Abstract
Long COVID (LC) involves a spectrum of chronic symptoms after acute severe acute respiratory syndrome coronavirus 2 infection. Current hypotheses for the pathogenesis of LC include persistent virus, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction and complement activation. We performed immunological, virological, transcriptomic and proteomic analyses from a cohort of 142 individuals between 2020 and 2021, including uninfected controls (n = 35), acutely infected individuals (n = 54), convalescent controls (n = 24) and patients with LC (n = 28). The LC group was characterized by persistent immune activation and proinflammatory responses for more than 180 days after initial infection compared with convalescent controls, including upregulation of JAK-STAT, interleukin-6, complement, metabolism and T cell exhaustion pathways. Similar findings were observed in a second cohort enrolled between 2023 and 2024, including convalescent controls (n = 20) and patients with LC (n = 18). These data suggest that LC is characterized by persistent activation of chronic inflammatory pathways, suggesting new therapeutic targets and potential biomarkers of disease.
Discussion
In this study, we found that individuals with LC were characterized by persistent activation of chronic inflammatory pathways compared with CCs. These pathways included proinflammatory cytokine signaling, complement activation, metabolic dysregulation and immune exhaustion and persisted for more than 180 days. These findings suggest that chronic inflammation may contribute to the pathogenesis of LC and define potential new therapeutic targets.
We observed that participants with LC exhibited reduced granzyme B and cytotoxic T cell signaling and increased immune exhaustion, suggesting dysregulated cross-talk between the innate and adaptive immune responses. Our findings are consistent with prior reports that the IL-6 and JAK-STAT signaling pathways were upregulated in individuals with LC, particularly in those with cardiorespiratory or multisystem symptoms. We also found that chronic upregulation of IFNγ signaling was associated with LC and correlated with signatures of reduced T cell activation and increased T cell exhaustion, suggesting that chronic immune stimulation may lead to functional impairment of T cells. These findings are consistent with prior observations and suggest the potential role of T cell dysregulation and exhaustion in LC pathogenesis.
Our study also confirms and extends prior reports of metabolic dysregulation in LC. We observed a decrease in amino acid metabolism and an increase in corticotropin-releasing hormone signaling, leptin signaling, fatty acid metabolism, bile acid and beta-alanine metabolism in LC. Moreover, these metabolic pathways correlated with proinflammatory pathways in the LC group, suggesting a link between metabolic dysregulation and chronic inflammation. We also observed decreased activity of the telomere maintenance and DNA damage recognition and repair pathways, chromatin regulation and DNA methylation in the LC group. Impaired telomere maintenance could be associated with premature cellular senescence or apoptosis that may impede tissue repair processes.
Our study is limited by relatively small cohorts of individuals with LC who were predominantly female and with symptom clusters that primarily involved fatigue, brain fog and pain. Larger studies from more diverse populations will be required to assess the generalizability of our findings. Nevertheless, we observed good concordance between the 2020–2021 initial cohort and the 2023–2024 validation cohort. Another limitation is the use of bulk RNA-seq, which limits more detailed resolution of pathways at the cellular level. Therefore, future studies should use single-cell transcriptomic and T cell profiling technologies to provide higher-resolution data. Nevertheless, our observations suggest potential therapeutic targets for LC that could be explored in clinical trials. Because the IL-6 and JAK-STAT pathways were among the top upregulated pathways in participants with LC in both the 2020–2021 and the 2023–2024 cohorts, we have initiated a clinical trial to evaluate the therapeutic efficacy of the JAK1 inhibitor abrocitinib for LC (NCT06597396).
In conclusion, our data demonstrate that LC is characterized by chronic inflammation, immune exhaustion and metabolic dysregulation. Current therapeutic efforts are largely focused on antiviral agents to address potential residual viral replication. However, the lack of efficacy of nirmatrelvir-ritonavir in treating LC highlights the need to explore alternative therapeutic strategies. Our data suggests that the JAK-STAT and IL-6 pathways, and the IFN and metabolic pathways, are potential therapeutic targets that could be evaluated for LC.
Honk if you've been experiencing unexplained and debilitating fatigue, brain fog, and shortness of breath since COVID
Very long rant:
So, I've been dealing with this for about ~~8~~ 9 months (and just treating the symptoms). I noticed a while back that the only things that seemed really helpful for my symptoms are Albuterol (even though I don't have Asthma and glucocorticoid inhalers don't seem to do much if anything) and weirdly Azithromycin (but not other antibiotics). There are a few other things that have been somewhat helpful, but it turns out that everything that does actually help, seems to help inhibits TNF-a.
I've seen a respiratory therapist, allergist/immunologist, and my PC several times. Lots of blood work, x-ray of my lungs, CT of my lungs. My blood work seems to show a lot of random markers for inflammation and different autoimmune diseases that don't fit into any one box, and I've gotten no real answers other than "you seem to have some inflammation. Treat the symptoms and leave us alone."
I've suspected for a while I have some kind of chronic activation of inflammatory signaling overwhelming my immune system, which is then leading to frequent colds and infections and the worsening fatigue. Given the findings from this study which was just published a little over a week ago that seems to make perfect sense.
It seems kind of ridiculous that after everything I've tried that hasn't worked over the last 8 months, and all the back and forth between doctors including seeing 3 different specialists, asking for somebody to run a cytokine panel wouldn't be a big deal right?
I saw a rheumatologist and tried asking about a TNF-a inhibitor because of what I had noticed. She wouldn't even consider it, and when I asked if she would at least order blood work she said that wasn't a thing... Cool.
My boss is getting so sick of me dragging behind at work, and he finally just asked me wtf is going on. I ended up crying in front of him and telling him all of my business, which basically amounts to "I don't know help." He suggested I just message my primary care doctor and ask him to run it because that's what he would do. So I messaged him and asked him to run a cytokine panel. He never responded but I did get a telehealth visit set up where I also ended up crying in front of him too and telling him how much this was fucking up my life, so he told me he was ordering a CT Scan with contrast and got me in early to see an ENT, but he wouldn't order the cytokine panel because he said he wouldn't know how to interpret it.
All of this seriously happened during the past week:
I attempted to get the CT with contrast. 4 different people tried and failed to insert my IV. Finally an RN said she "had to go deep" but got it in and it hurt like fuck (which seemed weird, but I just wanted to get it over with, so I tried to just deal with). Finally like an hour after they got it in, they start the infusion of the dye and the scan. The infusion hurts a lot but again, I just try to deal with it and get it over with.
I can't move bc of the scan so I don't even look at my arm even though it is very fucking painful. The nurse comes to check on me during the scan and suddenly goes "Woah!" It turns out the catheter blew and it was just filling my arm up with contrast dye the whole time. Cool.
She said she was stopping the scan and getting somebody else to insert it, but then she just left the catheter in my swollen arm. She came back with a different nurse who tried to dig around in my other arm unsuccessfully to find a vein (still have the huge bruise from 5 days ago). Finally I just told them to stop because I still had to go to work and take care of some shit.
I walked out of the hospital without even getting the scan, but with a swollen fucked up arm. I took a few minutes to cry in my car and on the way to work. Then I just went to work with one useable arm, took care of the shit that was most urgent but not everything I needed to do bc even though I feel like shit all the fucking time now, I felt way more like shit after that. From that day on last week it's been nonstop angry slacks from my boss, passive aggressive comments from my coworkers, typical bullshit. This is fine.
See the ENT on Thursday. It turns out they have a CT scan in their office, and they don't even use contrast anyway, so they'll just do it there. I'm pretty sure you're not supposed to get back to back radiation like that, but whatever who gives a fuck at this point. More angry slacks from work while I'm in his office. Cool.
Of course everything looks great. He can't help me, but he did at least listen. I asked if he would order me a cytokine panel and he also said he wouldn't know how to interpret it, but recommended I see a different allergist/immunologist. To my surprise I actually got an appointment with her right away on the 30th, so maybe she can at least just order this fucking blood work. I am so fucking broke right now, I can't even afford to pay for it out of pocket.
The ENT also wrote me a prescription for steroids because he thought they would hopefully help with the inflammation. I'm kind of surprised they don't seem to be doing much other than making me more irritable, but I also learned that apparently cytokine over activation can cause glucocorticoid resistance and prevent them from actually reducing inflammation (which maybe explains why GC inhalers haven't helped with my shortness of breath). Cool.
What a journey, how would you feel about keeping us updated somehow? I haven't caught covid but that sounds fucked
Sure, I will definitely try. I somehow went 5 full years without getting COVID. I feel like shit admitting this but I kind of assumed LC was an overblown thing. Lesson definitely learned I guess.
The consensus of most people (including scientists and most doctors) seems to be that especially in the post vaccination era, LC is not a real concern anymore because it only developed in people hospitalized with severe COVID.
I've been fully vaccinated and boosted every year since 2021, and I finally caught COVID in March 2025. I brought it home and ended up literally infecting my entire family including my elderly relatives and my young child.
All the adults in my family were also vaccinated and boosted, and it was also their first time getting COVID. It's always been somewhat difficult to get the COVID vaccine for kids under 5 in the U.S. compared to other vaccines. We had to really push to even get my child vaccinated, but I don't think she had ever received a booster afterwards. (Even this year the pediatrician only offered a flu shot but not COVID).
Anyway, I brought it home, and I tried very hard not to spread it but eventually everybody got it one by one. I definitely had the most severe case, and I ended up being the only one who developed LC.
Also, because of some ridiculous bullshit going on with my doctor's office, I didn't get to start paxlovid until the last possible day. It's expensive as fuck in the U.S., but it's really an amazing drug. It seemed to start working almost immediately, and I made sure all the other adults in my family started within a day or two of testing positive.
I probably won't ever know for sure why I was the only one to develop LC, but my guess would be:
I caught it while I was volunteering in a very crowded free clinic with back to back patients who didn't even realize they were positive until we tested them. So, I spent about 5+ hours in a small confined space getting exposed over and over (we were so packed that day I was literally having to triage people and taking vitals in a very narrow back hallway).
The last day you can start is 5 days after showing symptoms. I literally started on day 5.
I remembered that during early COVID (~2020) people were being told not to take things like elderberry because it could increase inflammation and cytokines. Everything I read when I actually got COVID in 2025 seemed to indicate that shouldn't really be much of a concern as long as you're fully vaccinated and healthy.
That was a very bad idea, because even fully vaccinated and boosted for 5 years, the level of inflammation I was dealing with was no fucking joke. My body is still out of whack almost 9 full months later.
I hope you never get COVID, but if you do, I recommend starting paxlovid as soon as possible if you can.
Paxlovid or not, do everything you can to avoid inflammation while you're sick, and try to take it easy for a while even when you're testing negative.
That's their consensus for every virus-borne chronic disease. Same shit with Lyme/EBV/etc. Sadly, your experience doesn't surprise me at all. I went through something very similar and I've essentially given up on being helped by doctors
I'm sorry to hear that, and it is absolutely ridiculous that doctors are so hesitant to just believe their patients. You deserve to have quality of life, and even if a doctor can't figure out how to help you, they shouldn't be so dismissive just because they're having a hard time figuring out how to treat you.