How do we treat long COVID and post-vaccine symptomatology?

After two+ years of the pandemic, clinicians are seeing millions of patients presenting with a wide array of symptoms, either post-COVID or post vaccine. An article in The Atlantic notes that while actual statistics relevant to long COVID patients are difficult to determine at this date, it is expected that the total numbers of people affected will continue to grow exponentially.

Additional reports note that more Americans in and out of the labor force are having trouble remembering and concentrating, experiencing overwhelming fatigue, shortness of breath, exercise intolerance, neuropathic and muscle pain, weakness, and a long list of other symptoms.
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And that despite a strong job market, with the number and rate of job openings at all-time highs, applications for Social Security Disability Insurance are (slowly) rising again in their first sustained increase since 2009.
 
Regarding post-vaccine complications, figures from the Vaccine Adverse Event Reporting System (VAERS) as of June 10, 2022, show over 28,000 deaths and 129,5327 adverse reports that have been submitted for review and verification.

Some basic definitions
 
Long COVID 
Experts note that while recovery times for an initial COVID infection can vary, long COVID refers to instances where symptoms persist for 90+ days. Long COVID is generally diagnosed when signs and symptoms of COVID that can't be explained by other causes are present four weeks after the initial infection.
Long COVID prevalence among hospitalized patients was 54%.
Approximately 25 to 35% or more of all patients who have had COVID are experiencing at least some of these long-hauler symptoms in varying degrees of severity.   
Up to 80% of patients may have some long-lasting symptom.
Long COVID tends not to be related to the severity of COVID.

Our previous blog explores long COVID in detail, you can learn more at:
https://www.suzannegazdamd.com/blog---long-covid/what-is-long-covid
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Post-vaccine injured  
Although no official definition exists for post-COVID-vaccine syndrome, a temporal correlation between a patient receiving a COVID-19 vaccine and beginning or worsening of clinical manifestations is sufficient to diagnose as a COVID-19 vaccine-induced injury, when the symptoms are unexplained by other concurrent causes. 

Since Phase 3 and Phase 4 clinical trials are still ongoing, the full safety and toxicity profile for COVID-19 vaccines cannot be fully determined. From a bioethical perspective, cases of any new-onset or worsened signs, symptoms, or abnormalities following any dose of COVID-19 vaccine must be considered as an injury caused by the vaccine, until proven otherwise. 
 
Patients with post-vaccine injury should not receive additional COVID vaccines.
 
There are significant overlaps between the symptoms and features of long COVID/long-hauler syndrome and post-vaccine syndrome. However, several clinical features appear to be characteristic of post-vaccine syndrome; most notably, severe neurological symptoms appear to be more common following vaccination. To complicate matters further, patients with long COVID are often also vaccinated, making the issue of definition more difficult. 
 
For the purposes of treatment or other discussions, we will refer to both disease states as long-haul COVID 19 syndrome (LHCS). 

To learn more about the pathogenesis of COVID vaccine injuries, see:
https://covid19criticalcare.com/wp-content/uploads/2021/06/FLCCC-Alliance-I-RECOVER-Management-Protocol-for-Long-Haul-COVID-19-Syndrome.pdf
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Various issues may occur post vaccine, including these mechanisms:
The FLCCC shares detailed mechanisms of injury which are extensively referenced.
https://covid19criticalcare.com/wp-content/uploads/2022/06/An-Approach-to-Vac-Injured-06-09-2022.pd

1. The acute, immediate reaction (within minutes to hours) is likely the results of an acute type I IgE mediated hypersensitivity reaction. The type I response may be due to preformed antibodies against mRNA, polyethylene glycol, or other components of the nano-lipid particle. 
2. The acute myocarditis/sudden cardiac death syndrome that occurs post vaccination (within hours to 48 hours), noted particularly in young athletes, may be caused by a “stress cardiomyopathy” due to excessive catecholamines produced by the adrenal medulla in response to spike protein-induced metabolic aberrations.
3. The subacute and chronic myocarditis is likely the result of a spike protein-induced inflammatory response mediated by pericytes and macrophages. The SARS-CoV-2 spike protein binds to heart’s vascular cells (pericytes) and S1 drives endothelial damage and platelet activation both which lead to high levels of vascular inflammation. 
4. The subacute (days) and chronic (weeks to years) vaccine-related injuries likely result from the overlapping effects of an S1-induced inflammatory response, the production of autoantibodies, activation of the clotting cascade, and secondary viral reactivation.  SARS-CoV-2 proteins have been shown to drive cross-reactive antibody responses; for example, as cited in one study, researchers (Kreye et al, 2020) identified high-affinity SARS-CoV-2-neutralizing antibodies that cross-reacted with gut, kidney, lung, heart, and brain, which can lead to the formation of immune complexes. These antigen-antibody complexes can be dangerous in some people as they can trigger type III hypersensitivity reactions; so, the neurological symptoms may be related micro- and/or macrovascular thrombotic disease, which appears to be common in severe COVID-19 disease. 
5. The inflammatory response is mediated by spike protein-induced mononuclear cell activation in almost every organ in the body, but most notably involving the brain, heart, and endocrine organs. High levels of inflammation result in the brain as well due to microglial cell activation. 
6. Mast cell activation (brain and body) Mast cells release proinflammatory mediators and have ACE 2 receptors, making them a prime target for spike protein   
7. Molecular mimicry a recent study in the Journal of Immunology, researchers identified significant cross-reactivity between SARS-CoV-2 proteins (spike protein, nucleoprotein, envelope protein, and membrane protein) with 55 different human tissues using monoclonal and polyclonal antibodies and performed epitope mapping to identify the relationships.  In my prior blog, I speak about the immune cross-reactivity that occurs with COVID; the work by Vojdani et al reported that the COVID virus reacted with 28 out of 55 human tissues, many of which were found to be in the brain.
8. Rogue antibodies  Scientists have also found high levels of proteins produced by the immune system known as autoantibodies, which attack cells and tissues in the body instead of the virus.  Many of the autoantibodies were directed against the immune system itself and those autoantibodies were also directed at many other parts of the body, from the brain and central nervous system to blood vessels and platelets. Essentially the immune system starts attacking the body and brain. This can result in any number of autoimmune diseases or worsening of underlying autoimmune pathophysiology. After a vaccine are antibodies are generated against spike protein, but  in some cases these antibodies may develop into autoantibodies. 

To read more about the mechanisms that may contribute to autoantibody formation:
https://www.science.org/content/article/rare-cases-coronavirus-vaccines-may-cause-long-covid-symptoms
 
https://health.ucdavis.edu/news/headlines/antibodies-mimicking-the-virus-may-explain-long-haul-covid-19-rare-vaccine-side-effects/2021/11
 
Our previous blog in our long COVID series also explores some of the mechanisms noted above:
https://www.suzannegazdamd.com/blog---long-covid/why-does-long-covid-happen
 
Treatment approaches
   
For both long COVID and post-vaccine injured patients, there are similar mechanisms involved.  
Most researchers believe that it is the lingering viral fragments (spike protein) that are wreaking havoc on the body and brain. Immune dysregulation is the common theme, and the downstream effects are discussed in our prior blog at: https://www.suzannegazdamd.com/blog---long-covid/why-does-long-covid-happen
 
The multiplicity of mechanisms may be one reason why almost every case “is different” and why each one of these patients requires a uniquely individualized and carefully constructed protocol pertinent to their specific issues.
 
Two different protocols but there are many more being studied around the world  
    
The treatment recommendations for LHCS are constantly evolving as we learn more about the condition. At present, we have two primary approaches that are being employed in the treatment of LHCS.
 

• Treatment must be individualized according to each patient’s presenting symptoms and disease syndromes. It is likely that not all patients will respond equally to the same intervention; this suggests that the treatment must be individualized according to each patient’s specific response. 

 
The Front Line COVID-19 Critical Care Alliance (FLCCC) provides the only published treatment protocol for vaccine-injured patients. https://covid19criticalcare.com/covid-19-protocols/i-recover-post-vaccine-treatment/
Please note their I-RECOVER Protocol is for management of long COVID patients, but there is significant overlap, and I will not review that protocol. You can find this detailed information at:
 https://covid19criticalcare.com/covid-19-protocols/i-recover-long-covid-treatment/

The FLCCC Recovery Protocol for Vaccine Injured Patients  
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I encourage everyone to periodically check the content of this link for the FLCCC is updating this protocol often.      
 
https://covid19criticalcare.com/wp-content/uploads/2022/06/FLCCC_Alliance-I-RECOVER-Protocol-PostVaccine-v3-English.pdf

Baseline Testing

• CBC with differential and platelet count
• Standard blood chemistries, including liver function tests
• D-Dimer—as a marker of clotting activation)
• CRP—as a marker of ongoing inflammation (A comprehensive extensive cytokine/chemokine panel is unnecessary and very costly, and the results will not change the treatment approach.) 
• Early morning cortisol—some patients develop autoimmune adrenal failure.
• TSH—to exclude thyroid disease
• HbA1C—Vaccine-injured patients are at an increased risk of developing diabetes
• Troponin, pro-BNP, Galectin-3, and ST2—to exclude cardiac disease.
• CMV, EBV, Herpes simplex, HHV6 and mycoplasma serology/PCR—to exclude viral/bacterial  reactivation (In patients who respond poorly to therapy, it may be helpful to check for Lyme (Bb), Bartonella and Babesia tick-borne diseases—e.g., https://igenex.com/ and https://www.mdlab.com/)
• Vitamin D level (25OH Vitamin D)
• In patients with allergic features and those who experienced an acute reaction to the vaccine, the following tests may be helpful: eosinophil count; IgE levels, RAST testing and/or skin testing. Serum tryptase, serum histamine and/or  24-h urine N-methylhistamine should be considered in MCAS. [29]
• Limited screening autoantibodies. Lupus anticoagulant (if positive B2 microglobulin etc.) and ANA. Vaccine-injured patients, particularly those with autonomic dysfunction/SFN frequently have an extensive array of autoantibodies directed against G-protein coupled cell surface receptors, [17,19] ACE-2, [35] neurons, myelin, and other self-epitopes. The presence or absence of these antibodies has little impact on the management of these patients.  
• More based on patient clinical presentation and history 

 
The FLCCC protocol has first, second- and third-line approaches:
 
First-line approach

• Time Restricted Eating or periodic daily fasts. Fasting has a profound effect on promoting immune system homeostasis, partly by stimulating the removal of damaged cells and mitochondria and clearing misfolded and foreign proteins. Intermittent fasting likely has an important role in promoting the breakdown and elimination of the spike protein. Fasting is contraindicated in patients under 18 (impairs growth) and during pregnancy and breastfeeding. Patients with diabetes, as well as those with serious underlying medical conditions, should consult their primary care provider prior to fasting, as changes in their medications may be required and these patients require close monitoring.

• Ivermectin is a key component in the FLCCC first line approach 
  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.                                                                          Dose: 0.2-0.3 mg/kg, daily for up to 4-6 weeks; best taken with or just following a meal. Due the possible drug interaction with quercetin, IVM and quercetin should not be taken at the same time.  IVM and intermittent fasting may act synergistically to rid the body of spike protein.                                                                                                      Low Dose Naltrexone .5-4.5 mg/day (compounded). The opioid antagonist naltrexone hydrochloride has been suggested to be a potential therapy at low dosage for multiple inflammatory conditions and cancers.
• Supplements                                                                                                                              ​

• Melatonin 2 to 6 mg slow release/extended release prior to bedtime. Melatonin has anti-inflammatory and antioxidant properties and is a powerful regulator of mitochondrial function. The dose should be started at 750 mcg (μg) to 1 mg at night and increased as tolerated. Patients who are slow metabolizers may have very unpleasant and vivid dreams with higher doses.
• It also has antithrombotic effects. 
• Vitamin C 500-1000 mg twice a day; vitamin C has important anti-inflammatory, antioxidant, and immune-enhancing properties, including increased synthesis of type I interferons. Avoid in patients with a history of kidney stones. Oral Vitamin C may promote the proliferation of Bifidobacterium in the colon.
• Omega 3 (Vascepa, Lovaza or DHA/EPA; 4 g/day). Omega-3 fatty acids play an important role in the resolution of inflammation by inducing resolvin production.
• Vit D3/ K2  4000-5000 IU/ day  The dose is adjusted based on the baseline Vit D level 
• Magnesium glycinate 500 mg / day to boost mitochondrial function. 
• Quercetin 250-500 mg / day decreases the production of pro-inflammatory cytokines TNFα, IL-6, G-CSF, GM-CSF and VEGF and activates sirtuins (SIRT1), to induce autophagy.  It also inhibits mast cells and has been shown to reduce neuroinflammation. The use of Quercetin has rarely been associated with hypothyroidism so monitor labs.
• Nigella Sativa; 200-500 mg twice daily This is also called Black seed oil. Thymoquinone (TQ), the main active ingredient of black seed oil, possesses antioxidant, anti-inflammatory, antiviral, antimicrobial, immunomodulatory and anticoagulant activities. 
• It should be noted that thymoquinone (the active ingredient of Nigella Sativa) decreases the absorption of cyclosporine and phenytoin. Patients taking these drugs should, therefore, avoid taking Nigella Sativa. Furthermore, two cases of serotonin syndrome have been reported in patients taking Nigella Sativa who underwent general anesthesia (probable interaction with opiates).

Second-line agents  

• Intravenous Vitamin C: 25 g/week, together with oral Vitamin C, 1000 mg (1 gram) 2-3 times per day.  Oral Vitamin C can be used and dosed to bowel tolerance. 
  
• Fluvoxamine: Start on a low dose of 12 mg/day and increase slowly as tolerated. 
  Brand name Luvox, this long-available serotonin-reuptake inhibitor has been typically used for treating depression.  Fluvoxamine activates sigma-1 receptors decreasing cytokine production.   Alternative mechanisms of benefit include direct antiviral effects via its lysosomotropic properties, modulation of the effect of IRE1 effects on autophagy, and SSRI inhibition of platelet activation. The dose can be increased to 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.  Caution: Start low and go slow.
  
• Non-invasive Brain Stimulation 
  
• Mitochondrial support with pyrroloquinoline quinone (e.g., Life Extension Energy Optimizer or ATP 360®); there are many others as well (Benfotiamine, CoQnol, Alpha Lipoic Acid, Melatonin etc.).
• N-acetyl cysteine (NAC); 600-1500 mg/day (lowers oxidative stress, boosts glutathione production and has a protective effect on mitochondria and renal function related to its observed capacity to preserve the S-glutathionylation process and glutathione levels in mitochondria. It also inhibits the release of excitatory neurotransmitters.
• Sulforaphane (broccoli extract); 400 mcg/day 
• Low dose corticosteroid; 10-15 mg/day prednisone for 3 weeks. Taper to 10 mg/day and then 5 mg/day, as tolerated. 
• Behavioral modification, mindfulness therapy and psychological support may help improve patients’ overall well-being and mental health. 
• Tai Chi is a health-promoting form of traditional Chinese martial art, shown to be beneficial for preventing and treating diseases including long COVID. 
• Non-invasive brain stimulation (NIBS) -- NIBS using transcranial direct current stimulation or transcranial magnetic stimulation has been demonstrated to improve cognitive function in patients with long COVID as well as other neurological diseases. NIBS is painless, extremely safe, and easy to administer. It is a recognized therapy offered by many Physical Medicine and Rehabilitation Centers. Patients may also purchase an FDA-approved device for home use.

Third Line Therapy
​   • Hyperbaric oxygen therapy (HBOT) 

1. decreases pro-inflammatory cytokines while increasing IL-10.
2. polarizes macrophages toward the M2 phenotype and improves mitochondrial function. 
3. While the optimal dose and dosing schedule is unclear, a pressure of between 1.5 and 2.0 ATM appears to be necessary to mediate the anti-inflammatory effects; however, others have reported improvements with a little as 1.3 ATM. Pressures above 1.3 ATM can only be achieved using hard shell chambers.
4. In this study, HBOT for the treatment of long COVID: a total of 10 patients received 10 sessions of HBOT to 2.4 atmospheres over 12 days. Each treatment session lasted 105 minutes, consisting of three 30-minute exposures to 100% oxygen, interspersed with 5-minute air brakes. The results showed significant improvement in cognition, fatigue, executive function, and motor scores. 

• Whole Body Vibration Therapy 

 
Other therapeutic options:

• Maraviroc (see below under Patterson protocol) 
• Plasmapheresis While plasmapheresis/plasma-exchange is a therapeutic option for the severely neurologically impaired patient following vaccination, additional data is required before this modality can be widely recommended.  
• Pentoxifylline (PTX) PTX ER, 400 mg three times daily, should be considered in those patients with severe microcirculatory disturbances. PTX is a non-selective phosphodiesterase drug that has anti-inflammatory and antioxidant effects.
  
• Valproic Acid or Depakote 250mg 2-3 times daily. Valproic acid has anti-inflammatory effects and polarizes macrophages towards a M2 phenotype.  Also has antiplatelet effects and may be neuroprotective.
  
• Sildenafil with or without L-arginine-L-Citrullin; Sildenafil doses titrated up from 25 to 100 mg 2-3 times daily with L-arginine/L-citrulline 5000 mg powder twice daily.  May be helpful for brain fog as well as microvascular disease with clotting and poor perfusion.
• VEDICINALS® 9 – Vedicinals are a unique phytopharmaceutical-based therapeutic suspension that consists of nine bioactive compounds with antiviral, anti-inflammatory, immune modulatory, anti-pyretic and analgesic properties. The compounds include Baicalin, Quercetin, Luteolin, Rutin, Hesperidin, Curcumin, Epigallocatechin Gallate, Piperine and Glycyrrhizin. A number of these compounds are very powerful antioxidants.  You can order internationally here https://www.vedicinals.com
• Sulforaphane (broccoli sprout powder) 500 mcg – 1g twice a day.
  While sulforaphane has many potential benefits in patients with COVID, long COVID and post-vaccine syndrome, there is limited clinical data to support it.  In a study described March 18 in the Nature journal Communications Biology, the scientists showed that sulforaphane, a plant-derived chemical, known as a phytochemical, already found to have anti-cancer effects, can inhibit the replication of SARS-CoV-2, the coronavirus that causes COVID-19, and another human coronavirus in cells and mice. We recommend a 100% whole broccoli sprout powder containing glucoraphanin and myrosinase.
• Dandelion (Taraxacum officinale).
  Root, flower and leaves contain an array of phytochemicals with antiinflammatory, antioxidant, hypolipidemic, antimicrobial and anticoagulant properties. Widely reported to be effective for ‘detoxifying’ spike protein, however, remains unclear whether dandelion extract actually binds to spike protein. A study that appeared recently on the bioRxiv* server describes a specific inhibitor of the virus found in an extract of the common dandelion that could provide a new and fruitful avenue of drug research. (In Vitro Effect of Taraxacum officinale Leaf Aqueous Extract on the Interaction between ACE2 Cell Surface Receptor and SARS-CoV-2 Spike Protein D614 and Four Mutants)
• Carbon 60 (C60) or C60 fullerenes.  Composed of 60 carbon atoms forming something that looks like a hollow soccer ball and considered as a “free radical sponge.” Considered the single-most powerful antioxidant ever discovered. 
• C60 or C60 fullerenes​ Composed of 60 carbon atoms forming something that looks like a hollow soccer ball and considered as a “free radical sponge.” Considered the single-most powerful antioxidant ever discovered. 
• Cold Hydrotherapy 
• IVIG is recommended in specific autoimmune syndromes which include Guillain Barré Syndrome, transverse myelitis, and immune thrombocytopenia. IVIG is also recommended in patients with Immune Deficiency Syndrome.

 
Disease Specific Therapeutic Adjuncts (Note: this section from the FLCCC is constantly being updated with new information, which we will share as available.)
 
Small fiber neuropathy (SFN)/autonomic neuropathy

• Tricyclic antidepressants (start at low dose and increase as tolerated)
• Gabapentin: 300 mg twice daily and increase as tolerated
• Alpha lipoic acid; 600 mg/day
• POTS – ensure sufficient hydration and consider use of compression stocking or abdominal binders
• POTS – Clonidine; 0.1 mg twice daily as tolerated 
• POTS – Fludrocortisone; 0.1 to 0.2 mg/day or licorice root (has glycyrrhizinic acid, an aldosterone-like compound).
• POTS – midodrine; 5-10 mg three times daily
• A trial of hyperbaric oxygen therapy (HBOT)

See our previous blog about SFN at https://www.suzannegazdamd.com/blog/update-even-more-results-for-ivig-in-treating-small-fiber-neuropath

Generalized Neurologic Symptoms/Injuries/”Brain Fog”/Fatigue 

• LDN appears to play a pivotal role in treatment of many neurological symptoms.
  
• Fluvoxamine; Start on a low dose of 12 mg/day and increase slowly as tolerated. Some patients report a significant improvement with fluvoxamine while other patients appear to tolerate this drug poorly. Fluoxetine 20 mg/day is an alternative, as are tricyclic anti-depressants. 
• Nigella Sativa; 200-500 mg twice daily.
• Valproic acid and pentoxifylline may be of value in these patients. 
• These symptoms may be mediated by Mast Cell Activation Syndrome (MCAS); see specific treatment below. 

Patients with an elevated DIC and those with evidence of thrombosis

• These patients should be treated with a NOAC or coumadin for at least three months and then reevaluated for ongoing anticoagulation.
• Patients should continue ASA 81 mg/day unless at high risk of bleeding.
• Lumbrokinase activates plasmin and degrades fibrin. Lumbrokinase appears to be well absorbed from the GI tract. 
• Turmeric (Curcumin) 500 mg BID. Curcumin has anticoagulant, antiplatelet and fibrinolytic properties.
• Triple anticoagulation should be considered in select patients.  Treat no longer than one month. Triple anticoagulation increases the risk of serious bleeding; patients should be counseled regarding this complication. 
• In those patients with marked microvascular disease/thrombosis, the combination of pentoxifylline and sildenafil should be given a therapeutic trial.  

 
Vaccine-induced myocarditis/pericarditis

• ACE inhibitor/ARB, together with carvedilol as tolerated to prevent/limit progressive decline in cardiac function. 
• Colchicine in patients with pericarditis – 0.6 mg/day orally; increase to 0.6 mg twice daily if required. Reduce dose if patients develop diarrhea. Monitor white blood cell count. Decrease dose with renal impairment.  
• Referral to a cardiologist or emergency center if persistent chest pain or other signs and symptoms of cardiac events are observed.

 
Herpes virus reactivation syndrome

• L-Lysine; 1000 mg twice daily [145,146]
• Valtrex; 500-1000 mg twice daily for 7-10 days

Tinnitus

• This a frequent and disabling complication reported in post-vaccine syndrome.
• Tinnitus refers to the sensation of sound in the absence of a corresponding external acoustic stimulus and can, therefore, be classified as a phantom phenomenon. Tinnitus sensations are usually of an unformed acoustic nature such as buzzing, hissing or ringing. Tinnitus can be localized unilaterally or bilaterally, but it can also be described to emerge within the head. 
• Ideally, patients should be evaluated by an ENT specialist or audiologist to exclude underlying disorders. 
• Several treatment approaches exist to manage this disabling disease including: 
  • Cognitive behavioral therapy 
  • Specialized therapy including tinnitus retraining therapy, hearing aids, sound therapy, auditory perceptual training and repetitive transcranial magnetic stimulation. 
  • Several pharmacologic agents have been used to treat tinnitus. Anticonvulsants including carbamazepine have generally been disappointing. The following drugs have shown some clinical benefit.
    • Tricyclic antidepressant agents particularly nortriptyline and amitriptyline.   In addition, the SSRI sertraline has shown some efficacy. 
    • Clonazepam and or other benzodiazepines. These drugs may provide temporary relief, however, due to issue of dependence, long term use is not recommended. 
    • Melatonin slow release 2-6 mg at bedtime. 

Bell’s Palsy/Facial Paresthesia, visual issues

• Low dose naltrexone. Begin with 1 mg/day and increase to 4.5 mg/day as required. May take 2-3 months for full effect. 
• Low dose corticosteroid: 10-15 mg/day prednisone for 3 weeks. Taper to 10 mg/day and then 5 mg/day as tolerated. 
• Reduced workload, stress, and light exercises for a couple of months.

The Patterson Protocol 
Our long COVID series includes an in-depth discussion about the Patterson protocol. 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 research has shown that the pathophysiology behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection.  CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance.  They believe targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC.
 
Dr Patterson has also used components of his protocol to treat chronic Lyme disease, learn more at: https://www.suzannegazdamd.com/blog---long-covid/chronic-lyme-disease-may-have-lessons-about-long-covid

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.

With this specialized program, a specialized series of labs - the IncellKINE test - are conducted (the Incell DX panel should be used only as guidance of treatment). Based on the results, patients are then typically prescribed these therapies below; but, every patient is different and unique so the protocol is specific for each patient’s needs. Many times, we will repeat the Incell DX panel to gauge treatment response and follow clinical response as well.  Now the Incell DX panel can not only measure the proinflammatory cytokines (chemical messengers) seen in Long COVID but can also quantify spike protein in monocytes and measure the monocyte subsets   All of this information can be valuable in some patients with LHCS.   
 
A. Maraviroc
A CCR5-antagonist, Maraviroc reduces cytokines and blocks migration of the intermediate and non-classical monocytes, as it also 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.
• Recommend obtaining baseline CBC and Chem LFTS Thyroid, plus /minus EKG prior to any treatment or medications.
• While on Maraviroc, monitor LFT’s and CBC monthly.
  
• Maraviroc has an FDA liver toxicity warning, but numerous randomized controlled studies suggest it is a very safe drug.
• Maraviroc is an expensive drug, but patients can seek assistance with the cost at: https://www.myviivcard.com. The website provides more information regarding eligibility and how to potentially get and activate a card that you can use when filling a prescription at your pharmacy. There is also a toll-free number to call for additional information, so please visit the site for full details.                                                       Possible side effects include:                                                                                        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. Statins are shown to possess broad anti-inflammatory effects. 

• 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.   Prednisone  Many LHCS 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, depending on 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.

D. Fluvoxamine:
 
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)
 
Expediency in treating individuals with LHCS is critical – so many patients have been suffering with numerous issues and already invested both the hours and finances in seeking help. But it is especially important to work with a clinician that understands the complexity of this problem and is committed to keeping up with the ever-changing paradigms. If we can help or answer any questions, please be sure to reach out to our offices.
   
And be sure to stay tuned for updates - we are learning more and more every day!  And remember … always be checking back with the FLCCC protocols for updates.
https://covid19criticalcare.com/covid-19-protocols/
 
In health and hope,
Dr. Suzanne K. Gazda
  
Mazer, B. Long COVID Could Be a ‘Mass Deterioration Event’. The Atlantic. June 15, 2022.
https://www.theatlantic.com/health/archive/2022/06/long-covid-chronic-illness-disability/661285/
 
Fox, J. Long Covid Is Showing Up in the Employment Data. Bloomberg. June 15, 2022.
https://www.bloomberg.com/opinion/articles/2022-06-15/long-covid-is-showing-up-in-the-employment-data
 
VAERS COVID data
https://openvaers.com/covid-data
 
Sisó-Almirall A, Brito-Zerón P, Conangla Ferrín L, et al. Long Covid-19: Proposed Primary Care Clinical Guidelines for Diagnosis and Disease Management. Int J Environ Res Public Health. 2021;18(8):4350. Published 2021 Apr 20. doi:10.3390/ijerph18084350
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073248/
 
Proal AD and VanElzakker MB (2021) Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front. Microbiol. 12:698169. doi: 10.3389/fmicb.2021.698169
https://www.frontiersin.org/articles/10.3389/fmicb.2021.698169/full#B120
 
FLCCC Protocol
https://covid19criticalcare.com/wp-content/uploads/2021/06/FLCCC-Alliance-I-RECOVER-Management-Protocol-for-Long-Haul-COVID-19-Syndrome.pdf
 
Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(22):2292–2300. doi:10.1001/jama.2020.22760
https://jamanetwork.com/journals/jama/fullarticle/2773108#jpc200006r26
 
Glebov OO (2021) Low-Dose Fluvoxamine Modulates Endocytic Trafficking of SARS-CoV-2 Spike Protein: A Potential Mechanism for Anti-COVID-19 Protection by Antidepressants. Front. Pharmacol. 12:787261. doi: 10.3389/fphar.2021.787261
https://www.frontiersin.org/articles/10.3389/fphar.2021.787261/full
 
Hyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising intervention. 
https://react19.org/wp-content/uploads/2022/05/33439.pdf
 
Vedicinals
https://www.vedicinals.com/vedicinals-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
https://pubmed.ncbi.nlm.nih.gov/32871846/
 
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; https://pubmed.ncbi.nlm.nih.gov/19109745/
 
Lipopolysaccharide-Induced Inflammation.
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/lipopolysaccharide-induced-inflammation
 
Patterson BK, Francisco EB, Yogendra R, et al. Persistence of SARS-CoV2-2 S1 Protein in CD16+
Monocytes in Post-Acute Sequelae of Covid-19 (PASC) up to 15 months post-infection. Front Immunol. 2022 
 
Patterson BK, Seethamraju H, Dhody K, et al. CCR5 Inhibition in Critical COVID-19 Patients Decreases Inflammatory Cytokines, Increases CD8 T-cells, and Decreases SARS-CoV2 RNA in Plasma by Day 14. International Journal of Infectious Diseases. 2021; 103:25-32.
 
Short-Term Treatment With Atorvastatin Reduces Platelet CD40 Ligand and Thrombin Generation in Hypercholesterolemic Patients  Circulation  Feb 2005 https://www.ahajournals.org/doi/10.1161/01.cir.0000153810.81187.7d#:~:text=Compared%20with%20diet%2Dassigned%20patients,of%20its%20cholesterol%2Dlowering%20effect
 
Patterson, BK., Yogendera, R., et al. Targeting the Monocytic-Endothelial-Platelet Axis with Maraviroc and Pravastatin as a Therapeutic Option to Treat Long COVID/ Post-Acute Sequelae of COVID (PASC). ResearchGate. (February 2022) http://dx.doi.org/10.21203/rs.3.rs-1344323/v1