July in Covidlandia

Staying up to date is brat.

Welcome back to some monthly highlights from a place I call Covidlandia, a forgotten land between black and white, carefree and cautious, pandemic beginning and end. Here I present recent news, scientific discoveries, and medical knowledge that caught my attention and that is of interest to primary care. I curate and comment, and realize that one human being cannot possibly keep up with everything. But I try to highlight useful, actionable stuff. January, February, March, April, May, June, and now JULY.

I worked pretty hard on this post, and it will take 10-15 minutes to read, so feel free to come back to it when you have time.

A postcard from Covidlandia, as painted by the 13 year-old Examined artist-in-residence. I couldn’t paint this!

What’s the Covid scenario right now?

July saw Covid cases surge, just as the experts said it would (and as I communicated in my June post). The wave is still getting larger in most parts of the country, although some places like Florida, California, and Texas have already hit peaks and are just starting to decline. KP.3 and its descendant KP.3.1.1 are the prime variants now. Current estimates in the U.S. from researcher J.P. Weiland are that close to a million people are being infected each day, with 1 out of every 37 people having Covid right now. This is 60% higher than the rolling 12 month average. Based on wastewater analysis, here is the visual:

The bad news is that each of these Covid infections has the potential to do some damage, and if we assume a 5% rate of long Covid, that’s 50,000 people per day who will be experiencing symptoms and problems for at least 3 months, if not permanently. The wave should crest for most places in the next couple weeks.

The much better news, at least as far as the CDC can still track this with more scant data reporting, is that weekly deaths are way down from the nightmarish days in which over 20,000 Americans were dying each week. Now it’s probably more like 300-400 a week:

I am certainly seeing Covid in my practice this week, as multiple people came in with symptoms and tested positive. I handled phone calls/messages and some telemedicine visits for Covid, too. Paxlovid has been in demand along with molnupiravir for those with tricky meds. A few people had trouble securing Paxlovid because of supply and demand. I’ve tried metformin with some motivated folks after explaining the results of the COVID-OUT prospective trial which showed a 40% reduction in long Covid rates for those taking a 2 week course. I estimate that a third of those who try metformin struggle to complete the full two week course, especially as the titration goes up to 500 mg in the morning and 1,000 mg in the evening. Gastrointestinal effects like nausea and diarrhea can be significant, in which case I tell people OK to just stop it, or continue at the lower dose they seem to tolerate better in the first week. The other two thirds are able to finish it. Hard to predict who will stomach it.

While deaths and hospitalizations still occur, my more common focus in primary care has been to help prevent long Covid and other complications. One of my still unvaccinated patients developed life-threatening bilateral pulmonary emboli 4 weeks after recovering from Covid, and had to be hospitalized. Unvaccinated people have up to 3X the risk of blood clots in the lungs during and after infections.

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Nasal sprays work!

I’m going to do a whole separate post on how underrated nasal saline is in the treatment of viral upper respiratory infections. I’ve already done posts reviewing and speculating a little on the protective effects of nasal sprays containing saline, nitric oxide, or beta-carrageenan with respect to possibly reducing viral infection rates and the severity of Covid illness.

So this new study published in The Lancet Respiratory Medicine, was right down that alley.

Researchers investigated the effects of nasal sprays on respiratory illnesses compared to usual care (and also looked at promoting physical activity and stress management). Conducted in the UK with 13,799 participants at risk of adverse outcomes from respiratory illnesses, this randomized controlled trial found that both gel-based (beta-carrageenan) and saline nasal sprays significantly reduced the duration of illness compared to usual care (by 1.7 and 1.8 days on average, respectively).

That’s better symptom resolution than Paxlovid was able to achieve with Covid, by the way, and better than Tamiflu with influenza. Intuitively it makes sense that creating an unfriendly nasal mucosa for viral replication factories likely reduces the potential severity of disease, viral load, and other good things. That’s what I’m talking about.

The behavioral intervention did not significantly reduce illness duration. All three interventions (both sprays and the behavioral website) led to reduced antibiotic use compared to usual care. The gel-based spray was associated with a higher incidence of headache or sinus pain despite quicker resolution.

The researchers conclude that advising the use of either nasal spray can reduce illness duration, and both sprays and the behavioral intervention can reduce antibiotic use, suggesting potential benefits from widespread implementation of these simple interventions.

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Feel empowered to wear a good mask, especially on planes, if you choose to

A post I wrote while traveling on a plane last month, in which I documented the terrible ventilation on planes, ended up being one of the more well-read pieces I’ve done. Metrics show that it got 10,000 views, was shared 150 times, and brought in about 100 new subscribers (welcome y’all!). It also earned me a direct message from another doctor who couldn’t handle the idea of people wearing masks, and tried to scare me about potentially dangerous carbon dioxide levels in masks. To which I responded:

Let's break this down into two parts: the size of CO2 molecules and the filtration capabilities of N95 masks.

1. Size of CO2 molecules: Carbon dioxide molecules are extremely small. The diameter of a CO2 molecule is approximately 0.33 nanometers (nm).

2. N95 mask filtration: N95 masks are designed to filter out at least 95% of airborne particles that are 0.3 microns (300 nanometers) in diameter or larger. This size is considered the most penetrating particle size and is therefore used as the standard for testing these masks.

Comparison: The CO2 molecule (0.33 nm) is significantly smaller than the particles N95 masks are designed to filter (300 nm). In fact, CO2 molecules are approximately 900 times smaller than the smallest particles N95 masks are rated to filter effectively. Footballs kicked through goalposts.

Given this size difference, CO2 molecules can easily pass through N95 mask filters. This is why N95 masks do not interfere with normal breathing much - they allow gases like oxygen, carbon dioxide, and nitrogen to pass through freely while still filtering out much larger particles like dust, bacteria, and virus-carrying respiratory droplets.

It's important to note that some people, such as those with COPD, will find the added work of breathing too difficult. They especially appreciate when you mask for them in doctors’ offices, as they don’t have the same freedom to choose as you do.

Two commenters on the note I posted added valuable thoughts:

This has to be one of the dumbest concerns raised about masking. Even if you assume a tiny rise in inhaled PCO2, a marginal increase in minute ventilation will more than easily reduce the resultant increased PACO2. If you are unable to accommodate that small increase in VA, you have bigger problems than a mask.

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This has been thoroughly debunked. Sure, due to recently exhaled breath, the little bit of air in the mask may have a higher CO2 concentration.

However, when we fill our lungs, the vast majority of that volume of air is drawn in through the mask, from outside, just as it normally would. There is slight resistance and pressure drop, but not something most of us can’t handle.

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Gaming the next vaccine update

I’ve heard that the updated vaccines should be here soon - the Novavax nanoparticle vaccine which is targeting the JN.1 variant, and the Pfizer and Moderna mRNA vaccines which are targeting the KP.2 variant. Impossible to perfectly keep up with the variants as these vaccine updates are both a couple steps behind, but hopefully close enough to KP.3 and KP.3.1.1.

The great Dr. Michael Osterholm stated on his podcast that Novavax might be here in as soon as three weeks, with the mRNA vaccines arriving early September. With so many people contracting Covid right now, it feels like many of us won’t make it to that baton pass without a recent case! Dr. Osterholm is older, and while he makes no medical advice to individuals, did share that he plans to get the Novavax as soon as it comes out in several weeks despite the fact that it targets the older but new variant JN.1, and then 4 months later (before the expected holiday surge) he plans to get an mRNA boost targeting the KP.2 variant, which is a bit closer to the variants going around right now. This is aggressive but might make sense for the older crowd concerned about this current wave and back to school. And he is very smart.

I’m tempted to get the Novavax updated vaccine ASAP, too, assuming I don’t contract Covid in the next couple weeks. There is also some chatter that the Novavax shots might provide more durable protection, but head-to-head proof of this within one study is lacking.

If I do contract Covid in the next couple weeks, or if my patients do, it makes sense per the CDC to wait at least 3-4 months after said Covid infection to get an updated vaccination/boost… which would be before the holiday surge.

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Covid is not necessarily just an acute infection; especially in Long Covid it can be a chronic one

A small study published in Science Translational Medicine provided more insight into the complex interplay between persistent SARS-CoV-2 infection and prolonged immune system activation.

Researchers used whole-body positron emission tomography (PET) imaging with a tracer that tags activated T cells to examine 24 participants up to 910 days after initial infection. They found higher tracer uptake in various regions, including the brain stem, spinal cord, bone marrow, cardiopulmonary tissues, and gut wall, compared to prepandemic controls. This T cell activation correlated with long Covid symptoms, particularly in the spinal cord, gut wall, and lung tissue. Furthermore, analysis of colorectal biopsies from five Long Covid patients revealed the presence of SARS-CoV-2 RNA in all samples, with some showing evidence of viral persistence up to 676 days post-infection.

These findings suggest that long Covid may be associated with ongoing viral presence and sustained immune activation, challenging the notion that Covid is solely an acute infection and providing new insights into potential mechanisms underlying prolonged symptoms.

It is unclear to me whether this is replication-competent virus, or just zombie RNA. But research has found that SARS CoV-2 zombies can be one mechanism by which people die from Covid or develop long disease.

It also makes me want to take antivirals and metformin, and use a nasal saline spray.

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No increase in birth defects with first-trimester Covid shots

If I were pregnant I would definitely stay up to date with recommended Covid vaccinations. Contracting Covid while pregnant increases the mother’s risk of severe disease, pregnancy complications, and preterm delivery among other problems.

A study published last month in JAMA Pediatrics found that mRNA vaccines given during the first trimester were not associated with an increased risk for major structural birth defects in babies.

This cohort study used electronic health data from 8 US health systems including 42, 156 eligible pregnancies, with the findings supporting the safety of maternal Covid vaccination in the first trimester

Previously postmarketing vaccine studies have shown no excess risk for pregnancy complications after immunization.

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A second study, also published last month in British Medical Journal (BMJ), showed that while mothers infected during their first trimester with SARS CoV-2 faced higher risks to their own health and for preterm labor, there was no increased risk of birth defects in their babies. Reassuringly, in mothers who received a vaccination during their first trimester, there was no increase in birth defects related to vaccination in this study either. So mothers picked up protection from severe illness by getting a jab with no significant risk to their babies.

In that second study, investigators studied 343,000 liveborn singleton infants in Norway, Sweden, and Denmark who were conceived between March 2020 and February 2022 and were followed for at least 9 months after birth.

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More evidence that vaccines reduced long Covid risks

A study published in The New England Journal of Medicine provides strong evidence that Covid-19 vaccines significantly reduce the risk of developing long Covid (LC). They used health records from the VA Department to build a study population of 441,583 veterans with SARS-CoV-2 infection between March 1, 2020, and January 31, 2022, and 4,748,504 non-infected contemporaneous controls.

Here's a summary of the risk reductions among vaccinated versus unvaccinated veterans with Covid, arranged by variants. Recall that younger people and women have higher rates of LC, so these percentages are skewed towards older, male veterans and probably underestimate the actual rates for all adults:

1. Pre-Delta era (unvaccinated only because we didn’t have vaccines yet):

   • 10.42% developed LC

2. Delta era:

   • Unvaccinated: 9.51%

   • Vaccinated: 5.34%

3. Omicron era:

   • Unvaccinated: 7.76%

   • Vaccinated: 3.50%

Overall trends:

• The risk of LC decreased over time for both vaccinated and unvaccinated individuals.

• Vaccination provided significant protection against LC in both the Delta and Omicron eras.

• 71.89% of the decreased risk was attributed to vaccines, with the rest attributed to changes in the virus

Despite the overall decrease, the study concludes that the risk of LC remained substantial even among vaccinated persons infected during the Omicron era. It’s still worth being cautious when you can, to not catch a case gratuitously during waves, and to treat Covid infections to further reduce risk. And also to be realistic that living in a bubble sucks, so everyone needs to make their own risk/reward calculus, and be compassionate with themselves during illnesses.

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More hating on Paxlovid

Another month, another study chipping away at Paxlovid with small niche trials, and another wave of doctors taking home the wrong conclusion that this antiviral is not worth prescribing. This most recent study, published in the prestigious New England Journal of Medicine, found that giving Paxlovid to household contacts of people sick with Covid did not significantly reduce transmission. It was funded by Pfizer actually.

Bottom line was this:

Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of the participants in the 5-day nirmatrelvir–ritonavir group, 2.4% of those in the 10-day nirmatrelvir–ritonavir group, and 3.9% of those in the placebo group.

So there was a difference of 2.4 - 2.6% with prophylaxis versus 3.9% without, but the difference was too small to be statistically significant. But I see some glaring problems with this study. First of all, there is no way that only 3.9% of household contacts of someone with Covid go on to contract this disease! That’s not my experience, nor has it been yours I’m sure. Even in the NEJM study they cite in their Supplementary Appendix on page 13: “The secondary attack rate among household contacts of individuals infected with the Omicron variant is estimated to be up to 81%.”

So why is the reported transmission rate in this study more than an order of magnitude lower? The authors speculate it’s because so many people have protection from prior infections and vaccines, to which I say scroll back up to the top of this post. If transmission rates in families were truly 3.9% we would not be seeing this summer wave at all.

Instead maybe the low rate is because they excluded family members who displayed signs of infection before randomization from being included in the study. Fair enough. Many of the household contacts were started on antivirals as late as 4 days (96 hours) after exposure, at which time an incipient infection is well on its way.

I’m a non-academic primary care doc, but this study doesn’t pass the sniff test. I don’t prescribe Paxlovid for preventing household transmission because there is no good evidence for doing this, so this study doesn’t change that. With influenza, however, we do offer tamiflu to household contacts who want to reduce their risk of contracting influenza from the person with flu, but there is good evidence of an 80-90% risk reduction there.

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So in addition to my defense of Paxlovid post, in which I reviewed the multiple high quality studies supporting this antiviral for treating people with Covid, I add this next one (actually published in June). If you read commentary on doctor websites, many clinicians won’t prescribe Paxlovid/antivirals because “they’ve read they don't help.” To the contrary:

• A systematic review and meta-analysis of nine observational studies published in The Journal of Infection showed an overall ~25% reduction in long Covid rates for people treated with Paxlovid during acute infection. The details:

  • Early use of oral antivirals reduced the risk of long Covid by 23% overall.

  • Nirmatrelvir-ritonavir appeared to perform better than molnupiravir:

  *Paxlovid reduced risk by 24%

  *Molnupiravir reduced risk by 12%

  • The analysis included 866,066 non-hospitalized patients across nine studies.

  • Early use was generally defined as within 5 days of Covid diagnosis.

  • Long Covid definitions varied, with some studies measuring outcomes at 30 days post-diagnosis and others at 90 days.

  • The protective effect was observed regardless of age or sex.

  • The findings suggest that broader use of antivirals could be considered to prevent long Covid, particularly in light of its high incidence rates (up to 10-30% in non-hospitalized patients in some studies, 50-70% in hospitalized patients). Recall that the other study estimates rates might be as low as 3.5% now.

  • The authors hypothesize that antivirals' ability to lower viral replication rates may contribute to reducing long Covid risk.

  • The study emphasizes the importance of timely antiviral intervention in mitigating long-term Covid effects

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Lightning round

“A study involving 46 million adults in England shows that the incidence of both heart attacks and strokes dropped following COVID-19 vaccination compared to the incidence before or without vaccination.”

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“Despite overwhelming evidence of the wide-ranging risks of COVID-19, a great deal of messaging suggests that it is no longer a threat to the public. Although there is no empirical evidence to back this up, this misinformation has permeated the public narrative. The data, however, tells a different story. COVID-19 infections continue to outnumber flu cases and lead to more hospitalization and death than the flu. COVID-19 also leads to more serious long-term health problems. Trivializing COVID-19 as an inconsequential cold or equating it with the flu does not align with reality.”

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“Visits for symptoms associated with long COVID make up a moderate burden of primary care visits and are marked by recurring symptoms including breathing problems and sleep disturbances.”

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Take home

A presidential candidate will be visiting Philly on Tuesday with her new VP selection, so it seems apropos to ask Claude.ai to summarize this post using bullet points, in the style of a political stump speech.

🤖

• My fellow Americans, the state of our nation's health is under siege from an invisible enemy - COVID-19 continues to ravage our communities!

• Cases are surging once again, with nearly a million new infections every single day. That's 60% higher than the average over the past year, folks!

• But let me be clear - we are not powerless in this fight. We have the tools to protect ourselves and our loved ones:

  • Nasal sprays, both saline and gel-based, can reduce illness duration by nearly two days. That's better than some fancy prescription drugs!

  • Masks work, especially on airplanes with poor ventilation. Don't let anyone tell you otherwise!

  • Vaccines are coming, updated for the latest variants. They reduce the risk of long COVID significantly!

• Speaking of long COVID, it's a real threat. Up to 50,000 Americans every day could be facing long-term health issues. We can't ignore this!

• But there's hope on the horizon:

  • Paxlovid, despite what some naysayers claim, reduces the risk of long COVID by about 25%

  • Even something as simple as metformin can cut long COVID risk by 40%

• To the expectant mothers out there - rest assured, COVID vaccines in the first trimester do not increase the risk of birth defects. Protect yourselves and your babies!

• In conclusion, my fellow Americans, we must remain vigilant. COVID is not just a cold or flu. It's a serious threat that demands our attention and action. Together, we can overcome this challenge and build a healthier, stronger nation!

🙋🏻‍♂️

Take good care out there in Covidlandia.

Spread the word and forward this at will.

And as always, thanks for your support.