29 June 2022 Blog Post: On SCOTUS an the Dismantling of Women’s Health

29 June 2022 Blog Post: On SCOTUS an the Dismantling of Women's Health

While last week’s decision to roll back the constitutional protections afforded to women by Roe v. Wade was traumatic, it was not the first first salvo in the assault on women’s health in the United States. Efforts to undermine the health and well being of women convincingly began during the Trump Administration as evidenced by the rise maternal mortality rates for both 2019 and 2020 (Figure 1 below; “1” superscript designates statistically significant increases).

Unsurprisingly, the United States lags far behind its peers in maternal mortality rates – which makes the comments by world leaders regarding the SCOTUS decision all the more prescient. Figure 2 below shows how the US stacks up against other countries (2018 are the latest data in this figure, the current situation in the US is even worse with 23.8 deaths per 100,000 live births).  Note that a pregnant woman in New Zealand has a 14 fold reduced risk of dying as compared to an American woman. A pregnant African-American woman is 32 times more likely to die as compared to her New Zealand counterpart. Putting that in perspective, smoking cigarettes increases your risk of lung cancer by 25 fold.

There are only two factors that significantly modify the risk of maternal mortality: first, access to contraception, and second, access to safe abortion. This makes it straightforward in one sense but, in another, makes it incredibly easy to dismantle health safeguards.

How do we know this?  Countries with better training of and access to abortion providers have lower maternal mortality rates (Darney et al. Obstet Gynecol. 2020;135(6):1362). This relationship is also true in the United States; states that have restricted abortion access have increasing maternal mortality while it is declining in states with improved access to abortion services (Addante et al. Contraception. 2021;104(5):496. Epub 2021 Mar 26).

Governors in three western states (California, Washington and Oregon) have committed to making pregnancy termination services accessible to all. A number of companies have already stated that they will provide transportation services for employees to states that have such services. 

Those that would wish harm on women are not going to stop here. With only two factors modifying maternal health, the next logical point of attack will be on contraception availability.

Safeguarding maternal health is simply not within the purview of the 9 lawyers of SCOTUS; it is a public health issue. Their reckless disregard for the limits of their knowledge will have one simple downstream effect – it will kill women. 

𝗦𝗶𝗴𝗻 𝗨𝗽 𝗳𝗼𝗿 𝗢𝘂𝗿 𝗡𝗲𝘄𝘀𝗹𝗲𝘁𝘁𝗲𝗿

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24 June 2022 Blog Post: Overturning Roe v. Wade

24 June 2022 Blog Post: Overturning Roe v. Wade

On May 3rd I wrote a blog about the, then, leaked Supreme Court majority opinion on overturning Roe v. Wade which has now become reality (link: https://www.cnn.com/politics/live-news/roe-wade-abortion-supreme-court-ruling/h_9a4458b69569b8f7ff46c76cb2238577). Even more disturbing (if such a thing is even possible) is that the ruling further opens the door to the reconsideration of same-sex marriage and contraception. As the dissenting opinion points out:

“The right Roe and Casey recognized does not stand alone,” they wrote. “To the contrary, the Court has linked it for decades to other settled freedoms involving bodily integrity, familial relationships, and procreation. Most obviously, the right to terminate a pregnancy arose straight out of the right to purchase and use contraception. In turn, those rights led, more recently, to rights of same-sex intimacy and marriage.” 

Stated simply woman’s right to access competent and safe pregnancy termination care is, quite simply, a public health issue and those that voted in an administration permitting this travesty, have mixed politics and health.

As it stands, maternal mortality in the United States has already increased in every ethnic group (Figure below) since 2018 with statistically significant rises in the aggregate for both 2019 and 2020. For all US women, a total of 23.8 women die per 100,000 live births. 

Countries with better training of and access to abortion providers have lower maternal mortality rates. We suffer (as with most healthcare outcomes) disastrously by comparison (Figure 2 below; 2018 data).

Access to safe abortion care is an essential component of health care, not politics. As it stands, hundreds of pregnant American women die unnecessarily each year and that will only get worse. The Supreme Court can frame their opinion as constitutional law, but in reality, they have strayed far out of their lane. Evidence-based health policies and good reproductive health care from well trained professionals is needed – not a dangerous majority opinion from political appointees.

What’s worse, is that their overreach has only just begun.

𝗦𝗶𝗴𝗻 𝗨𝗽 𝗳𝗼𝗿 𝗢𝘂𝗿 𝗡𝗲𝘄𝘀𝗹𝗲𝘁𝘁𝗲𝗿

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22 June 2022 Blog: On COVID in Europe

22 June 2022 Blog: On COVID in Europe

Media outlets, like CNN and The Guardian, are reporting on a rising wave of cases in Europe as the traditionally busy summer travel season on the continent begins.

Link: https://www.cnn.com/2022/06/22/world/coronavirus-newsletter-intl-06-22-22/index.html

Link: https://www.theguardian.com/world/2022/jun/21/covid-surges-europe-ba4-ba5-cases

As an interesting aside, note that the CNN article references raw numbers while the Guardian article speaks (more appropriately and accurately) in terms of case rates. Prior blog posts here have discussed the importance of rates over raw numbers to ensure accurate comparison of data.

Portugal and France have had the most dramatic surge with Germany also experiencing a rapid rise in case rates (Figure below). Summarized neatly by the Guardian:

Multiple European countries are experiencing a significant surge in new Covid-19 infections, as experts warn that with almost all restrictions lifted and booster take-up often low, cases could soar throughout the summer leading to more deaths.”

These figures fit with our anecdotal reports from patients who are currently in Europe or have recently returned. Firstly, there are no masks to be seen – from Italy, to Portugal, France and Germany. Significant summer heat has been an additional barrier to mask wearing. Crowded tourist spots, restaurants and the lifting of restrictions of mask wearing in airports and airplanes gives ample and redundant opportunities to be exposed to the Omicron subvariants now circulating. Multiple patients in our practice have fallen ill and tested positive for COVID-19 while traveling in Europe.

Complicating the situation in Europe is the lack of Paxlovid availability. Although there is no evidence that Paxlovid is effective in prevention after a close exposure and has limited (if any) utility among those at low risk, it does seem to have some efficacy among those individuals that are older, at high risk of progression or are unvaccinated.

It is a reasonable question at this point as to whether or not COVID-19 infection is simply inevitable. While I don’t believe that we are doomed, it does seem that any activity that is outside of the sphere we have established over the past two years leaves one at considerable risk, augmented by a higher prevalence of infection, abandoned mitigation practices and more transmissible variants. That is not to say that one should not attend a wedding, travel to Europe or have that 40 person family reunion. But do so with the expectation that time, proximity and widening your social circle will, in all likelihood, leave you at risk of acquiring COVID-19.

𝗦𝗶𝗴𝗻 𝗨𝗽 𝗳𝗼𝗿 𝗢𝘂𝗿 𝗡𝗲𝘄𝘀𝗹𝗲𝘁𝘁𝗲𝗿

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31 May 2022 Blog Post: Making Sense of Antibody Levels

31 May 2022 Blog Post: Making Sense of Antibody Levels

As BA.12.2.1 begins to cut through a wider swath of the population, we are in clinic noticing a significant uptick in cases. This May we have had 27 new cases of COVID-19 in the practice, as opposed to only 4 in April. This has led to a number of questions about booster vaccinations and their role in neutralizing the virus – i.e. stopping its entry into cells and therefore preventing illness.
 
Two studies were published in 2021 based on vaccine trials which connecting neutralizing antibody responses to SARS-CoV-2 with vaccine efficacy allowing for a ‘correlate’ of protection for vaccines (and boosters) against COVID-19. We have discussed these studies in prior posts (Khoury et al. and Earle et al.).
 
Khoury link: Khoury, D.S. et al. Nat. Med. https://doi.org/10.1038/s41591-021-01377-8 (2021).
Earle link: Earle, K.A., et al. Vaccine https://doi.org/10.1016/j.vaccine.2021.05.063 (2021).
 
But before launching into the specifics, let’s take a step back. In general, testing for antibodies is used as a marker of prior infection and recovery. In some cases, such as HIV antibody testing, it can be used to identify an infection (HIV viral load can also be tested to quantify viral activity, the goal being an ‘undetectable’ viral level with treatment). Antibodies are generally long lasting but their interpretation is more complicated than it first appears. They can provide clues about the following:
 
1. When was the person exposed?
2. Has immunity waned or never formed?
3. Was the person exposed or vaccinated?
4. Did the person have the disease or just infection?
 
When antibody testing for SARS-CoV-2 is considered, two main antibody classes are considered:
 
1. 𝐍𝐮𝐜𝐥𝐞𝐨𝐜𝐚𝐩𝐬𝐢𝐝: The viral “coat” that packages the SARS-CoV-2 RNA genome in a protective covering. Antibodies to this protein motif indicate prior community acquired exposure and likely clinical infection with the virus. I have had rare cases of individuals who do not recall having COVID-19 but have positive nucleocapsid antibodies but this is quite unusual. These individuals likely had very mild symptoms and, therefore, went unnoticed. These antibodies do seem to be very long lived as I can still detect nucleocapsid antibodies among those with documented clinical infection as early as March 2020.
2. 𝐒𝐩𝐢𝐤𝐞: This antibody test is used primarily to detect an adaptive immune response to the SARS-CoV-2 vaccine. In some instances, this antibody level may return detectable levels as a result of community acquired infection alone (I have seen this in some patients who were unvaccinated but had the infection). However, SARS-CoV-2 vaccines preferentially target the spike protein of the virus and typically generate a robust quantitative response beyond that seen from infection alone.
 
Using both the nucleocapsid and spike protein antibody results can distinguish between vaccination alone, community-acquired infection alone or infection (primary or breakthrough) and vaccination together.
 
Adding further complexity to this picture is the fact that the spike protein antibody returns a numeric value which can be different based on the performing laboratory. LabCorp for instance returned values up to a maximum of 2500 from the test inception (Summer 2021) through early 2022. However, in 2022 the test parameters changed to accommodate values up to 25,000. Theoretically higher levels of antibody should provide “better” protection against infection but, again, there is significant nuance to the role of these neutralizing antibodies. What we do know is that they protect against severe disease, hospitalization, need for mechanical ventilation and death.
 
Understanding a correlate of protection and, more specifically, an ‘absolute correlate’ (meaning a protective threshold) has significant downstream implications. Firstly, new vaccine candidates (ones that can be made more cheaply and distributed more widely) would not necessarily need to go through expensive clinical trials if they could simply demonstrate that they generate a sufficient immunity threshold. Similarly, those that are immunosuppressed could also quantitatively determine if their vaccine response was sufficient for protection (and if not would be clear candidates for Evushield). Lastly, serosurveys could be undertaken to determine the proportion of the population that has achieved adequate protection.
 
Results for the two studies referenced above showed a significant correlation between vaccine efficacy and vaccine-induced neutralizing antibody activity. But getting at these numbers (spike protein antibody levels), is no easy task. Digging through Supplementary material, Khoury et al suggest the following levels are adequate for protection against symptomatic disease:
 
⊛ Pfizer: 19
⊛ Moderna: 32
⊛ J&J: 105
 
Earle et al. hedge their bets a bit more but suggest the following:
 
⊟ Pfizer: A mean value of 361 (CI: 235, 541) provides 94.6% protection
⊟ Moderna: A mean value of 360 (CI: 273, 476) provides 94.1% protection
⊟ J&J: A mean value of 224 (CI: 158, 318) provides 66.5% protection
 
But here’s the real challenge – these neutralization antibody studies were done during vaccine development, when alpha was the primary circulating variant. As the figure below shows, there has been a steady progression in variants – each seemingly more infectious than the last. That would, logically, mean that a level of 361 providing 94.6% protection against alpha would provide far less protection against Delta or Omicron. But how much less?
 
 
 
 
 
But wait – more bad news. Also, remember too that there is a well described a decline in neutralization titer with time for up to 8 months after SARS-CoV-2 infection or vaccination (perhaps even less with repeated boosters). Frequent re-testing of antibody levels is simply not practical, both at the individual and population levels.
 
So how do we interpret spike protein antibody levels and, more practically, how can we contextualize these levels with protection against infection? Of course, there is no actual answer but here’s my approach.
 
In discussing spike protein antibody levels with patients, I first “benchmark” their results against what might be expected. Although these data are not great, our expectations can be set based on the NIH “Mix and Match” study (which I have also previously discussed). After a primary series and one booster, levels taken two weeks after that second booster are in the 3,000-6,000 range (for the mRNA series which are most typical in the US). Those who have had J&J and add an mRNA booster (one shot, as recommended) can expect levels in the 2,500-3,200 range (Table below). There are no available data on levels after the 2nd booster.
 
In our practice, we are seeing levels anywhere from 3,000 to above 25,000 (this is the upper range). I think at this point, 5,000 should be about the minimum level we should be seeing.
 
And why do I think that should be the minimum? Well let’s look at the data above showing 94% protection against even mild symptomatic disease for Pfizer and Moderna at levels of 360. But Beta was about 50% more transmissible than Alpha. Delta was about twice as transmissible as Beta and Omicron has been estimated to be 5 times more transmissible than Delta. So: 1.5x2x5 = 15.
 
Revising upwards, 360 multiplied by a factor of 15 gives us 5,400.
 
This isn’t terribly scientific and, admittedly, is a decent amount of statistical hand waving. But it does attempt to draw on what we know from the vaccine trials and what we have seen in terms of transmissibility across the subsequent variants.
 
Happy to hear thoughts and rebuttals! Comment below! 

𝗦𝗶𝗴𝗻 𝗨𝗽 𝗳𝗼𝗿 𝗢𝘂𝗿 𝗡𝗲𝘄𝘀𝗹𝗲𝘁𝘁𝗲𝗿

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18 May 2022 Blog Post: State of COVID in LA County

It is increasingly difficult to ascertain the contours of the COVID-19 epidemic / pandemic / endemic event in Los Angeles County due to profound shifts in how the Health Department….

18 May 2022 Blog Post: State of COVID in LA County

It is increasingly difficult to ascertain the contours of the COVID-19 epidemic / pandemic / endemic event in Los Angeles County due to profound shifts in how the Health Department collects and tracks testing data. Until recently, case counts could be considered to be fairly accurate as most individuals tested via PCR or rapid antigen test at a medical center or via a laboratory with mandated reporting. Even through the Omicron surge, case counts in the County were more or less reflective of the underlying population trends as (unfortunately) there was a shortage of rapid antigen tests. So rather than testing at home, folks still needed to go to a testing center, medical office or through a reporting laboratory.

As it stands now, most cases (I would imagine at least 50%) are ascertained via home testing and are never reported to the County Health Department by their own case reporting rules. If, for instance, a patient calls my office and lets me know that they are symptomatic and have a positive test – even this is not reportable to the Health Department. If I prescribe them Paxlovid or arrange for monoclonal antibodies?  Still not reportable.

Nevertheless, upon logging into the County Health Department’s COVID-19 webpage, the following information is presented: Case Count, Testing, Testing Positivity Rate, Deaths, Death Rate, and Hospitalizations. Other than Deaths, one could argue that all of the remaining measures are highly skewed. Of concern is that the County (unlike case and testing numbers) does not publish raw hospitalization numbers but instead only provides a graph. Further, there is no discussion of whether or not hospitalized cases are there primarily due to COVID-19 infection or if such is an incidental finding as part of routine surveillance.

Based on the incomplete data that are collected by the County, it does appear that cases are on the rise, increasing from 5.8 new daily cases per 100,000 the week of 3/22/2022 to 23.4 new daily cases per 100,000 the week ending 5/10/2022 (Figure 1 below). This is undoubtedly an undercount of the true number of cases.

The profoundly good news is the continued decline in mortality rates, even in the face of rising cases (Figure 2 below). The County-wide mortality rate due to the infection is now 0.014 daily deaths per 100,000 population. At its highest for the week of 1/10/2021, this rate was 2.79. Expressed differently, for every person that dies in the County today from COVID-19, there were 200 that died in January of 2021.

So what is going on in the County then, in terms of caseload?  One potential clue is from school surveillance data which has been ongoing in Santa Monica / Malibu since the beginning of this year (Figure 3).  One can see that these data seem to be a bit ahead of the County-wide graph which would make sense as both symptomatic and asymptomatic cases would be ascertained. Illustrating such, is that the highest case rate was seen January 1st in the school district but not until January 11th in the County. 

Santa Monica / Malibu Unified School District has noted a steady rise in cases since mid March (note the data gap from April 2-18th due to Spring Break). That upward trend has continued taking the prevalence of positive cases from 0.04% March 5-12th to 1.01% May 9-15th.

At that point in time, there was a shortage of home tests so the incidence case rate for the County was a more accurate reflection of the true rate. With school prevalence of 9% this translated to a County-wide rate of 453 new daily cases per 100,000. Extrapolating to this most recent week, a school prevalence of 1% should mean a population rate of 50.3 new daily cases per 100,000.  The County is reporting half of that at 23.4.

Wastewater surveillance is telling a similar story, at least that the Hyperion plant in Los Angeles. Data collection of gene copies per Liter of wastewater began in early February (Figure 4 below). But similar to the school surveillance detailed above, the lowest gene copy levels were seen Feb 27th (6,579 copies) and March 8th (7,718). This copy level has climbed steadily (with the exception of one outlier on 3/29) and now stands at 216,240. It would have been more helpful to correlate these values with measurements obtained in January of 2021 during the Omicron surge.

So what can we conclude? First, the current caseload reported by the County is inaccurate by at least 2 fold. However, even with this rate adjustment the number of cases are far below that of the January Omicron surge. There is evidence from school surveillance and wastewater that these numbers will push even higher, given the expected lag in case reporting. Despite such, mortality rates continue to decrease which is likely the conjoint effect of vaccination, booster shots, typically mild disease from Omicron subvariants, early detection and early initiation of treatment.

Of course nobody wants to get the infection – but the impact of SARS-CoV-2 in terms of severe disease and mortality has been significantly blunted. Contact tracing efforts would better delineate the extent of transmission (my supposition has been that those who are vaccinated/boosted and treated are not particularly good vectors of spread) as well as the potential role of ‘superspreaders’ at large gatherings. However, the County Health Department has never shown much zeal for this most basic of Public Health activities (current contact tracing is at about 20% and about 85-90% is a reasonable metric for complete case ascertainment). Until somebody decides that it is worth doing contact tracing, we will continue to wonder why some folks get exposed and do not develop the infection (even in close contact, like a household) yet dozens will fall ill after a single celebratory gathering.

 

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3 May 2022: On Roe v. Wade

Yesterday’s leaked Supreme Court majority opinion on overturning Roe v. Wade is, once again, an example of politically appointed officials without public health training making public health decisions

3 May 2022 Blog Post: On Roe v. Wade

Yesterday’s leaked Supreme Court majority opinion on overturning Roe v. Wade is, once again, an example of politically appointed officials without public health training making public health decisions. We saw this in the early days of the COVID-19 pandemic when Riverside County Sheriff Chad Biaco refused to enforce mitigation measures in the County. It is not without some irony that he is listed on the Riverside County website as Sheriff – Coroner (link: https://www.riversidesheriff.org/).

While some will frame it otherwise, a woman’s right to access competent and safe pregnancy termination care is, quite simply, a public health issue. Let me explain why – epidemiologically.

An estimated 25 percent of pregnancies worldwide end in induced abortion. Similarly, in the United States, close to one in four females will have an abortion during their reproductive life. Readers will know that I bristle at percentages, so here are the rates specific to the United States (from CDC data):

  1. The rate of pregnancy termination was 11.3 per 1000 females ages 15 to 44 years, or 189 per 1000 live births. 
  2. The vast majority of pregnancy terminations were performed in the first trimester: 78 percent at ≤9 weeks and 92 percent at ≤13 weeks of gestation. 

The rate of complications associated with pregnancy termination depends on:

  1. Procedure type
  2. Gestational age
  3. Patient characteristics
  4. Clinician experience. 

In general, the risk of a major complication is low. In a retrospective study of California Medicaid data from 54,911 abortion procedures, the overall complication rate was 2.1 percent. The overall death rate from all legal abortions is far less than the maternal mortality rate among live births in the Unites States.  One study reported no maternal deaths in 170,000 consecutive first-trimester suction curettage (D&C) procedures.

Now that we have set the stage – here’s the crucial data.  Maternal mortality in the United States has not improved whatsoever over the past 20 years – this in sharp contrast to the worldwide experience where maternal mortality is falling. US States with restrictions on access to contraception and safe abortion have seen the highest rates in maternal mortality and are the root cause of this stagnation in care (link: https://www.sciencedirect.com/science/article/abs/pii/S0010782421000901). 

Countries with better training of and access to abortion providers have lower maternal mortality rates. A comprehensive study by The Global Health Policy Summit’s Maternal Health Working Group analyzed factors that explained maternal mortality rate decreases of which the most cost-effective interventions were, first, access to contraception, and second, access to safe abortion.

Access to safe abortion care is an essential component of health care. Unfortunately, a large portion of abortions are considered “unsafe,” and these abortions are a major contributor to both maternal morbidity and mortality. The risk of complications and death from unsafe abortion is inversely related to the provider’s training, skill, conditions for performing the procedure, and availability of appropriate equipment. 

At a national level, governments which expanded reproductive health services (like the UK) such as family planning improved women’s health, in the United States, federal and many state governments have done the opposite through restrictive legislation and decreased funding. 

Twenty years ago, the United States and the United Kingdom had the same maternal mortality rate. Currently the United States has a rate about three times that of the United Kingdom

(link: https://dktwomancare.org/article_pdf/VQFbQlSIeXeIhr9NzYnvyDyDFyJKM9LBNI3l5S92.pdf )

As it stands, hundreds of pregnant American women die unnecessarily each year. The Supreme Court can frame their opinion as constitutional law, but in reality, they have strayed far out of their lane. Evidence-based health policies and good reproductive health care from well trained professionals is needed – not a dangerous majority opinion from political appointees.

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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

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.

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/

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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.