28 April 2022 Blog Post: Dissecting Headlines

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Dissecting Headlines

Percentages make great headlines, like this one from Fox News Los Angeles, blaring “COVID cases in LA spiked 62% in the last week” (link: https://www.foxla.com/news/covid-cases-in-la-county-spiked-62-in-the-last-week), but readers should demand additional information. As Hans Rosling points out in “Factfulness”, when you see one number you should always ask for another.

The headline, in fact, simply isn’t true. Cases are up over the past week, from 10.47 new daily cases per 100,000 for the week ending 4/19 to 14.41 cases/100,000 for the week ending 4/26.  Reading further in the article, it notes that “the county averaged 1,553 new COVID cases per day over the past seven day, up from 960 two weeks ago – an increase of just over 61%.

Oh, so now we are talking about the last two weeks then?  62% increase from two weeks ago.  Well, that’s still not true but they are getting closer. There were 9.27 new daily cases per 100,000 population for the week ending 4/12 and the most recent rate does represent a 55% increase from such. In fact, our case rate has nearly tripled since the end of March.

Would it surprise you to learn though that our current case rate in 2022 is the highest of any in the three years we have been tracking COVID-19 cases?  I was a bit surprised by that to be honest, but it’s true (Figure 1 below). 2022 is in orange with 2021 in red and 2020 in blue

I found this a bit disheartening until I looked at mortality rates due to COVID-19 over the same timeframe (Figure 2 below). This same final week in April of 2020, the County suffered 0.43 deaths daily per 100,000 population due to SARS-CoV-2 infection. In 2021 that rate was 0.07 and currently is 0.01 deaths per day per 100,000 population.

 The Los Angeles County Health Department does not publish the raw data for hospitalizations, so this analysis cannot be performed independently. They do produce a graph of the raw numbers on their Dashboard (link: http://dashboard.publichealth.lacounty.gov/covid19_surveillance_dashboard/)

It will be helpful, moving forward, for our state and local health departments to begin to include additional metrics to help gauge the effect of SARS-CoV-2 infection regionally. Hospitalization and ICU numbers should be more readily available as should prescriptions of Paxlovid and Evusheld. Currently, case numbers are a significant underestimate as, at least in my practice, most positive cases are identified via home testing which is not reportable to our Health Department. School based testing may be one useful metric – except during the summer and breaks. The fiscal utility of continuing to perform weekly PCR testing on this population needs to be considered as well for the 2022/2023 school year.

But, overall, the fact that mortality rates are reaching historic lows despite rising case rates is encouraging indeed.

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Another rare virus puzzle: They got sick, got treated, got covid again

Another rare virus puzzle: They got sick, got treated, got COVID again

Shortly after he served on a jury in March, Gregg Crumley developed a sore throat and congestion. The retired molecular biologist took a rapid test on a Saturday and saw a dark, thick line materialize — “wildly positive” for the coronavirus.

Crumley, 71, contacted his doctor two days later. By the afternoon, friends had dropped off a course of Paxlovid, a five-day regimen of antiviral pills that aims to keep people from becoming seriously ill.

The day he took his last dose, his symptoms were abating. He tested each of the next three days: all negative.

Then, in the middle of a community Zoom meeting, he started feeling sick again. Crumley, who is vaccinated and boosted, thought it might be residual effects of his immune response to the virus. But the chills were more prolonged and unpleasant. He tested. Positive. Again.

Crumley, like other patients who have experienced relapses after taking Paxlovid, is puzzled — and concerned. On Twitter, physicians and patients alike are engaged in a real-time group brainstorm about what might be happening, with scant evidence to work with.

It is the latest twist — and newest riddle — in the pandemic, a reminder that two years in, the world is still on a learning curve with the coronavirus.

Infectious-disease experts agree that this phenomenon of the virus rebounding after some patients take the drug appears to be real but rare. Exactly how often it occurs, why it happens and what — if anything — to do about it remain matters of debate.

What’s clear is that patients should be warned it is possible so they don’t panic — and so that they know to test again if they start feeling ill. More data is needed to understand what is going on. Paxlovid, made by the drug giant Pfizer, remains a useful drug, even though it has sparked a new mystery.

“I’m not negative on Paxlovid,” said Crumley, who lives in Philadelphia and whose last positive test was a week after his second wave of illness began. “I don’t know whether it’s just stopping [viral] replication for that five-day period of time, and it comes back.”

One of the top worries accompanying antiviral drugs is the threat of resistance, when the virus evolves to evade the treatment. A Food and Drug Administration analysis of Pfizer’s clinical trial of the drug showed the virus rebounded in several subjects about 10 to 14 days after their initial symptoms but found no reason and no evidence that their infections were resistant to the treatment.

Michael E. Charness, chief of staff at the VA Boston Healthcare System, published a detailed case study of one 71-year-old patient who had a relapse. The man, who was vaccinated and boosted, received Paxlovid and quickly felt better. When he developed cold symptoms a week after his case of COVID had resolved, researchers sequenced the virus’s genetic code and found it was the same virus surging back. That ruled out a reinfection, the emergence of a variant or the virus becoming resistant.

Charness would like to see more data and other questions answered. Should antivirals be given longer, to assure the virus is cleared? Should people be treated a second time? What are the implications for people returning to their normal lives?

“If you have a resurgence of viral load, and that happens on day 10, when CDC says you’re back to work, no mask, what are you supposed to do about isolation? Is that a moment when you’re contagious again?” Charness said. “The person we studied, we advised to isolate until their viral load was gone the second time.”

Pfizer is collecting data, in clinical trials and in real-world monitoring of the drug’s use. The company’s trial data indicates there is a late uptick in viral load in “a small number” of people who take the drug, but the rates appear to be similar among study participants given a placebo, according to company spokesman Kit Longley. The people who experienced such increases also did not develop severe disease the second time around.

Those findings suggest that Paxlovid isn’t the reason people are relapsing, because that’s happening in untreated people, too.

If that turns out to be true, it raises the concern that some people — whether they have taken the drug or not — could be infectious long after they think they are in the clear, and after guidelines suggest they can stop taking precautions.

“Although it is too early to determine the cause, this suggests the observed increase in viral load is unlikely to be related to Paxlovid,” Longley wrote in an email. “We have not seen any resistance to Paxlovid, and remain very confident in its clinical effectiveness.”

The limited evidence leaves most physicians favoring the idea that Paxlovid knocks the virus down but doesn’t knock it out completely. It’s possible that by holding the virus in check, the immune response doesn’t fully ramp up, because it doesn’t see enough virus. Once the treatment ends, the virus can start multiplying again in some people.

Philip Bretsky, a primary care doctor in Santa Monica, Calif., said he has encountered two cases among patients, both of whom were vaccinated and boosted at least once.

A double-boosted 72-year-old who had chronic medical conditions that raised his risk for severe illness started to feel unwell at the end of March. He tested positive and began a course of Paxlovid. He felt better and tested negative. Then, 12 days later, he started feeling crummy again — and tested positive.

Reinfection seemed improbable, and Bretsky thought resistance was unlikely with a five-day course of treatment.

In well-vaccinated people, being reinfected so quickly would be“like getting struck by lightning or winning the lottery,” Bretsky said. “I don’t think this is reinfection. I think this is recrudescence of the original infection.”

Experts don’t know how common this phenomenon is. Many people may not test if they get sick again after their initial infection has receded, making it hard to track.

That almost happened to Holly Teliska, 42, of San Francisco. Teliska got sick shortly after returning home from a trip to New York. She has a risk factor for severe illness and got access to Paxlovid right away. When she finished her treatment course, she took a home PCR test that was negative and felt much better, though remained fatigued.

Four days later, she came down with a runny nose and cough. She assumed she had caught her daughter’s cold and powered through. Five days later, with plans to visit an immunocompromised friend, she took a test.

Teliska almost felt silly testing herself. She had been vaccinated and boosted, then infected.

“We’ve been saying I’m her safest friend now, now that I’ve had covid, so for three months, I can go spend time with her pretty safely,” Teliska said. “That really threw that narrative out the window. … This entire experience has been a real reminder there is still so much to learn.”

Paxlovid is new. It only began to be used in December, so reports people share on social media of resurgent illness may be the tip of the iceberg — or might simply reflect the eagerness to learn more about a rare, intriguing outcome.

If such cases turn out to beexceedingly rare, thenthese case reports may be a sporadic curiosity — something to warn patients could happen. If more common, it could lead to tweaks in treatment regimens.

The mounting anecdotes are compelling to many physicians, but it’s also possible the virus might rarely rebound. Yonatan Grad, an associate professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, has studied the viral loads of NBA players and staff during the course of an infection. That data, he said, shows that viral loads can bounce around.

What’s “exceptionally uncommon,” Grad said, is for the viral load to plunge for a few days to a level that suggests they are negative and then go up again.

Paul Sax, an infectious-diseases specialist at Brigham and Women’s Hospital in Boston, recently shared the story of a patient who became infected and then relapsed after taking Paxlovid. He has heard from lots of colleagues with similar stories. But the anecdotes raise more questions than they answer.

Even if the virus has not been shown to develop resistance to the treatment during a resurgence, that’s doesn’t mean it won’t happen, he points out. Does the treatment knock the virus down so successfully that people aren’t generating a robust immune response? That could have implications for understanding whether being infected acts as a potent booster.

The phenomenon is so new that many doctors aren’t aware of it. Jennifer Charness, a 31-year-old nurse who lives in Brookline, Mass., had the benefit of knowing about her father’s work at the Boston VA.

Charness started sneezing in early April and got a blaringly positive coronavirus test. She has a history of asthma and was prescribed Paxlovid. As she took the drug, she saw her positive test line grow fainter and her symptoms resolve. She swabbed to make sure she was negative before going back to work, as a precaution. Then, two days later, she felt the symptoms come back and tested positive — again.

“I’m so frustrated,” Charness said. “I don’t think I’m going to get very sick. It’s the concern of what does this mean for my viral load, and how contagious am I? And when will I not be contagious? I’m stuck back in my home again.”

Charness’s primary concern is that she doesn’t pose a risk to anyone else. She consulted a doctor via telemedicine Friday. The practice hadn’t heard of any cases like hers and decided to treat it as a reinfection and reset the isolation clock.

“I’m Day 4,” she said. “Or am I Day 13?”

CTO: https://www.washingtonpost.com/health/2022/04/27/paxlovid-second-case-covid/

𝗦𝗶𝗴𝗻 𝗨𝗽 𝗳𝗼𝗿 𝗢𝘂𝗿 𝗡𝗲𝘄𝘀𝗹𝗲𝘁𝘁𝗲𝗿

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26 April 2022 Blog Post: On Paxlovid

26 April 2022 Blog Post: On Paxlovid

During medical residency training, much of your time (especially during internship year) is spent ‘presenting’ cases, first to your more senior residents and then to attending staff physicians. This process is, at its core, storytelling with the first part of it answering the essential question of – ‘How did this patient end up here?’

In one memorable exchange, I presented a case of congestive heart failure where, through a combination of missed clinic visits and delayed modification of his treatment regimen, I noted that “the patient failed medical therapy” as the reason for his admission. My attending physician replied, “did the patient fail the therapy, or did the therapy fail him?”

In the past month I have had two cases where Paxlovid, a 5 day antiviral treatment for symptomatic COVID-19, has failed the patient. In each instance, patients ultimately had a full recovery but, rather than the usual 5-7 days, their experience lasted nearly three weeks. One patient was male, the other female and both in their 70s with well-controlled comorbidities (e.g: hypertension, high cholesterol, overweight). Both had a primary mRNA vaccine series and at least one booster (one patient had one booster shot, the other had received a second booster as well). The general timeline for both was as follows:

 

Day 0: Began feeling unwell, mild upper respiratory symptoms, cough, congestion, no fever

Day 1: Positive home antigen test

Day 2: Paxlovid begun

Day 3-5: Mild symptoms persist, in one instance a patient had a low grade fever as well. No shortness of breath.

Day 5: Negative antigen test (one patient)

Day 7: Negative antigen test (second patient)

Day 8-13: Returned to daily activities, errands, social gatherings without restriction

Day 14: Very mild symptoms return, post-nasal drip, slight cough, ‘tickle’ in the throat

Day 15: Positive home antigen test

Day 16-17: Mild symptoms resolving

Day 18: Negative home antigen test

 

Here are the CDC guidelines for home isolation after a positive home antigen test:

“Stay home for 5 days and isolate from others in your home. Wear a well-fitting mask if you must be around others in your home. Do not travel. End isolation after 5 full days if you are fever-free for 24 hours (without the use of fever-reducing medication) and your symptoms are improving.”

The difficulty now seen in these Paxlovid treated cases is one of a bimodal / biphasic clinical infection and one, as evidenced by the two separate positive antigen tests, where the patient is also infectious. This has implications not only for the affected individual but also for their close contacts and the general public’s health. The question is, why did this happen?

Logically there are four possible explanations, but only two are likely:

  1. The SARS-CoV-2 variant infecting these individuals was or became resistant to Paxlovid
  2. Both patients sustained a second (unique) infection from another source
  3. Treatment duration was insufficient for viral clearance (should have been 7-10 days instead of 5)
  4. The combination of vaccination+booster+Paxlovid was so effective in suppressing viral replication that the virus was never presented to the immune system and only once Paxlovid had been metabolized and the virus able to replicate once again was it apparent to the immune system

While options #1 and #2 are logical possibilities and would require additional investigation, they are both highly unlikely. While we have seen the potential for SARS-CoV-2 to mutate into different variants, this process takes months not hours or days making #1 unlikely. In terms of #2, a second unique infection, given the low prevalence of disease we are seeing in Los Angeles currently this is statistically unlikely – the general consensus is that those with a community acquired infection being safe for a re-infection for 3-6 months notwithstanding.

It is important to note that the EPIC-HR study (link: https://www.nejm.org/doi/full/10.1056/NEJMoa2118542) upon which Paxlovid’s FDA EUA was based studied UNvaccinated adults at high risk for progression to severe disease.  A total of 1,039 patients received Paxlovid and 1,046 received placebo (and not monoclonal antibody infusions either). Among these, 0.8% who received Paxlovid were hospitalized or died during 28 days of follow-up compared to 6% of the patients who received placebo.

The Biden Administration today is touting Paxlovid as a ‘miracle drug’ – and it really is not. The real miracle is vaccination which massively reduces the risk of hospitalization, ICU admission, mechanical ventilation and death. No doubt Paxlovid has a role for treatment, particularly among those at higher risk of severe disease (due to age, chronic conditions, obesity for example) – but cases with a bimodal distribution of transmissible SARS-CoV-2 infection are a cause for concern and point to a need for specific study of Paxlovid in vaccinated patients.

21 April 2022 Blog Post: Much Ado about BA.2

Much Ado About BA.2

Goodness, you’d think that BA.2 was fast upon us based on press reports. Granted, moving forward cautiously does make sense – particularly since the pandemic to date has consisted of a series of spikes and lulls. The epidemic curve for Los Angeles County suggests that we have had four surges to date (Figure 1 below). 
On some occasions these surges have been preceded by rising case rates in Europe – most notably the initial seeding of the US epidemic by travel from Europe to New York and again prior to the Delta wave. Popular press reports will also mention that Europe had an Omicron spike before we did in the US, but that actually is not the case. Two of the most commonly cited countries are Germany and the Netherlands, but neither had an Omicron spike that preceded that of the US. Figure 2 below shows that the US spike clearly preceded that in each of those countries. Both Germany and the Netherlands have now entered a sharp downslope as well.
At this point in time, about 35% of COVID-19 cases sequenced in the US for the week ending March 19th were caused by BA.2.
 
Wastewater surveillance (link: https://covid.cdc.gov/covid-data-tracker/…) is one promising way to monitor for potential outbreaks – remembering of course that COVID-19 transmission historically in the US has been highly regional with a hopscotch pattern criss-crossing the country. Both wastewater surveillance sites in Los Angeles County (one covering 100,000 individuals and the other 3.5 million) are in the “-10% to -99%” category over the last 15 days. This fits with the continued decline in cases we are seeing as well – both in incident (new) and prevalent (existing) cases (Figures 3 and 4 below)
 
One point of modest caution, however, does exist when looking at Santa Monica / Malibu (SMMUSD) school-based data which has become an unintended passive surveillance cohort (I say unintended because I don’t think the school districts ever considered their weekly PCR testing having more broad use than simply isolation / quarantine). Also, because they do not delineate whether or not these are new cases reported week over week we are forced to assume that the number represents prevalence rather than incidence rates. Nevertheless, these rates do seem to share some predictive relationship with case rates of the County at large. For instance, for the week ending January 7th, the prevalence in the school district was at its highest rate of 9%. The week following, cases peaked in Los Angeles County. Understanding the massive number of limitations that exist in generalizing a single school district to a County of 10 million individuals – nevertheless, a small uptick in cases is observed for the week ending March 26th.
 
But, all in all, I do not expect BA.2 to remotely approach the massive surge we experienced with Omicron. Both the Santa Monica Malibu and Los Angeles Unified School Districts will be sending students home with rapid antigen tests to be performed prior to returning back to class after the upcoming Spring Break. It is at once encouraging and deflating to see schools embrace the kind of test, trace and isolate mechanisms that could have been employed in September of 2022 to keep schools open during the pandemic.

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19 April 2022 Blog Post: Different States, Different Standards

19 April 2022 Blog Post: Different States, Different Standards

My blog posts generally tend towards more “sciency”, statistically based observations and viewpoints so today’s will be somewhat of a departure. What follows will be somewhat of a departure – but there will be mathematics at the end!

I returned to the office yesterday after Spring Break with my family. During the break we covered two states outside of California: Arizona and New Mexico. To my surprise, masking mandates and adherence were quite different between the two. 

Not unexpectedly, Arizona was the Wild West when it came to COVID. Nobody was masked – not restaurant workers, patrons, hotel staff, or anybody else it seemed. Fortunately, the weather was nice, our activities were essentially all outdoors and restaurants had outdoor seating. But after a few days there I noticed that even my usual fastidious mask-wearing had regressed – I began walking into indoor public areas without a mask, especially if I was passing through or only expected to be there for a short time. Arizona lags the United States as a whole in vaccination with only 61.3% of their population having received at least one dose as compared to 65.9% of the total US population.

New Mexico was an entirely different story – in Santa Fe, indoor mask mandates remained for businesses, restaurants and museums. Standing on line (outdoors no less!) for museum tickets one morning outdoors while not wearing a mask, I received enough sideways glances that I sheepishly donned my N95. New Mexico’s vaccination rate (at least one dose) exceeds that of the US average at 70.7%

California also exceeds the US aggregate vaccination rate with 71.8% of the population having received at least one dose of the COVID-19 vaccine

What is interesting is that US territories are far outpacing the mainland US 48, Alaska and Hawaii. Vaccination rates in American Samoa are 87.1%, Palau 84.1%, Northern Mariana Islands 83.4%, Puerto Rico 82.8%, and Guam 82.3%. The most vaccinated US state is Rhode Island at 82.1%.

All of these machinations and observations emphasize that risk mitigation efforts and vaccinations are, at their core, community efforts. It seems that the two are interrelated, certainly when it comes to mask wearing behaviors and vaccination rates. It was also sobering for me to realize how quickly I could regress into the general approach of Arizona before being snapped back to attention in New Mexico.

Having promised mathematics at the outset, I will fulfill that promise by looking at the formula used to calculate vaccine efficacy. 

The basic formula is written as:

Our reflex, when translating this formula into English, is to, well the vaccine “works” 95% of the time. However, it is mathematically correct to say:

“The observed vaccine efficacy indicates a 95% reduction in disease occurrence among the vaccinated group”

Even in mathematics, we cannot escape that the key concept here is that vaccination (like mask wearing) is a group or population activity leading to protection across that community or population. Simply getting a shot does not eliminate one’s chance of getting the infection or having a breakthrough infection. Instead, the Pfizer COVID-19 vaccine (as an example) markedly reduces the number of cases (symptomatic and laboratory confirmed) experienced among the group vaccinated as compared to our expectation. At the individual level the vaccine itself is either 0% effective or 100% effective. Its utility lies in the aggregate, not the individual.

𝗦𝗶𝗴𝗻 𝗨𝗽 𝗳𝗼𝗿 𝗢𝘂𝗿 𝗡𝗲𝘄𝘀𝗹𝗲𝘁𝘁𝗲𝗿

 

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