Covid-19

The Chat

We had a #NephJC chat Tuesday March 17 at 9pm EDT and Wednesday March 18 at 9pm GMT and IST. This was a joint project with the ASN and we were joined by Drs. Alan Kliger and Jeffrey Silberzweig.

However this will be a topic which will be of interest for us for many days (Months? Years?) to come so the summary below is going to be much bigger, broader, and deeper than what we typically do for a typical NephJC chat. Additionally this page will continue to be updated to be kept current through this medical emergency.

Terminology

SARS-CoV-2: name of the virus, ie Severe Acute Respiratory Syndrome, CoronaVirus - 2

COVID-19: name of the disease, ie Corona Virus Infectious Disease 2019

As Dr Anthony Fauci said, this is similar to HIV (virus) and AIDS (disease)

This preprint covers the taxonomy for those interested in the fine print. 

FOAMed Resources

Nephrology FAQ

Vaccines

Good news: We have marvellously effective vaccines, way before anyone vaccinated.

Bad news: We don’t know if they work well in kidney disease. It seems two doses of the mRNA vaccines do stimulate a very good immune response in dialysis, but less so in transplant. There are caveats.

Read the full coverage for more.

Acute Kidney Injury

Read our deep dive for more on this topic

Brief points:

• The risk of AKI is 2-5% in certain papers, but as high as 20-40 % for hospitalized or critically ill patients, especially with data coming from UK and US. The definitions of AKI do vary, so see the deep dive for more on this

• The cause of AKI seems to be mostly acute tubular damage, however there is some intriguing data on the presence of the virus in the kidney, discussed at depth

• Treatment of AKI is the same as you would for any other AKI, but logistics, drug dosing need to be considered in detail

• Prepare for contingencies. Including detailed discussion on dialysis machine and supply shortages and acute PD:

COVID-19 and Hypertension; ACE2 involvement

See separate blog for more detailed discussion of this fascinating and confusing topic.

What is ACE2 anyway?

See figure below. ACE2 is different from ACE (the latter is inhibited by…you guessed it, ACE inhibitors). ACE2 is also not the same as the AT2 receptor (which is also different than the AT1 receptor which is blocked by ARBs).

If the previous two sentences are confusing, just go ahead and skip to the end of this section. So far we don’t know that this matters. See this table as well. It may, or may not help.

Now… What in the world is the link between ACE2 and coronavirus?

Many coronaviruses, including the SARS-CoV-2, uses the ACE2 to enter cells. So if ACE2 levels are higher or lower in some individuals, then the severity of disease might be different. Animal and human data don’t actually paint such a clear picture. Go ahead and read the details.

Can ARB/ACEi use (and increased ACE2) actually be beneficial in coronavirus? Or harmful?

Not really.

We have no evidence to support this. For now, check out the carefully worded ESC statement that we wholeheartedly agree with. If you have hypertension, keep taking your meds, and don’t stop them .

What about hypertension and COVID-19 severity?

This data is also summarized in a separate blog post.

The TL; DR version is:

• Hypertension increases with age

• Older people seem to have more severe COVID-19 disease and worse outcomes

• So do hypertensive patients

What about the link between NSAIDs and COVID-19?

There are rumors floating around of patients being on NSAIDs having more severe disease compared to acetaminophen/paracetamol. The theory again follows an effect on ACE2. However, this is likely confounding since patients with more severe symptoms are likely to take NSAIDs (versus acetaminophen).

This excellent commentary from Garrett Fitzgerald discusses the pharmacology. See this excellent thread from David Juurlink for more:

Dialysis and CKD

See the link to the dedicated page for more information on COVID-19 prevention, management and logistical challenges for dialysis patients.

Brief Points:

• We don’t know the risk of COVID-19 in dialysis patients, for in-centre hemodialysis, coming in 3 times a week does seem to put them at high risk

• Many resources are available for attempting to reduce this risk to patients, including prescreening, and much more

• Pay attention to patients transportation needs

• Drug dosing (if any experimental drugs are started) is complicated

• Home dialysis remains a possiblility

• Prepare for contingencies

• Immunosuppression is tricky, check here for some advice:

Transplant

See the dedicated page for detailed FAQs for Patient and Professionals, with links to relevant sources.

Brief Points:

• The presumed risk of COVID-19 in kidney transplant recipients is high

• Pre-emptive decrease of immunosuppression seems unnecessary

• Many programs have or will be stopping most transplant surgeries, though this is a local decision based on extent of community spread and trade-offs

• For managing COVID-19 in the transplant recipient, the first step often is to stop the antiproliferative agent (azathioprine or mycophenolate). Then it gets complicated

• When using experimental therapies, beware of drug interactions, discussed here:

Drug dose considerations

These are discussed separately on the dedicated AKI, dialysis, and transplant pages.

Note on Hydroxychloroquine and Chloroquine

These drugs have leapfrogged from speculation into clinical use on the basis of one poorly done study (Gautret et al, Int J Antimicrobial Agents, 2020, PDF link) and social media virality. The study on which this is based is quite flawed: it was not a trial, patients on hydroxychloroquine who did poorly were excluded, the controls were not comparable and were from different centres, the outcomes were surrogate, the study was published in a journal where many authors are on the editorial board. For a detailed review, see this link (Dahly et al, 2020).

In a study by Jun (J Zhejiang Univ 2020) there was no difference in viral clearance between usual care and hydroxychloroquine (HCQ) 400 mg daily.

On day 7, COVID-19 nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). The median duration from hospitalization to virus nucleic acid negative conservation was 4 (1-9) days in HCQ group, which is comparable to that in the control group, 2 (1-4) days, (P>0.05)

Chen et al (medRxiv 2020) published a pre-print on a trial of hydroxychloroquine in patients with mild disease. As a demonstration of how hungry the world is for information of hydroxychloroquine and COVID-19 this pre-preint got coverage in the New York Times. The study showed a shortened duration of illness but suffers from numerous methodologic flaws. These are best outlined in this twitter thread:

Additionally, misuse of these drugs will (has already) lead to a shortage of these lifesaving medicines for patients who need them (eg lupus, malaria). Read a statement from the COVID-19 Global Rheumatology Alliance for a discussion of these issues (Kim et al, Annals IM 2020).

Are these drugs dangerous? They can cause prolongation of the QT interval. This risk is higher with other concomitant drugs that have an effect on QTc (eg azithromycin) and with other electrolyte abnormalities. We are unfortunately sure to see some cases of poisoning with these drugs as well. For an overview of that, see Leon Gussow’s post, as well as a deep dive from Annie Arens, Jon Cole, and Justin Corcoran here.

Lastly, despite these drugs being shown to kill the virus in vitro they may not really work in humans. A large trial done in influenza showed precisely that (Paton et al, Lancet Inf Dis, 2011). There has been a similar experience with chloroquine and dengue and chikungunya, as mentioned in this article in Science, which reviews the clinical trials being started by the WHO.

Might these drugs really work in COVID-19? They might, but they have known toxicity and unknown efficacy, as of the time of this writing.

• Also listen to a 15 minute clip of David Juurlink with JAMA (released March 25)

• Nice summary of the hydroxychloroquine knowledge by Raghu Chivukula, MD, PhD.

Update Aug 4

Since the time of this writing, many trials have now been completed. All of them are negative. Lets put this to rest. Read an excellent review of this on Medscape by Perry Wilson, see the table below, or chec kout the video embedded below that. Enough with HCQ.

Transmission

Update April 20, 2021

The aerosol argument is accepted widely. See this Lancet paper (Greenhalgh et al, Lancet 2021) that discusses this in detail.

Our 2020 summary (now out of date) follows

The WHO and CDC both take the position that SARS-CoV2 is transmitted by respiratory droplets and contact with contaminated surfaces. Resipiratory droplets have a range of 3 feet (1 meter). Here is the statement from the WHO website:

Droplet transmission occurs when a person is in in close contact (within 1 m) with someone who has respiratory symptoms (e.g. coughing or sneezing,) and is therefore at risk of having his/her mucosae (mouth and nose) or conjunctiva (eyes) exposed to potentially infective respiratory droplets (which are generally considered to be > 5-10 μm in diameter). Droplet transmission may also occur through fomites in the immediate environment around the infected person.7 Therefore, transmission of the COVID-19 virus can occur by direct contact with infected people and indirect contact with surfaces in the immediate environment or with objects used on the infected person (e.g. stethoscope or thermometer).

The CDC has a bit more nuance in their recommendation:

Early reports suggest person-to-person transmission most commonly happens during close exposure to a person infected with COVID-19, primarily via respiratory droplets produced when the infected person coughs or sneezes. Droplets can land in the mouths, noses, or eyes of people who are nearby or possibly be inhaled into the lungs of those within close proximity. The contribution of small respirable particles, sometimes called aerosols or droplet nuclei, to close proximity transmission is currently uncertain. However, airborne transmission from person-to-person over long distances is unlikely.

(Emphasis added by the editors of NephJC)

Additionally some procedures generate aerosolized SARS-CoV2 particles and additional protection should be used during these procedures:

• Endotracheal intubation

• Bronchoscopy

• Open suctioning

• Administration of nebulized treatment

• Manual ventilation before intubation

• Turning the patient to the prone position

• Disconnecting the patient from the ventilator

• Non-invasive positive-pressure ventilation

• Tracheostomy

• Cardiopulmonary resuscitation

SARS-CoV2 RNA has been isolated from the stool so there is potential of fecal-oral route transmission but this has not been documented.

Santarpia et al. (medRxiv 2020) documented their experience looking for viral RNA in rooms occupied by patients with confirmed COVID-19. They were able to find it on personal items including cell phones, remote controls and grooming items. More concerning was finding viral RNA on surfaces that patients did not touch including elevated window frames and underneath the bed. This indicates aerosol transmission. Additionally they tested the air and found viral RNA though they were not able to confirm intact, infectious virus.

Cheng et al (Infect Control Hosp Epidemiol 2020) was unable to find SARS-CoV2 in 8 air samples collected at a distance of 10 cm from a patient's chin with or without a surgical mask. Similarly Ong et al (JAMA 2020) was unable to find virus in air samples from heavily contaminated rooms.

Currently the CDC does not recommend wearing masks while out in public but they are re-evaluating that position and this could change. From the New York Times:

In recent days, an assortment of scientists, health experts, pundits and influencers has vigorously advanced their position that everyone venturing into public or crowded places should wear a mask or face shield — even a homemade one — to lower the rate of transmission of covid-19, the disease caused by the coronavirus.

Thomas Inglesby, director of the Johns Hopkins Center for Health Security, said in an interview the CDC should urge people to use nonmedical masks or face coverings.

“I think it would be a prudent step we can all take to reduce transmission” by people who are infected but have no symptoms, he said. DIY coverings — like the ones his children just fashioned from old clothes for his family — aren’t perfect and should not be used as an excuse to stop social distancing, he said.

This long piece covers both sides of the debate and the changing recommendations very well (Ed Yong, The Atlantic, 2020).

List of updates

(we are keeping track of updates from March 21st onwards in this list)

• March 21: Shortened AKI section, moved to dedicated AKI page

• March 23 11:00: Section on Hydroxychloroquine and Chloroquine added

• March 23 21:50: Links to DoD protocol and Gautret study added

• March 24 17:00: Dialysis section shortened with link to dedicated page; addition of QTc issue with CQ/HCQ

• March 25: Our World in Data link changed; David Juurlink interview link and Leon Gussow’s EM News post added

• March 26: Link to ‘Everything is Osm’ deep dive into chloroquine and hydroxychloroquine toxicity added

• March 29 Additional podcasts and added section on transmission.

• March 31: Shortened Transplantation section with link to dedicated page; Added link to statement by Kim et al in Annals IM

• April 2: April 2: Added coverage of the Chen trial of hydroxychloroquine in mild COVID-19 and the possibility of people wearing masks when they are in public.

• May 21: Added embedded charts from Our World in Data

• Aug 5: Updated hydroxychloroquine data

• April 20, 2021: World In data chart embed changed; Aerosol transmission link added; link to Vaccine article added

Summary curated by Matt Sparks, Joel Topf & Swapnil Hiremath