Treatment options for Post-Acute Infectious Syndromes like Long Covid and Long Lyme

Introduction

Post-Acute Infectious Syndromes (PAIS) are an emerging medical challenge, particularly as we witness the long-term consequences of viral infections like COVID-19. Many patients who recover from the acute phase of an infection continue to experience debilitating symptoms, including chronic fatigue, cognitive dysfunction, and widespread inflammation. These lingering effects can last months or even years, greatly impacting patients’ quality of life and placing a burden on healthcare systems. In this context, PAIS has gained attention for its wide-ranging effects on various organ systems.

The SARS-CoV-2 virus (which causes COVID-19) is not the only pathogen linked to post-acute syndromes. Similar conditions have been observed following infections such as influenza, Lyme disease, Ebola, and West Nile Virus. Despite these conditions being recognized for years, there is still no standardized or universally effective treatment. The symptoms vary greatly from patient to patient, indicating that PAIS is a multifactorial condition requiring a diverse and individualized treatment approach. In their article, Steenblock et al. (2024) propose a multimodal treatment strategy for PAIS, recognizing the need to address both the physiological and neurological dimensions of these syndromes.

Mechanisms Behind Post-Acute Infectious Syndromes (PAIS)

One of the most challenging aspects of treating PAIS is its complex, poorly understood pathology. The authors highlight several possible mechanisms driving these chronic conditions:

1. Diminished Tissue Perfusion: Poor blood flow can lead to reduced oxygen delivery to tissues, worsening symptoms like fatigue and cognitive impairment. Tissue perfusion issues may arise due to viral damage to blood vessels or persistent inflammation.
2. Viral Infiltration and Persistence: Some evidence suggests that in certain patients, viruses such as SARS-CoV-2 or Borrelia (Lyme disease) persist in tissues, causing ongoing inflammation and damage long after the initial infection clears.
3. Chronic Inflammation: Inflammation in both the brain and peripheral organs may be a hallmark of PAIS. This chronic inflammatory response contributes to a cycle of tissue damage, oxidative stress, and immune dysregulation.
4. Reactivation of Latent Viruses: Dormant infections, like Epstein-Barr Virus (EBV), may be reactivated by the initial infection, further complicating recovery and contributing to prolonged symptoms.
5. Microclot Formation: Studies of Long-COVID have uncovered persistent microclots that are resistant to the body’s normal clot-busting processes. These microclots can disrupt normal circulation, leading to further tissue damage and inflammation.

Importantly, the authors propose that these mechanisms do not operate independently but may be interrelated. For example, inflammation triggered by viral persistence or microclots can further impair blood flow and lead to tissue hypoxia, exacerbating symptoms.

Impact of Metabolic and Endocrine Disorders

The connection between metabolic and endocrine health and PAIS is another key area of focus. Chronic stress, obesity, and other metabolic disorders can worsen the course of PAIS by activating the hypothalamic-pituitary-adrenal (HPA) axis, a key regulator of the body’s response to stress. When the HPA axis is overstimulated—due to factors like chronic illness or obesity—it can lead to dysregulated cortisol release and a heightened inflammatory response. This low-grade, chronic inflammation weakens the body’s defenses and increases susceptibility to new infections or the reactivation of old ones.

For example, SARS-CoV-2 has been shown to directly infect endocrine tissues such as the pancreas and adrenal glands, potentially causing long-term damage. Similarly, adipose (fat) tissue, which is abundant in inflammatory cells, has been identified as a reservoir for viral particles, further promoting inflammation. In this context, PAIS becomes not just an infectious disease but also a metabolic and endocrine disorder, requiring therapies that address both immune dysregulation and metabolic health.

Pharmacological Approaches

Given the multifactorial nature of PAIS, Steenblock and colleagues suggest combining several pharmacological agents, including metformin and low-dose naltrexone (LDN), which target inflammation and oxidative stress.

1. Metformin: Traditionally used to treat type 2 diabetes, metformin has gained attention for its broader anti-inflammatory effects. It reduces the production of reactive oxygen species (ROS) in cells and decreases levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β). Metformin also enhances the body's ability to regulate inflammation through the AMP-activated protein kinase (AMPK) pathway. In the context of PAIS, metformin’s ability to dampen inflammation could help alleviate chronic fatigue and improve recovery. Studies have already shown that metformin reduces the risk of developing Long-COVID in patients with SARS-CoV-2.
2. Low-Dose Naltrexone (LDN): Another promising therapy, LDN is traditionally used in much higher doses to treat opioid and alcohol dependence. In low doses, however, it modulates the immune system by blocking Toll-like receptor 4 (TLR4), which is responsible for triggering inflammatory pathways. LDN has been used off-label to treat autoimmune diseases, fibromyalgia, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—conditions that share many features with PAIS. Recent trials show that LDN can reduce fatigue and inflammation in patients suffering from Long-COVID, making it a valuable tool for treating PAIS.

Physical Therapies for PAIS

Beyond pharmacotherapy, Steenblock et al. argue for the inclusion of physical therapies to address the neurological and systemic aspects of PAIS:

1. Extracorporeal Apheresis: This procedure involves filtering the blood to remove harmful substances like lipids, autoantibodies, and inflammatory molecules. Initially developed to treat severe dyslipidemia, apheresis has shown surprising benefits for patients with chronic fatigue and Long-COVID. It reduces inflammation and oxidative stress by removing fibrinogen and other inflammatory markers, improving blood viscosity and reducing microclots that might otherwise hinder recovery.
2. Transcutaneous Electrical Nerve Stimulation (TENS): This non-invasive therapy, which stimulates the vagus nerve, has been used to treat conditions like depression and migraines. TENS shows promise in reducing cognitive and neurological symptoms in Long-COVID by modulating neurotransmitter release and dampening inflammation in the brain. Early studies have shown that patients treated with TENS report improvements in memory, concentration, and fatigue.

Multimodal Treatment Approach

The authors propose a multimodal treatment strategy that combines both pharmacological and physical therapies. They emphasize that treating PAIS requires a comprehensive approach that addresses the various physiological, metabolic, and neurological dysfunctions seen in these patients.

• Combination Therapy: Metformin and LDN target the inflammatory and metabolic roots of PAIS, while therapies like apheresis and TENS help reduce neurological symptoms and restore normal blood function. This approach not only targets the underlying pathophysiology but also helps alleviate the diverse symptoms seen in PAIS patients.
• Personalized Treatment Based on Biomarkers: Given the heterogeneity of PAIS, the authors suggest the development of a biomarker-based scoring system to guide treatment. Biomarkers could include inflammation markers (e.g., C-reactive protein), blood clotting factors (e.g., D-dimer, fibrinogen), and immune markers (e.g., autoantibodies). Patients would be assessed based on their biomarker profiles, allowing clinicians to tailor treatments to each individual’s specific needs.

Conclusion

Post-Acute Infectious Syndromes represent a major challenge in both clinical practice and research. The multifactorial nature of these conditions means that no single treatment will be effective for all patients. Instead, a multimodal approach that combines pharmacotherapy, physical therapy, and biomarker-driven diagnostics is necessary to improve outcomes for patients suffering from PAIS. While much research remains to be done, the promising results of treatments like metformin, LDN, and apheresis provide hope for more effective management of these complex syndromes.

Further investigation is needed to refine treatment protocols and identify the biomarkers that can guide personalized medicine for PAIS. As new therapies emerge, clinicians should be encouraged to integrate diverse treatment modalities and continue exploring innovative approaches to managing these challenging conditions.

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Reference:

Steenblock, Charlotte, et al. "A Multimodal Approach for Treating Post-Acute Infectious Syndrome." Brain Medicine, vol. 1, 2024, pp. 1–7, https://doi.org/10.61373/bm024p.0064. Accessed 30 Aug. 2024.