Jason C. Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS, is a clinical professor at Temple University (TU) School of Pharmacy and a clinical pharmacy specialist in infectious diseases at Temple University Hospital in Philadelphia, Pennsylvania. He also is director of the PGY2 Residency in Infectious Diseases Pharmacy at TU.

Jason Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS*

COVID-19 has been quite an educator. One of its lessons has been a work in progress on how clinicians keep up-to-date on best practices while dealing with the sheer volume of studies about the disease. Fortunately, many groups have created guidelines to treat COVID-19, including individual hospitals, government organizations like the National Institutes of Health,

and professional organizations such as the Infectious Diseases Society of America (IDSA).

 No organization can claim a “best” guideline, but because I have had the experience of serving on the IDSA guideline panel for the past 2 years, I would like to explain how these guidelines have been developed “on the fly” and how the recommendations are formulated.

The IDSA guideline panel consists of a mix of clinicians and methodologists. The clinicians are a mix of physicians and pharmacists, with expertise in infectious diseases, microbiology, pediatrics, and critical care. The methodologists serve as experts in research design and analysis and construct the evidence summaries for clinical questions as they develop. Some of these questions are natural, such as when novel therapies are made available by emergency-use authorization or when arms or analyses of landmark trials are completed. Others are prompted by panel members themselves. Meetings occur on a generally biweekly basis using video conferencing software.

The literature evaluated is primarily randomized controlled trials (RCTs) when they are available, but other types of studies are considered when RCTs are not available or when the alternative design appropriately supplements RCTs, such as real-world safety studies. Peer-reviewed publications are, unsurprisingly, preferred, but the panel also evaluates data in preprints. When press releases are the only data available, preliminary assessments are made, sometimes with the benefit of additional data.

The methodologists create evidence summaries and synthesize clinical questions by PICO format (population, intervention, comparison, and outcomes) using GRADE (grading of recommendations assessment, development, and evaluation working group) methodology.

 If data from more than 1 trial are available with comparable outcomes, the data are analyzed together. This evidence is reviewed by panelists before meetings and discussed during them, often leading to a recommendation.

Only clinical panelists vote on recommendations, and the language is specific (

). The term “recommend” is a strong one, made only when the panel believes that both the evidence is of sufficient quality and that the recommendation could be reasonably adapted into policies. The term “suggest” is used when the evidence is not sufficiently strong to justify a recommend (such as due to fragility of the effect found) or when the intervention is one that patients may reasonably refuse. Thus far, the high threshold for a 

has limited this level to only one positive recommendation—the use of glucocorticoids for patients with critical COVID-19 disease.

Although the most-read statements from the panel are the recommendations themselves, effort is also directed into clarifying the recommendations with the remarks that accompany them, which may direct clinicians to specific subpopulations in whom benefits appear most substantial or may clarify other elements of the recommendation, such as dosing. The evidence summary is also posted for each recommendation, containing the data evaluated from the included studies. Also, a narrative is written for each recommendation to put it into context.

Admittedly, the guidelines are not the most user friendly. Because COVID-19 is a novel disease and each therapeutic has been studied compared with standard of care, each PICO is written as a comparison between the agent and not receiving the agent. This makes many of the recommendations read as binary, without the nuances that clinicians consider in their patient evaluations. Clinical questions are more along the lines of “How should I treat this patient with COVID-19 who requires supplemental oxygen?” than “Should remdesivir (Veklury) or not remdesivir be given to patients who require supplemental oxygen?” With few exceptions, COVID-19 therapies have not been studied comparatively, so choosing therapies to preferentially recommend is difficult and is done, instead, by strength of evidence and quality of data.

Another area in which miscommunications occur is in the use of therapies in combination. As the science of studying therapies during the pandemic has progressed, combination therapies have been studied more frequently as comparisons with standard-of-care regimens, strengthening the ability to recommend them. However, important deficits in the knowledge base about combination therapies remain, and the guidelines largely eschew recommendations about them where those deficits exist. Because the guidelines take an evidence-based approach, recommendations are dependent on the evidence generated.

The guidelines are quite long, keep growing, and will hopefully continue to grow with the evaluation of successful therapies. Most people look no further than the recommendations and possibly the remarks, but reading the narrative is important when these recommendations do not line up with preexisting expectations or are not sufficiently clear. The evidence summary shows the data the panel used to determine its recommendation and is included near the end of each section, showing not only the data from the studies themselves, but the determination of the strength of those data, the risk of bias from the study design(s), and the certainty that the effects seen are real.



Clinicians commonly note that “guidelines are not rules” but that people often treat them that way. The oft-mentioned phrase in guidelines that they do not substitute for clinical judgment is important though, in ways that I did not appreciate before serving on the guideline panel. First and most obviously, not every patient’s nuance will make it into a clinical trial. The recommendations made are for the broad base of patients with COVID-19—and plenty of exceptions exist. For example, patients with deficient antibody response may benefit from antiviral and antibody therapies in later stages of disease than the majority of patients enrolled in studies.

It is also important for guideline readers to realize that therapies that are not explicitly recommended in guidelines may have utility for some patients. For a therapy to reach the level of a guideline recommendation, it needs a sufficient evidence base for a judgment to be rendered. Now that effective therapeutics exist, if a promising but incompletely studied therapy is recommended before sufficient evidence justifies its use, then people may utilize it in lieu of one with greater evidence, potentially causing harm. However, that does not mean those therapies are not good choices for individual patients, and the lack of a recommendation for them does not mean they should be avoided.

Finally, the panel is careful to avoid making recommendations against therapies when clinical trials are continuing to explore their utility. Negative recommendations are made when the totality of evidence leads to a conclusion that a therapy is ineffective. However, new evidence can change a recommendation, particularly when populations studied are refined to those most likely to benefit.

Creating guidelines during a pandemic has been a continuous work in progress. Although the guidelines are a living document, parts can inevitably grow stale as the pace of SARS-CoV-2 and COVID-19 therapies change. A notable example of this is the recommendation for neutralizing antibody therapies, for which literature evaluated becomes out-of-date quickly as variants evolve and become less (or more) susceptible to various monoclonal antibodies. To date, the panel has taken the position of recommending that local variants are considered when these therapies are chosen instead of trying to keep up with the rapid changes being seen. Another major challenge is keeping up with the sheer volume of literature generated about COVID-19 therapy. Fortunately, the methodologists consistently review for updates, and most major studies and therapies receive the attention of multiple panel members as well.

The guidelines are a document that, although not without flaws, have hopefully helped guide treatment decisions that have aided numerous patients with COVID-19. The panelists are some of the most dedicated people with whom I have had the pleasure of working, and they are committed to the improvement of our collective work.

Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. Updated April 8, 2022. Accessed April 18, 2022. 

https://www.covid19treatmentguidelines.nih.gov

IDSA guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America. April 11, 2020. Updated March 23, 2022. Accessed April 18, 2022.

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

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With few exceptions, COVID-19 therapies have not been studied comparatively, so choosing therapies to preferentially recommend is difficult and is done, instead, by strength of evidence and quality of data.

Taking It As It Comes: Creating Evidence-Based Guidelines During a Rapidly Changing Pandemic

refreshing experience of my first in-person infectious diseases meeting since 2019. It was wonderful catching up with colleagues and friends that I haven’t seen in years, but it was also nice to talk infectious disease outside of COVID-19.

® is dedicated to just that. We are marking over 2 years since the disease began its domination of our lives, inboxes, and literature. Each 

In Acute Infections, Maureen McElligott, MD; Alice Gallo de Moraes, MD; and Kelly Cawcutt, MD, describe the complex issues that sepsis in patients with COVID-19 represents. Although much has been learned about this issue, complications with antibiotic use, infection control, and appropriate use and interpretation of laboratory results remain issues that clinicians in the intensive care uni t confront.

In Multidrug-Resistant Infections, Eli Goshorn, MD, describes the continued issue of multidrug-resistant organisms in patients with COVID-19 and the often-contrary literature around the topic.

For HIV, Jina Saltzman, PA-C; Caroline Teter, PA-C; Renslow Sherer, MD; and David Pitrak, MD, write an intriguing comparison of what HIV teaches us about COVID-19. I believe you will enjoy the perspective they bring, using a retrospective lens to remind us of history’s lessons and how they inform the future. I appreciate this—as the need to learn and take notes during the beginning of the pandemic was the first editor-in-chief column that I wrote about COVID-19.

In Antimicrobial Stewardship and Prevention, Anna Zhou, PharmD, BCIDP; Richelle L. Guerrero-Wooley, MD; and Karen Tan, PharmD, describe the multitude of impacts that COVID-19 has had on antimicrobial stewardship programs (ASP). They take us through both the obvious (burnout) and subtle (multidisciplinary collaboration) effects resulting from working on the pandemic together. If anyone has the bandwidth to conduct a before-and-after survey of what ASPs look like after the peak phases of the pandemic pass, it could be revealing.

In Emerging and Re-emerging Infections, Jessica Malaty Rivera, MS, and Katrine Wallace, PhD, discuss mandatory vaccine policies for students. This topic may heat up in the future as vaccines hopefully become available for young children soon and as emergency use authorizations for other age groups become full approvals.

Finally, for News and Breakthroughs, I wrote about the experience of developing treatment guidelines for COVID-19 “on the fly.” This piece covers not only how it was (and is) done, but also how to read and use the guidelines from the Infectious Diseases Society of America by hopefully providing a translation from “guideline-es e” to English.

As we recently surpassed the 2-year mark of the pandemic, the May issue reflects on lessons learned thus far.

An Issue About COVID-19

the world again finds itself wrapped in a heavy blanket of COVID-19, driven by the remarkably infectious Omicron variant. How many times can we go through the same pattern? Individuals are fatigued and confused as overpromises and misunderstandings about the degree of protection from vaccines do not live up to their understandably inaccurate expectations. Acceptance of a future with COVID-19 is settling in. Building strategies that improve quality of life as we live with this viral disease requires addressing the unknowns that still exist after 2 years of COVID-19. It is unclear what a future with endemic SARS-CoV-2 will look like. Will it be seasonal, like many other respiratory viruses? This seems likely, although so far changes in dominant variants have affected infection incidence at least as much as the weather has, so it is difficult to measure. Will SARS-CoV-2 be circulating at the same time as influenza and respiratory syncytial virus?

Future variants are inevitable, but their impact on society is difficult to predict. The combination of increased transmissibility and immune evasion led to the rapid dominance of Omicron. The plan to vaccinate the world and decrease the amount of mutable circulating virus needs to be scaled rapidly to protect us all.

“Long COVID-19” is an enormous unknown. Our diminished ability to control Omicron infection means most individuals will likely be exposed to it, with significant proportions of them becoming infected. Will the somewhat milder course of infection with Omicron, whether innate to the virus or due to partial immunity, attenuate cases of long COVID-19? What is the mechanism of long COVID-19, and can we come to a consensus on its definition? This problem may require resources for many years to come.

Antiviral benefits and pathways to access

A significant step forward in 2022 is the availability of oral antivirals. These therapies, highlighted in this issue of 

®, have prevented progression to hospitalization in clinical trials, with nirmatrelvir/ritonavir (Paxlovid) looking particularly promising. However, we know that starting antiviral therapy early in the course of infection is key to its success. How useful will these therapies be in real-world use? When availability improves, will test-to-treat 

protocols be established that shorten time from symptom development to clinician assessment to prescription to dispensing? Because at-home antigen tests are (intermittently) available, can patients utilize them in clinician-aided self-diagnosis to expedite this process?

Our vaccines had been a home run before Delta and Omicron each took some of the shine from their luster. They are still proving highly effective in preventing hospitalization, but can we improve their ability to prevent transmission? Will changing variants require constantly updated vaccines or can a pan–COVID-19 vaccine be created? And how long are they protective? We have learned much in these 2 years, but understanding COVID-19 is a work in progress. Filling the remaining knowledge deficits starts with identification.

The idea of a future with COVID-19 is settling in, and building strategies that improve quality of life as we live with this viral disease are paramount.

A Future of Living With COVID-19: Defining the Known Unknowns

What are the roadblocks with the COVID-19 booster recommendations? What do we do about them? How do we address them? Donald, do you have any suggestions?

Yes. One roadblock is the messaging around boosters. There’s always late-breaking news on boosters and how the eligibility criteria change over time. The public has yet to be able to keep up with those changes. Vaccinators are also finding it difficult to keep up with these changes. When people come to our vaccine events, they’re confused about whether they’re eligible. They show up, but some of them don’t understand that they have to get this booster 6 months after their complete vaccination with the 2-dose regimen. Being able to find [availability for] these boosters is difficult for some underserved populations as well. We see a lot of things happening with the boosters, but boosters are out there for people who want them. One problem is that so many people don’t want them or the first or second dose as well.

Of these 2, I get the sense that the priority is to get people their first and second doses.

Are there enough boosters out there that everybody who wants a booster can get a booster? Jason?

Jason Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS: 

In the United States, there’s absolutely no shortage of supply. If anything, it’s the opposite. We have a relative oversupply. To give a little perspective: I live in New Jersey, which despite popular opinion is a wonderful state, and 1 major way of getting vaccines in the first and second dose into people was through these megasites, old department stores and so forth. Those have closed down. The boosters have been shunted largely to smaller clinics, pharmacy chains, and so forth. So the logistics have changed as well. I wonder what that’s like in more vaccine-hesitant communities. Have similar problems have occurred?

What about employees and employers? There’s a lot of controversy over requiring employers to vaccinate, much less boost, their employees. There’s a lot of pushback. I saw an article in the newspaper the other day that many large retailers are reluctant to implement mandatory vaccination, even large retailers with huge employee populations. They need the employees without regard that unvaccinated employees may turn these large stores into superspreaders. Is that a fair criticism, Jason? What do you think?

I’ll throw this out there: I strongly support vaccine mandates. The only way forward is through vaccinating our public. Booster mandates aren’t something I’m willing to go down. I don’t think it’s the same degree of importance. Truthfully, I haven’t thought about it, and don’t want to think about it yet. I don’t think that’s the major goal. It’s trying to get those first and second doses into more people to protect one another: the customers and especially the patients they serve.

All right, let’s look at the future. Nobody is being asked to do anything but prognosticate, which means it’s uncertain and we’re not going to hold you to it, although we’re being recorded. People are going to be boosted. A year from now, will this influence hospitalization rates? Will the boosting influence severe disease rates? Angie, what do you think?

In vaccinated populations, in immunized populations, we see hospitalization rates decrease. One way or another, people are going to be exposed to the spike antigen from SARS [severe acute respiratory syndrome] coronavirus 2. A year from now we’re probably going to have a lot of unvaccinated people who have at least some residual immunity through exposure and infection. I wish that weren’t the case, because anybody who dies in that situation is a preventable death, but that’s the reality. We’ll see increased immunity at the population level without vaccines.

Immunity from infection can be incredibly variable; it may not be that long lasting. But we also expect this virus to become endemic, which means we’re not going to be rid of it anytime soon. In the United States, we’ll eventually move from being in constant crisis mode to a more “normal.” I hate to use that term, but for a lot of people their lives will go back to being more like they were in 2019, before we had heard about SARS coronavirus 2. In other parts of the world, that process is going to take different periods of time, and that has to do with vaccination.

The real wild card is that this is a zoonotic virus. It’s also a very generalist virus; it can infect many species. We already know that other animal reservoirs have been established, including white-tailed deer, cats, and several small carnivores such as raccoons that are susceptible to this virus. There’s a lot of opportunity to establish an animal reservoir, and we’ve seen zooanthroponotic transmission or, as some people call it, reverse zoonosis, in which people are giving the virus to animals and then they’re giving it back to people. That’s exactly what happened after the mink farm outbreaks in Denmark.

I’m concerned, and several of my colleagues have observed that omicron is so evolutionarily different. One explanation for why it wasn’t detected before it emerged in the human population is that it’s the result of transmission through a different animal species. Given that, it’s going to be very hard to predict the new variants we might be dealing with and how they might impact a vaccinated population. But the good news, as Donald pointed out at the beginning, is that the vaccines have proven to be very cross-protective against severe disease, hospitalization, and death for all the variants of concern that we’ve looked at. That’s going to be the marker that we’re always going to have to look to. In a year’s time, in the United States, Canada, and countries that have adequate access to vaccination, we’ll stop living in acute pandemic times and move into the chronic phase of endemicity.

Did I take from what you said that you’re expecting there to be some degree of herd immunity in a year or 2 in the United States?

I think so. I know we don’t have time to get into this, but this has been confusing for a lot of people who say, “I had COVID-19. Why do I have to get vaccinated?” I don’t think we’ve done a good job explaining to people that infection-acquired immunity exists, but it’s not as reliably robust and durable as vaccination-induced immunity. This has been a real problem, but it does confer some level of immunity. If unvaccinated people are exposed, especially if they’re reinfected and exposed multiple times to the virus, eventually they’ll develop memory immune responses. That may be somewhere on a protective spectrum.

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Drs Angela Rasmussen and Donald Alcendor detail the roadblocks facing COVID-19 booster shots.

COVID-19 Booster Shot Roadblocks

Can you mix and match? In other words, if you get a Pfizer vaccine, can you boost with Moderna? If you get the mRNA, can you boost with one of the recombinant DNA vaccines?

The answer to that about the mix and matching is finally data based. We have some of that information from a study the NIH [National Institutes of Health] has done. They mixed and matched, and they took the people with the 3 US vaccines and boosted them with different combinations of the other ones. Some with Moderna got Moderna, some got Pfizer, some got J&J [Johnson & Johnson]; we have data on all of those. All of them resulted in immune response. We don’t have clinical data on it as to how many infections were prevented, but the immunologic evidence is there and is sound. The answer to your question is yes.

I’ll add that beyond the NIH study there have been studies coming out of Europe, the United Kingdom, and Canada where they have been doing heterologous vaccination just because of supply issues for quite some time. In fact, that’s why I’m also a hybrid. I got Johnson & Johnson in the United States, and then I moved to Canada, and I got a Pfizer shot. Part of that was because I thought I might need one. I wasn’t entirely confident with the J&J data that were continuing to come out. However, part of that was also because I couldn’t figure out how to transfer my vaccination record from the United States to Canada. What made me make the decision was when Canada finally had resolved its supply issues and vaccines were available to everybody, NACI [National Advisory Committee on Immunization], which is Canada’s immunization advisory board, made a recommendation that heterologous vaccination is actually desirable, at least if you start with an adenovirus-vectored vaccine and follow it up with mRNA vaccine. At least people have higher antibody responses.

Now, whether that is going to have a meaningful effect in the real world in terms of increased protection, we don’t know. However, we certainly know that it’s safe. We’ve been doing heterologous vaccinations for a long time for many other vaccine platforms. In general, it’s not something that is a huge mystery. I think it’s only a mystery to people now because they are paying more and more attention to different types of vaccines. Before this pandemic, I certainly wouldn’t think of anybody coming in and saying, “I got whatever the flu vaccine I got is and you got something else. I got recombinant, you got egg based.” I’ve never heard of people doing that. I think that’s just because people probably haven’t put a lot of thought into vaccine brand names.

Actually, I would beg to differ. I think it’s because they put way too much thought into vaccine brands.

I want to answer your first question, that is why they prefer one or other. What I’m hearing, and I’m embedded with vaccine teams to vaccinate folks, what I’m hearing from them is one, they want the Pfizer vaccine because the Pfizer is the one that’s been fully approved. That’s one reason. The other one from Moderna is because if you go to the mix and match results of vaccines, then you see that Moderna had better efficacy when the mixing and matching was done. Some people have read that, and that helps their decision.

People are reading, people are listening. I haven’t seen this before. Angela’s right, people would come in and say, “Give me a shot,” in the past. Not anymore. Tell me about the actual amount of vaccine in the booster. Is it the same as with the first 2? Is it different? Is it different across manufacturers?

The Moderna one is a lower dose. The other 2 are the same is the short answer to that. As Donald pointed out, the response was the greatest in the study with the Moderna vaccine, but the dose was different. It was 100 μg in that mix and match study, and the booster’s being used as 50 μg. However, for the Pfizer and the J&J vaccines, the dose is the exact same. There’s no difference from what people received earlier.

I suppose from a logistics perspective it’s easier. One vaccine, 1 dose, you distribute it, you give it 1, 2, or 3. Otherwise, you must keep track of what you’re giving, right?

Yes, and keeping track of it has become important as the pediatric vaccines have moved forward because there have been a few mix-ups where adult doses have been given and so forth.

I will tell you that some people I know, when they get their children vaccinated, refuse to go and get their booster on the same day. They don’t want there to be any question on that table with these syringes about which one is the adult dose and which one is the pediatric dose. I think that’s fair.

I just want to say something about vaccine formulations here. That is, in the vaccine for the children, there has been a bit of a change in the formulation to include a tris buffer. I got a tremendous amount of media attention to answer this question about why is there a change to include a tris buffer in the children’s vaccine as opposed to leaving it the same formulation. It turns out, I had to explain to people that the tris buffer is there in an amount that wouldn’t affect anybody. They were saying this tris buffer would cause all sorts of problems. However, the tris buffer is there to improve the shelf life of the vaccine. They have misinformation saying that this tris buffer is there to cause all sorts of injury to children who would receive the childhood vaccine.

Isn’t that the same argument people made about mercury as a preservative? That led to the individual doses that were preservative free?

It’s the same argument. It’s the same strangeness. But you understand that people are concerned about their children.

I’m saying that buffer is a plus, too. If you look at where these vaccines are being given, increasing its shelf life is going to be necessary when you move it from large vaccination centers into pediatricians’ offices.

That’s a real difference. People are hearing about this; the problem is they may be hearing about it in a way that makes no scientific sense.

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A panel of doctors explains whether or not someone can get a different COVID-19 booster from their original vaccinations and how they compare.

Mix-and-Matching COVID-19 Vaccinations

Something is buried in your answer that I don’t want to get lost. Early on, people said this is a brand new experimental vaccine, nobody’s used it before, it has never been tried, when in fact as you point out, it’s not that new. It has been developed, and there are diseases for which this has been implemented. That is important. Nobody is talking about that. Why is that?

That’s right. It’s part of the misinformation cascade that is going on. Again, you won’t know this unless you’re most likely in medical or biomedical research.

I was going to say I do think that’s a big part of it, this bevy of misinformation. However, it’s not just that to me. The part that’s facing forward to the public was the fast part. To get it from clinical trials to authorization in a fairly short time is incredible. They didn’t see all the development that went on over those years. However, the only part people have seen is that last part: disease detected, being described, and then a vaccine developed in the space of roughly a year by the time it got to people. What Donald was pointing out and what you’re highlighting is important, that we take that time to describe that history. People don’t know it, and it doesn’t make sense to them. When I describe it, I’m talking about the fact that it’s easy to demonstrate efficacy when you work, when you’re in the middle of a pandemic giving you subjects who develop infection all the time, versus if it’s something that’s less common.

Let’s do a couple of more pieces of housekeeping. Jeff, who would be the prime people who need the booster?

Remember, we started vaccinating those in nursing homes a lot earlier. Certainly, our older patients who are in congregate living, nursing homes, are the first ones we need to give the booster. We also know because they‘re older, they don’t mount as robust of an immune response. Those who originally got the vaccine earlier need to be boosted, not only for preventing transmission, but there may be also prevention of hospitalizations and severe disease that they’ll benefit from with the booster.

What about people who work in high-risk settings, all of us for example? What about other people out, public facing—I’m not sure I like that phrase but that’s one that’s been in use—first responders?

Frontline workers are very important. I think the medical health care folks must be boosted. Then of course: teachers, policemen, firemen, people who work in daycare centers, people who are taking care of children. I think this is also a group of people who need to be boosted as well.

As we talk about the different populations, those frontline workers are really not necessarily the ones who are going to end up in the hospital, however they are the front line, in the public, therefore they’re part of the transmission chain.

Experts discuss who is eligible for COVID-19 booster shots and the misinformation around COVID-19 vaccinations.

Jason Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS*

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