COVID 19 infections from SARS-CoV2 have been the gift that keeps on giving in so many ways such that we never know when it is over. Many government and public health officials prophesied an end to the pandemic with a two-week isolation, but that was obviously a pipe dream. Many medical professionals hoped that with herd immunity to the original strain, we would put this behind us. Again, wishful thinking. For the individual, recurring infections and returning symptoms after feeling better never let one truly breathe easy. While many are focusing attention on the long marathon of Post-COVID or Long Hauler, these articles in focus studied the shorter-term symptoms which often recur up to 2-3 weeks after the infection seemed to have gone away.
From experience, medical professionals and those afflicted by acute COVID recognize that while many recover after 5-10 days of COVID without any subsequent relapse, a significant number fall back into some symptoms within a month after COVID before full and lasting resolution. One article looked at whether treatment with the approved protease inhibitor Paxlovid had a similar rate of symptom relapse as compared to relapse without treatment by the drug. The other just looked at the rate of untreated individuals getting more symptoms after 2 days without symptoms.
A few principles of medical study comparison deserve mention before looking at the conclusions. First, rarely if ever are two studies on humans an exact replica of each other if for no other reason than the people being studied are not the same. Even if they were, the second study would have to work with people who were “tested” in the first study and somehow potentially changed. In this case, there were several more differences. In the one study, they looked at individuals who had been infected with the original SARS-CoV2 strain prior to any vaccine or available medication. They also monitored the group for symptoms up to 28 days after initial infection. The other study occurred when vaccines and Paxlovid was available, which could significantly change outcomes. They only evaluated comparisons between relapsing patients versus non-relapsing patients up to 1 week after the symptoms had subsided for 2 days.
Second, another principle regards what question is each trying to answer. The former looks to describe what percentage of patients experience symptoms up to 1 month after 2 days of no symptoms and which symptoms recur. It does not consider mechanisms or therapy options. The latter looks at whether Paxlovid causes more relapse and evaluates potential immune mechanisms by which the symptoms could recur.
With these principles and contrasts in mind, we can learn a few things from the combination of these studies. Overall, as we know, most recover from acute COVID symptoms in under 14 days. On the other hand, besides those who go on to develop Long COVID, a number estimated at 10-30% depending on sources, a signficant number of acute COVID patients get a recurrence of symptoms. This recurrence is defined as going 2 days symptom free before returning to experience some symptom associated with acute COVID. These patients do not go on to experience long COVID but do have this second wave of symptoms lasting beyond the initial 10-14 days of acute disease.
A question arises whether treatment with the drug Paxlovid improves or worsens the risk of symptom relapse. Normally, one would reasonably hope that treatment would decrease relapse, but experience has proven that many still do relapse. Researchers at National Institute of Allergy and Infectious Diseases could not say definitively whether the rates were higher or not in the treated group due to the small number of patients in the study but did produce evidence that alterations in immune function did not seem hindered by the treatment with Paxlovid. This was a possibility as the drug’s mechanism of action was to inhibit a protein enzyme of the virus to limit growth. Limiting viral growth might hinder immune response, but the study indicated that antibody response and T cell response was equal or better in those not treated with the drug. At this point, while we can say that post symptom resolution relapse occurs with or without Paxlovid therapy, it does not seem to be an effect of immune suppression.
Interestingly, in the Paxlovid study, they did look at viral replication after treatment. In the 8 patients with symptom relapse (a very small number in a study), 5 of 8 were shown to have some measurable virus still present which was able to infect cells in a culture. 4 of the 8 required an additional chemical to enable infectivity, but at the very least, some virus seems to persist even after symptom resolution and with relapse.
For those reading this and wondering what in the world you should do with this information, I offer the following. Other studies indicate that resurgence of symptoms (without a symptom free period) are often related to a heightened inflammatory response. For those patient in our care, we advise increasing anti-inflammatory natural therapies and less focus on anti-viral therapies. For these describe as having symptom free days followed by relapse, we include the anti-inflammatories, but given these studies, we will do another 5 to 7 days of anti-viral support like zinc, C, quercetin, and “medications we know work”.
Helping our patient restore healthier more abundant lives requires keeping up with new studies like these while applying the time-tested principles of discerning clinically useful information out of studies like these.
Davey M. Smith, Jonathan Z. Li, Carlee Moser, Eunice Yeh, Judith S. Currier, Kara W. Chew, Michael D. Hughes, Eric Daar, David Wohl, Joseph Eron, Arzhang C. Javan, Mark Giganti, Justin Ritz, Lara Hosey, Jhoanna Roa, Nilam Patel, Kelly Colsh, Irene Rwakazina, Justine Beck, Scott Seig, Courtney Fletcher, William Fischer, Teresa Evering, Rachel Bender, Sandra Cardoso, Katya Corado, Prasanna Jagannathan, Nikolaus Jilg, Alan Perelson, Sandy Pillay, Cynthia Riviere, Upinder Singh, Babafemi Taiwo, Joan Gottesman, Matthew Newell, Susan Pederson, Joan Dragavon, Cheryl Jennings, Brian Greenfelder, William Murtaugh, Jan Kosmyna, Morgan Gapara, Akbar Shahkolahi, Peter Kim, William Erhardt. Recurrence of Symptoms Following a 2-Day Symptom Free Period in Patients With COVID-19. JAMA Network Open, 2022; 5 (10): e2238867 DOI: 10.1001/jamanetworkopen.2022.38867
Brian P Epling, Joseph M Rocco, Kristin L Boswell, Elizabeth Laidlaw, Frances Galindo, Anela Kellogg, Sanchita Das, Allison Roder, Elodie Ghedin, Allie Kreitman, Robin L Dewar, Sophie E M Kelly, Heather Kalish, Tauseef Rehman, Jeroen Highbarger, Adam Rupert, Gregory Kocher, Michael R Holbrook, Andrea Lisco, Maura Manion, Richard A Koup, Irini Sereti. Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment. Clinical Infectious Diseases, 2022; DOI: 10.1093/cid/ciac663
Thanks to Science Daily:
University of California – San Diego. “Treated or not, COVID-19 recurrence seems symptomatic for some: In a study group of untreated COVID-19 patients, more than one-third experienced a return of symptoms after at least two consecutive days of being symptom-free.” ScienceDaily. ScienceDaily, 31 October 2022. <www.sciencedaily.com/releases/2022/10/221031124632.htm>.
NIH/National Institute of Allergy and Infectious Diseases. “COVID-19 rebound not caused by impaired immune response, findings suggest.” ScienceDaily. ScienceDaily, 6 October 2022. <www.sciencedaily.com/releases/2022/10/221006120701.htm>.
Sanctuary Functional Medicine, under the direction of Dr Eric Potter, IFMCP MD, provides functional medicine services to Nashville, Middle Tennessee and beyond. We frequently treat patients from Kentucky, Alabama, Mississippi, Georgia, Ohio, Indiana, and more... offering the hope of healthier more abundant lives to those with chronic illness.