A year ago, I wrote about post-vaccination syndrome (PVS) after mRNA COVID-19 vaccination as a real, patient-reported problem that remains poorly defined and understudied. I described my wife’s experience and called for serious study of patients with persistent symptoms after vaccination.
My wife’s prolonged, relapsing illness prompted me to write publicly about PVS. Her symptoms began approximately two weeks after her third mRNA COVID-19 vaccination in late 2021. Since then, she has experienced inflammatory flares, joint pain and swelling, fatigue, cognitive fog, and substantial functional limitation.
Her case does not prove causation, establish a diagnosis, or define a syndrome. It does, however, make one point clear: When patients say something changed after an exposure and they have not recovered, physicians should listen before reaching for either dismissal or certainty. Medicine has enough of both already.
The Yale LISTEN Study has offered a modest biological foothold. In a small, selected cohort, investigators identified differences in immune cell populations, frequent serologic evidence consistent with recent reactivation of Epstein-Barr virus and herpes simplex virus, and elevated circulating spike protein levels in a subset of affected participants. These findings are intriguing and warrant independent replication. They do not establish causation. Biology rarely signs a confession after one interview.
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Patients who identify with the PVS label often report a fluctuating, multisystem illness: fatigue, exertional intolerance, neuropathic symptoms, arthralgias or inflammatory flares, autonomic symptoms, poor sleep, cognitive dysfunction, and, in some cases, thromboembolic disease. Symptoms may persist for months or years and can substantially impair daily life. The overlap with long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), dysautonomia, mast-cell disorders, autoimmune disease, medication effects, and other post-infectious conditions is extensive. A careful search for alternative or concurrent diagnoses is therefore not optional. Unfortunately, the differential diagnosis is not known for its brevity.
I have a handful of patients whose illnesses seemed to arise without a clear explanation, including new myasthenia gravis, unexplained deep-vein thrombosis, rheumatoid arthritis, autoimmune hepatitis, aortitis, and peripheral neuropathy in a patient with longstanding Sjögren syndrome; I found high anti-spike IgG levels (3,500 to >25,000) and positive nucleocapsid antibodies, indicating prior SARS-CoV-2 infection. I cannot say what these findings mean. These were uncontrolled observations, not proof of cause and effect, and antibody levels do not explain why a patient becomes ill. Still, I find it difficult not to wonder whether, in some susceptible people, infection, vaccination, or the immune response that follows may help trigger, unmask, or worsen an immune-mediated illness. That is not a conclusion. It is a question medicine should be willing to ask.
In patients I have followed, including my wife, inflammatory markers have sometimes risen and fallen with clinical flares, and symptoms have at times been steroid-responsive. That may be meaningful for an individual patient, but it does not establish a unifying mechanism. Persistent antigen, immune-cell dysregulation, viral reactivation, autoimmunity, endothelial dysfunction, and impaired inflammatory resolution remain hypotheses, not proven explanations for PVS as a whole. The immune system, as usual, has not returned our calls.
Diagnosis remains clinical and incomplete
There is no validated diagnostic test or universally accepted case definition for PVS. Cytokine panels may show elevations in IL-6, TNF-alpha, IL-1 beta, or interferon-related signals, but these patterns are heterogeneous and overlap with long COVID, autoimmune disease, infection, obesity, and nonspecific inflammation.
A commercial spike-antigen assay is not available. Normal results do not exclude PVS, and abnormal results do not prove it. Management remains individualized and symptom-directed, borrowing cautiously from long COVID care, ME/CFS, rheumatology, autonomic medicine, and mast-cell treatment approaches.
The treatment frontier: promise, risk, and uncertainty
Corticosteroids may quiet inflammatory flares and provide short-term relief. In my wife’s case, flares often responded until cumulative adverse effects became too costly. Long-term exposure carries familiar risks, including osteoporosis, infection, hyperglycemia, hypertension, cataracts, adrenal suppression, and myopathy. Steroids may be a bridge; they are rarely a permanent address.
Low-dose naltrexone may modestly improve pain, fatigue, sleep, or function for some patients, but controlled PVS-specific data do not exist. Colchicine may be appropriate for a clearly colchicine-responsive inflammatory disorder, including conditions in which NLRP3 inflammasome activity is relevant, but no controlled trials support its chronic use for PVS.
Statins, hydroxychloroquine, and glucagon-like peptide-1 (GLP-1) receptor agonists have established cardiovascular, rheumatologic, metabolic, and obesity-related indications, respectively, but their direct role in PVS remains unproven. GLP-1 receptor agonists may be most useful when gastrointestinal symptoms suggest mast-cell involvement, given their effects on gastric motility and gastrointestinal transit; however, gastrointestinal adverse effects are common and require careful patient selection.
Amlexanox, nicotine, maraviroc, and rituximab have theoretical or disease-specific rationales but no convincing evidence for nonspecific PVS. Nicotine does not displace spike protein, but it may activate the cholinergic anti-inflammatory pathway through α7 nicotinic acetylcholine receptor signaling. That possible mechanism has not translated into convincing clinical benefit and comes with meaningful toxicity concerns. Rituximab should be reserved for a compelling, independently established autoimmune indication. A plausible mechanism is a reason to study a treatment, not a permission slip to declare it successful.
Therapeutic plasma exchange: promising, but unproven
Of the interventions my wife has tried, therapeutic plasma exchange (TPE) has produced the most substantial and durable improvement in her case. Her inflammatory markers have fallen, and improvement in fatigue, cognitive fog, and inflammatory flares has outlasted what she had achieved with steroids, low-dose naltrexone, and supportive measures alone. She has now been off steroids for five months.
At my wife’s first TPE session, we met another woman with a similar, though not identical, illness. Her symptoms began almost immediately after her first mRNA vaccine. She was encouraged to receive a second dose, after which her symptoms worsened markedly. For nearly five years, she has experienced body pain, difficulty ambulating, fatigue, cognitive problems, inflammatory symptoms, and relapsing functional impairment.
We shared my original KevinMD article with her on the day we met. She said she could have written it herself. We recently reconnected, and after five exchanges, she wrote that she had “gotten her life back.” These experiences have obvious human meaning. They are also patient reports, not proof of efficacy. They are a reason to ask better questions, not a reason to announce that the questions have been answered. An encouraging anecdote is not a press release.
TPE, also called plasmapheresis, separates plasma from blood cells, discards the plasma, and replaces it (usually with albumin and saline). It can remove autoantibodies, immune complexes, complement proteins, fibrinogen, cytokines, and other soluble mediators. If a circulating inflammatory factor, pathogenic antibody, or pro-inflammatory plasma environment drives symptoms in a subgroup of patients, TPE could theoretically interrupt that cycle.
The AMBAR trial in mild-to-moderate Alzheimer disease found that albumin-replacement plasma exchange was associated with slower cognitive and functional decline than sham treatment. The 2025 ARGENTIA study, a small real-world cohort with historical controls, reported similar cognitive findings. I cite these studies not as evidence that TPE treats PVS, nor as proof of a single mechanism, but because together they illustrate an important principle: Repeated albumin-replacement plasma exchange may alter a broad circulating biologic environment rather than merely remove one pathogenic antibody or molecule. That conceptual possibility includes removing or diluting inflammatory mediators, autoantibodies, immune complexes, and other circulating factors while restoring albumin’s binding, transport, and antioxidant functions. It is a proof of principle, not a treatment recommendation.
That principle may also matter in the larger post-COVID landscape. A 2025 observational U.K. Biobank study found that SARS-CoV-2 infection was associated with plasma biomarker changes consistent with greater beta-amyloid pathology, particularly in more vulnerable participants; the findings were also associated with Alzheimer-like brain imaging patterns and modestly lower cognitive performance. These observations do not prove that COVID-19 converts mild cognitive impairment into Alzheimer disease. They do, however, raise the possibility that infection-associated inflammation, endothelial injury, blood-brain barrier dysfunction, or impaired amyloid clearance could accelerate underlying neurodegenerative processes in susceptible people, including some already living with mild cognitive impairment.
Whether TPE can interrupt any of these processes is unknown. The AMBAR and ARGENTIA findings provide a rationale to study whether modifying the circulating milieu can influence cognitive decline in selected inflammatory or post-infectious states. They do not establish that TPE clears brain amyloid, prevents progression from mild cognitive impairment to Alzheimer disease, or improves post-COVID cognitive symptoms. That distinction is important, even if it makes for less exciting headlines.
For now, TPE should not be routine or first-line therapy for PVS. Nevertheless, it may be reasonable to discuss in carefully selected patients who have failed less invasive approaches, have evidence suggesting ongoing inflammation or autoimmunity, and understand that any benefit remains unproven and may not persist.
Supportive care: not glamorous, still essential
Supportive care remains the foundation: pacing, sleep optimization, treatment of orthostatic intolerance when present, carefully calibrated rehabilitation that avoids post-exertional crashes, management of pain or neuropathic symptoms, and treatment of mast-cell features when clinically supported. We still need standardized diagnostic criteria, clinically useful phenotypic subgroups, accessible biomarkers, reproducible immune signatures, natural-history studies, and randomized trials in well-characterized PVS cohorts.
Until those gaps close, treatment will remain empiric, individualized, and imperfect. Patients deserve clinicians who take their symptoms seriously, investigate alternative and concurrent diagnoses, offer thoughtful symptom-directed care, and avoid both reflexive dismissal and uncritical enthusiasm for unproven protocols.
One final point: The arrival of mRNA influenza vaccines should intensify, not end, the discussion prompted by PVS. Approval establishes that a product has met the regulatory standard for its intended use; it does not settle every mechanistic question, identify every susceptible subgroup, or eliminate the need for long-term surveillance. Patients with persistent, unexplained illness deserve transparent reporting, careful investigation, and physicians willing to listen without reflexive dismissal or certainty. My wife’s experience does not answer those questions. It is why I believe we must keep asking them.
Harry Oken is an internal medicine physician in practice in Howard County and an adjunct professor of medicine at the University of Maryland. He graduated from the University of Maryland in 1983 and completed internal medicine training there from 1983 to 1987, including a year as chief resident.
He taught ambulatory medicine to internal medicine residents for twenty-eight years as a clinical professor of medicine, and he served for fourteen years as chairman of medicine at Howard County General Hospital. He has been medical director for the Columbia Association since 2007.
Oken has been recognized as a Best Doctor in America and as a Baltimore magazine “Top Doc.” He has published articles in professional journals and is the coauthor of BOOM: Boost Our Own Metabolism.
