A protocol for treatment starts with tamping down inflammation.

Evolving events mean staying on top of new information as it becomes available or as any recommendations shift.

As we’ve continued to note in our long COVID blog series, increased inflammation and corresponding cytokines, the hallmarks of so many immune-mediated diseases, are clearly also at work in this complex syndrome. 

In “Why does long COVID happen ?” we discussed the many contributing factors and interactions of processes that in some patients lead to chronic, ongoing issues affecting many aspects of health – and subsequently, daily lives. 
 
Dr. Bruce Patterson, formerly the Medical Director of Diagnostic Virology at Stanford University Hospitals and Clinics, California and now the founder of IncellDX, has with a team of clinicians designed a protocol that seeks to assess patient status through comprehensive lab analysis and then reduce the over-arching inflammation that can continue to cause symptoms. 
 
Dr. Patterson’s protocol has two main goals:

1. The use of CCR5 antagonists to reduce CCL5/RANTES levels, and therefore prevent the non-classical monocytes carrying spike protein from getting to the blood vessels.
2. Tamping down the CX3CR1/fractalkine pathway to turn off the survival mechanism, so over time, the monocytes carrying the coronavirus protein will die off.

 
To explain a bit further, non-classical monocytes are capable of causing inflammation throughout the body in response to a chemokine called fractalkine/CX3CL1 (chemokines are important factors for cellular recruitment into inflamed tissues) and RANTES/CCR5.
 
CX3CL1 is abundantly expressed by activated endothelium and is an important regulator of many aspects of endothelial function and dysfunction, including thrombosis.  When upregulated, it is contributing to a pro-thrombotic environment and immune cell recruitment
Chemokines are important factors for cellular recruitment into inflamed tissues
RANTES is a chemokine that is stored in the alpha granules of platelets that can be rapidly released after platelet activation RANTES binds to the chemokine receptor CCR5.    
CCR5 is a chemotactic molecule that can amplify inflammatory responses and is expressed on immune cells such as T-lymphocytes, macrophages, and NK cells. 
CCL5/RANTES acts like a magnet for these immune cells expressing CCR5.    
 
CCL5/RANTES is a marker for the early stages of immune dysregulation in COVID-19 and as a possible therapeutic marker to determine when and how long therapy targeting CCR5 or RANTES should be continued.
 
The Protocol
Important reminder: this protocol should be utilized ONLY by those clinicians who understand the mechanisms behind long-haulers syndrome and who have experience treating this complex patient group.

The treatment protocol is usually given for four to six weeks, with the goal to restore immune balance. A follow-up visit is then to done to assess response to the protocol; note that some patients may need longer courses of therapy dependent upon variable factors including their individual health issues and/or response to treatment.
 
With Dr. Patterson’s protocol, a specialized series of labs, the IncellKINE test, are conducted (note: the Incell DX panel should be used only as guidance of treatment). Based on those results, patients are then typically prescribed these therapies below; but, every patient is different and unique so each protocol is specific for each patient. Many times we repeat the Incell DX panel to gauge treatment response and follow clinical response as well.
 
A.  Maraviroc
A CCR5 antagonist, Maraviroc reduces cytokines and blocks migration of the intermediate and non-classical monocytes and repolarizes the macrophages and modulates the immune system. We know that CCL5/RANTES is commonly elevated in long COVID and as an antiretroviral, Maraviroc also has been used in combination with other drugs to treat diseases including human immunodeficiency virus (HIV).

• The dose in long COVID is 150-300 mg, twice daily. Note: if patients are taking any other drug that inhibits CYP5A, then the dose must be decreased. Conversely, if the patient is on a drug that induces this enzyme then the dose is 600 mg, twice daily. For most cases, the general dose recommendation is 300 mg, two times a day.

 
Possible side effects
Orthostatic hypotension    
One case of hepatotoxicity 
Black box warning for liver toxicity so liver function tests and complete blood counts should be checked monthly while undergoing treatment with Maraviroc. 
 
B.  Statins to tamp down the CX3CR1/fractalkine pathway
In order to turn off the long-term monocyte survival mechanism that’s allowing these cells to endure longer than usual. As such, statins are the second prescribed drug in the protocol. They work by inhibiting fractalkine, which stops the monocyte cells from attaching to endothelial cells on the blood vessels. 

• Pravastatin, at 10-20mg per day or Atorvastatin, 20-40 mg per day, may be administered.
• Alternately, fenofibrate can be used in those patients who cannot tolerate statins, e.g. TriCor (brand name) dosed at 145 mg, once daily.

 
C.  Ivermectin
As an immunomodulator and anti-parasitic drug prescribed because of its immunomodulating effects, ivermectin is the third prescribed medication in Dr. Patterson’s protocol. It is thought to help detach and then bind to the spike protein, thereby rendering it incapable of attaching to the cell membrane. The ivermectin docking to ACE2 receptors may interfere with the attachment of the spike to the human cell membrane; it has been shown to inhibit lipopolysaccharide (LPS) induced, proinflammatory cytokines and improve survival in mice. Note that LPS is an endotoxin that can cause systemic inflammation. 
 
Ivermectin lowers these cytokines: 
↓TNF--α
↓IL-1ss
↓IL-4
↓IL-5
↓IL-6
↓IL-13
                
Recommended dosage is .2-.4mg/kg each day, for 3-5 times a week (note that higher and/or longer dosing are sometimes needed). After 3-5 days, reduce dosing schedule to 1-2 times/week then discontinue after 2-4 weeks.
 
D.  Mast cell stabilization
It all has been suggested that mast cell activation can play an important role in long COVID or   post-acute sequelae of COVID-19 (PASC) due to atypical responses to SARS-CoV-2 by the dysfunctional mast cells. Therefore, stabilizing mast cell activity can be a critical effort in treating long COVID patients.
 
The Front Line COVID-19 Critical Care Alliance (FLCCC) offers a protocol of care to address mast cell activation, as noted in the following chart:

Other ways to address mast cell activation
  

• Leukotriene receptor antagonist: Montelukast (brand name Singulair) has antiviral activity against zika and dengue viruses, modulates the immune system, inhibits macrophages, and can protect against influenza-induced viral infection of type 1 alveolar epithelial cells and modulating proinflammatory mediators. It lowers TNF Alpha and IL 6, increases glutathione and and superoxide dismutase, and has been shown to lower mortality related to sepsis. Recommended dosage is 10 mg per day.
• Supplements including luteolin, quercetin, vitamin C, local raw honey, bromelain, probiotics, astragalus, butterbur.
• A low histamine diet: check out The Histamine and Tyramine Restricted Diet by Dr. Janice Joneja or the Food Compatibility List from the Swiss Interest Group for Histamine Intolerance.

      *     LDN (Low Dose Naltrexone) .5-4.5 mg per day 
 
E. Monocyte repolarization from M1 to M2 

• Vitamin C  - 500 mg, twice a day 
• Omega 3 - once a day 
• Atorvastatin or Pravastatin as prescribed
• Melatonin – Two to 10mg at bedtime  
• Vitamin D3/K2 -  5000 IU each day  (optimum Vitamin D level is 60-100) 
• Intravenous immunoglobulin therapy (IVIG)

 
F.   Fluvoxamine:
Brand name Luvox, this long-available serotonin-reuptake inhibitor has been typically used for treating depression. The protocol here recommends 25-50-100 mg twice daily, (can substitute 20- 30mg Prozac QD) to activate sigma-1 receptors decreasing cytokine production. Fluvoxamine has been found to have positive effects on autophagy and SSRI inhibition of platelet activation.     
 
G.  Prednisone
Many Long Hauler protocols will utilize short courses of steroids. Sometimes even a low dose of 5 mg per day can be helpful; higher doses may be necessary as well dependent upon patient status and tolerance.
 
A tapering dose of prednisone of .5 mg/kg for 5 days; .25 mg/kg for 5 days; followed by 
.12mg/kg for an additional 5 days. Patients should take in the morning to lessen impact on sleep. In some cases, a steroid-sparing agent such as methotrexate, dosage 7.5 mg/week, along with folic acid supplementation may be helpful.
 
H.  IVIG
In some patients, intravenous immunoglobulin (IVIG) treatment can be helpful in recovery. IVIG has been demonstrated to:

• inactivate auto-reactive T-cells
• restore the balance of cytokines (IVIG contains antibodies and antagonists to pro-inflammatory cytokines)
• down-regulate antibody production by B-cells
• boost innate immunity by interrupting the steps in the complement activation cascade and blocking Fc-receptor mediated activity, which results in down-regulation of macrophage activity. In this study, results showed that IVIG affects the polarization of both classically and alternatively activated macrophages.
• prevents the passage of auto-immune T-cells into the blood-nerve barrier
• reduces and eradicates harmful autoantibodies
• mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy…note that a defective autophagy process is associated with various autoimmune and inflammatory diseases. As research found, IVIG-induced autophagy is restricted to inflammatory cells like monocytes, dendritic cells, and M1 macrophages, but not in cells associated with Th2 immune response like M2 macrophages. M1/M2 describes the two major and opposing activities of macrophages. M1 activity inhibits cell proliferation and causes tissue damage while M2 activity promotes cell proliferation and tissue repair. 

IVIG is not approved for Long Haulers but sometimes if there is another approved diagnostic code,  we can use IVIG for dual purposes 

I. LDN  (immunomodulation) 
Low Dose Naltrexone  .5-4.5 mg / day  
The opioid antagonist naltrexone hydrochloride has been suggested to be a potential therapy at low dosage for multiple inflammatory conditions and cancers.

• reduces activity of toll-like receptor 4 (TLR4)  Toll-like receptors recognize conserved molecular patterns and nucleic acids as part of the innate immune response 
• reduces the  production of IL-6 and TNFα by monocyte and plasmacytoid dendritic cell subsets
• reduced  plasma concentrations of  multiple proinflammatory cytokines including interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF)

https://pubmed.ncbi.nlm.nih.gov/28536359/
Dr. Patterson’s protocol and his team’s work has done much to better understand the mechanisms involved in long COVID so the medical community subsequently can provide the most effective treatments. 
 
Coming soon!
 
Given the complexity of issues that we are seeing occur every day and that vary from one patient to another, Dr. Robin Rose and I are creating a comprehensive integrative medicine program to help long haulers. Dr. Rose is known for her work in the field of internal medicine and gastroenterology that targets the human gut microbiome and understanding its link to health and disease. Our protocol and upcoming discussion will cover in more detail a number of other therapeutic measures including, but not limited to: 

• vascular support
• combatting oxidative stress
• lowering chronic inflammation
• mitochondrial support
• addressing prions
• the role of senescence
• the influence of and promoting gut microbiome health
• detoxification strategies
• And boosting the immune system through such means as ozone therapy and Nano Vi™, which may help repair cells even after damage has occurred.

 
It’s important to keep in mind that as new information arises, so may some of the recommendations for therapies change with the evolution of this novel disorder. And as always, if you are experiencing any issues or symptoms that haven’t resolved with initial care, please don’t hesitate to consult your physician for guidance or feel free to reach out to our offices. We are here to help!
 
In health and hope,
Dr. Suzanne Gazda
 
References:
 
Sayana S, Khanlou H. Maraviroc: a new CCR5 antagonist. Expert Rev Anti Infect Ther. 2009;7(1):9-19. doi:10.1586/14787210.7.1.9
 
Lehrer S, Rheinstein PH. Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2. In Vivo. 2020;34(5):3023-3026. doi:10.21873/invivo.12134
 
Zhang X, Song Y, Ci X, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res. 2008;57(11):524-529. doi:10.1007/s00011-008-8007-8
 
Lawrence B. Afrin, Leonard B. Weinstock, Gerhard J. Molderings. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. International Journal of Infectious Diseases. November 2020.
 
Glebov, Oleg O. Low-Dose Fluvoxamine Modulates Endocytic Trafficking of SARS-CoV-2 Spike Protein: A Potential Mechanism for Anti-COVID-19 Protection by Antidepressants. Frontiers in Pharmacology. 2021. https://www.frontiersin.org/article/10.3389/fphar.2021.787261
DOI 10.3389/fphar.2021.787261
 
Gazda Integrative Neurology
https://www.suzannegazdamd.com/blog/more-reasons-for-more-vitamin-d
 
incellDX
https://incelldx.com/
 
Saha C, Kothapalli P, Patil V, ManjunathaReddy GB, Kaveri SV, Bayry J. Intravenous immunoglobulin suppresses the polarization of both classically and alternatively activated macrophages. Hum Vaccin Immunother. 2020;16(2):233-239. doi:10.1080/21645515.2019.1602434
 
Das, M., Karnam, A., Stephen-Victor, E. et al. Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy. Cell Death Dis 11, 50 (2020). https://doi.org/10.1038/s41419-020-2249-y