVID-19 tests pending. 161 of the 432 COVID patients require ICU care (about 37%). There are 361 patients receiving mechanical ventilation in the state. We have a statewide supply of 1,231 ventilators.

For our area in Milwaukee: We seem to be a little more stressed on our bed capacity with only 525 beds of our 4,305 beds available. That puts us at about 88% capacity. There are 126 patients with COVID tests pending. 130 of the 341 patients require ICU care, about 38%. In our area, there are 224 patients receiving mechanical ventilation and we have a supply of about 494 ventilators.

What’s going on in the Pediatric ICUs?

In Pediatric ICUs, the VPS dashboard keeps up up to date with information from participating sites. As of this evening, there have been 186 COVID-19 positive patients in peds ICUs throughout the country (there are about 90-100 sites reporting data daily)

67 of these patients were in New York
26 were reported in New Jersey
11 reported in Michigan
There were 3 deaths in Peds ICUs, with 2 of those in NY and 1 in NJ.

Taken from VPS dashbord on 4/14 https://covid19.myvps.org/

What you can see is that the ages of the PICU positive patients is increasing as more sites are taking up to 30 years old. In the graph above the purple and pink accounting for patients over 18 years old, about 40% of the positive PICU cases reported.

The normal, mild/moderate, and severe comorbidities seem to be evenly distributed with 1/3 of patients in each category. Looking at cumulative PICU days data and the therapies used most patients are requiring conventional ventilation. (total PICU days)

Conventional Ventilation: 72% (478 days)
Non-invasive Ventilation: 11% (72 days)
High Flow: 15% (100 days)
ECMO 1.6% (11 days)
HFOV <1% (6 days)

Other updates?
- Our last post commented on the SOLIDARITY trial which is still underway. Tomorrow we will have an update on hydroxychloroquine….What is it? What does the data show? What do we know?
- The debate on masks is still ongoing, but for now the CDC is recommending masks and face coverings in public (but reserving surgical masks and N-95s for the healthcare system).
  - We are currently in N-95s with shields while in patient care areas, and our social masks at all other times… check the PPE site for updates and cleaning/reusing information!
- Testing is still the best way to identify where the virus is and allows us to target the sources and stop the spread. We have updated our testing criteria at CHW.
- We will be sure to continue update frequently over the next few weeks so be sure to follow us on our home page for that update delivered straight to your inbox!

Stay Safe Everyone! As always you can contact us here with questions or comments!

-Kellie

3.27.20

March 27, 2020July 6, 2020 / Kellie / 1 Comment

Hi Everyone! Just a brief update to wrap up the week. Earlier today the World Health Organization (WHO) held a media briefing on COVID-19 which I am sharing below. (I have tried to make a habit of tuning in live while I am working from home.) This is a great way to keep up to date with numbers and facts in a time where there is a lot of information out there on COVID-19. Distinguishing fact from fiction can be challenging and these briefings definitely help.

Dr. Tedros Adhanom Ghebreyesus, Dr. Maria D. Van Kerkhove, and Dr. Michael J. Ryan take an hour a few days a week to brief on the latest updates surrounding COVID-19 and answer questions regarding current management and cases worldwide.

One of my favorite comments was by Dr. Michael J. Ryan:

“We should commend countries that are testing. And we should not punish countries for getting larger numbers. We should recognize when countries recognize reality. We should reward countries and governments for looking. If we create a situation where we overreact to the daily number then there is a disincentive to actually test. Countries who test and find cases and do lots of testing and know where the virus is should be commended.”
-Dr. Michael J. Ryan

In the US our cases still continue to rise. As of Friday evening, according to the CDC the US had 85,356 cases under investigation with a total of 1,246 deaths. Looking at the data reported to the WHO by the CDC (seems to be a 1-2 day lag) this week there appeared to be a couple hundred deaths a day reported. Worldwide, the number of cases has surpassed 500,000 cases.

However, part of this rise, as pointed out by Dr. Ryan is due to increased detection from better testing and when cases are identified, we know where the virus is.

In the Peds ICU world the VPS Map Shown below has become a platform for us to share our data on pediatric patients with COVID-19, including their age, respiratory support, and comorbidities.

As you can see from the data above, there are 11 reported COVID-19 positive patients in Peds ICUs that are reporting data, with a majority of those patients over 2 years old. As of this evening 70% of those patients are currently being mechanically ventilated, and no positive COVID-19 pediatric patient reported to VPS is currently requiring the oscillator or ECMO. About 80% of the patients have pre-existing comorbidities. There have been zero deaths reported in Peds ICUs reporting to VPS, although there is report of a death in a 17 yo boy in California. Read the New York Times article here.

If we follow the same trend of pediatric cases as seen in China, we can expect to see the rise in cases, especially pediatric ICU cases, and we want to be best prepared to handle them. Today our anesthesia team and critical care team developed an airway plan for intubation of PUI or COVID-19+ patients. Find it here.

Chloroquine, antivirals, and other treatments have reported as possible treatment options, but the data has not yet been definitive. While we plan to address the treatment options over next week, I wanted to wrap up today’s post with where the WHO is on treatment recommendations. Today a patient in Norway was the first to be enrolled in the SOLIDARITY trial which includes more than 45 countries around the world and will “dramatically cut the time needed to generate robust evidence about what drugs work.” This trial, as described by Science Magazine, will randomize patients to one of four drug regimens (see image below for a great image):

Remdesivir
Chloroquine
A combination of the HIV drugs lopinavir and ritonavir
Combination listed above plus interferon-beta

Kupferschmidt K, Cohen J. Race to find COVID-19 treatments accelerates. Science. https://science.sciencemag.org/content/367/6485/1412. Published March 27, 2020. Accessed March 28, 2020.

Thanks for following along! Feel free to contact us here with comments or questions. Next week we’ll address the studies behind chloroquine, and the data behind ACE/ARBs and COVID-19.

Stay Safe this Weekend!

A PRIMER ON SOCIAL DISTANCING IN THE TIME OF COVID…

March 25, 2020July 6, 2020 / Kellie / Leave a comment

Written by our MCW Pediatric Residents: Dr. Michelle Hwang and Dr. Swathi Prasad.

We’ve all heard quite a bit of terminology about what cities, towns, counties and countries have asked of their citizens for the purpose of community safety. So we wanted to take some time to clarify what some of these terms might mean and what appropriate activities might be.

Let’s start with some definitions.

What is… Social Distancing:

Deliberately increasing physical space between people and minimizing contact with people outside of your immediate household in order to avoid spreading a contagious disease. The CDC defines social distancing as it applies to COVID-19 as “remaining out of congregate settings, avoiding mass gatherings, and maintaining distance (approximately 6 feet or 2 meters) from others when possible.” For a detailed account of their definitions and guidance, click here.
- The evidence? First, data gathered from the 1918 Spanish Flu pandemic found that “cities that deployed multiple interventions at an early phase of the pandemic—such as closing schools and banning public gatherings—had significantly lower death rates.” You can see a chart and more info here.
- More recently? Experts say that “an early study, not yet peer reviewed, showing the different experience of peak coronavirus rates for two Chinese cities. The city of Guangzhou, which implemented disease control measures early into the outbreak, had significantly lower numbers of hospitalizations from COVID-19 on its peak day than the city of Wuhan, which put measures in place a month into the outbreak.”
- What does this actually entail? A How to Guide for Social Distancing
  - These guidelines are for individuals without symptoms. If you are feeling sick click here for what to do.

What is… Self Quarantine?

The practice of separation of a people who have been exposed to a contagious disease (but not yet symptomatic) from others who have not been exposed in order to prevent the potential spread of disease. If you have a known exposure to COVID19, it is recommended to stay at home and restrict contact with other individuals for a 14 day period (as recommended by the CDC) to monitor for symptoms. This provides enough time for an individual to know whether or not they will become ill and contagious to other people.
- Who should practice self quarantine?
  - If you have recently returned from traveling to a part of the country/world where COVID-19 is spreading rapidly
  - If you have knowingly been exposed to an infected person
- What does self quarantine involve?
  - Using standard hygiene and frequent handwashing
  - Not sharing things like towels, cups, and utensils
  - Washing your own dishes and clothing
  - Staying at home and not having visitors
  - Staying at least 6 feet away from other people in your household

What is… Mandatory Quarantine?

This is referring to city-wide lockdowns that force people to stay in their homes and cut off all travel to and from an impacted area. This helps to separate and restrict the movement of people who were exposed to a contagious disease.
- What does this actually look like?
  - In Wuhan, China, all residents were ordered to stay in their homes and all transit within and out of the city was shut down.
  - In Italy, residents of cities were banned from travel within and out of the city without a permit.
  - In the US, six counties in San Francisco announced on March 16th a “shelter in place” order restricting all residents to their homes (with few exceptions including grocery stores, pharmacies, and care of vulnerable family members) until April 7th at the earliest. As of March 24 2020, the newest state to enact a similar “Stay home, stay safe” order which should last one month is the state of Wisconsin. By March 26th, Alaska and Hawaii will have issued orders mandating a 14 day quarantine for all visitors and residents arriving at state airports. Florida issued an executive order requiring anyone flying to Florida from New York, New Jersey, or Connecticut to self-isolate for 14 days upon arrival.
- Who determines a mandatory quarantine in the US?
  - As usual, there is no standardization and decisions are split between federal, state, and local public health departments. The federal government also has the power to step in and overrule state and local governments’ quarantine decisions.
- Is anyone else doing it?
  - YES. (Click here for constant updates.)
  - Though China’s was the first with 16 cities at the end of January, and more as time went on, close to one-third of the global population is now on a lockdown. As of March 24 2020, India had just declared a mandatory quarantine on its population of over 1.3 billion people. South African will go into a 21 day lockdown on March 26th. New Zealand is planning for a month, Saudi Arabia has locked down the capitol and two holy cities, and the UK prime minister reversed his previous declarations against a quarantine by implementing their own lockdown on the 23rd. Australia is slowly expanding it’s lockdown and closures plan, Jordan and Argentina are on strict indefinite lockdown, and the list goes on…

What is… Isolation?

Separating people (or communities) who are known to be infected with a contagious illness away from people who are not infected in order to prevent the spread of contagious disease. Isolation may be voluntary, or compelled by governmental or public health authorities.
- Who should be in isolation?
  - People who are confirmed to have COVID-19
  - People who have been tested for COVID-19 while awaiting test results
  - People who feel sick with fever and respiratory symptoms (even if you did not get tested for COVID-19). Click here for tips if you feel sick.
- What does isolation involve?
  - Staying at home if you have a mild illness. If you live with others, try to minimize your movements and avoid sharing utensils, dishes, food with those you live with.
  - Staying at a hospital or care facility if you have severe illness. If this is the case, special personal protective equipment (PPE) will be used to care for these patients

What is… Flattening the curve?

Refers to using protective practices to slow the rate of COVID-19 so hospitals have enough rooms, supplies, and doctors for the patients who need care.

Why is this important?
- A large number of people becoming sick from COVID19 over a short period of time could overwhelm a hospital and result in shortages of hospital beds, equipment (such as ventilators) and doctors. This would ultimately mean making difficult choices between which patients get medical care (this has already happened in Italy). If instead, the disease spread at a lower rate (over the course of several months), then each day there would be fewer patients on average requiring medical attention. This would give hospitals a better chance of keeping up with adequate supplies, beds, and health care workers.
- Current projections of our ventilator capacity approximate under 175,000 ventilators available at hospitals or in the National Strategic Stockpile. With, as of March 25 2020, a total of 55,600 cases confirmed and a daily increase in 6-10,000 confirmed cases per day (and rising) over the past week, our confirmed cases (with severe to critical symptoms) will surpass our vent capacity within two weeks. Even more concerning, data from China states that “for every known case of infection, there could be up to 10 people with the virus that remain[ed] unidentified in the community”…which could make this timeline even shorter.

Why does this all matter?

The Washington Post has a great simulation that gives a visual on why outbreaks like Coronavirus spread exponentially and how to “flatten the curve”.

Here are the basics: The number of new cases of Coronavirus in the United States have begun to follow an exponential curve, with the number of cases doubling every 3 days. If this continues there will be about a hundred million cases in the United States by May. The spread can be slowed, however, by practicing “social distancing” and quarantines.

Let’s look at how different countries adopted this and their results.

China (Hubei): China is the most aggressive country to quarantine. Seems to be working.
In January, Wuhan became the epicenter of the COVID19 outbreak. In the attempts to slow the spread of Coronavirus, the Chinese Government imposed a mandatory quarantine on Wuhan’s 12 million residents. This lockdown was initiated quickly after about 30 deaths. The lockdown was then extended throughout Hubei Province (50 million people were locked in their homes). The lockdown continues and now most means of transportation have been shut down in Hubei. China continues to lead the world in the number of confirmed cases but has recently begun to slow the rate of infection. On March 19, China reported not a single new case of domestic transmission.

Italy: Aggressive social distancing but too late, and large elderly population doesn’t help
Italy’s first identified case of community transmission of COVID19 was in mid February. Shortly after, Italy announced a lockdown affecting just 50,000 people who were prohibited from leaving “hotspot towns”. As cases grew to >2500 by March 4, Italy announced the closure of schools and universities nationally. Finally by March 8, with 5,900 confirmed cases, the government ordered a lockdown for 16 million people and closed museums and theatres across the country. And by the next day, March 9, with 7400 cases, the lockdown was extended to the rest of the country. By March 11, with nearly 12,500 cases, the government halted all commercial activity aside from supermarkets and pharmacies.

South Korea: Adopted aggressive testing and contact tracing/isolation. Working so far.
South Korea identified its first COVID19 case on Jan 20. With only 30 new cases confirmed in the weeks following this President Moon Jae-in urged citizens to resume regular activities. However after a breakout in Daegu related to a religious sect in February, SK saw an exponential growth in infections. Recently however, SK appears to have greatly slowed its epidemic. Cases have gone down 90% from the peak. The government has dismissed the idea of lockdowns and though SK promotes social distancing there is no ban on mass gatherings, only recommendations. Rather than enforcing strict social distancing, SK has focused more on contact tracing, even retracing steps of diagnosed individuals using GPS phone tracking. They have focused extensively on isolating infected individuals (case isolation) and quarantining their contacts. Another part of SK’s success is an expansive and well-organized and aggressive testing program.

US: Social distancing but a delay in ramping up testing. Still waiting for our peak.
The United States had its first case of community transmission of COVID19 in California on Feb 28. In the first 2 weeks of March, schools and university closures became the new norm, workplaces went remote, and state and local governments banned large gatherings. Sports leagues suspended their seasons. What does the US government have to say about it now? On 3/16/2020, the White House announced new guidelines for the next two weeks, urging Americans to avoid gathering in groups of more than 10 people; to avoid discretionary travel, shopping trips, or social visits; and not to go out to restaurants or bars.

UK: Trying to balance social distancing with practices that are sustainable for the people and economy in the long haul.
UK has come under scrutiny as it seemed like the initial response of the country was to allow the infection to run its natural course and allow the population to develop “herd immunity”. They have been slow to adapt aggressive social distancing methods. The argument is that strict social distancing will be hard to sustain over time so it must be saved for when it is truly needed. Recently the UK came out with new guidance encouraging social distancing for all and the NHS in England is contacting particularly high risk individuals (age >70 and those with complex underlying health problems) with advice for more stringent measures.

What can we learn from other countries?

China seemed to slow its spread from adopting robust quarantine measures (and implementing them quickly). However, some have argued the sustainability and morality of such strict measures.
South Korea’s success seems to stem from aggressive testing measures. They created an effective test quickly following identification of their first case and used it widely. By testing and identifying infected individuals, they have been able to slow the spread by tracking down exposed individuals and individual quarantines. Through these measures they have had good success even without implementing strict social distancing. The US on the other hand did not quickly develop testing and we are still testing far less than these other countries due to lack of supplies.
Singapore, Hong Kong, Taiwan, South Korea, and China have all flattened their curves despite an initial explosion of cases. Gives us hope and something to emulate.
The UK’s slow response to implement social distancing reminds us that the consequences of strict social distancing and quarantines (including that to mental health and national economy) must be taken into account as projections continue to predict many more months of COVID-19 spread.

How long will social distancing last for?

This is the tough part. Per expert models, if we are successful in “flattening the curve”, then we will both slow the spread of COVID19 so that it does not overwhelm the health-care system but also elongate the curve. We will end up stretching it out over a longer period of time (see graph above on flattening the curve). That means that all of our strict social distancing measures will have to be maintained until either a vaccine becomes available or transmission slows, probably a matter of months rather than weeks. Basically, socially distancing will have to continue indefinitely for now and we don’t know how long it will last for. To make matters worse, epidemiologists are predicting a second wave in the fall. As of March 24, 2020, President Trump is proposing reducing restrictions by Easter but…we’ll have to wait and see.

For all you other questions including:
How do I Practice Social Distancing?
What to do if I feel sick?
What if I can’t afford to work?
Click here.

Written on March 24, 2020. Last updated March 25 by Dr. Michelle Hwang & Dr. Swathi Prasad. All sources hyperlinked within article.

Worldwide…

In the United States…

In Children…

So what does all this data tell us?….

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First up, Remdesivir

Now onto, Dexamethasone…

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Earlier this week, Pediatrics pre-published an article titled “Pediatric Critical Care and COVID19.”1

“Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2” 2

I also want to share a few quick articles on COVID-19 that are important to stay informed!

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This syndrome has caused such a stir in the pediatric community that it has received a couple different titles. One is “Pediatric Inflammatory Multisystem Syndrome Temporally related to SARS-CoV-2” which even has its own hashtag on twitter: #PIMSTS.

The CDC has also given it a different name: Multi Inflammatory Syndrome in Children aka MIS-C.

CDC has the following case definition for MIS-C:1

The literature….

Those ten patients in Group 2 presented between the dates of March 17 and April 14, 2020.

When comparing the patients presenting with Kawasaki like disease before and after the SARS-CoV-2 epidemic…

Yes, there are clinical differences between the two groups, but what is intriguing as well is that the incidence of Kawasaki-like disease incidence increased by 30-fold.

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4.1 MILLION...

PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME.

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All the important information summarzied here courtesy of MCW Peds Resident:Dr. Swathi Prasad.

Coronavirus is…

Vaccines are…

Why do we think a vaccine might work for COVID-19?

But there are still a few unknowns about the coronavirus that will also impact vaccine development…

So, what’s out there right now? (as of April 23, 2020)

Why do we need to consider so many platforms?

Ok, fine. But I’m really here for an update on who has ACTUALLY got a vaccine going.

Moderna, CanSino, and the first human trials (source)

Sinovac (1)

Inovio Pharmaceuticals (1, 2)

University of Oxford (1, 2, 3)

Beijing Institute of Biological Products (1)

Who is funding all of these efforts?

How long will we have to wait?

Thank you Dr. Swathi Prasad for this great summary!

Where did we find all this info? See our sources with their links below!

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First, the new numbers…

So we are still seeing more COVID-19 cases, and can expect to see more cases as our testing capabilities expand and potentially as stay at home orders are lifted or violated… so let’s recap the treatment option that has been the topic of much debate and discussion..

Hydroxychloroquine

What exactly is it?

How does it work?

But why the discussion about using it for COVID treatment?

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So what has been happening over the last couple of weeks?….

How are we with our hospital capabilities in the state?

What’s going on in the Pediatric ICUs?

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Written by our MCW Pediatric Residents: Dr. Michelle Hwang and Dr. Swathi Prasad.

What is… Social Distancing:

What is… Self Quarantine?

What is… Mandatory Quarantine?

What is… Isolation?

What is… Flattening the curve?

Why does this all matter?

What can we learn from other countries?

How long will social distancing last for?

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Earlier this week, Pediatrics pre-published an article titled “Pediatric Critical Care and COVID19.”¹

“Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2” ²

CDC has the following case definition for MIS-C:¹

All the important information summarzied here courtesy of MCW Peds Resident:
Dr. Swathi Prasad.