Amy E. Clarke, DNP, RN, IgCN®
Chief Clinical Officer
Immunoglobulin National Society
Calabasas, California
Luba Sobolevsky, PharmD, IgCP®
President and CEO
Immunoglobulin National Society
Calabasas, California

insightsFrom

Post-acute sequelae of SARS-CoV-2 infection (PASC, commonly referred to as long COVID) has emerged as a chronic multisystem consequence of the COVID-19 pandemic, representing a growing clinical and societal burden. It affects an estimated 1 in 3 survivors worldwide, with symptoms in 36% of patients at 12 months.1,2

02260101 Antibody AS206072578
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Mechanistic studies characterize long COVID as a neuroimmune dysregulation syndrome characterized by chronic inflammation, viral antigen persistence, complement activation, endothelial injury, and autonomic dysfunction. The biological heterogeneity of long COVID underscores the need for immune-restorative therapies that modulate and promote vascular recovery, without suppressing immune function. Symptoms persisting beyond 12 weeks include fatigue, cognitive dysfunction, dyspnea, and autonomic disturbance, reflecting complex immune and vascular dysregulation.2-7

This review summarizes the recent advances in immunopathogenesis and therapeutic modulation of long COVID, highlighting the scientific rationale for targeted immunotherapy and practical considerations for integrating these approaches into multidisciplinary care.

Clinical Presentation

Risk Factors for Long COVID

The risk for long COVID is influenced by host, viral, and clinical factors, underscoring its multifaceted nature (Table 1).1-3,5,7-10

Table 1. Established Risk Factors for Long COVID
Table 1. Established Risk Factors for Long COVID
Risk factorEvidence and clinical insights
Female sexWomen have a nearly 2-fold higher risk for persistent symptoms, influenced by hormonal and immune differences.
Severity of acute infectionHospitalization, high viral load, and oxygen requirement correlate with later cognitive and pulmonary sequelae.
Preexisting immune or metabolic dysfunctionAutoimmune disease, diabetes, obesity, and dyslipidemia impair immune resolution and endothelial repair.
Age, 35-60 yMiddle-aged adults represent the highest burden of prolonged symptoms.
Low baseline antibody titers/delayed seroconversionAssociated with impaired viral clearance and complement overactivation.
Genetic predispositionVariants in FOXP4 and other immune-regulatory genes increase susceptibility to persistent inflammation.
Based on references 1-3, 5, and 7-10.

Impact on Women

Women represent nearly two-thirds of long-COVID cases, a disparity consistently observed across global and US cohorts. Several biological and social factors contribute to this pattern1-3,7,10-12:

  • Hormonal influence. Declining estrogen and progesterone levels influence cytokine regulation and endothelial repair, contributing to fatigue and dysautonomia.
  • Genetic susceptibility. FOXP4 and X-linked immune genes enhance antiviral sensitivity but predispose to immune persistence.
  • Autoimmunity and immune priming. Women exhibit higher baseline antibody reactivity and risk for autoreactive B-cell expansion.
  • Socioeconomic impact. Women report greater productivity loss and caregiving disruption; more than one-fourth of all affected individuals have reduced work hours or have left the workforce temporarily.

These findings underscore the need for sex-aware trial design and for monitoring long-COVID phenotypes through reproductive transitions, pregnancy, and menopause.

Clusters of Symptoms in Long COVID

Long COVID presents with heterogeneous but reproducible symptom clusters that often align with specific immune-pathophysiologic endotypes. Five major clusters account for most patient presentations (Table 2).1-4,7,8,10,13-15

Table 2. Clusters of Symptoms in Long COVID
Table 2. Clusters of Symptoms in Long COVID
Symptom cluster/endotypeDominant features
Neurologic/cognitive Brain fog, memory loss, headache, insomnia, paresthesia, dysautonomia
Cardiopulmonary/vascularDyspnea, palpitations, chest pain, exercise intolerance, orthostatic tachycardia
Musculoskeletal/fatigue predominantMyalgia, arthralgia, post-exertional malaise, chronic fatigue
Gastrointestinal/autonomicNausea, diarrhea, early satiety, reflux, abdominal pain, temperature dysregulation
Multisystem/inflammatory (“systemic”)Low-grade fever, skin rashes, thyroid dysfunction, glucose instability
Based on references 1-4, 7, 8, 10, and 13-15.

Temporal Patterns1,2,9,10,14

Longitudinal analyses show that symptom prevalence declines over time but with variable trajectories:

  • 0 to 3 months: fatigue, cough, anosmia, and low-grade fever;
  • 3 to 12 months: palpitations, sleep disturbance, and neuropathic pain; and
  • >12 months: cognitive impairment, dysautonomia, and musculoskeletal pain.

The severity of acute infection, female sex, and the presence of autoantibodies predict a longer duration and multi-cluster involvement.

Pathophysiology and Immune Dysregulation

Viral Persistence and Immune Activation

Autopsy and molecular studies have demonstrated that SARS-CoV-2 RNA and the spike protein can persist for months in the brains, gut microbiota, and endothelial tissues of immunocompetent individuals. These residual antigens act as chronic immune stimulants, maintaining interferon signaling and cytokine production (interleukin [IL]-1beta, IL-6, tumor necrosis factor-alpha) and driving ongoing inflammation.3,7,13,16

Accumulating evidence indicates that persistence of SARS-CoV-2 antigens in tissues also triggers complement activation and platelet–fibrin interactions, amplifying coagulation pathways and immunothrombosis. While reinfection can also contribute, current studies highlight viral persistence as a key driver of this complement–clotting feedback loop.5,15,17-19

Complement Overactivation and Microvascular Injury

Abnormal elevation of C3a, C5b-9, and mannose-binding lectin–associated serine protease 2 has been reported months after infection. Cardiovascular imaging confirms microvascular endothelial injury, platelet hyperreactivity, and perivascular inflammation, even in patients with mild acute disease. Resistant fibrinaloid microclots likely perpetuate a complement–coagulation feedback loop and tissue hypoxia.5,15,18,19

Immune Exhaustion and Autoantibody Formation

Peripheral immunophenotyping reveals a decrease in naive T and B cells, expansion of CD8+ T cells and non-classic monocytes, and emergence of autoantibodies targeting interferon and G-protein–coupled receptors. These findings help explain fluctuating symptoms and incomplete viral antigen clearance.3,7,16,20,21

Neuroimmune and Autonomic Dysregulation

Neuroimaging and neurocognitive studies reveal microglial activation, reduced frontocortical metabolism, and elevated chemokine levels, which parallel the changes observed in cancer therapy–related cognitive changes. Autonomic testing identifies persistent tachycardia, orthostatic intolerance, and thermoregulatory disturbance, linking systemic immune activity to central and peripheral autonomic networks.4,5,22

Therapeutic Landscape: Bridging Mechanisms to Targeted Interventions

Rationale for Immune-Restorative Therapy

As mechanistic clarity improves, treatment priorities are shifting from symptomatic control to targeted interventions that restore immune balance and vascular integrity (Table 3). The convergence of chronic inflammation, complement dysregulation, and immune exhaustion provides a rationale for therapies that modulate, rather than suppress, the immune response.3,7

Table 3. Representative Immune-Targeted Therapies In Long COVID by Primary Mechanism
Table 3. Representative Immune-Targeted Therapies In Long COVID by Primary Mechanism
Therapy classPrimary mechanism/target
IVIGFc receptor blockade; modulation of T- and B-cell signaling; complement inhibition; neutralization of autoantibodies
Complement inhibitors, anti-C5 mAbsInhibit C1 or C5 activation ? reduce microvascular injury and complement–clotting feedback loop
ECTViral clearance + immune reset (antivirals + corticosteroids + IVIG/mAbs)
FcRn inhibitorsAccelerate catabolism of pathogenic IgG to reduce autoantibody load
Convalescent plasma/hyperimmune IgProvides polyclonal neutralizing IgG and opsonizing antibodies for viral clearance
ECT, early combined therapy; FcRn, neonatal Fc receptor; Ig, immunoglobulin; IVIG, intravenous immunoglobulin; mAbs, monoclonal antibodies.
Based on references 3, 5, 6, 21, and 23-27.

Intravenous Immunoglobulin: Immune Recalibration

Intravenous immunoglobulin (IVIG) exerts multifaceted immunoregulatory effects, neutralizing pathogenic autoantibodies, inhibiting complement deposition, and modulating Fc receptor signaling. Clinical data, although limited, show encouraging outcomes in selected populations (Table 4).

Table 4. Clinical Evidence for IVIG in Long COVID and Related Post-Infectious Syndromes
Table 4. Clinical Evidence for IVIG in Long COVID and Related Post-Infectious Syndromes
Study and yearPopulation/designIVIG dose and durationMain findings/outcomesEvidence strength
Hogeweg M, et al, 2022 (J Intern Med)10 patients with post-COVID fatigue and cognitive dysfunction vs matched controls; retrospective case–control study0.5 g/kg every month × 3-4 coursesSignificant ISARIC-4C score improvement vs controls Most benefit in fatigue, listlessness, brain fog Well toleratedObservational (case–control study)
Thompson J, et al, 2023 (Front Immunol)9 long-COVID patients with neurologic, pulmonary, or cardiac symptoms (6 treated, 3 untreated); open-label case series0.5 g/kg every 2 wk (=3 mo)Marked functional and symptomatic improvement in most treated patients Subjective data No controlsCase series
GrÖning R, et al, 2024 (Int J Infect Dis)16 immunocompromised, vaccine nonresponders with persistent SARS-CoV-2 infection20 g daily × 3 d (median, 60 g total)Clinical cure in 15/16 patients Viral clearance in 13/16 at 4-mo follow-up Safe; 1 case of deep vein thrombosis reportedRetrospective cohort study
RECOVER-NEURO (NCT05350774, NIH)NIH randomized, placebo-controlled trial in patients with neuro-PASC symptoms0.4 g/kg × 5 dPrimary end point: change in PROMIS and cognitive scores Estimated completion: 2026Interventional
ISARIC 4C, UK International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterization Consortium; IVIG, intravenous immunoglobulin; NIH, National Institutes of Health; PASC, post-acute sequelae of SARS-CoV-2 infection; PROMIS, Patient-Reported Outcomes Measurement Information System.
Based on references 6, 23, 26, and 27.

Mechanistically, IVIG down-regulates activated macrophages and normalizes regulatory T-cell signaling. Collectively, these studies support IVIG as a potential immune-reset therapy for immune dysregulation and hypogammaglobulinemia.3,6,23,26,27

Limitations and Considerations3,6,23,26,27

  • No targeted antiviral effect. IVIG does not directly neutralize SARS-CoV-2, and antibody content varies by manufacturing year, leading to inconsistent anti–SARS-CoV-2 titers.
  • Evidence remains limited. Most data derive from small, uncontrolled case series; larger randomized studies such as RECOVER-NEURO are ongoing.26
  • Access barriers. Payor approval often requires documentation of hypogammaglobulinemia or autoantibodies, restricting use despite reported benefit in neuroimmune dysautonomia.

Early Combined Therapy: Disrupting The Inflammatory Cascade25,27,28

In early or subacute long COVID, combining antivirals, corticosteroids, and immunoglobulin may prevent chronic immune activation. Studies show that use of antivirals plus IVIG in antibody-deficient or immunocompromised patients with persistent SARS-CoV-2 antigenemia leads to viral clearance and symptom resolution. Early combined therapy aims to:

  • reduce residual viral load;
  • suppress hyperinflammatory cytokine responses; and
  • reestablish immune homeostasis.

While larger controlled trials are pending, this strategy illustrates that the early intervention could prevent transition to chronic immune activation.

Complement Inhibitors: Targeting The C3/C5 Axis

Persistent complement activation contributes to vascular injury and organ dysfunction in long COVID.5,15 Therapeutic agents under investigation include the following:

  • Recombinant C1 esterase inhibitor. The phase 2 trial (NCT04705831) completed in 2024; the drug reduced fatigue and normalized C5b-9.29,30
  • Eculizumab and ravulizumab-cwvz. Anti-C5 monoclonals were used compassionately for long-COVID–associated microangiopathy.31,32
  • Small-molecule C3 inhibitors set the preclinical stage for complement–clotting inflammation.33

By directly blocking the complement-mediated vascular injury, these agents may restore perfusion and reduce neurovascular symptoms.

Multispecialty Care Pathways And Validated Assessments

Effective management of long COVID requires a multidisciplinary, data-driven approach anchored in objective functional tracking and measurement of therapeutic response. Validated tools such as the Composite Autonomic Symptom Score-31 scale, Montreal Cognitive Assessment, 6-Minute Walk Test, and PROMIS Fatigue (Patient-Reported Outcomes Measurement Information System) scale are widely used to quantify autonomic, cognitive, and exercise outcomes (Table 5).26,34,35

Table 5. Interdisciplinary Care Model for Immune-Targeted Therapy in Long COVID
Table 5. Interdisciplinary Care Model for Immune-Targeted Therapy in Long COVID
Team rolePrimary responsibilitiesKey assessment tools/metrics
NeurologyEvaluate autonomic and small-fiber neuropathy; assess cognitive and neuroimmune dysfunctionCOMPASS-31 (autonomic), Neurobehavioral Symptom Inventory for cognitive–fatigue screening, MoCA
ImmunologyIdentify autoantibodies, cytokine signatures, complement activationAutoantibody panel, cytokine panel (IL-6, TNF-alpha), complement C3/C5b-9 profiling
CardiologyCharacterize microvascular injury, dysautonomia, and exercise intoleranceTilt-table test, orthostatic heart rate assessment
PharmacyEnsure infusion safety, lot traceability, and protocol adherence for IVIG or complement biologicsInfusion rate monitoring, adverse event documentation, EHR lot tracking
Rehabilitation/physical therapyGuide energy pacing and graded reconditioning; monitor functional recovery6MWT, PCFS scale, PROMIS Fatigue, gait and balance assessment
6MWT, 6-Minute Walk Test; COMPASS-31, Composite Autonomic Symptom Score-31; EHR, electronic health record; IL-6, interleukin-6; IVIG, intravenous immunoglobulin; MoCA, Montreal Cognitive Assessment; PCFS, Post-COVID Functional Status; PROMIS, Patient-Reported Outcomes Measurement Information System; TNF, tumor necrosis factor.
Based on references 26, 34, and 35.

Integration relies on shared dashboards, regular multidisciplinary rounds, and standardized patient-reported outcome measures.

Barriers and Ethical Implications for Off-Label Immunotherapy6,7,34,36

Despite emerging clinical evidence, IVIG and complement inhibitors remain off-label for long COVID, creating payor resistance and access inequities. Most insurers require documentation of at least 1 of the following before approving IVIG:

  • quantitative IgG deficiency;
  • proven autoimmune diagnosis; or
  • failed trial of standard symptomatic therapy.

This poses challenges for patients with immune dysautonomia, small-fiber neuropathy, or complement abnormalities, who often lack positive autoimmune markers despite objective dysfunction. The time-sensitive nature of immune modulation in long COVID amplifies the clinical and ethical concern.

From an ethical standpoint, Immunoglobulin National Society Standards of Practice recommend that off-label use of biologics include informed consent, transparent documentation of the rationale, shared decision-making, and longitudinal outcome tracking to ensure therapeutic accountability and patient safety.

Conclusion

Long COVID represents a novel intersection of viral persistence, immune dysregulation, and multi-organ sequelae. Multidisciplinary coordination and scientifically grounded patient selection are essential as the field moves toward a precision immunology framework for extended COVID-19 care. Ongoing clinical trials will help define optimal timing, dosing, and candidate selection for immunomodulatory treatments, bringing long COVID closer to a condition that can be treated with precision.

The authors reported no relevant financial disclosures.

References

  1. Hou Y, et al. Open Forum Infect Dis. 2025;12(9):ofaf533.
  2. Geng LN, et al. JAMA. 2025;333(8):694-700.
  3. Peluso MJ, et al. Cell. 2024;187(20):5500-5529.
  4. Takao M, et al. Psychiatry Clin Neurosci. 2023;77(2):72-83.
  5. Bayarri-Olmos R, et al. JCI Insight. 2025;10(16):e194314.
  6. Hogeweg M, et al. J Intern Med. 2023;293(5):656-658.
  7. Gupta G, et al. Compr Physiol. 2025;15(3):e70019.
  8. Xie Y, et al. N Engl J Med. 2024;391(6):515-525.
  9. Shah DP, et al. JAMA Netw Open. 2025;8(1):e2455430.
  10. Lammi V, et al. Nat Genet. 2025;57(6):1402-1417.
  11. Gottlieb M, et al. JAMA Netw Open. 2025;8(8):e2526310.
  12. RECOVER Initiative. RECOVER study examines how a person’s sex impacts long COVID risk. Published 2025. Accessed December 11, 2025. recovercovid.org/news/recover-study-examines-how-persons-sex-impacts-long-covid-risk
  13. Stein SR, et al. Nature. 2022;612(7941):758-763.
  14. Davis HE, et al. EClinicalMedicine. 2021;38:101019.
  15. Tsampasian V, et al. Eur J Prev Cardiol. 2025;32(6):485-498.
  16. Garmendia JV, et al. Curr Issues Mol Biol. 2022;45(1):33-50.
  17. Lupi L, et al. Pathogens. 2024;13(5):388.
  18. Cervia-Hasler C, et al. Science. 2024;383(6680):eadg7942.
  19. Kell DB, et al. Res Pract Thromb Haemost. 2024;8(7):102566.
  20. Klein J, et al. Nature. 2023;623(7985):139-148.
  21. Hurme A, et al. Front Immunol. 2023;14:1146500.
  22. Morse BA, et al. Brain Behav Immun. 2025;123:725-738.
  23. Thompson JS, et al. Front Immunol. 2023;13:1033651.
  24. Senefeld JW, et al. JAMA Netw Open. 2023;6(1):e2250647.
  25. Rotundo S, et al. BMC Infect Dis. 2025;25(1):616.
  26. Immunotherapy for neurological post-acute sequelae of SARS-CoV-2. ClinicalTrials.gov Identifier: NCT05350774. Accessed December 11, 2025. clinicaltrials.gov/study/NCT05350774
  27. GrÖning R, et al. Int J Infect Dis. 2024;144:107046.
  28. Piano Mortari E, et al. Clin Exp Immunol. 2022;209(3):259-261.
  29. Melamed I, et al. Front Neurol. 2025;16:1523814.
  30. Study to evaluate the benefit of RUCONEST in improving neurological symptoms in post-COVID-19 infection. ClinicalTrials.gov Identifier: NCT04705831. Accessed December 11, 2025. clinicaltrials.gov/study/NCT04705831
  31. Aurora T, et al. Haematologica. 2022;107(10):2517-2522.
  32. Shahid K, et al. Cureus. 2023;15(9):e46185.
  33. Guaschino V, et al. Front Immunol. 2025;16:1620996.
  34. Immunoglobulin National Society. Immunoglobulin Therapy Standards of Practice. Edition 3.2. Published 2024. Accessed December 11, 2025. ig-ns.org/product/ig-therapy-standards-of-practice-version-3-2
  35. COVID-19 treatment clinical care for outpatients. CDC. June 11, 2025. Accessed December 11, 2025. cdc.gov/covid/hcp/clinical-care/outpatient-treatment.html
  36. Insurers block immunoglobulin access using multiple tactics. Immune Deficiency Foundation Policy Brief. May 1, 2024. Accessed December 11, 2025. primaryimmune.org/resources/news-articles/insurers-block-immunoglobulin-access-using-multiple-tactics

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Restoring Immune Homeostasis In Long COVID: Evolving Insights Into Pathophysiology And Therapeutic Strategies

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