Long Covid has forced clinicians to confront an uncomfortable reality. A significant subset of patients do not follow a trajectory of gradual recovery, nor do they fit neatly into existing diagnostic or treatment frameworks. Instead, they present with persistent, fluctuating, multisystem symptoms that strongly suggest immune dysregulation, yet remain poorly served by conventional symptom focused management.
In this context, interest in immunotherapies and monoclonal antibodies has grown rapidly. Patients ask about them. Clinicians search for evidence. Insurers question their rationale. What exists is a growing but fragmented body of data, marked by biological plausibility, early signals of benefit in selected cohorts, and substantial uncertainty.
This article reviews what is currently known, what has been trialled, what remains hypothetical, and why immune targeted therapies may help some people with Long Covid while being ineffective or inappropriate for others.
The Immunological Rationale Behind Long Covid
Multiple lines of research now suggest that Long Covid is not a single entity, but a spectrum of post viral syndromes with overlapping immune mechanisms. These include persistent immune activation, autoantibody production, impaired immune resolution, endothelial dysfunction, and autonomic instability.
Studies have demonstrated abnormalities in T cell exhaustion profiles, altered B cell subsets, elevated inflammatory cytokines, and in some patients, the presence of autoantibodies targeting adrenergic, muscarinic, and other receptors involved in vascular and autonomic regulation. This has led to the hypothesis that a proportion of Long Covid cases represent an immune mediated condition triggered by SARS-CoV-2, rather than ongoing tissue damage alone.
Importantly, these immune signatures are not uniform. This heterogeneity is central to understanding why immunotherapies cannot be approached as a single solution.
Monoclonal Antibodies: What Has Been Explored
Monoclonal antibodies entered the Long Covid discussion initially through their use in acute Covid infection. Early observational reports suggested that some patients with established Long Covid experienced partial symptom improvement after receiving anti SARS-CoV-2 monoclonal antibodies for reinfection. However, these observations were uncontrolled and inconsistent.
More recently, attention has shifted toward monoclonal antibodies targeting immune pathways rather than the virus itself. B cell depleting therapies, such as rituximab, have attracted interest due to parallels with other post infectious and autoimmune conditions. Small case series and mechanistic discussions suggest potential benefit in highly selected patients with evidence of autoimmune features, but controlled trial data in Long Covid remain extremely limited.
Cytokine targeting agents, including interleukin inhibitors, have been proposed where persistent inflammatory signalling is suspected. To date, there is insufficient evidence to support routine use outside research settings. Most available data come from extrapolation rather than direct Long Covid trials.
Intravenous Immunoglobulin and Immune Modulation
Intravenous immunoglobulin has been considered in Long Covid primarily due to its established role in immune mediated neuropathies and dysautonomia. Case reports describe improvement in selected patients with small fibre neuropathy, autonomic dysfunction, or suspected immune mediated neurological involvement following Covid infection.
However, IVIG is resource intensive, costly, and not without risk. Evidence remains currently limited to small cohorts and individual cases, with no large randomised trials in unselected Long Covid populations. Where benefit appears to occur, it is most often in patients with objective neurological findings or overlapping autoimmune diagnoses.
Why Some Patients Respond and Others Do Not
One of the most important clinical insights emerging from Long Covid research is that immune therapies are unlikely to benefit all patients equally. Long Covid includes inflammatory dominant phenotypes, autoimmune dominant phenotypes, autonomic dominant phenotypes, and those driven more by metabolic or endothelial dysfunction.
Patients with demonstrable autoimmunity, immune mediated neuropathy, or clear inflammatory signatures may theoretically benefit from immune modulation. Those whose symptoms are driven primarily by autonomic instability or post exertional symptom exacerbation without active immune inflammation may not.
This distinction is critical. Treating Long Covid as a uniform condition risks both therapeutic failure and unnecessary harm.
Risks, Costs, and Ethical Considerations
Immunotherapies are not benign. Monoclonal antibodies and IVIG carry risks including infection, infusion reactions, thrombotic events, and immune suppression. In Long Covid, where many patients are already physiologically vulnerable, risk benefit assessment must be particularly rigorous.
Cost is also a significant factor. Treatments such as IVIG or biologic monoclonal antibodies can cost tens of thousands of pounds per year. In the absence of strong evidence, routine use raises ethical and health economic concerns.
These realities underscore why most experts currently advocate restricting immune targeted therapies to clinical trials or highly selected cases under specialist supervision.
What Clinicians Can Do Now
While definitive immune therapies remain elusive, clinicians are not without tools. Recognising immune mediated patterns, screening for overlapping autoimmune disease, identifying autonomic dysfunction, and validating post exertional symptom exacerbation are all evidence informed steps.
Equally important is avoiding harm. Over exertion, premature return to work, and inappropriate graded exercise can worsen immune and autonomic instability. Understanding the biological rationale behind pacing, rest, and symptom guided management is itself a form of immune protection.
Research Directions and What Remains Unknown
Ongoing studies are exploring immune phenotyping to identify subgroups most likely to respond to immunotherapy. Trials investigating antiviral persistence, immune reset strategies, and targeted immune modulation are underway, but results are still emerging.
Key unanswered questions include whether immune abnormalities represent drivers of ongoing symptoms or downstream markers of earlier injury, whether immune modulation can restore normal regulation rather than suppress symptoms, and how to identify responders without exposing non responders to unnecessary risk.
Conclusion
Immunotherapies and monoclonal antibodies represent a biologically plausible but as yet unproven approach to treating selected cases of Long Covid. Current evidence supports caution rather than enthusiasm, precision rather than generalisation, and research rather than routine use.
For clinicians, the task is not to dismiss immune based approaches, nor to adopt them prematurely, but to integrate emerging evidence with careful patient selection, honest uncertainty, and a commitment to do no harm.
Long Covid challenges medicine not because it lacks treatments, but because it demands a more nuanced understanding of immune dysfunction, recovery, and variability than many current systems allow.
Selected Evidence and Further Reading
Emerging research has been published in journals including Nature Immunology, The Lancet, BMJ, and Clinical Immunology, alongside cohort studies from the UK, Europe, and the United States examining immune dysregulation, autoantibodies, and post viral syndromes following SARS-CoV-2 infection.
Disclaimer
This article is for educational and informational purposes only. It does not constitute medical, advice and should not replace individual clinical judgement or specialist consultation.
Long Covid Journey 