AAPS News March 2020: A Viral Black Swan

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Volume 76, no. 3  March 2020

At the time of this writing, the outcome of the novel coronavirus pandemic is unknown, but certain lessons are apparent. One of the main advantages we have now compared to the time  of the 1918 influenza pandemic—the capacity for rapid worldwide “viral” communication—is being hampered by government and its private partners. The pretext is to protect us against misinformation or, especially in China, “social instability.”

The first cases of an unusually lethal infection were recognized by physicians. A solo, horse-and-buggy physician in Kansas, Dr. Loring Miner, recognized the outbreak very early and did all he could to sound the alarm, according to John Barry in The Great Influenza: The Epic Story of the Deadliest Plague in History (reviewed at tinyurl.com/ton84br). The Chinese ophthalmologist who first notified colleagues of the outbreak, Dr. Li Wenliang, has died of COVID-19 at age 33. The U.S. Public Health Service ignored Dr. Miner; the Chinese Communist authorities arrested Dr. Li.

News from China has been tightly controlled, but reports of brutally repressive quarantine measures have leaked. It is impossible to calculate the mortality rate without knowing the number infected or the number of deaths: only “confirmed” cases are counted. Testing is limited, and reportedly the bodies of undiagnosed patients were simply sent to continuously operating crematoria. In the U.S., unauthorized information about COVID-19, like reports of vaccine adverse reactions (AAPS News, February 2020) may be quickly deplatformed by technology giants.

Censorship also fuels distrust and  panic.

Testing

Now that private laboratories and academic medical centers are finally being permitted to test patients whose physicians believe the test is warranted, the degree of community spread within the  U.S. may be possible to determine. Before this, only 500 U.S. patients had been tested, virtually all of whom had had recent contacts from China, and initially all specimens had to be sent to Atlanta. Sophisticated laboratories are capable of modifying existing protocols for the new virus, but they could lose the license required by the Clinical Laboratory Improvement Act (CLIA) if they did so. Test kits need to be approved by the Food and Drug Administration, a process that can take weeks (tinyurl.com/slszst6).

The initial CDC kits were defective and had to be withdrawn. Ironically, the inaccurate cytologies (Pap smears) that prompted CLIA’s control of all clinical lab testing in the U.S. were done in government laboratories.

Meanwhile, other nations are testing extensively. South Korea has 500 test sites, which have screened 100,000 people. The number of confirmed cases surged from 31 to more than 4,200 in two weeks. Some sites offer drive-through testing; one reportedly tested 384 people in one day. People have specimens taken, by workers in protective gear, without leaving their cars.

Only persons with a probable exposure are tested (tinyurl.com/rxfmdju). As with all diagnostic tests, the predictive value of a positive test is lower in low-risk persons. Both false positives and false negatives occur, and the test will take some time to convert in an infected patient.

Prevention and Treatment

Official sources—AMA, CDC, and WHO—publish frequent updates (see https://tinyurl.com/tmw45r7). Most information  on prevention is equally applicable to other infections such as influenza: e.g. frequent hand-washing. Masks are recommended (required in China), but how well do they work? Regular surgical masks limit spraying of droplets, so patients should surely be masked. These will not filter out tiny aerosolized virus particles; N95 masks with a good fit to prevent leakage around the edges are needed. One study showed no significant difference in the incidence of confirmed influenza or acute respiratory illness in outpatient medical personnel using medical or N95 masks. The incidence of influenza was about 7–8% per season (https://tinyurl.com/tykt762). Participants were not using eye protection.

Masks are in short supply. HHS Secretary Azar Health and Human Services Secretary Alex Azar said last week that the U.S. has a stockpile of 30 million N95 masks but needs at least 270 million more for medical workers alone to prepare for a more widespread outbreak (https://tinyurl.com/t2c6dq6).

The U.S. outsourced most of its mask manufacturing to China (https://tinyurl.com/soetwt2), along with its ability to make ascorbic acid, penicillin, and most other prescription or over-the-counter drugs (https://tinyurl.com/vxuek9m).

Researchers are working feverishly on a vaccine and on drugs that might specifically fight COVID-19. One proposed approach is to focus on the angiotensin converting enzyme 2 (ACE2) receptor that serves as the viral entry point in lungs and kidneys. No, ARB antihypertensives don’t work and may be detrimental by increasing the number of receptors (tinyurl.com/tfpcxdx).

Meanwhile, 50 tons of vitamin C has been shipped to Wuhan, and Chinese doctors are studying intravenous doses of 24 g/day for 7 days. Information on vitamin C is apparently absent from official websites, and a 10-minute video was scrubbed from Facebook (https://tinyurl.com/r5fsf4w).

The economic Black Swan effect (see p 2) is likely to be disastrous, even if the worst-case scenario of millions of deaths from respiratory or other organ failure does not materialize.


Resources

Registry of clinical trials: https://tinyurl.com/uxoftaz.

News, commentary: from Physicians for Civil Defense: https://tinyurl.com/u6uoyhz.

Self-help: Three Seconds until Midnight by Steven Hatfill, M.D, et al. provides on-line references for home care of contagious patients: https://tinyurl.com/sna8g2n and https://tinyurl.com/s3wugbm. According to Dr. Hatfill, U.S. pandemic preparedness is hardly better than in 1918, despite government expenditures of $80 billion for this purpose.

Live dashboard from Johns Hopkins: tinyurl.com/uwns6z5.

Expiration Dates

Some U.S. stockpiles on N95 masks are beyond their expiration dates. CDC reports that many models continue to perform to NIOSH standards (https://tinyurl.com/sn8rqsz).

The expiration date on the ReadiMask N99 combined eye shield and respirator is said to apply to the adhesive—which apparently still works fine. These masks are primarily designed for law enforcement and also protect against pepper spray and tear gas (https://tinyurl.com/rhrrfzr).

Expiration dates on drugs indicate that date at which the manufacturer can still guarantee full potency and safety. The military found that 90% of more than 100 drugs were good to use even 15 years after their expiration date. Exceptions include insulin, nitroglycerin, and liquid antibiotics. Some say expired tetracycline may be unsafe, but this is contested (tinyurl.com/y7geve67).

Before discarding drugs, consider that replacements may be unavailable for quite some time.


Previously Approved Drugs

Chloroquine and the anti-HIV combination of lopinavir and ritonavir are under investigation in China as potential COVID-19 therapeutics and could be rapidly employed off-label. Results from 100 patients have shown sufficient efficacy and safety that chloroquine will be included in the next version of Chinese guidelines (tinyurl.com/uxe6dye). A Chinese expert consensus document is available (tinyurl.com/vdfmzo3)—retrieve the full text and use Google translate. Hydrochloroquine (Plaquenil) might be effective and more available (tinyurl.com/v43gmc6). Chlorpromazine and loperamide also inhibit MERS-CoV in vitro (tinyurl.com/t2kvoxk).

  The UK has placed export restrictions on chloroquine and lopinavir to prevent a potential shortage (tinyurl.com/rvmcha7). 


“For so it had come about, as indeed I and many men might have foreseen had not terror and disaster blinded our minds. These germs of disease have taken toll of humanity since the beginning of things–taken toll of our prehuman ancestors since life began here. But by virtue of this natural selection of our kind we have developed resisting power; to no germs do we succumb without a struggle, and to many—those that cause putrefaction in dead matter,… our living frames are altogether immune. But there are no bacteria in Mars…. By the toll of a billion deaths man has bought his birthright of the earth, and it is his against all comers; it would still be his were the Martians ten times as mighty as they are. For neither do men live nor die in vain.”

H.G. Wells, War of the Worlds


Ascorbic Acid

Since 1949, the use of high-dose intravenous vitamin C has been reported to be of benefit in many illnesses, including polio. The case of Allan Smith in New Zealand, who recovered from respiratory failure due to influenza, was featured on 60 Minutes  in October 2010. Vitamin C was tried as a last resort before his extra-corporeal membrane oxygenation (ECMO) was to be withdrawn because lung function was not recovering. When he began to improve, the vitamin C was withdrawn, and his family had to launch a legal battle to have it continued (tinyurl.com/tdsmg4e).

Vitamin C affects factors related to cytokine storm and vascular dysfunction, and is rapidly depleted in infections.

A randomized controlled study of “high-dose” (50 mg/kg or 3.5 g in a 70-kg patient q6h for 96 h) vitamin C in sepsis (JAMA 10/1/19) found that mortality was significantly less with treatment (29.8% vs 46.3%, hazard ratio 0.55), although all primary outcomes and most other secondary outcomes showed no difference. Pre-treatment plasma levels of vitamin C were low in all patients (they may be at near-scurvy levels in septic patients), and all were in an advanced stage of sepsis.  Although the JAMA article and editorial concluded that “further evaluation seems warranted,” a news release posted by the American Association for the Advancement of Science (AAAS) is headlined “Study Quashes Controversial Vitamin C Treatment for Sepsis with Global Trial” and  concludes that research “must now focus on other interventions” (https://tinyurl.com/smgoseq).

An ‘Inverse Neutron Bomb’?

The deadly radiation of the neutron bomb kills everyone in its radius and leaves the buildings standing, whereas COVID-19 seems to leave 98% of the infected population standing, but has lethal effects on the global supply chains, writes David Stockman (Contra Corner 2/27/20). Stockman blames the grand delusion of  Keynesian central banking for encouraging maximum feasible out-sourcing and off-shoring in order to increase earnings, while drastically underinvesting in supply chain redundancies, just-in-case inventories, and liquid financial reserves. Just as banks cannot print antibodies to stop the disease, they can’t print raw materials, intermediates, and components to restart broken supply chains. Super-QE (quantitative easing) wouldn’t do it, and double digit subzero rates wouldn’t help. 

“Capital has been artificially drafted into financial speculation and money dealing…, rather than investing for the long haul and positioning to weather the unpredictable vicissitudes of…life”—such as wars and pestilence (https://tinyurl.com/udgf26s). 


AAPS Calendar

[CANCELLED] Mar 20-21. Workshop, Board Meeting, St. Louis, MO

Sep 30-Oct 3. 77th Annual Meeting, San Antonio, TX

Sep 29-Oct 3. 78th Annual Meeting, Pittsburgh, PA


Root of Supply Chain Problems

On Apr 9, 2019, physicians, black pastors, and the Black Healthcare Coalition  warned the FDA about the national security risk posed by the inability to make critical medications, including antibiotics to treat anthrax, in the U.S. In its report on drug  shortages, the FDA did not elucidate the existence of the secret contracts between group purchasing organizations (GPOs), pharmacy benefits managers (PBMs), manufacturers, and hospitals as the root cause of the shortages and sole or limited-source contracting. In a letter to FDA officials, James Thomas, M.D., writes that “our laws and regulations have created the drug shortages.”

Just as the Federal Aviation Administration (FAA) has people who have allegiances to Boeing embedded in the organization, the FDA has embedded people who have allegiances to entities that benefit financially from the high prices and limited suppliers and even from cheap generic precursors made in China that cost little but are sold for high prices that yield great profits through  “sharebacks.” The Dept. of Health and Human Services (HHS) has not been demanding the secret contracts that divert money from manufacturers willing to make medications in the U.S. to middlemen. Congress members with huge conflicts of interest refuse to close the safe harbor from the Anti-kickback Statute that enables these arrangements [see https://tinyurl.com/qmqj6tu].

Dr. Thomas also asks FDA to let hospitals and others know whether ultraviolet light kills the SARS-CoV-2 virus and advise whether hospitals need to disinfect rooms and air ducts with UV  light. He recommends emphasizing the long incubation period (27 days or more) and universal precautions (no handshaking or cup sharing, frequent disinfection of surfaces, etc.).


Unproved Remedies and Preventives

The FDA is sending threat letters to those who sell unapproved products for COVID-19—so far it has not approved any therapies or preventives  (https://tinyurl.com/r2grb38). Physicians must always remember their duty to “do no harm,” including the harm of impoverishing patients by promoting useless nostrums, for financial gain. But when patients’ lives or health is threatened, a good physician might look beyond the official guidelines. AAPS members have provided references that their colleagues might wish to consider:

Vitamin D to prevent acute respiratory infections: https://tinyurl.com/t7v45zw; https://tinyurl.com/sogm4jd.

Spirulina extract vs. influenza in vitro and in animal models: https://tinyurl.com/tk9vjrn.

Resveratrol inhibition of MERS-CoV infection: https://tinyurl.com/rpp4h4o.

Radiation therapy: In the early 20th century, low-dose radiation was used to treat pneumonia, gas gangrene, carbuncles, and arthritis. Research on pneumonia treatment, mostly bacterial lobar with some cases of viral or interstitial pneumonia, was reviewed in 2013. Of 863 reported cases, 717 were said to have been  cured. A controlled trial, alternating x-rays with serum therapy, was stopped because patients receiving x-ray treatment were relieved of distress within 3 hours. With the advent of sulfanilamide, interest was lost, though 50,000 patients annually are still treated for arthritis in Germany (tinyurl.com/s7ua856). Might a trial of 30-50 rads to the chest be preferable to intubation?


Vaccination

Vaccines against SARS-CoV-2 are being developed in record time.  Inovio is accelerating clinical trials of its DNA vaccine INO-4800, with human trials to begin in the U.S. in April and soon thereafter in South Korea and China (https://tinyurl.com/tzhu6fb). It plans to deliver 1 million doses by year’s end.

Meanwhile, the top advice from the Dept. of Defense is to “get a flu shot” (tinyurl.com/umzgjyk). One might, however, want to consider the results of a 2017-2018 study of influenza vaccination and respiratory virus interference in DoD personnel (tinyurl.com/sovt626). The odds ratio for influenza in vaccinated vs. unvaccinated persons was 0.57 (95% CI 0.52-0.63). There was also significant protection from some non-influenza respiratory viruses—except coronavirus, for which the OR was 1.36 (95% CI 1.14-1.63) for vaccinated vs. unvaccinated patients.

In a 2003 review article about the first SARS vaccine, researcher Rino Rappuoli cautioned that trials in cats had caused fatal “immune enhancement.” He stated that each of those approaches, including passive immunotherapy, need to be carefully evaluated as some vaccines developed against feline coronavirus actually exacerbated the disease when vaccinated animals were challenged with the wild-type virus (tinyurl.com/tlcscea). Antibody-dependent enhancement of virus infectivity has been described for feline coronaviruses (https://tinyurl.com/wwrdq9j), suggesting the need for caution in fast-tracking approval.


Medical News Discussion: Coronavirus and More

The public health committee of the Pima County (Arizona) Medical Foundation invites contributions to its Facebook page: search for “medical news discussion”—on COVID, cannabis, homeless camps, excess screen time, and more. Please comment on existing posts and send new topics to [email protected]


EEOC Sues Yale Hospital for Age Discrimination

The U.S. Equal Opportunity Commission (EEOC) sued Yale New Haven Hospital, the teaching hospital of the Yale School of Medicine, on Feb 11 over the hospital’s “late career practitioner policy,” which requires any individual aged 70 and older who applies for or seeks to renew staff privileges to take neuropsychological and eye examinations. Because the requirement is solely based on age, it violates the Age Discrimination in Employment Act (ADEA), the suit said (tinyurl.com/th7f5vm).

About one in eight practicing U.S. physicians is 65 or older.


It’s Only a Joke, Comrade!

This 2018 book by Jonathan Waterlow, subtitled Humour, Trust and Everyday Life under Stalin (1928-1941), chronicles how and why Soviet citizens used humor to help survive the terrible oppression—even at the risk of 10 years in the Gulag or even execution if caught. How chilling it is to learn that thousands of people—in Scotland!—have been logged onto a police data base for making potentially offensive remarks, even if meant as jokes, online. These “non-crime hate incidents” could be revealed to employers as part of a background check if police deem them relevant to the job (https://tinyurl.com/s57bq4d).

Freedom of speech is not to be taken for granted!


Correspondence

An Irrevocable Choice. Just like dangling a flashy lure before a fish, HMOs dangled “free stuff” before seniors who were eager to bite on the promise of something for nothing. Dental, vision, hearing, drugs and a “free” gym membership. The price is that if you become seriously ill, the Medicare Advantage Plan will look for ways to skimp on or outright deny care.  If the best specialist to treat your cancer is not in their narrow network, too bad. With MA, it’s everybody in, no one allowed to escape. 

The patient featured in a New York Post article (tinyurl.com/v8s9uc8) wanted to go back to original Medicare and leave the Medicare Advantage Plan because the best specialist to treat his cancer was not in-network. However, he learned that the decision to join an MA Plan is effectively irrevocable. Who knew? Ultimately, after expending a lot of energy and time, he was allowed to switch to another MA plan in which his preferred specialist was in-network. But “there is no guarantee that his new plan will include his oncologist indefinitely. Advantage plans can drop providers at any time, and they do,” writes the Post.

If his preferred physician had been opted out, the patient could have paid out of pocket, but those who swim willingly toward the HMOs’ lure are not likely to choose that route. 

Lawrence R. Huntoon, M.D., Ph.D., Lake View, NY


CDC Botched COVID-19 Testing. The U.S. lost precious weeks in rolling out COVID-19 testing, and one factor was our centralized permission-based system for innovation in diagnostic   testing: “FDA rules initially prevented state and commercial labs from developing their own…tests, even if they could develop coronavirus PCR primers on their own. So when the only available test suddenly turned out to be bunk, no one could actually say what primer sets worked” (https://tinyurl.com/wjc89dy).

Craig M. Wax, D.O., Mullica Hill, NJ


Disastrous Policies. There are a lot of “don’t worry” pieces out there by people who—unlike us—don’t have to worry. Even if the virus doesn’t kill us, it is already seriously disrupting the economy. Our hospitals will soon lack antibiotics and other lifesaving drugs because even if made here, the precursors come from China. As former Navy SEAL Matt Bracken said, when we look back  in history at colossal mistakes we will count the Titanic setting a speed record through an iceberg field without enough life boats, placing all the battleships together with planes wingtip to wingtip at Pearl Harbor, and allowing critical supplies to be monopolistically controlled by potential military enemies.

Lee Merritt, M.D., Logan, IA


Unmatched. Despite a terrific education and great recommendations, I was one of those unmatched medical students 25 years ago. Fortunately, I was offered a position in a new program during the “scramble” (now called SOAP) and have had a successful career. Most of my residency class did not match at first despite being great candidates. Now the U.S. has an unprecedented number of unmatched graduates, some applying five times before getting a position or giving up. This bottleneck was created by the Balanced Budget Act of 1997, which capped the number of residency programs Medicare would fund—even though medical schools have since expanded. The sponsor of the first Associate (or Assistant) Physician program bill in Missouri saw the value in utilizing these unmatched medical doctors who were being ignored by the medical establishment. The bill was opposed by nurse practitioners, physician assistants, and members of the Missouri Academy of Family Physicians. It was supported by the Missouri State Medical Association [and by the Missouri chapter of AAPS]. We should not turn our backs on these new doctors.

Natalie Newman, M.D., https://tinyurl.com/ranzuzw


Controlled Substances and the Constitution. A great article in the New York Times Magazine on how the new conservative majority on the U.S. Supreme Court could reshape the future inspired me to comment (https://tinyurl.com/u24zy7g). I suggested that if the conservative justices were even-handed in their application of originalism, then most of what Congress has been enacting would be unconstitutional. Amongst federal laws that should be challenged given current repercussions is the Controlled Substance Act, which formed the Drug Enforcement Administration (DEA). The DEA is supposed to control the flow of drugs but is going beyond its jurisdiction and invading physician offices, though the CSA explicitly exempts medical use. Suddenly DEA agents with 12 weeks of training can decide what is legitimate medical use? Chronic pain patients are suffering and physicians are being imprisoned longer than heroin and cocaine traffickers.


Cathleen London, M.D., Milbridge, ME, thevillagedoc.org

Education and Medicine in Bernie’s Cuba. Bernie Sanders  has frequently praised Cuba for its advances in education and medical care as reasons why the Cuban people did not overthrow Castro. The real reason was that they were disarmed. Cuba in 1957 already had a relatively high literacy rate (80%) and more doctors per 1,000 people than did Norway, Sweden, and Great Britain. Sanders conceals the fact that many innocents were executed for simply expressing a dissenting opinion.

Ileana Johnson, Ed.D., https://tinyurl.com/ubj2juf