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This Week in Virology
Host: Vincent Racaniello
Guest: Daniel Griffin
Aired 4 June 2022
Pdf of this transcript available (link)
Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick.
[music]
VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 905, recorded on June 2nd, 2022. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.
Daniel Griffin: Hello, everyone.
VR: Daniel, are we close to kids getting vaccinated, you think?
DG: I think this month is when it’s going to drop down to six months and up, so this will be an exciting month. June 2022.
VR: Excellent.
DG: We’re excited for those. Let’s get right into it. We actually have a lot to cover today. I will start off with my quotation. “Glance is the enemy of vision.” That’s Ezra Pound. I think that’s something we try to do, is not just give a glance at things, but hopefully go a little bit more into detail, hopefully give people a little deeper understanding. Hopefully that education helps them understand what’s going on, what is all this information and hopefully allows them to move forward with a little more confidence.
Let’s start off with our update from the IDSA, the ID Society of America, on famotidine or Pepcid for the treatment of COVID-19. New recommendations. Recommendation One: Among ambulatory patients with mild to moderate COVID-19, the IDSA panel suggests against famotidine for the treatment of COVID-19. Recommendation Number Two: Among hospitalized patients with severe COVID-19, the IDSA panel suggests against famotidine. I already saw we already have our updates on our Web page, if people want to go a little bit into what was the science, the data behind those recommendations. I know there’s still some docs out there giving people heartburn medicine to treat their COVID. Let’s use stuff that is evidence-based and effective.
Children, COVID, other vulnerable populations, children are at risk of COVID, and as we just discussed right up front, we hope this is the month when we have vaccination opportunities for the youngest among us. With summer approaching, we have updated operational guidance for K-through12 schools and early care and education programs to support safe, in-person learning. I guess I would also say, and safe, in-person camp activities.
This is from the CDC, and really, no surprises in here. Just good guidance on ventilation, on testing, on nonpharmaceutical mitigation, et cetera. We’ll put a link in our show notes, because why are we getting school updates? Well, in many ways, this also is going to help with camp decisions. All right. Testing. I’m now saying use our tests intelligently, use tests intelligently. This is one of those coming attraction-type things. Next week we will have the battle of the dogs versus the rapid antigen tests. Stay tuned and be ready for that exciting episode. Active vaccination. As I say, never miss an opportunity to vaccinate. We do have an update here. Just pay attention for a second. Take your notes.
This is this concept of fully-vaccinated versus up to date. If you are up to date with your vaccines, if you have completed your primary series but you’re not eligible for a booster, well, seems like everyone is, you have received one booster but so far are not recommended to get a second booster or you’ve received one booster but are not eligible for a second booster, those tying together. This is, I think, the interpret this for people. Everyone over the age of 50, it’s now recommended that you get your fourth shot. If you do not get that fourth shot, you are not considered up to date and you are again subject to quarantine.
VR: Not getting it. Not getting it.
DG: [laughs] I know, Vincent’s shaking his head but when this drops, I will have gotten my fourth shot. I’m telling you what the recommendations are. I will put in a note here. I think this is really important. I think we do a good job. We try to discuss the science around vaccinations, we try to discuss the timing of second, third, maybe fourth shots for different populations, but one thing I just want to be really clear on: Physicians are united in our endorsement of vaccines.
If you hear a scientist or a physician out there with hesitations, that’s not the other side. That’s the lunatic fringe. There’s no controversy or uncertainty around vaccines. Vaccination’s perhaps the most effective and safe medical intervention we can bring to COVID or any other infectious disease. We’re having discussions about how many doses, the role of those, but there was a really nice Nature article, I think Amy sent it my way, “Communicating Doctors’ Consensus Persistently Increases COVID-19 Vaccination.”
Let’s move on to passive vaccination, Evusheld. We have some exciting developments here. Remember, Evusheld is that passive vaccination approach for individuals who cannot get the benefits of vaccination. We have two really nice articles, real-world experiences. The first article, “Tixagevimab, Cilgavimab,” I’m going to just replace this with Evusheld, “for Prevention of COVID-19 During the Omicron Surge. Retrospective Analysis of National VA Electronic Data,” posted as a preprint. This was a retrospective cohort study with propensity matching and difference-in-difference analysis done in the U.S. VA system. Basically, what you’re trying to do is match your groups to get a sense of the impact.
Participants were veterans aged equal-to-or-greater than 18 years as of January 1st, 2022, receiving VA healthcare. They compared a cohort of 1,848 patients treated with at least one IM dose of Evusheld. They matched these two controls selected from the 251,756 patients who were immunocompromised or otherwise at high risk. I read this paper on Memorial Day, which really seemed appropriate to me. When they compared to those that got Evusheld, they had a lower incidence of a composite COVID-19 outcome.
Let me break it down. Individually, the risk of SARS-CoV-2 infection, the hazard ratio, was 0.34 so a 66% reduction, hospitalization hazard ratio 0.13, so 87% reduction, and they even saw a reduction in all-cause mortality, hazard ratio 0.36. Let’s think about that as about a 64% reduction in all-cause mortality. Pretty impressive real-world efficacy for Evusheld. I like this next article because I think it is hopefully informative for a lot of those physicians who are withholding this precious, wonderful therapeutic for people whose antibody levels are, in their mind, too high.
This is the article, “Efficacy of Anti-SARS-CoV-2 Monoclonal Antibody Prophylaxis and Vaccination on Omicron COVID-19 in Kidney Transplant Recipients,” published in Kidney International. In this study, the occurrence of infection, symptomatic infection, hospitalization, ICU hospitalization, and COVID-19 death was significantly decreased with passive vaccination with Evusheld. If you look through, and there’s a really nice figure that I put up there, it didn’t matter if those antibodies were up or down. There was really consistent benefit versus those who did not receive Evusheld. Don’t withhold Evusheld just because those antibodies look good to you. [crosstalk]
VR: Daniel, give everybody Evusheld every six months instead of vaccinating them every six months. These numbers are great.
DG: They actually are really impressive. The amazing thing is for most of these participants, this is on top of receiving four doses of vaccine. For these individuals who are at high risk, for instance, here we’ve got kidney transplant recipients, why is it sitting on shelves? You and I, we were involved in a little bit of communication recently with a patient of mine that lives in New Jersey. In New Jersey it’s sitting on shelves. They’re very limited in their access, so this patient may have to jump in a car and come here to New York. You folks in New Jersey, you don’t want to be second fiddle to New York, so get on with it. [laughs]
Post-exposure period. That’s where we have testing, quarantine, for those not up to date with vaccines. The CDC has a nice calculator for how long you need to be locked away. Let’s move to the meat of what we’re going to talk about today, the period of detectable viral replication. Much of what we’re going to talk about is going to relate to potential transmission. I want people to be reminded, I feel like I have to keep doing this, reminding people of the stages of COVID-19. People seem to have forgotten this. They’re sick for a few days, now they feel better and they think it’s all over. I’d like to remind people, and I’m going to tell the story of a pediatrician that I’m actually caring for.
This pediatrician initially experienced COVID-19 in the early days prior to vaccine. She was sick for about a week, felt crummy, body aches, fever. That second week, just like Ian Lipkin, then she got the COVID, then she had trouble breathing, and then she actually had the oxygen level drop a little bit. I always love that story. I don’t know if you remember this TWiV, Vincent, where Ian was on. He said, “I had some kind of a virus for the first week and then the second week I got the COVID.” I’m like, “No, Ian, you had the second week, the second week of the disease, the early inflammatory, the cytokine storm.”
She experienced that. Then she recovered, and about day 15, day 16, was feeling better for about a week. Then about eight to 10 days later, she had a couple of days when she felt bad again. Was, “Oh my gosh, is it coming back?” Then she had recovery. She’s gotten her three shots of vaccine and recently she got the COVID again. She was put on Paxlovid and we’ve been working together. About day 3, she said, “I really started to feel better.”
The nice thing was she did not experience much of that second week, the cytokine storm. At about day nine or 10, she still had some viral symptoms, still some congestion, a bit of a headache, but the nice thing, and we’re going to talk about this, is, I think in part because of vaccines, maybe in part because of the Paxlovid, maybe in part because of that prior experience, we did not see much of a second-week cytokine storm.
Hopefully, we’ve got our stages in mind as we talk about the literature. A number of papers. First off, we’re going to start off, I really like this one. If you’re sitting around and you can pause the recording here, bring up this paper because we’re going to talk about one of the figures. Panel B in that figure is what I’m excited about. Here’s the preprint, “Duration of Viable Virus Shedding in SARS-CoV-2 Omicron Variant Infection.”
In this study, the investigators followed symptomatic outpatients newly diagnosed with COVID-19 with longitudinal sampling of nasal swabs for viral load, it’s really RNA copy number, sequencing, and viral culture. A subset of specimens also underwent laboratory-based antigen testing. They enrolled 56 individuals, including 37 sequenced as Delta, 19 sequenced as the Omicron variant. All but one participant had symptomatic infection. We’re mostly talking about symptomatic folks.
Viral load and time to negative PCR did not differ between participants infected with Omicron versus Delta and the duration of shedding of viable virus as measured by time to culture conversion was similar by variant. We’re going to hit on that again. That seems to be consistent. It’s helpful to say that we are seeing the similar kinetics with Delta, with Omicron. They found that over 50% of individuals had replication-competent cultural virus at Day Five, and 25% had culturable virus at Day Eight. I see Vincent taking notes. He’s going to have some comments here.
We’ll also address this again in our next paper. It’s worth looking closely at Figure 2b. Here’s what I want to point out from what we see here in this. Antigen test missed about 20% of the culture-positive samples during the first zero to five days. The majority of the antigen-positive results during days six through 10 were not associated with positive viral cultures. While viable virus is seemingly required for viral transmission, it may not be sufficient. Someone who has viable positive viral cultures may not be transmitting, but it seems hard to transmit without that. We do not know if all these people with viable virus are infectious. Do you have a comment there, Vincent?
VR: Yes. The way they do this is they take the nasal swab, they put it into a dish of cells, and then they see if the cells get infected. They do not quantify the amount of infectious virus. It’s a plus or minus. If you remember the study from the University of Geneva, a couple of weeks ago, they said, “Simply asking if it’s culture positive is not sufficient to understand transmission,” because you don’t know how much virus is there, therefore, just because you’re culture positive, does not mean you’re transmitting as you intimidated.
They should have gone the extra step and done a plaque assay. However, one could argue, what does that mean? Because we don’t know how much virus you have to shed to transmit. I think basing policy on these kinds of results is flawed, because these people who are culture positive, how do we know they’re transmitting? They may not be. You said that many of them are antigen-negative. That’s probably because there’s not enough virus to transmit, I would guess. We have a lot of uncertainty here that needs to be sorted out.
DG: This is a preprint. If you’re listening, the reviewers or the researchers – No, I think these are helpful. Those are a couple of things that it would be helpful for us to know at what level of virus culturability is a person transmitting. Not just the binary. Not just, “hup, there; it’s not there.” Again, how sensitive. We’re thinking, “Boy, if you don’t have a viable culture, how can you spread it?” How sensitive are our assays?
VR: Exactly right.
DG: It’s one point in time.
VR: That’s the other. We don’t know the limit of detection here. These are all issues that need to be addressed.
DG: The next preprint. We got more. “Viral Dynamics of Omicron and Delta SARS-CoV-2 Variants with Implications for Timing of Release from Isolation, a Longitudinal Cohort Study.” They get in the title. Why are people interested? This is a longitudinal study on a university campus looking at 92 SARS-CoV-2 RT PCR positive participants. All completed the initial vaccine series. These are young, vaccinated individuals.
18.5% with Delta, 81.5% with Omicron. Those add up to 100%. 17% of participants had positive cultures beyond Day Five from symptom onset with the latest on Day 12. 17% versus 25%, slightly different populations but roughly in the same ballpark. About 20% of people still having positive cultures past that Day Six. There was no difference in time to culture conversion by variant or vaccination status.
Let us just go a little bit deeper, but let us start with the introduction, because I think it’s important to get some context. Why do we care so much? Why not just look at everyone? Just lock them away for 21 days. That zero-tolerance that I used to impose on the NHL and the movie industry, and then we need a negative PCR after 21 days just to be safe. Well, let’s see.
Actually, I like the introduction here because I thought it was reasonable. It was hitting on what are the topics. Here’s what they go on to say. Early pandemic U.S. CDC guidelines for isolation were based on estimates of the duration of infectivity with early studies showing rare culture positivity and transmission beyond 10 days in immunocompetent hosts. Rare, but not zero. I put that in.
Based on increased awareness of the mental health, economic, and social impacts of prolonged isolation, in January 2022, U.S. CDC guidelines shifted to recommend five days of strict isolation from symptom onset or positive test if asymptomatic, followed by an additional five days of strict mask-wearing. This study looks at PCR, RDT, those are rapid antigen tests, and viral culture. It didn’t include any transmission tracing.
First, Figure 1, I’ve got this up. Nice to watch, this incredible amount of spread. I’m glad they actually– Here’s a plot where we actually get to see in Figure 1, all the CT values all over the place. Some are up there, less than 15, some are greater than 35, even at zero and 1 and 2. I would’ve liked if they had one where you got to watch each person. Pull all these people out, because otherwise, it gives you this sense that for everyone it’s a linear experience or a unidirectional predictable, but it’s all over the place.
We also have in this figure in Section D, we can see, again, binary, the culture growth, whether or not it’s negative or positive. We see most of the positives being clustered early, interesting. They’re getting more positives on Day Four than they did on Day One or Two, and then you see it tail off, but we’re still getting positive viral cultures on Day 12. Actually in this, a little bit more on 12 than we did on 10 or 11. Interesting. Again, all the caveats we’re putting here is how does that positive viral culture correlate? A positive viral culture on Day 12, is that person infectious? Negative viral culture on Day 12, is that person non-infectious? Do we have the sensitivity and qualification there? Just to go a little more.
What are we going to do to determine who is still infectious after Day Five? Because this is about 17% still have positive viral cultures. This is consistent. We’ve said for a while about 15% of transmission is occurring after Day Five. Here we get to Table 3 and those rapid tests. This is only a small subset, so only 14 participants were in this antigen sub-study. Here the numbers are from the date of the diagnostic test. Here when you looked at people after Day Five, the positive predictive value for antigen testing for cultural virus was about what was reported in the first study with this being only about 50%.
I’m going to try to pull these two together, and Vincent, you can tell me if I’m leaving something out. The majority of people have a limited period for which they remain viral culture positive for SARS-CoV-2. I tried to make sure I was being really exact with the language here. Beyond five days from symptom onset, about 20% of people remain culture positive. No major differences in culture conversion or viral load decay between Delta and Omicron variants in these studies among participants who used an antigen, rapid detection test, to check for, let’s say, infectious virus. People are trying to use rapid tests to say, “Do I have culturable virus in the first five days?”
About 20% were missing positive viral cultures during what we know is the peak of infectiousness. Really good on day one for diagnosis. I don’t want people to walk away with, “Oh, those antigen tests don’t work.” The antigen tests are incredibly good for what they were designed and validated to do, and this is, it’s Day One, you started symptoms yesterday. Today you do your antigen tests, maybe you repeat it tomorrow, higher than 90% sensitivity for picking up those folks, but if you’re using it for this other purpose, which is, is this a surrogate for viral culture positivity?
After Day Five, only about 50% of people with a positive antigen test had positive viral cultures and the majority of people with positive viral cultures had negative antigen tests. I will say, enough to detect does not mean enough to infect with antigen test, and a negative test after Day Five does not necessarily mean a negative viral culture.
VR: I would argue that the negative antigen tests, even if it’s viral culture positive, probably means you’re not transmitting because you’re not shedding enough virus to give you an antigen test positive and you’re not shedding enough virus to transmit. Again, this is culture positivity. This is not a useful metric. The Geneva study concluded it’s not a good metric for how much virus you’re shedding. These people who are culture positive, I think most of them, it’s irrelevant. They’re not shedding enough to transmit, maybe it’s not always zero, maybe a few are, but the vast majority are not, so culture positivity simply isn’t good enough.
You mentioned an earlier study where they looked at culture positivity and transmission by contact tracing. I think that’s flawed. Knowing who transmitted to who is a flawed study. It doesn’t even come close to a plaque assay in its accuracy. Let’s leave that behind and just say culture positivity is not necessarily what you want to hang your hat on if you’re going to make policy. The other thing, Daniel, is, are we going to do this forever? If not, and I don’t think we are, you might as well stop now because nothing’s going to change in a year or two, or three, or four, or five, the virus is still going to be here.
DG: I think that’s a big issue, this how long are we extending isolation on these people? How long are we keeping them in isolation, and what is the implication of what we’re doing? The last preprint, “COVID-19 Symptoms and Duration of Direct Antigen Test Positivity at a Community Testing and Surveillance Site January 2021 through 2022,” if you look at asymptomatic people on Day 11, these are people who tested and they never had symptoms, 33% of them on Day 11 still have a positive antigen test or have a positive antigen test on Day 11.
Should one-third of these people be continued in their lockup until 13 and 14? Where’s the science here? What’s the public health implication? Hopefully, well, all these links will be shared in our show notes so people can see why this is not so straightforward. OK. All right. Now we have all this background. We’re finally ready for the article. “Virological Characterization of Symptom Rebound Following Nirmatrelvir-ritonavir ( Paxlovid) Treatment for COVID-19,” posted as a preprint. Here, the researchers enrolled seven individuals, it’s not a lot, with recurrent symptoms after following Paxlovid treatment. I’m going to translate, high RNA copy number was detected at enrollment and for a median of 17 days after initial diagnosis.
Three of seven had culturable virus, we’re not sure what that means, as we’ve discussed, for up to 16 days after initial diagnosis. No known resistance-associated mutations were identified. This is actually, again, one of those papers, I think people should look at the figure. It’s a wonderful figure, but there’s a few things here that I think are important. As we discussed on the last TWiV with regard to David Ho’s paper, this is not a person going through the first week or the viral phase, then experience the inflammatory phase or second week like our friend Ian Lipkin, when they get the COVID after having a cold, and then feeling this relapse, then having a period of time before this.
These individuals are still within the 14 days, they’re still within the two weeks of the acute illness. These patients are reporting not having much of an experience of that early inflammatory phase, that cytokine storm, and then getting a few days of symptoms at the end of that second week beginning of the third. When this happens, the researchers found that there were positive antigen tests, positive PCR, and in some cases, virus could be cultured in their BSL-3 lab.
I think if you look at the figure, you can see people come in with symptoms, they have this period of the early inflammatory phase, they’re feeling pretty good, but then symptoms, nine, 10, 11. These are those folks, the current idea would be, “Boy, it’s Day 11. You’re not feeling well. You’re not really supposed to end your isolation.” Well, the current CDC is then you tag on another 10 days because you’re not feeling well in this scenario. I probably can guess how you feel about that, Vincent.
VR: Yes, I think we mentioned a similar case last time, where are these people, do they need to be quarantined, locked up for an additional period of time? I don’t think this makes a case for that. As we have said multiple times today, just because you’re culture positive doesn’t mean that you’re transmitting. I think this is a feature of the pathogenesis and doesn’t have implications for transmission.
DG: I would have loved to see, and then we have seven other people who didn’t get treatment who were somehow matched and had the same information. Is this in any way different than just the natural history of the disease as the CDC suggests.
VR: You should know, Daniel, you see patients. Aren’t there a subset that have symptoms, they feel better, and then they have more symptoms…
DG: Yes, we see it all the time, and I think what may be happening is now that other clinicians feel like they can do something, they’re doing something and then they’re seeing the person the next week to see how they’re doing, I’ve been doing that for two years now.
[laughter]
DG: If anything, I’m just seeing that they do better during the early second week and I’ve got to keep reinforcing like, “No, no.” The second week is when I’m concerned. The first week, it’s when you’re concerned because you feel crummy. The second week is when you end up becoming hypoxemic and you might end up on a ventilator. I had this with a patient recently. It was Day Five. They’re like, “I’m all better now.” They’re an older, high-risk person and they have home nursing, hopefully to try to keep them out of the hospital, sending the nurses away, I’m all better. I’m like, “No, no, no. You’re about to enter that second week. That’s when I’m concerned, that’s when you might need the nurses.”
All right. Remember, this is not a five-day illness. This is a two-week acute and it’s that second week, which is the high-risk for the cytokine storm. What do we do? What should we be doing during this time? Number One, Paxlovid; Number Two, Remdesivir; Number Three, we’ve got Bebtelovimab or monoclonal antibody; Number Four, Molnupiravir, and the big thing, don’t do things that are harmful. I’m spending my days now stopping steroids and stopping antibiotics in acute COVID cases, because apparently, there are physicians out there not comfortable with antivirals but very comfortable suppressing someone’s immune system during the first week.
Well, how does that go? The article, “The Association Between Pre-Exposure to Glucocorticoids and Other Immunosuppressive Drugs With Severe COVID-19 Outcomes,” was published in Clinical Microbiology and Infection. The authors found here that folks on glucocorticoids, this was 20 milligrams per day or higher of prednisolone, that’s about three milligrams or so of Dex, so six would be quite a bit, were associated with, what are the bad outcomes? Your adjusted odds ratio 2.5 for hospital admission, cardiac events adjusted odds ratio 1.93, pulmonary embolism adjusted odds ratio 2.78, and mortality adjusted odds ratio 3.48.
Being on steroids during that early replication phase was associated with an increased risk of ending up in the hospital about two- to three-fold, about double the risk of a cardiac event, about triple the risk of a PE, and about a 3.5-fold increase of dying. Yes, not ideal to have folks on steroids during that first week. Then six, remember isolation for the infected, which is getting more and more complicated.
The early inflammatory phase, that’s that second week. That’s when we worry about them. That’s when some folks may require steroids, not the first week, maybe when they start to become hypoxic, when we see evidence of the cytokine storm of the pulmonary phase, pulmonary support, maybe Remdesivir if this is happening early enough and there’s still a viral replication going on, maybe Toci, for those people that progress, anticoagulation. Remember, avoid antibiotics and unnecessary unproven therapies unless there’s a clear indication.
The paper, “Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurological Symptoms Compared With Control Participants Without Infection or Neurological Symptoms,” published in JAMA Network Open. These are the results of a cross-sectional study performed from March 1, 2020 to June 30, 2021 in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurological symptoms or within a study protocol, healthy volunteer and pre-pandemic control groups were also included.
This is an interesting one. I know this has been, I think, maybe taken in an interesting way by the media, so hopefully we’re going to clarify what does this study actually show. Forty-four patients and 10 healthy controls and 41 patient controls, COVID negative without evidence of CNS infection were included. 21 patients were neuroasymptomatic, 23 were neurosymptomatic. Interesting terms. 21 of those neurosymptomatic encephalopathy. In 31 of 35 patients for whom data was available, 89% CSF nucleocapsid antigen was detected. Viral RNA test results were negative in all. Can you interpret that for us, Vincent? Does that mean there’s virus in the CSF?
VR: No. The end protein is probably getting in there from the blood, right?
DG: Excellent. Excellent.
[laughter]
DG: That’s why we get along. Nucleocapsid antigen was significantly correlated with CSF neopterin and interferon gamma. No differences in CSF nucleocapsid antigen concentrations were found between patient groups. Basically, I’m going to go ahead and say there was significantly higher inflammatory biomarker profile in people with the nucleocapsid antigen found in the CSF. Really, the important point here is that this does not suggest that there’s viral neuroinvasion, but rather that there is detectable nucleocapsid in the CSF.
Correlation doesn’t necessarily mean causation, so this may have some – maybe driven by a permeability of the blood-brain barrier. We’re not sure exactly what’s driving it, but no, this is not saying like, “See, I knew that the virus was getting into the brain.”
VR: These cytokines can get in from the circulatory system, right?
DG: Yes.
VR: What’s neopterin?
DG: It’s another inflammatory CSF protein.
VR: All of these could enter via the blood, right?
DG: They really could, yes. All the interleukins that they describe, yes, TNF alpha, et cetera. It is interesting. When people are sick, you actually get increased permeability of the blood-brain barrier and stuff will get in, so it’s not– Tail phase Long COVID, perhaps some progress here. The article, “Generalizable Long COVID Subtypes: Findings from the NIH N3C and RECOVER Programs,” was posted as a preprint. These RECOVER researchers hypothesized that consistent subgroups of patients with Long COVID could be defined based upon a spectrum of phenotypic features in the patient’s EHR records. They ultimately found six clusters or six subgroups.
I was trying to go through these to put them into clinical groups that maybe could be recognizable. I think at this point they might be clusters that are helpful for looking at different trial interventions. Hopefully this is going to be helpful but I’m not sure this translates for me into, “Oh, you fall into Subgroup One and I’m going to treat you this way.” Still waiting for that evidence-based interventions to help us with these subgroups. [crosstalk]
VR: Daniel, if you just did this with people who’ve never had COVID, how many of these would you find?
DG: How many subgroups? This is like that PCA, that principal cluster analysis, where you just get things into buckets. It is interesting because they report that the sickest people are in Cluster One and Cluster Six. It was very hard for me to turn this into something that I could immediately use clinically. The article, “Rehabilitation Interventions for Post-Acute COVID-19 Syndrome: A Systematic Review,” published in the International Journal of Environmental Research and Public Health.
This really touches on this topic that I think we’ve been very sensitive to, is that certain people have post-exertional malaise with COVID. In those individuals, if they’re not properly identified, you can make things worse with a lot of these, exercise them up. It does look here like there are individuals that can benefit. Here, the authors looked at three randomized control trials comparing experimental rehabilitation interventions with no or minimal rehabilitation.
Rehabilitation in the patients that were enrolled seemed to improve dyspnea, anxiety, kinesophobia, that is the fear of pain due to movement. I did not know that word before. Results on pulmonary function were inconsistent but they were seeing improved muscle strength, improved walking capacity, sit to stand performance and reported quality of life. For some individuals, it looks like there is some benefit to enrolling in some of these rehab programs.
No one is safe until everyone is safe. What about the world? The article, “Transmission Dynamics of COVID-19 in Ghana and the Impact of Public Health Interventions,” was published in the American Journal of Tropical Medicine and Hygiene. I have a personal connection with Ghana so I found this interesting. I also think it’s educational to look at the different approaches that the pandemic and the outcomes and they have a really nice chronology of when different things were implemented.
As of January 15, 2022, 153,514 cases of COVID-19 were confirmed in Ghana with 1,343 deaths and 9,020 active cases. Among African countries, Ghana controlled COVID-19 transmission with a 14-day mandatory quarantine for all persons who entered the country. They also employed school and church closures, a lockdown of major cities, and internal movement restrictions.
Ghana and its regions experienced four pandemic waves in 2020 and 2021 with epidemic peaks in July 2020 and January, August, and December 2021. There’s a really nice Table 1 which follows the different interventions and then Figure 1 which then follows case numbers in different regions over time. Looking at all of Ghana, the greater Accra area, the Ashanti area which is up north, lots of limitations the authors are very honest about, such as how accurate are the numbers with testing capacity limitations.
They did, however, analyze the impacts of different interventions, seeing a decrease in case numbers after implementation of mandatory mask wearing and then some increase with relaxation on restrictions on social gatherings. I want to stop right here. This is when everyone goes to parasiteswithoutborders.com and they click on that Donate button. If you like what we do, help support us so we can continue our work. During May, now we’re into June and July, donations made to Parasites Without Borders will be matched and doubled up to a potential donation of $40,000 to help Foundation for International Medical Relief of Children, with focus on our clinic in the Bududa District in Eastern Uganda.
VR: Time for your questions for Daniel. You can send yours to Daniel at microbe.tv. This one came up last night in our live stream. Catherine had a question and I said you better send it to Daniel. Here it is. Some time ago, she took Tamiflu and hemorrhaged, basically. She said, I bled from everywhere except my face. This is a person with– 65 years old, 250 pounds, untreated Sjogren’s, treated for Hashimoto’s. She’s been vaccinated. She wants to know if she gets COVID and she takes Paxlovid, will she do the same, will she bleed out all over again. I said I have no idea, ask Daniel.
DG: No, I’ll also say I have no idea, but the nice thing is we have other options. Some people that we’re worried about, we might do remdesivir as an alternative. The nice thing there is very similar efficacy if given in the first five to seven days. With Paxlovid, we’re talking 89, 88, the remdesivir study, right about 87. We actually have much more experience with remdesivir.
In patients like you, a lot of times – I recently had a patient like this, actually a nurse that I know, worked in one of the hospitals, and they went to one of our ProHealth Urgent Cares. We had a whole discussion. They said, “You know what, I’m just not comfortable.” We sent them over to one of the hospitals where they were able to get their three days of IV remdesivir. Monoclonal is also another option in an individual like this. It’s nice that we don’t just have one option.
VR: Daniel, do you know anything about hemorrhaging after Tamiflu?
DG: It’s got to be rare because it is not something that I’m familiar with.
VR: Josh writes. I’m writing to reach out regarding allergy to chemotherapy drugs. My sister-in-law is in her last couple of rounds of breast cancer chemotherapy, has had allergic reactions to the drug, apparently to carboplatin. She mentioned the doctor saying that since the vaccinations for COVID had started there had been an increase in allergy to some chemotherapy drugs and the conversation became a game of telephone and whispers from other practitioners.
I immediately thought, “Well, there’s a lot of infection with a brand new virus that could be responsible. Maybe some component is similar, maybe there’s another explanation.” Josh has researched and hasn’t found anything. He wants to know, have you come across any links between COVID vaccination and allergy to chemotherapeutics?
DG: No, I have not. Actually, that’s one of those things that I’d be surprised. If there really was a demonstrable connection there, you think you would see someone writing up a paper because those Heme/Onc docs, there’s a lot of MD, PhDs in that arena all excited to publish. I would expect that if there was some significant connection, we would see that, but I’m not hearing that, we’re not seeing that in the literature.
VR: All right. Our last is from Judy who is a retired pediatrician in Southern California and writes, my 23-year-old granddaughter lives in Brooklyn, tested positive in December 2020. In the first quarter of 2021 got J&J. Six months later got a second vaccine. She’s going to France tomorrow, June 3rd, and as her second J&J vax was six months ago, she said should I get a booster? I said yes, having been a TWiV clinical update listener.
Then followed a week of frustration, she went to two different pharmacies, a couple of medical clinics in Brooklyn. Everywhere she went she was told she did not qualify for a booster, but I checked the CDC website, she clearly qualifies. I kept thinking of your mantra, never miss an opportunity to vaccinate. Here’s a willing young woman, eager to protect herself and others, being turned away time and time again. Am I missing something? Why are so many providers refusing to vaccinate? If only they listened to your podcasts.
DG: That’s frustrating. One of the things, I had a conversation with a couple of pharmacists I know today. Pfizer and Moderna, they’re fully licensed vaccines. All you need is a physician just to say they think it’s a good idea. That gets you over this, but yes, it is odd to me that you would have these barriers. People going to get a vaccine and, “No, we’re not going to give it to you.” What odd times we now live in.
VR: She notes that now it’s too late for her daughter to be vaccinated. She’s going to mask and be very careful. That’s probably good enough.
DG: Yes.
VR: All right. That is COVID-19 clinical update Number 117 with Dr. Daniel Griffin. Thank you, Daniel.
DG: Thank you, Vincent. Everyone, be safe.
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