Introduction and General Commentary: Dr. Ted Rosen
1. This is truly a time of national crisis. We must put aside our legitimate differences of opinion on other issues and work together to vanquish this virus.
2. At this point in time, social distancing is the most effective way we can combat the spread of COVID-19. Any way you can contribute to that concept will be of value, including reducing the number of patients coming for face to face office visits. Postpone elective procedures, delay return visits for stable established patients, and practice teledermatology in any way and as often you can.
3. While the literature cited below suggests there may be utility of hydroxychloroquine in both post-exposure prophylaxis and therapy of active disease, keep in mind this treatment has not been verified in a rigorous randomized controlled study. Prevention of spread is still paramount. I would hate for people to just rely on this drug instead of getting thorough and appropriate evaluation.
4. While small scale successful studies of remdesivir have proven promising, it will be a while until larger trials verify efficacy, alert us to common adverse events and allow mass production and distribution. This may be the "next Tamiflu" but this won't happen overnight.
5. Testing on at least one vaccine has started. There are multiple vaccine products in various stages of development. We will have a vaccine, but not in time to deal with this acute pandemic.
6. Practice good hand hygiene and remind all patients you encounter to do the same.
7. It may come to a mandatory national lockdown which will extend for some period of time; maybe 14 days, maybe longer. Be prepared for the possibility you may need to shelter in place.
Relevant Papers
1
- Combined therapy using HCQ + azithromycin results in viral clearance in COVID19 infections: International J. Antimicrobial Agents in press: 17 March 2020 DOI: 10.1016/j.ijantimicag.2020.105949 (ARTICLE REF. AT BOTTOM OF PAGE)
This study looked specifically at viral clearance of the nasopharynx of the SARS-CoV-2 virus using Day 6 of treatment as the 10 endpoint. Patients who tested PCR positive for SARS-CoV-2 were grouped into 3 categories: asymptomatic, upper respiratory tract infection when presenting with rhinitis, pharyngitis or isolated low-grade fever and myalgia and lower respiratory tract infections when presenting with symptoms of pneumonia and bronchitis. SARS-CoV-2 RNA was confirmed by PCR from nasopharyngeal swab. 10 endpoint was PCR confirmed nasopharyngeal swab virologic clearance at day 6. Dose of HCQ 200 mg tid x 10 days. Azithromycin was dosed prn based on clinical assessment of the treating physician. • 42 pts: 26 treated w/ HCQ vs. 16 controls; 6 HCQ lost to f/u -> 3 sent to ICU and were PCR + through day 3 , 1 died (although PCR negative day 2), 1 left hospital and 1 stop HCQ due to nausea/vomiting - 70% of HCQ pts cleared their virus vs. 12.5% of controls
- 100% of HCQ/AZ pts cleared their virus vs. 57.1% HCQ only pts
Dr. George Martin: Although it was a small study, HCQ when dosed at 200 mg TID x 10 days results in significant clearance of the SARS-CoV-2 viral load in the nasopharynx of COVID-19 patients compared to non-treated controls. This effect is enhanced by the addition of azithromycin (dose not specified but usual dose is 250 mg per day). Of significance is that patients with advanced disease may have their disease rapidly progress while actually becoming PCR negative for SARS-CoV-2. As in all therapies, early intervention is critical.
2
- HCQ vs chloroquine in vitro activity against SARS-CoV-2 and rationale for using HCQ in COVID19 confirmed cases.
In vitro HCQ vs chloroquine testing on viral inhibition and dosing:
https://drive.google.com/file/d/1Zm0hsOSJTEydAvxnYR2obhQOhX3aCcKy/view?usp=drivesdk
Dr. George Martin: The results of this in-vitro cell culture experiment suggest that hydroxychloroquine works better at inhibiting SARS-CoV-2 than chloroquine. The dose that was modelled and suggested is: 400 bid x 1 day and 200 mg bid x 4 days (note the differing dose compared to the French Study above)
What would I do as prophylaxis IF I was working with an ICU full of COVID 19 patients?
Dr. George Martin commentary: Given the 50 years of safety data of HCQ used as a DMARD in rheumatology for RA, SLE/DLE and dermatomyositis, I would do the following: 1 HCQ 200 mg BID or TID…indefinitely until the virus passes. (would stop my statin – neuropathy risk) - Zinc supplementation
- Zycam intranasal spray to hopefully minimize nasopharyngeal colonization in a manner similar to influenza virus
3
Wonder how long the Corona virus hangs out on surfaces and in the air?
https://www.nejm.org/doi/10.1056/NEJMc2004973
Drs. Ted Rosen/George Martin comments: as you look at the SARS-CoV-2’s ability to remain airborne consider door handles harboring the virus for 2 days, tight quarters (elevators) and small rooms where a sneeze could leave virus aerosolized for hours.
Also of note: SARS-CoV-2 viral shedding lasted a mean of 20 days (longest 37 days) when measured in COVID-19 patients. This therapy can significantly reduce viral shedding.
Short take:
Aerosol (airborne): 3h
Copper: 4h
Plastics: 72h
Cardboard: 24h
Stainless Steel: 48h
4
COVID19 in children: 2 very recent papers
Dr. Albert Yan (Chief of Pediatric Dermatology Children’s Hospital of Philadelphia)
COVID in children, Dong et al.
In this large pediatric case series based in China that involved over 2100 children, several important observations were noted: 1 Kids generally have milder disease than adults with 90% having non-severe/critical disease- They got diagnosed quickly (median 2 days)
- Vulnerability to severe-critical disease was highest among infants with 10.6% of infants being so affected, with risk decreasing as age increased.
- About 4% of kids were asymptomatic but had detectable virus.
- The risk of severe-critical disease within the pediatric age group was 6% compared to 18.5% in adults, and there was only a single pediatric death in this large series. As to why kids are less severe than adult centers on the relative immaturity of ACE2 in children, which is presumed to be the cell-receptor for the virus based on its similarity to the previous SARS virus. This relative immaturity may make children less receptive hosts for the virus.
Take home points: • Kids with COVID19 are generally milder than adults but a significant subset can develop severe disease, especially infants. - Some of the reasons behind why kids are generally less severe may provide appropriate targets for identifying future therapies.
- It is also important to note that children on immunosuppressive medications and with predisposing medical issues are likely at higher risk.
Regarding Table 1 (Below): Additional pediatric data from a cohort of 171 children <10yo with confirmed SARS-CoV2 showed a surprisingly high rate of asymptomatic infection (16%). Of those infected there was a strikingly high proportion who developed pneumonia (65%). Between 76-90% had a relative with confirmed infection highlighting the likelihood of intra-familial spread.
J Peds
https://drive.google.com/file/d/1YdaGs9-lrV51sFrDYIY_QZrt5MsdKocv/view?usp=drivesdk
NEJM article March 18, 2020:
https://www.nejm.org/doi/full/10.1056/NEJMc2005073
5
MUST READ: The single BEST epidemiology modeling data based on Wuhan, Korea, Italy, Italy and endemic US. It is in summary form available updated 3/13.
Dr. Ted Rosen: This is an annotated comment on Puyeo article: This article is a long one, and a difficult read. Heavy on statistics, it's not the type of manuscript anyone likes to read. Take the time. Digest the message. It's simple: we are facing a crisis beyond compare in modern times. There are official COVID-19 cases reported daily which grossly underestimate the true number of cases, and many asymptomatic but infected individuals are unknowingly spreading the disease. Quickly. The overall death rate may be "only" 0.5-0.9%, but that depends upon availability of optimal health care. The latter will be impossible as the system is overwhelmed, and both personnel and equipment become scarce. The only real solution is a nearly universal and immediate lockdown. In effect, a virtual population-wide quarantine. Now.
https://medium.com/@tomaspueyo/coronavirus-act-today-or-people-will-die-f4d3d9cd99ca
6
Outcomes in the elderly in Italy
Dr. George Martin: Individuals over 70 yo infected with COVID19 had > 35% mortality. This group of patients, particularly those with co-morbidities (diabetes, heart, lung disease, etc) were most severely affected. The lack of available ICU beds in the many severely affected areas likely contributed very significantly to the high mortality rate.
https://drive.google.com/file/d/1ZWvzBgC_nuafFeMoLsfgy-kS0YJEgZwb/view?usp=drivesdk
7
- This week’s MMWR Report early release; Volume 69; March 18, 2020
Severe outcomes among patients with Coronavirus Disease 2019 (COVID-19) – United States, Feb 12-March 16, 2020 • 4,226 COVID-19 cases were reported in this time period in the US, excluding repatriated and cruise ship cases. - 31% of cases, 45% of hospitalizations , 53% of ICU admissions and 80% of deaths associated were among adults aged > 65 yrs.; those >85 yrs at particular risk.
This data generally mirrors that reported from Wuhan, China
Dr. Sheila Fallon-Friedlander’s Commentary
It is hard to believe that less than 2 months ago we were pondering “Where have all the Viruses gone?” at Maui Derm. We were also breathing a small sigh of relief that Zika, SARs and other pandemics we have previously seen did not prove prolonged nor significant risks.
At the January meeting we did discuss that Corona virus was looming, and that there was much we did not yet understand. Was transmission mainly droplet or aerosolized? Was it bats? Or bats and snakes?
We now know more, but not enough. Respiratory droplet spread definitely occurs, but unfortunately aerosolization (a riskier form of spread that may leave virus suspended in air for hours) likely plays a role. Thus staying away from each other is critical!
However, effective social distancing may require a level of discipline hard to come by for the American public. When my toddler granddaughter runs toward me, I want to hug her. Unfortunately her altruistic, health worker parents are on the front line of care and at risk for infection. Little Emmy may not get sick, but could easily transmit infection to her at-risk grandma. It takes all of my effort to refrain from grabbing her. I need to remember that we must “flatten the curve of infection” so that our health care system is more gradually—rather than acutely—taxed.
Amidst all these fears, there is some good news. The FDA’s approval of chloroquine and hydroxychloroquine for research and compassionate use identifies off-label options involving these two relatively innocuous drugs. Preliminary trials utilizing these antimalarials with azithromycin suggest that this combination therapy may provide even more hope. As Dr. Rosen points out, this does not diminish the importance of evaluation.
Dr. Yan’s comments regarding childhood disease are reassuring. Excluding neonates, this age group tends to do well. This may well be related to the immaturity of their pulmonary ACE inhibitors. However, we do not yet know if they are carriers.
MMWR’s recent report also confirms that those less than 19 years of age are at low risk for disease, and that those >65 are at high risk. I think their findings substantiate a risk that has been downplayed previously: Yes, 80% of deaths have occurred in those >65, but that means that the 20% of deaths occur in those 20-64 years of age. We need to share that info with those found partying and ignoring social distancing protocols. Members of this age group must be aware they can get sick, and they can spread disease to others, even if they aren’t feeling so bad.
Global scientific ingenuity will lead us out of this. Until then, keep your distances and consider asking about anti-malarials and azithromycin should you or your patients contract this vexing virus!
8
- Remdesivir: Currently in phase 3 studies.
Remdesivir (RDV,GS-5734) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families including Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae, through the targeting of the viral RNA dependent RNA polymerase (RdRp).
Dr. George Martin: My understanding is that there is a fast track phase 3 trial of 1,000 patients here and in China. This is a therapeutic “game changer” based on its success when used in compassionate use outcomes in a limited number of people. It has a therapeutic window when used in the first 5-10 days before the cytokine storm sets in. Currently IL-6 inhibitor are being studied to attenuate the inflammatory response i.e. “cytokine storm” caused by the immune response in the lung to COVID19
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04302766
Contact: Sandi K. Parriot, 301-619-6824, sandi.k.parriott.mil@mail.mil
Ages Eligible for Study: Child, Adult, Older Adult
Sexes Eligible for study: All
Inclusion Criteria: • DoD-affiliated personnel (including active and reserve component service members, US civilian employees, contractors, other US personnel, and dependents of any age, as well as allied military forces and local nationals) who have been granted access to the medical facility - Have a COVID-19 diagnosis
•Available for clinical follow-up for duration of the treatment and follow-up period
Exclusion Criteria:
• Unable or unwilling to meet the requirements of the protocol
Sponsors/Collaborators: U.S. Army Medical Research and Development Command
Stay safe and God bless everyone
With aloha,
George
George Martin MD
Medical Director: Dr. George Martin Dermatology Associates
41 E. Lipoa St
Suite 21
Kihei, HI 96753
W. 808 875 0511
F. 808 875 8595
drmauiderm@gmail.com