TWiV 961 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 10 December 2022

pdf of this transcript available (link)

Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick.


VR: From MicrobeTV this is TWiV, This Week in Virology, Episode 961, recorded on December 8, 2022. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today from Uganda, Daniel Griffin.

Daniel Griffin: Hello, everyone. I’m recording this, as I told Vincent, outdoors using my iPhone for light. I’m on the banks of the source of the Nile, the eastern part of Uganda here. Hopefully, the quality will be fine. There’s a bit of a storm going on so if you hear crashing that’s OK. That’s just lightning and thunder.

VR: What’s the city that you’re in, Daniel?

DG: It’s called Jinja. You can check that out. All right, well, let me start. Let’s get right into this. “Education is the most powerful weapon which you can use to change the world,” and that’s Nelson Mandela. We’ll continue on our focus on education, and I’m hoping to share a bit of information today. I’m going to start off with measles. This week I am adding measles. So, people may be aware of the current outbreak in Ohio. I was going to say here, but I’m not in Ohio. We’re up to over 50 cases. Last I checked it was 50 died, 20 individuals hospitalized. I just want to say they are all unvaccinated and actually the majority of the cases are in children less than 2 years of age.

As I mentioned, I’m recording this from Uganda and at the Foundation for International Medical Relief of Children (FIMRC) Clinic. On Monday I saw a 2-year-old boy who came in with fever, runny nose, feeling irritable, and that’s an understatement. Just miserable. Eye irritation, cough, poor appetite. This was going on for about five days. Just really miserable according to the mother. Initially there was no rash then after about five days he started to develop a rash on his face, spread down the neck and onto the chest, so we see him he’s got this rash. Lungs were clear. Child just incredibly miserable. Odd white, grain-like lesions inside the mouth on the sides.

Testing, including blood smear for malarial parasites, was negative. That’s a little bit more. The child was not vaccinated so here we made the presumptive diagnosis of measles, started the individual on vitamin A and paracetamol. Just for those parents out there, what a miserable experience for an unvaccinated child to get infected. Influenza. I put up for Vincent here, not doing great on vaccination and the numbers keep increasing.

I know Yogi Berra said the hardest thing to predict is the future, but with the spread of respiratory pathogens, predicting the future is not that hard. If we start to see influenza activity before Thanksgiving, before Christmas, we could pretty much be assured, with all the travel in our country, that all the areas that were green are going to turn to red and dark purple, very high. Vincent, can you see looking at this picture which is the pre- and which is the post-Thanksgiving photo?

VR: For sure, the pre’s got a lot of green and yellow and the post is a lot of purple and red, for sure.

DG: This is continuing to strain our hospitals. This is when we see spread of respiratory pathogens. We’ll talk a little bit as we get into our COVID section just about what we know about respiratory pathogens, how to prevent their spread and the biggest thing for influenza. There’s still time to get your flu vaccine so go out there, get that done and think about your kids. Get them that flu vaccine as well.

Our mpox update. Mpox is not a gay disease or an African disease. Mpox is an infectious disease. I started saying this from the beginning, as I fear that the bias of only testing the MSM population would lead to missed cases and delayed diagnoses leading to more severe cases in women and children and, yes, the article “Mpox, (Formerly Monkeypox) in Women: Epidemiological Features and Clinical Characteristics of Mpox Cases in Spain, April to November 2022,” was published as a rapid communication in Eurosurveillance. One-hundred-fifty-eight mpox cases in adult women ≥ 16 years were reported in Spain. Two of them were pregnant. There was a statistically significant delay in diagnosis, as I suggested, warned.

I do want to highlight the fact that despite a reduction in mpox cases in Europe and the U.S., people continue to struggle in Africa with mpox without access to vaccines and medications. I should say limited access. I’m going to leave a link to a nice PBS NewsHour video. Now on a positive note, on the same lines, we did hear that the government of the Republic of Korea, that’s South Korea, for those of you that have been watching FIFA, through the Korea Disease Control and Prevention Agency, there’s going to be a donation of a batch of mpox vaccines to Africa through the Africa Centers for Disease Control and Prevention, the Africa CDC.

The donation was announced during a bilateral meeting between the acting director of Africa CDC and KDCA commissioner on the margins of the seventh Global Health Security Agenda Ministerial Meeting held in the Republic of Korea in Seoul.

All right, Ebola. Perfect timing to be talking about Ebola and being in Uganda, mostly good news here. Just this week, you can tell me if this was updated, Vincent, Uganda discharged its last Ebola patient. We may need to wait a little longer to get past the incubation period but all signs look good. When I was in Bududa I had the opportunity to see patients with one of the clinical officers Jamila Makame. She actually did a CME on Ebola for the clinic on Tuesday evening.

In Uganda the expectation is not if, but when the next Ebola outbreak will occur. This is the fifth Ebola outbreak in Uganda. We had one with Zaire in 2019, one with Ebola Taï Forest, we had now five with Ebola Sudan. Here in Uganda it’s a question of when. It’s also a question of how well we’re going to do. Also, I’m going to say a little bit of encouraging news. The night I arrived in Jinja, this town, I arrived in Jinja on my way to Bududa last Saturday night, by the chance meeting with Hans Joerg Lang, who’s actually been part of the Ebola response efforts here in Uganda. Standard science nerd chat where out came the computer and he shared with me a PowerPoint full of data and photos.

I was in heaven. A bit of this is actually in an article that he published, a communication published in the Lancet Infectious Diseases, “Triage of Patients with Ebola Virus Disease.” This can be accessed for free. He’s very focused on ensuring that treatment is focused on creating and maintaining a patient-centered approach with lots of communication and transparency. Actually there’s some pictures of these in the article. But there are these rapidly deployable treatment cubes and you can actually see pictures. There’s this concept of creating this transparent cube where you’ve got the high-risk area inside that cube where the patient is, the patient is being taken care of, but there’s a low-risk zone right outside.

The mother, the family, the community leaders can see what’s going on. I think a lot was learned from the large West African Ebola Zaire outbreak where a lot of efforts were really focused on isolation and containment and not as much effort was focused on treatment. Actually, as I spoke with my colleague, because of this transparency because of the communication, it was felt that this was much more rapidly controlled. The other thing he talked about, I think this is really important, is in the entire country of Uganda it takes, well, from my clinic and the FIMRC clinic in Bududa, it takes about eight hours to get to Entebbe.

That’s the only place in the entire country where you can get an Ebola test So really a lot of effort to let’s have testing access all throughout the country so when there’s a problem you’re not waiting eight hours, 10 hours, 14 hours for that diagnosis while someone is in an isolation situation. You can get that diagnosis, rule it in, rule it out, either start treatment or move forward if that’s not what they have.

All right, COVID. Yes, we are there. There is a post-holiday increase in COVID related hospitalizations in the U.S. after the Thanksgiving holiday. I’m not sure who predicted that wasn’t going to happen but we are seeing a COVID hospitalization increase stressing hospitals already dealing with RSV, the flu, and the other medical challenges.

COVID hospitalizations passed 35,000, being higher than it has been in over three months. We’ll need to see if this translates into an increase in deaths in the coming weeks, so we’ll keep everyone updated. I’m really curious to watch that. Are the vaccines holding out against what I think is the hardest parameter, is deaths? People may get hospitalized for COVID now during that first week, a new phenomenon, they’re nauseated, they just can’t do well at home, maybe that outpatient doc is not comfortable starting Paxlovid so they end up in the hospital, but we’ll have to see, is the effect of the vaccines durable against death, the most severe outcome? You got a hand up there, Vincent.

VR: I have a question. You show this graph of rise in hospitalization, do we know is this for COVID or with COVID?

DG: I think there’s two questions there. The first is, it’s hard to know how reliable is that? Does it get coded as COVID when it really was something else and they tested positive for COVID? That’s important. That’s why I think that death is a much better or harder number to work. The other is there’s two types of hospitalizations for COVID. There’s COVID first week, “I feel crummy,” and then there’s COVID week two, early inflammatory, hypoxic, pulmonary support. We don’t have a different code. We really should have a different code. The other topic that we have touched on periodically is whether most of us have already had COVID, including that chunk of asymptomatic cases.

The MMWR report, “SARS-CoV-2 Serology and Self-Reported Infection Among Adults – National Health and Nutrition Examination Survey, United States, August, 2021 through May, 2022,” was released. In this report we hear that a total of 91.5% of adults included in the NHANES and SARS-CoV-2 Anti-S antibodies had, 91.5% had anti-S antibodies. That could come from infection or vaccination, and 41.6% of a convenient sample of adults had both. They have spike and anti-nucleic antibodies, suggesting that about 44% or so, about a little over 40%, have actually been infected.

As I’ve discussed with Rich Condit, we also know that having anti-nucleocapsid antibodies, this is not 100% sensitive for infection, particularly in those with prior vaccination. I’m going to leave a few links here to the papers that discuss this. The paper, “Serological Markers of SARS-CoV-2 Infection; Anti-Nucleocapsid Antibody Positivity May Not Be the Ideal Marker of Natural Infection in Vaccinated Individuals,” published in JID. I like. That’s like a surgeon title. They looked at the antibody response following vaccination in over 4,000 healthcare workers. Of the participants that went on to become PCR positive, only 26% had detectable anti-N antibodies, so a bit of a surprise there.

The other paper, “Sensitivity of Anti-SARS-CoV-2 Nucleocapsid Protein Antibody for Breakthrough Infections,” my favorite term, “During the Epidemic of the Omicron Variants,” was published in the Journal of Infection. Here they reported a 78% sensitivity with PCR-confirmed infection occurring in the two months after a booster vaccination. They looked at 200 individuals. Still missing some. Not quite as bad as that first paper.

COVID, children and other vulnerable populations. As I like to repeat over and over again, children are at risk from COVID. Now, we’ll move into that pre-exposure transmission testing, have a plan, use tests intelligently, let’s try to be safe out there.

Now, non-pharmaceutical interventions. Masks. Lots of concerns, as I’ve discussed, with the quality of the studies, risk for bias, but a few important studies that are informative. In general, the science favors mask use and suggests a hierarchy, with N95s offering the highest level of protection. We discussed one-way masking for personal protection with KN95s and N95s, but we just heard that CDC director Dr. Rochelle Walensky said wearing a mask is an everyday precaution that people can take to reduce their chances of catching or spreading a respiratory virus. It’d be nice if in addition to her saying that there was something formal out of the CDC. Last week we discussed a single RCT comparing surgical to N95 mask use that failed to show a difference.

As we mentioned, and as I got lots of communications, significant limitations. First off, thank you. Those are some really, I think, well thought out, intelligent, and nice and respectful communications, so thank you for those that emailed me. I’m going to drop in a link to the CIDRAP that provide some good criticisms, and as Vincent suggested last week, this is not a study showing that masks fail to work. Also, the comments by Michael Osterholm  that 70% of participants came from Pakistan and Egypt amid community surges fueled by the Omicron variant later in the pandemic.

As he says, it’s highly likely that many, if not most, of these healthcare workers were infected outside of clinical care by virtue of high community rates of infection. Really important that if we discuss this study, realizing that just because it says those magic words RCT, that doesn’t mean we can trust everything that comes out if it’s not well designed and if there’s limitations. What about eye protection? The article,”Effect of Wearing Glasses on Risk of Infection with SARS-CoV-2 in the Community, a Randomized Clinical Trial,” magic words, published in JAMA Network Open. These are the results that a randomized clinical trial conducted in Norway from February 2 to April 24, 2022.

All adult members of the public who did not regularly wear glasses had no symptoms of COVID-19 and did not have COVID-19 in the last six weeks were eligible. The intervention was wearing glasses, sunglasses, when close to others in public spaces for two weeks. That’s an interesting study. A total of 3,717 adults, mostly women, 65.6%, mean age, 46.9, they were randomized, all identified and followed up in the registries. 87% responded to the end. The proportions with a reported positive COVID test in the national registry were 3.7% in the intervention group and 3.5% in the control group. In this very short, limited RCT, wearing glasses in the community did not demonstrate protective effect for the primary outcome.

Again, lots of limitations here. If looking for small effect, a longer, larger study would be required, and this leaves open questions about eye protections as part of PPE for COVID and other diseases, but interesting nonetheless, and I will keep wearing my goggles with built-in readers in the bottom there. Don’t forget about ventilation. We’ve been talking about that over and over again. We got another big holiday on the horizon, so now is the time to think about upgrading those systems.

COVID active vaccination. Never miss an opportunity to vaccinate. Vaccinated people still get infected, they are just less likely to die or have severe disease. I got asked about this last week, and as an update, Pfizer BioNTech did ask the FDA to authorize the bivalent COVID-19 vaccine for children under age 5. Just for some context, children in this age group already have an authorized vaccine option, primary series, but only 2% of children under 2 and only 4% of 2-to-4-year-olds have gotten their primary doses so far according to the CDC. We’ll have to see the data regarding what benefit this might provide, also a question of what people will be considering uptaking this. For high-risk people I think this will be a very important bit of information. I’m going to be moving right on to COVID, the early viral upper respiratory non-hypoxic phase, that first week.

This has become really simple. Paxlovid number one, remdesivir, three-day IV therapy if you have access, and then molnupiravir. Last and least, monoclonals, pretty much gone. There are now no approved monoclonal therapeutics in the United States. Some other parts of the world perhaps, but really avoid doing those harmful things. Now we move into the early inflammatory. This is week two. I would love a separate code because this is what we care a lot about. Not exclusively. We care a lot about this in understanding those hospitalizations. Steroids at the right time, anticoagulation, pulmonary support, remdesivir early, immune modulation, perhaps with tocilizumab or baricitinib.

Avoid those unnecessary antibiotics and unproven therapies. As I hoped, we actually have a good chunk for our late phase PASC Long COVID. The article, “Data-driven Identification of Post-acute SARS CoV-2 Infection Subphenotypes,” was published in Nature Medicine. This is a study where researchers use the electronic health record data of two large cohorts, INSIGHT and OneFlorida+ from the national Patient-Centered Clinical Research Network.

They created a development cohort from INSIGHT and a validation cohort from OneFlorida+, including 20,881 and 13,724 patients respectively, who were SARS-CoV-2 infected, and investigated their newly incident diagnoses 30 to 180 days after a documented infection.

Through machine learning analysis of about 137 symptoms they identified four reproducible PASC sub phenotypes. One, cardiac and renal. That was about 34% and 25.4% of the patients in the development and validation cohorts. A respiratory sleep and anxiety, 32.8% and then 38.5%. That’s development and validation. Then musculoskeletal and nervous, 23% and, again, 23%. The digestive and respiratory, an interesting grouping here, 10% and 13%. They reported that these subphenotypes were associated with distinct patient demographics, underlying condition before SARS-CoV-2 infection and acute infection phase severity. Really interesting. I’m not going to go through all the subtypes in detail, but that’s subphenotype one, subphenotype two, three and four. Really interesting to look at the different patients that made up these subgroups.

Also, getting a sense of what the acute presentation might foretell for the future. I’m going to wrap it up there in this stormy night on the banks of the Nile with what I always like to say, no one is safe until everyone is safe. I do want everyone to pause the recording right here and go to and click, ‘Donate.’ Even a small amount helps. We are now having our MicrobeTVfundraiser, so during the months of December and January, donations made to Parasites Without Borders will be matched and doubled by PWB up to a potential maximum donation of $40,000 to MicrobeTV. I see Vincent’s smiling.

VR: Yes, I’d like that. I encourage everyone to donate so that we can continue to do our science education work. It’s time for your questions for Daniel. You can send them to Amy writes, “I was just listening to Saturday’s episode of TWiV and heard a question about typhoid vaccination. We see lots of patients requesting vaccines and chemo prophylaxis for foreign travel. Vivotif is once again available at local pharmacies here in Brooklyn Heights. I have prescribed it a couple of times in the last month and patients have been successful in getting it. Until a couple of months ago it wasn’t even listed as an option in the prescription formulary in our EMR. This is good news for our patients as we don’t carry the IM vaccine in our offices. Hope that’s helpful to you and your listeners.” Amy is an emergency physician at CityMD.

DG: All right, well, thank you to my colleagues at CityMD and nice to know we’ve got that oral typhoid vaccine option again. Thank you.

VR: Nina writes, “As a 67-year-old asthmatic I’ve been cautious about possible COVID-19 infection. After all this time I was starting to think either I had already had COVID but was asymptomatic or I was somehow immune. I volunteer regularly in a kindergarten classroom. I received a text last week that a student had tested positive for COVID and three days later I did as well. Thanks to your podcast I had a plan and had started Paxlovid. I’m happy to report that my doctor knew about Paxlovid, verified my last kidney function test, and my disease timeline and I got the prescription right away.”

DG: Well, that is great to hear. So thank you for listening and it’s great to see that we’re having an impact.

VR One more of these feel-good emails, Daniel. Steve writes, “I’m a retired internist in the Philadelphia area. Early in the pandemic one of my professors from medical school, who is 93 and still active in medicine, told me about TWiV and I have been watching ever since. The past weekend, I was visiting my grandchildren in Massachusetts. As I was watching your discussion, Owen, my 19-month-old grandson, climbed into my lap and for a few minutes watched you very intently before climbing down to play with his toys. I have concluded that one is never too old, 93, or too young, 19 months to watch TWiV. Many thanks to you and Vincent for your excellent discussions.”

DG: All right, thank you very much. I’m glad to hear that.

VR: All right, now we have a question from Linda. Question on what we do know when we are most infectious and do rapid tests equate infectiousness. “I had a sore throat, day zero rapid test negative, no surprise with sneezing and a little tired the next day, ran another test on day two continued to approve, figured it was not COVID. A friend mentioned testing much later. I retested four and a half days after symptoms and was strong positive. Retested day six, strong positive. I understand we can show symptoms earlier since vaccinated and the body reacting to the virus, but I was isolated when I was sick and not when I was not and later found out I did have COVID.

When was I likely to spread? I was fine on day four. Just some not unusual for me sneezing here and there. I’m fine now and in positive so I’ve isolated. Michael Mina says rapid tests do correlate with virus cultures and that this is not just non-infectious particles. CDC says most contagious early on. When I was actually negative, granted, I did not test on day three. Any studies on when one is most likely contagious? Things seem to be changing. In retrospect, I might have put people at risk. Thankfully I was masked so perhaps I did not.”

DG: OK, this is a good one. I expect some hate mail from the Michael Mina followers, the cult he’s created there. Let’s talk about the science, because I’m going to be critical. Michael Mina says stuff. He doesn’t always reference an article, he doesn’t always reference the science. He just says stuff. I’m going to say stuff but I’m going to actually reference the science. What is the science? What do we know? We’ve talked about a lot of the data over time. One of the things that we know and this is really well studied from the early days, is the day or two prior to symptomatic symptoms we do see asymptomatic transmission.

As we know, some people continue to antigen-test negative during that period of time. There can be pre-symptomatic, pre-test, positive transmission. Now, when we were doing all the stuff for Netflix and all the movie industry Lionsgate, we were actually doing PCRs because we wanted to pick folks up before they spread it to others. Antigen tests sometimes take that day. Sometimes they actually don’t turn positive until the day after symptom onset. A negative antigen test when you are having symptoms is not a reliable indicator that you’re not infectious. We have a lot of studies that demonstrate transmission during that period of time before the antigen test turns positive.

Now you’ve made your diagnosis with the antigen test. One of the other things we know is that 85% to 90% of transmission occurs one to two days before up to day five of illness. There is some, but a very minimal amount, about 10% or 15%, that occurs day six through day 10. We do know that a positive antigen test may correlate with culture positivity, but a positive antigen test after day 10, this is the science, does not correspond with transmission studies. This whole idea, enough to detect enough to infect, that may be catchy, but show me the science.

VR: I thought I’d give you a break today, Daniel, on the questions since you’re in Uganda and it’s pouring. Time to wrap it up. That’s TWiV weekly clinical update with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you, Vincent, and, everyone, be safe.


[00:28:29] [END OF AUDIO]

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