**Updates on 03/28/20**

Please see this article by Devaux et al entitled “New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?” It contains excellent text and image explanations behind the multiple proposed antiviral mechanisms of action behind hydroxychloroquine & chloroquine.

French physician Didier Raoult and his colleagues have followed up with another larger study entitled “Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study.”
”A rapid fall of nasopharyngeal viral load tested by qPCR was noted, with 83% negative at Day 7, and 93% at Day 8. Virus cultures from patient respiratory samples were negative in 97.5% patients at Day5. This allowed patients to rapidly discharge from highly contagious wards with a mean length of stay of five days. We believe other teams should urgently evaluate this cost-effective therapeutic strategy, to both avoid the spread of the disease and treat patients as soon as possible before severe respiratory irreversible complications take hold.”

**Updates on 03/23/20** (See below for the original post - which now contains updated information as well.)

Treatment: As of 03/23/2020 the CDC has now updated their treatment guidance as well. “Although optimal dosing and duration of hydroxychloroquine for treatment of COVID-19 are unknown, some U.S. clinicians have reported anecdotally different hydroxychloroquine dosing such as: 400mg BID on day one, then daily for 5 days; 400 mg BID on day one, then 200mg BID for 4 days; 600 mg BID on day one, then 400mg daily on days 2-5.”

Prophylaxis: India has recommended that “asymptomatic healthcare workers involved in the care of suspected or confirmed cases of COVID-19: 400mg twice a day on Day 1, followed by 400mg once weekly for the next 7 weeks; to be taken with meals. Asymptomatic household contacts of laboratory confirmed cases: 400mg twice a day on Day 1, followed by 400mg once weekly for the next three weeks, to be taken with meals. The drug is not recommended for prophylaxis in children under 15 years of age. The drug is contraindicated in persons with known case of retinopathy.” This is also mentioned in this news story.

Telemedicine: The FSMB has provided this summary document about waived licensure rules related to COVID-19. More FSMB details are available here. The AMA has this quick guide to implementing telemedicine in your practice.

Clinical characteristics of hospitalized patients with SARS‐CoV‐2 infection: A single arm meta‐analysis, a study by Sun, P et al shows that, among these patients, the incidence of:
- fever was 0.891 (95% CI: 0.818, 0.945)
- cough was 0.722 (95% CI: 0.657, 0.782)
- muscle soreness or fatigue was 0.425 (95% CI: 0.213, 0.652)
- acute respiratory distress syndrome (ARDS) was 0.148 (95% CI: 0.046, 0.296)
- abnormal chest computer tomography (CT) was 0.966 (95% CI: 0.921, 0.993)
- the percentage of severe cases in all infected cases was 0.181 (95% CI: 0.127, 0.243)
- fatality rate of patients with SARS‐CoV‐2 infection was 0.043 (95% CI: 0.027, 0.061)
If you cannot get any testing done and need a rapid answer due to respiratory distress then the ER will likely want to perform a chest CT and treat you based on those results since 97% of patients with COVID-19 will have an abnormal chest CT. Young patients are not immune to worsening pulmonary function.

Original Post Follows:

Hello everyone,

I don’t know where to begin, so I’ll start with a quote and end with a quote. The first one comes from the evil Gordon Gekko played by Michael Douglas in the movie Wall Street - “the most valuable commodity I know of is information.”

Information is moving quickly on all fronts. By the time you are reading this blog post it may already be out of date, and I may not have the time to update it due to other obligations. We do indeed find ourselves in a crisis causing exponential deaths worldwide (if we were to do nothing there would be an estimated 10 million dead in the US - according to an excellent Medium article by Tomas Pueyo about the concept of “Hammer and Dance” viral suppression). This Flowing Data example demonstrates how the curves can change with various actions. You can use this predictor to see when the peak patient volumes are expected for your area.

Some upfront information that may be helpful: Here are links to handouts I drafted at Proactive MD (for patients and for employers). Here is a checklist from AAFP for COVID-19 (also see the AAFP’s overview page). This ACEP page on COVID-19 and this NCCHC Covid-19 page are both worth following as well.

Physicians are being hit hard by this virus as well, even those that know everything there is to know about PPE and are not at high risk based on their age. There are national PPE shortages and debates about how effective our current PPE protocols are in the first place. I gave a talk with Hint Health on 03/19/2020 about COVID-19. I do not spend time in the ICU these days, so my resources are all outpatient focused, but I will link to this comprehensive Chinese inpatient COVID-19 treatment guide that some people may find helpful (especially regarding more effective PPE guidelines).

The ideas that follow are my own, and mine alone. They do not necessarily reflect the views of any of my employers or organizations to which I am a member. I am sure they are controversial. I am making an effort to summarize all these resources in one place. Review the cited links and make up your own mind. This is a long post. Patients reading this post will likely want to skip the next “Policy / Law Changes” section which was written for a physician audience and jump to the section titled “Stay Home.” Here we go…

Policy / Law Changes

HHS Section 1135 Waivers and CMS Blanket Waivers were passed initially for a 60 day time period starting on 03/15/2020. The HHS Secretary may keep extending in 60 day blocks if needed.

Many DPC physicians "opted out" of Medicare so that they could privately contract with Medicare patients for covered services. If you are in this group you may want to read the March 13th Waiver letter. It states that "Pursuant to Section 1135(b) of the Social Security Act (the Act) (42 U.S.C. § 1320b-5), I, Alex M. Azar II, Secretary of Health and Human Services, hereby waive or modify... to the extent necessary, as determined by the Centers for Medicare & Medicaid Services... Certain conditions of participation, certification requirements, program participation or similar requirements for individual health care providers or types of health care providers, including as applicable, a hospital or other provider of services, a physician or other health care practitioner or professional, a health care facility..."

By my reading of this letter CMS now has the authority to permit Medicare "opted out" physicians to cover shifts in hospitals as hospitalists and in other standard arrangements without fear of the hospital not receiving reimbursement for these services. I have emailed CMS asking them to clarify this question or (even better) point me to an online resource that makes it clear that CMS is permitting "opted out" physicians to see Medicare patients in the traditional manner (if desired) during this national emergency but I have yet to receive a response. Over one week later CMS has not replied to my email inquiry, but they do have this overview page up with many COVID-19 updates along with these two summary documents:

Physicians and Other Clinicians: CMS Flexibilities to Fight COVID-19
COVID-19 Emergency Declaration Blanket Waivers for Health Care Providers

Note that under the provider enrollment category they will now “Allow opted-out physicians and non-physician practitioners to terminate their opt-out status early and enroll in Medicare to provide care to more patients.” This does not answer the question that most opted out physicians would like to have answered though.

EMTALA sanctions have been waived so that ERs are no longer required to screen every (COVID-19) patient that arrives at their doors. Simply allowing these patients in an overflowing facility could worsen the disease burden for other patients and there is an expectation that many hospitals may run out of inpatient beds and even ER beds / triage space.

Telemedicine – the flood gates have been opened here in many ways. Medicare will now pay for these visits and allow you to waive patient co-pays even if you are still participating in Medicare. If you do not want to use a free option such as Hale or Spruce you are actually permitted to use Skype or a similar unsecure format without HIPAA concerns at this time. Medicare beneficiaries can now receive telehealth from home (historically they needed to live in a rural area and drive to a local clinic to do telehealth with another physician). According to CMS “clinicians can bill immediately for dates of service starting March 6, 2020. Telehealth services are paid under the Physician Fee Schedule at the same amount as in-person services. Medicare coinsurance and deductible still apply for these services. Additionally, the HHS Office of Inspector General (OIG) is providing flexibility for healthcare providers to reduce or waive cost-sharing for telehealth visits paid by federal healthcare programs. No federal approval is needed for state Medicaid programs to reimburse providers for telehealth services in the same manner or at the same rate that states pay for face-to-face services.”

President Trump attempted to waive state licensure requirements, but he does not have authority to take this action. This is a state law issue (not federal). Many states are taking action. Colorado is one example, and others are being linked and aggregated by the National Law Review and by this Morgan Lewis article. An interstate compact license does not change this analysis. I do not recommend pursuing an interstate compact license for reasons that are outside the scope of this blog post.

The current Senate version of the ‘‘Coronavirus Aid, Relief, and Economic Security Act’’ or the ‘‘CARES Act” includes the language from the prior Primary Care Enhancement Act that was passed by the house last year. See Section 4403 Treatment of Direct Primary Care Service Arrangements page 171-175. I support this legislation and I have explained why in prior posts. If you don’t like portions of the bill, then lobby to make additional corrections later. Bank the good parts of this bill, and work to make any lingering obstacles disappear in future years. If you expected the IRS to suddenly change their mind on this issue by last December due to presidential attention… then you might be waiting a long time. If this language is passed it will end the HSA debates that have limited wider adoption of DPC by employers for 99% of DPC practices. (It also solves any HRA and FSA confusion too.)

STAY HOME

First – make sure you and your patients get the message to “stay home.” If you are going out to do ANYTHING social in a large group – you are probably making a mistake. Do not let your “normalcy bias” fool you. No one alive today has ever seen this exact virus, and much information remains unknown. I’ve summarized some basic information for patients here. Droplet precautions are not enough. Airborne precautions need to be taken. Know the difference between a quarantine and social distancing. Understand that a quarantine causes only a brief delay in spread and that social distancing is a REQUIREMENT to actually limit disease incidence in the originally unaffected population because quarantines ultimately fail over time (i.e. - we halted all travel to China and the virus still made it to the USA).

When large groups of people ignore suggestions to self-isolate and stay home, it results in state wide quarantines. Quarantines are drastic, disruptive, fear-engendering (this is why you cannot buy toilet paper or groceries) and less effective than social distancing. See this Washington Post explanation of why social distancing (including excellent visual examples) is the only option with great long term effect. When we (as individual citizens) act irrationally and fail to socially distance the government reacts by trying to force ever narrower (and much more disruptive) quarantines. Governors make efforts to close businesses state wide (Wyoming is generally prohibiting gatherings of more than ten people) and the CDC makes recommendations to end all meetings of more than fifty people for eight weeks. The more successful your country is at social distancing, the longer you are obligated to do it (until you come up with a treatment or vaccine), and the more lives you will save.

If you believe you are at low risk based on any number of assumptions (based on your age, lack of chronic conditions, your O blood type rather than A blood type - who knows the truth at this stage?) and believe that this social distancing recommendation does not apply to you, then I have two comments: 1) if you are right about your low risk then your decision to not to socially distance is merely selfish – you could still be an asymptomatic spreader (for up to 37 days), and 2) there is a good chance your assessment of your own risk is inaccurate (maybe you smoke tobacco or take immunosuppressive medications), and then your decision becomes medically foolish as well.

Social distancing means:

Don’t go out in public if not necessary. Don’t put your children in daycare. In fact, don’t let them play with any large groups. Keep the young away from the elderly– there are many young asymptomatic spreaders. If you are “going out” then it should be for: 1) critical work that could not be done from home, 2) obtaining medications, 3) food, etc. Going out for a study group, a church worship service, a library meeting, a yoga class, etc are unwise moves. Meet remotely with your groups online using resources such as zoom.

Washing your hands and not touching your face are important steps, but I believe that this virus is airborne. Why do I believe this is airborne (when the CDC simply states droplet precautions are all that are required)?
1) Symptomatic patients often had a dry cough, and are not even sneezing - where are the droplets?
2) There are lots of asymptomatic spreaders - no coughing or sneezing at all - where are the droplets?
3) In China healthcare workers dress like this (scroll to the 4th picture), so I don’t think we should promote obtaining nasopharyngeal samples from patients with a simple surgical mask - this weaker PPE effort is not going to cut it. Many US physicians feel disposable and plan to quit medicine.

MEDICAL DISCUSSION

This virus tends to cause fever, cough, and shortness of breath – often in that order. Here is a discussion of the most common clinical characteristics - your diarrhea is more likely you being nervous than an initial presentation of COVID-19. It may cause a lost sense of smell, sometimes in the absence of any other symptoms. The fever might last one week before the shortness of breath begins, and I have read reports that the shortness of breath can progress and be fatal fairly quickly (consistent with prior SARS infections). Consider these COVID-19 chest CT images from Radiopaedia (you don’t need a medical degree to note the ground glass opacifications). Those that need hospitalization and survive often leave with chronic lung disease. Some suspect that asymptomatic patients have lung changes (that may be permanent) as well. Assuming there were no supply shortages and based on my own interpretation of the medical literature so far I might do the following:

Easy (low risk) steps:

1) Everyone should take vitamin C - maybe 500mg PO TID. This might help your immune system fight the virus. It is water soluble. Very low risk (though high doses can increase susceptible individuals to kidney stone formation). If this medication is useless, why was 50 tons of Vitamin C shipped to Wuhan?
2) Everyone should take vitamin D 5,000 IUs daily. This might decrease your chance of getting a more severe infection. This is a fat soluble vitamin, meaning that overdoses are possible, but doses under 10,000 IUs daily have not lead to documented overdose issues.
3) Zinc might be beneficial to the immune system as well (usually between 20 to 50 mg daily)

Controversial steps:

4) According to the American College of Cardiology “Angiotensin converting enzyme 2 (ACE2) receptors have been shown to be the entry point into human cells for SARS-CoV-2, the virus that causes COVID-19. In a few experimental studies with animal models, both angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression in the heart.” Smoking increases ACE2 receptors in the lungs and this is one of the theories why so many more Chinese men were affected than women (since 54% Chinese men smoke compared to 3% of Chinese women). There is no consensus yet whether an ACE or ARB increases your COVID-19 risk, but if you simply want to control your blood pressure, you might consider a different hypertensive option in the short term. COVID-19 has a twenty fold higher affinity for the ACE2 receptor compared to similar MERS virus from a few years ago (explaining in part why this virus spreads so easily).

5) Consider avoiding ibuprofen in the event you have a fever. Acetaminophen may be safer. Your fever may help you fight the virus, and taking ibuprofen also interferes with your ability to know whether your condition is worsening or improving. Lack of a fever might discourage you from isolating yourself.

6) Consider whether you would want to take hydroxychloroquine for treatment and/or prevention purposes (more on this below). You will need to review the research in this area and make a calculated risk vs benefit decision. I believe that the benefits outweigh the risks for using this medication for both treatment and prophylaxis at this time.

Desperate Steps:

I could not find any published evidence behind these claims, but I mention them here in the interest of full disclosure. Some researchers argue that the sinuses are the main reservoir for the virus, and that these viruses can be destroyed with heat, but this is unclear. This video explains ways that you might try to heat your sinuses on a serial basis to decrease viral load within the sinuses - again - I make no endorsements of this approach. This New York Times article explains why doing these things is likely a waste of your time. This presentation from Dr. Lee Hieb Merritt made some interesting arguments about the possible origins of the virus, and other steps you could consider. I’m not endorsing any of these claims at this time beyond what I have already described elsewhere in this blog post.

Hydroxychloroquine Background Facts

Onset: May take 4-6 months to show response for many autoimmune conditions
Half-life: 32-50 days

The medication has many potential proposed mechanisms of action for autoimmune diseases. It impairs complement-dependent antigen-antibody reactions; inhibits locomotion of neutrophils and chemotaxis of eosinophils. Increases pH and interferes with lysosomal degradation of hemoglobin, which in turn interferes with digestive vacuole function.

The dose for lupus, rheumatoid arthritis, and other autoimmune conditions is typically 200-400mg daily (COVID-19 treatment doses have been in this ballpark as well, often with a loading dose.)
A periodic CBC is helpful if used chronically, but not required
Typically discontinue in six months if improvement in the condition is inadequate
It can prolong the QT interval (thus be careful when combining it with azithromycin - though chloroquine and azithromycin have been used together in the past)
It can lower HgA1cs and there are documented cases of hypoglycemia
It can cause skeletal muscle myopathy or neuropathy
Limit use of this medication in those with G6PD Deficiency
It can make you sun sensitive
You should not consume alcohol while taking it

Ocular examination is recommended within first year of therapy (if taken chronically); baseline exam should include: best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain ocular coherence tomography (SD-OCT)

Irreversible retinal damage was observed in some patients who had received hydroxychloroquine sulfate; significant risk factors for retinal damage include daily doses of hydroxychloroquine sulfate greater than 6.5 mg/kg (5 mg/kg base) of actual body weight, durations of use greater than five years, subnormal glomerular filtration, use of some concomitant drug products such as tamoxifen citrate and concurrent macular disease

Hydroxychloroquine Research Resources

Hydroxychloroquine is one of several medications (according to Medscape) receiving lots of research attention, and I believe it is the medication that deserves the most attention overall due to safety, cost, ease of use (PO form), ability for multiple pharmaceutical companies to mass produce it, and very promising early data. Why did hydroxychloroquine start to get my attention last week? I paid attention to the serendipitous observations of other physicians, and then began to research the academic literature.

Sub-Saharan Africans routinely take chloroquine (for malarial purposes), according to this NEJM article historically “Chloroquine was widely available in both public and private sectors, and it was used in industrial quantities; hundreds of metric tons were consumed each year.” Use has decreased due to malarial resistance, but many countries continue to widely use chloroquine. Take a look at this incidence map from Johns Hopkins. Did you notice the dearth of cases in Sub-Saharan Africa? Does the warm weather help? Maybe. Is it a lack of testing, reporting, travel? Maybe. Does the broad chloroquine use make a difference? Possibly.

If you maintain a healthy skepticism and want to review the data on your own (and you should)…

1) Start by reviewing some history of hydroxychlorquine’s antiviral properties (there were many HIV related research efforts in the 1990s). The working theory is that the medication will alkalinize the viral acidic vesicles and inhibit RNA protease and other mechanisms to inhibit COVID-19 replication. In other words, it alters the acidity of the intracellular compartment and interferes with the viruses ability to escape the cell and replicate. Consider this 2007 summary article entitled “Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century.” According to this review (see table 1) hydroxychloroquine has been used to treat 14 different bacteria, 5 different fungi, and 29 different viruses.

See this 2003 Lancet Study entitled “Effects of chloroquine on viral infections: an old drug against today's diseases.” Recall that SARS was also caused by a coronavirus strain and that “Recent studies support the idea that coronaviridae infect their target cells by an endocytic pathway and that chloroquine might inhibit their replication. Preliminary data obtained from our group confirm these reports and show that chloroquine potently inhibits the replication of a canine coronavirus at therapeutically reachable concentrations. The anti-inflammatory properties of chloroquine/hydroxychloroquine should also be considered. The clinical worsening of individuals with SARS in week 2 is apparently unrelated to uncontrolled SARS coronavirus replication but may be related to immunopathological damage.”

2) Then review some in vitro studies

3) Then consider some additional background studies

A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19

COVID-19: combining antiviral and anti-inflammatory treatments

Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Chloroquine and hydroxychloroquine as available weapons to fight COVID-19

Discovering drugs to treat coronavirus disease 2019 (COVID-19)

4) Read this small French Study (Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial) - This group noticed that some Chinese researchers recommended 500mg of chloroquine twice daily for ten days. Their primary endpoint was virological clearance at day six post-inclusion in the study. Did this study have some flaws?

Yes it was small = 48 patients = 24 treatment (average age 51) & 24 controls (average age 37).
Yes it was not blinded.
Yes the group relied on nasopharygeal swabs (historically not an excellent test).
Yes 6 out of 24 treatment patients were lost to follow up because of early treatment cessation (and one of these patients did die on what would have been day #3 of treatment in the ICU - weirdly after testing PCR-negative on day 2 via nasal swab - meaning we either have an inaccurate swab (most likely) or the treatment worked quickly but was still too late for this patient to recover due to altered pulmonary function).

Of the remaining 18 patients, 16% of patients were asymptomatic, 61% had upper respiratory tract symptoms (URTI), 22% had lower respiratory tract symptoms (LRTI) - and all of these lower respiratory tract patients had confirmed pneumonia on chest CT scan.

The researchers concluded that the “[d]rug effect was significantly higher in patients with symptoms of URTI and LRTI, as compared to asymptomatic patients with p < 0.05.” Six patients ultimately received azithromycin as well, which seemed to boost the effect of the hyroxychloroquine. “We show here that hydroxychloroquine is efficient in clearing viral nasopharyngeal carriage of SARS-CoV-2 in COVID-19 patients in only three to six days, in most patients. A significant difference was observed between hydroxychloroquine-treated patients and controls starting even on day 3 post-inclusion. These results are of great importance because a recent paper has shown that the mean duration of viral shedding in patients suffering from COVID-19 in China was 20 days (37 days for the longest duration).”
Only 10% of the controls were negative on day six.
57% of the hydroxychloroquine only treatment arm patients were negative by day six.
100% of the hydroxychloroquine + azithromycin patients were negative by day six.

Dr. Raoult’s office (the French study author) put out this statement and is now following this protocol:

Hydroxychloroquine (200 mg x 3 tabs per day for 10 days) + Azithromycin (500 mg on the 1st day then 250 mg per day for 5 more days), as part of the precautions for use of this combination (with in particular an electrocardiogram on D0 and D2). In cases of severe pneumonia, a broad-spectrum antibiotic is also used.

As of 03/23/2020 the CDC has now updated their treatment guidance as well. “Although optimal dosing and duration of hydroxychloroquine for treatment of COVID-19 are unknown, some U.S. clinicians have reported anecdotally different hydroxychloroquine dosing such as: 400mg BID on day one, then daily for 5 days; 400 mg BID on day one, then 200mg BID for 4 days; 600 mg BID on day one, then 400mg daily on days 2-5.”

5) Then consider some current trials (here for treatment and here for prophylaxis). Many countries, including Belgium are already including hydroxychloroquine in their treatment protocols. Please see this Interim Clinical Guidance for Patients Suspected of/confirmed with COVID-19 in Belgium document. Northwestern University is treating patients with hydroxychloroquine as well.

Teva, Mylan, Novartis, and Bayer are all mass manufacturing hydroxychloroquine. Bayer and Novartis already have already made more tablets available. Mylan and Teva have started production as well. Fortunately the chemical formula for this medication is fairly straightforward. “The pledges from Novartis, Mylan and Teva follow Bayer's Thursday donation of 3 million tablets. Together, the commitments represent nearly 200 million chloroquine and hydroxychloroquine tablets for the global COVID-19 response.”

So… for my fellow physicians reading this post. I have great optimism that we will find our way out of this crisis with widespread social distancing and hydroxychloroquine prescriptions. This solution sounds like it will be much faster than waiting on a vaccine that could take years to develop.

If you made it this far I have two questions:

1) Are any of you treating autoimmune patients that were already taking hydroxychloroquine? Have any of these same patients been diagnosed with COVID-19? Could we all put together our own DPC-wide retrospective study? Please comment below!

2) Has your state waived any aspects of your licensure laws due to the national emergency? Maybe allowing for easy telemedicine with any state license? Are you doing extra telemedicine work? Please comment below!

I’ll end with a final quote: As Sir William Osler once said in a 05/23/1896 JAMA article “Humanity has but three great enemies: fever, famine and war; of these by far the greatest, by far the most terrible, is fever.”