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TABLE 2021, COVID-19: THERAPEUTIC PLAN AND POTENTIAL THERAPIES. January 2021.

January 2021

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Authors:

Gustavo Aguirre Chang

National University of San Marcos

Aurora Natividad Trujillo Figueredo

SIGESA

José Aníbal Córdova Masías

Instituto nacional de ciencias Neurológicas, Lima, Perú

TABLE 2021, COVID-19: THERAPEUTIC PLAN AND POTENTIAL THERAPIES. January 2021. Early treatment is important, and in those who do not have a rapid therapeutic response, the doses of drugs should be increased to reduce Viral Load. After 27 to 30 hours of starting treatment, the response to this should be evaluated. If it does not present a significant improvement in symptoms, it indicates that the Viral Load is High and there is a tendency to make a Persistent Infection, so it is worth increasing doses and medications.

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I. INITIAL, or NASAL and PHARYNGEAL + Intest. II. PULMONARY

ENOXAPARIN SC 40 mg every 24

h. In >70 Kg: 60 mg ev/ 24 h.

NATTOKINASE: 300mg/d.x 20d,or

LUMBROKINASE: 120mg/d. x 20d.

LYSINE 500mg at 7am, 4 and 10pm

FLUVOXAMINE50mg ev/12h x10d

ENOXAPARIN SC 0.5mg/kg ev/12h.

NATTOKINASE: 400mg/d x 20d, or

LUMBROKINASE: 160mg/d. x 20d.

LYSINE 1000mg 7am, 4 and 10pm 8d

CÚRCUMA 3000-4000 mg/d. x 14 d.

GARLIC: 5000 to 7000 mg/d. x 14 d

III. MULTI-ORGAN

Therapeutic Plan

5) ENOXAPARIN AMP SC 40mg.

DOSE FOR CRITICAL CASES:

If the Sat. O2 drops to less than

80%: give 0.5 mg. x kg. of weight

every 8 hours x 2 to 3 days until

recovered the Sat. O2 > 80% and

changed to every 12 hours.

6) CYPROHEPTADINE start with

0.3 mg/kg/day, divide into doses

every 8 h x 3 d. Then 0.2 mg/kg.

7) FIBRINOLYTICS: EV or VO.

ACETYLSALICYLIC ACID (ASA)

300-500mg 1 time on the 1st day.

Ambulation at home, change

position every half hour during

the day, avoid crossing the legs,

flexion and extension exercises.

COVID-19:THERAPEUTIC PLAN AND POTENTIAL THERAPIES. Aguirre-Chang, Gustavo; Trujillo F, Aurora; Córdova M, José Aníbal. February 2021b

IVERMECTIN: 0.6mg x Kg of weight 2 times a day (breakfast and

lunch). Take until to 6 to 10 days after you have no symptoms.

SPIRONOLACTONE TB: 100 mg every 12 or 24 hours for 8-10 d.

FENOFIBRATE TB: 160-200 mg/day x 14 days. And add one of

the following alternatives for 10 days: DUTASTERIDE 1 mg/day,

or FINASTERIDE 10mg/day, or BICALUTAMIDE 150mg/day.

NEBULIZE* x 15 min. c/12 h x 3d. with: -HYDROGEN PEROXIDE,

at 3%, mix 3 ml with 3 ml of 0.9% NaCl; or Neb. with HCQ: grind

1 TB of 200mg, pour into 8 ml of distilled water, or boiled cold.

IVERMECTIN: 0.4mg x Kg x doses, after

breakfast and dinner for 5 to 7 days.

If there is fever + than 24 hours, add 3rd

dose a day, and: NIFUROXAZIDE TB

give 400 mg every 6 to 8 hoursx 3 to 15

days, according on severity. The

alternative is RIFAXIMINE TB 200 mg:

Give 400mg every 8 hours x 6-12 days.

FAMOTIDINE 60 mg at 7.30am, 3pm, 11pm

x 7-14d.. If weighing >75kg give 80mg x3.

PHASES

1) IVERMECTIN: 0.6mg/Kg x dose,

2-3 times a day. Take up to 9 to 15

days after you have no symptoms.

2) NIFUROXAZIDE 200mg 3TB ev/

8h x 6-9 d. >95 kg give 3TB e/ 6 h

3) NITAZOXANIDE or NICLOSAMI-

DA, TB 500 mg every 6h. x 9-15 d.

For <56 kg give 1TB every 8hours.

4) SPIRONOLACTONE 100 mg ev/

12 h. x 6 d., then 100 mg/d. x 8 d.

Days that are + hospitalized Requires ICU

The first 3 to 4 days there is no pulmonary involvement or this is little

LOCATION

Very HIGH Total Body Viral Load

VIRAL LOAD The Vir. load is estimated according to the response to treatment, 27-30h. after the treat begins

DOXYCYCLINE

100mg ev/12h x 7

d. >90kg ev/8h; or

AZITHROMYCIN

500 mg/d x 5 days

If there is fever, investig. Coinfection

Alte. Oral: CEFIXIME 400, LEVO 750,

MOXIFLOXACIN 400. IV: CEFTRIA-

XONE 2gr., CEFIPIME, MEROPENEN

Progress to Lungs, Intestines, Myocardium/Pericardium, Brain.

MEDIUM to HIGH ViralLo.

Investigate Kidney, Liver, others

IF IT

PROGRESSES Req. VM

DEXAMETHASONE 4 mg. TB or

AMP: 6 to 8 mg. x day x 2 - 5 d, or

METHYLPREDNISOL.125mg x 2dor

CYCLOSPORIN: 6 to 10 mg/kg/d.

in 2 doses, x 4-6d.,accord.resp.

INMUNOGLOBULIN (IGIV)AMP

400 mg/kg/d slow infusión. x 3d.

Use High Flow Nasal Cannula HFNC

ZINC: 200-250mg x day x 12d. Away from

food (11 am and / or 4 pm) and dairy.

Vit. D:60,-90,000 IU/d.x 6d. or 300,000/1d.

Vit. C: 2 gr every 8 hours x 6 to 12 days

Vit. A: 75,-100,000 IU x day x 3 d., do not

take x 4 days and repeat x 3 d. the same.

Sodium Bicarbonate: 1 sachet of Andrews

Salt or 1/2 teaspoon of Baking Soda in a

glass of water at 11am and 10pm x 3 days.

COLCHICINE TB 0.5 mg, 1 ev/12 h. x 15 d. If

you weigh >75 kg: give 2 TB in the morning.

N-ACETYL CYSTEINE 600 mg. sachet or TB.

2 sachet dissolved every 6-8h x 6 to 10days

BUDENOSIDE or CYCLESONIDE: 2 inhalati.

in the morning, noon and afternoon x 10 d.

QUERCETINE 1 TB 500mg every 8h. x 12d.

NIACIN (B3) 300mg x 2days, then 600mg/d.

OMEGA 3: TB 3000 mg/day x 15 d.

VIT. C: 50mg/kg.ev/ 8 or 12 h x 6 d.

VIT.B12 TB 3000 mcg/day x 8-12 d.

THYAMINE TB 600 mg/day x 8-12 d.

MELATONIN TB, before sleeping.

Increase from 3, to 6 and to 10mg.

MAGNESIUM TB 800mg/day x 14 d

SELENIUM TB 200mcg 2-3/d. x 30d

ASA TB : 300mg per day (100 mg after meals) x 4-9

d. For weigh more than 95kg give 500-600 mg/day.

Alternatives to ASA are: -CLOPIDOGREL 75mg/d. x

4-9d. If weigh is <56kg give 37.5mg/d. –GINGER: 1100

mg 3 times /day. For >95kg give 4400mg/day. DIPYRI-

DAMOLE: 1 TB 75 mg 3-4 times/day, away from food.

IVERMECTIN: 0.4 mg per Kg. of

weight x dose a day, after lunch

or dinner for 3 to 4 days. If you

have a fever over 38°C for more

than 12 hrs or semiliquid stool,

add the 2nd dose in the day.

Additional Hydration: 1-2 lt./day.

Nasal Washes: 3-4 times /d. with

a 20 ml syringe with 1 glass of

water with 1/2 teaspoon of salt.

Treat NUTRIENT

DEPLETION,

OXIDATIVE

STRESS,

LYMPHOPENIA

and IMMUNE

DYSFUNCTION

Treat PLA-

TELET HYPER-

ACTIVITY and

Coagulopathy

Avoid: coffee, alcohol; nuts, peanuts,

almonds, pecans; orange, lemon,

tangerine, banana, chocolate; chili;

seeds, oats, wheat, corn; tomato,

cabbage; sausages; fish, shellfish.

Consume more: turkey,chicken,egg,

beef; mango; potato, quinoa; yoghurt

Do not use PARACETAMOL. Only if

the fever is> 38.5 °C give antipyretics

Rapid response to treatment, w/

improvement from 97 to 100% =

LOW ViralLoad.RhinoPharyngit.

Initial Pulmonary Edema,

InvestigateGastroenter.,

Myocarditis/Pericarditis.

Mod/Sev ARDS, SIRS, Thrombo-

embolic disease, Myocarditis, in-

vesti.Heart-Renal failure, Enceph.

Gargle: 4-5 times a day. Mix 10 ml of cold boiled water with 5 ml of Hydrogen

peroxide of 3 %, 10vol. Or w/ 0.05% Cetylpyridinium Chloride,10ml undiluted.

Give IVERMECTIN to Contacts: 0.4 mg for Kg of weight for 3 continued days.

In Men aged over 70 years give 5 days. In Caregivers give 6 continued days.

Add to what is

indicated:

NITAZOXANIDE:

TB 500 mg ev/8h x

8-14 d. If weigh is

>90kg give ev/6h.

BROMHEXINE:

FCO. 8 mg (5ml)

every 8 h x 6-8 d.

Partial response to treatment, 25 to 96

% improvement = MEDIUM Viral Load.

But if it affects the intestines, it is high.

Response <25%=

HIGH and Persis-

tent Viral Load

Moderate ARDS, Pulmonary Coa-

gulopathy,Gastroenteritis. Investi-

gate Myocarditis/Pericard., Enceph.

Response to treat-

ment, Diagnosis

and Severity

Days since

symptoms start

HIGH VL: Lungs, Intestines, Heart.

For Pulmonary Edema :

put in Prone position.

Restrict liquids, salt, do

not give Sodium Chloride:

NaCl (yes Dextrose 5%).

Reduce the

VIRAL

LOAD

and cover

Co-infections

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 8 9 10 11 12 13 14

goes

to SIRS

* When nebulizing, take into account that aerosols will be generated, which increases the risk of contagion to other people. When doing it at home, teach the patient how to turn off the nebulization, and that there is no other person in the environment while nebulizing.

Nose and Pharynx. The Variants affect the intestines and the heart. In children it is multi-organ.

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INCLUSION OF FIBRINOLYTICS IN THE THERAPEUTIC PLAN FOR COVID-19.

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Apr 2021

INCLUSION OF FIBRINOLYTICS IN THE THERAPEUTIC PLAN FOR COVID-19. Thrombosis in COVID is not solved only with Anticoagulants, the early use of Fibrinolytics and Antiplatelet Agents is necessary. Since March 2020, after studies that included autopsies were published in which it was found that the main cause of complications and deaths from COVID-19 was the presence of micro and macrothrombosis, from that date the indication of anticoagulants became a standard and were included in the Treatment Protocols for moderate and severe cases of COVID-19. More than 1 year has passed since the use of anticoagulants such as heparins in COVID became widespread, however, despite their use, new studies that include autopsies continue to frequently identify micro and macro thrombosis at the pulmonary and the systemic microvasculature. This evidence makes it necessary to review the therapeutic indication of using only anticoagulants in COVID-19. Several studies have already identified that the state of hypercoagulability and thrombophilia that occurs in COVID-19 is mainly associated with abnormal hyperactivity of platelets and their precursors, megakaryocytes, which are the largest cells in the bone marrow. For a few years it has been identified that megakaryocytes are not only produced at the bone marrow level, but are also produced in the lungs, and in COVID, pathology studies have identified an increase in the number of megakaryocytes at the lung level, which has led to increased production of platelets and thrombi [1]. Similarly, in autopsy studies performed on patients with COVID, the abnormal presence of megakaryocytes has been identified at the brain level. observing that the nuclei of megakaryocytes generate embolisms at the level of the microvasculature of the brain, with the consequent decrease in blood circulation at the cerebral level. Other alterations that are generated is the greater release of extracellular vesicles, and the greater release of existing serotonin reserves within platelets, with the consequent increase in plasma serotonin [2]. These findings support the recommendation to include antiplatelet and fibrinolytic agents in the Treatment Scheme for the different stages of COVID. Since mid-2020, we have included the use of Acetylsalicylic Acid (Aspirin) in the Therapeutic Plan that we publish for Acute COVID, as it is the most widely available antiplatelet agent, at the lowest cost, and with decades of experience in its use. [3]. Subsequently, we expanded its indication and since July 2020 we included ASA in the "Therapeutic Test" prepared for Post-Acute COVID Syndrome or Long COVID [4], and later in November 2020 we have included ASA in Post-Exposure Prophylaxis aimed at Contacts of sick people, and for “People at Higher Risk” in Pre-Exposure Prophylaxis [5]. Regarding Fibrinolytics, we have included them since the Therapeutic Plan that we published in January 2021 [6]. In this, the inclusion of Fibrinolytics for oral use such as Lumbrokinase, which is a proteolytic enzyme from Lumbricus rubellus, a species of earthworm, has been recommended. This enzyme favors the breakdown of clots and thrombi [1,6]. Other oral alternatives for fibrinolytic enzymes are Serrapeptase and Nattokinase, which can be indicated together. We reaffirm the importance of the use of fibrinolytics in COVID-Acute, and we maintain the indication to take antiplatelet agents from the first day of symptoms in COVID-Acute, and we also maintain their indications for their prophylactic use. The most frequent presentation of Lumbrokinase is that of 20 mg tablets, the recommended dose for COVID being between 4 to 6 tablets per day, it is marketed as a supplement and does not require a prescription. We indicate it together with an antiplatelet agent such as ASA at a dose of between 100 and 300 mg per day to be taken after food, always accompanied by Famotidine to reduce the risk of digestive bleeding and due to its favorable effects observed in patients with COVID. It should be taken into account that the simultaneous use of drugs with effects on reducing coagulation can cause bleeding, more so due to the use of ASA. Oral fibronolytics have a significantly lower risk of causing bleeding than ASA. In Acute Post COVID Syndrome (PACS), Persistent COVID or Long COVID we also frequently indicate 1 or 2 Fibrinolytics together with an Antiplatelet [6]. The details of the doses of the Fibrinolytics and Antipaquetes, according to the severity of the disease and the weight of the patient, are available in the documents of references 6 and 7.

PERSISTENT INFECTION BY SARS COV-2 IS CAUSE OF FORMATION OF ARTERIAL PLAQUES, ATHEROSCLEROSIS AND INCREASED RISK OF MYOCARDIAL INFARCTION

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Oct 2023

PERSISTENT INFECTION BY SARS COV-2 IS CAUSE OF FORMATION OF ARTERIAL PLAQUES, ATHEROSCLEROSIS AND INCREASED RISK OF MYOCARDIAL INFARCTION. Autopsy study shows a causal relationship between SARS CoV-2 infection and the formation of arterial plaques, increasing the risk of heart attacks. As they fulfill a similar function to Biofilms, we propose to call them Atheroma Bioplaques. SUMMARY. A study based on autopsies performed on patients who had severe COVID has shown the presence, replication and persistence of the SARS CoV-2 virus in the walls of the coronary vessels of the heart and especially inside the macrophages. In the first parts of this document we describe the evidence shown by this study regarding the causal relationship between persistent SARS CoV-2 infection with the formation of arterial plaques and the development of atherosclerosis. The identification of the SARS CoV-2 virus in 100% of the autopsies reported in this study indicates that in all cases the infection persisted throughout the illness and until the patient's death. We also performed a review of other previous related studies. In these, it has been shown that cardiac macrophages have a half-life of almost 9 years, so these cells alone would act as shelter and viral reservoirs. On the other hand, we describe how microorganisms group and organize with the aim of persisting and surviving, forming so-called biofilms. It may also happen that microorganisms take advantage of the presence of structures that form in the body (such as amyloid deposits, fibrin and clots) to use them to their advantage. Infections whose persistence is associated with the existence of reservoirs and biofilms frequently develop multidrug resistance (MDR), which we have observed occurs in a significant proportion of patients with COVID Chronic or Long COVID. Dental plaque existing in the oral cavity was historically the first biofilm described in the human body. For our part, we have proposed the name bioclots for the biofilm-like structures that form inside blood vessels. We have also proposed that amyloid and fibrinoamyloid deposits be called bioamyloid and biofibrinoamyloid, respectively. We propose these names because these structures frequently serve as a refuge and reservoir for viruses and other microorganisms, thus fulfilling a function similar to Biofilms. In the same sense, as macrophages and other cells of arterial plaques are used by viruses to take refuge and persist, since these atherosclerotic plaques fulfill a function similar to Biofilms, we propose that they be called Atheroma Bioplaques. The evidence described supports our treatment protocols, which mainly include drugs with effects against the viral load, since by eliminating or significantly reducing the causal or triggering etiological factor, the entire subsequent sequence of pathological events that lead to the formation of arterial plaques and atherosclerosis. Additionally, our protocols include fibrinolytics, antiplatelets, antihistamines, vitamines and colchicine. Study based on autopsies of patients with COVID. A peer-reviewed study by researchers at the New York University School of Medicine in the United States, which has been published in the journal Nature Cardiovascular Research [1], has shown the presence, replication and persistence of the SARS CoV-2 virus in the walls of the coronary vessels of the heart and especially inside the macrophages that have a high content of low-density lipoproteins (LDL). This study was funded by the National Institutes of Health (NIH) of the United States. The study was based on autopsies performed on patients who died with COVID-19. They included 8 people between 59 and 84 years old (mean age: 69) who already suffered from coronary artery disease and had 3 or more cardiovascular risk factors, such as hypertension (8/8), overweight or obesity (7/8), hyperlipidemia (7/8), type 2 diabetes (6/8) and/or chronic kidney disease (4/8). In all autopsies (100% of cases) it was evident that SARS-CoV-2 directly infects and replicates inside the different cells existing at the walls of the coronary vessels and fundamentally in the arterial intima layer, which is the place where the so-called arterial atheroma plaques begin to form. SARS-CoV-2 is not only a respiratory virus. During the first months of 2020, SARS CoV-2 was described as a respiratory virus, hence its name as Severe Acute Respiratory Syndrome (SARS) virus. However, multiple studies have shown that when disease progresses in severity and/or persists over time, disseminated involvement of blood vessels occurs [1,2] and it has been identified that people who had COVID-19 have a higher risk of suffering from cardiovascular diseases, such as acute myocardial infarction (AMI) and cerebrovascular accidents (stroke) [3] so this pathological history constitutes a risk factor for cardiovascular diseases. Macrophages and Foam Cells in the Pathogenesis of arterial plaques and atherosclerosis. For more than a decade, several studies and review articles have been published in which the important role of macrophages in the pathogenesis of arterial plaques and atherosclerosis is pointed out and described [4,5,6,7,8]. It has been identified that in the initial stage of the formation of arterial plaques, there is a significant increase in the number of macrophages at the level of the vascular walls. These macrophages capture and internalize low-density lipoproteins (LDL), accumulating multiple vacuoles containing lipids inside them, which gives them a vacuolated appearance, which is why they are called Foam Cells, which play a central role in the appearance and progression of arterial plaques and atherosclerosis. In the autopsies it was evident that the Macrophages and Foam Cells of the arterial plaques are infected by SARS CoV-2. This autopsy study showed that, in 100% of the 8 cases evaluated that died from Severe COVID, SARS-CoV-2 infects, replicates and persists in the macrophages and foam cells that are accumulated at the level of the vascular walls of the coronaries. When evaluating the capacity of SARS-CoV-2 to replicate in both types of cells, it was evident that replication was significantly greater in foam cells, and it was also observed that in these there is a greater accumulation of SARS-CoV-2 RNA compared to macrophages, which indicates that inside the foam cells there is greater replication and viral load, which would be favored by the high content of LDL type lipids

REVERSIBLE SIDE EFFECTS BY DOSE OF 180 MG OF IVERMECTIN. Report of 4 Cases: 1 with COVID and 3 with severe Dengue

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May 2023

Background. Ivermectin (IVM) is considered an essential drug by the World Health Organization (WHO), it is approved by the US FDA and has been widely used worldwide for almost 40 years. It is, then, a drug of which there is wide knowledge of its use in humans, it is not an experimental drug, it is free of patents, it is well tolerated, its use has been reported in much higher doses than usual [1,2,3], it continues to be administered massively to large populations including children for effective control of endemic infections [4,5,6,7], this with the support of the WHO [7,8] who have recently published that population-based treatment with IVM (also known as mass drug administration or MDA) is the current core strategy to eliminate the transmission of onchocerciasis [8] and it has been used by medical specialists in prestigious hospitals, including in the US and the UK, even in its presentation for veterinary use [9-19]. Of the publications made, it is worth highlighting the detailed study by Guzzo, Lasseter et al. [1], which concluded that IVM is well tolerated even at doses of 1.5 and 2 mg per kilo of body weight. In this study, of the 24 people who received either IVM 90 or 120 mg as a single dose, only 2 experienced transient side effects. Forty 3 mg tablets were required to reach the 120 mg dose. ... Conclusion. In summary, of the 4 cases that took daily doses of 180 mg of IVM, 3 presented visual alterations as side effects, mainly blurred and darkened or yellowish vision. These side effects on vision began to occur after 9 p.m. and 5 to 10 hours after completing the 180 mg of IVM and disappeared completely after 3 to 6 hours of waking up the next day. The side effects in these 4 cases were temporary, reversible and without subsequent consequences. After 24 hours of taking this dose of IVM, the patients reported having significantly improved from the disease they suffered from.

Sub-Acute and Chronic COVID: THERAPEUTIC PLAN FOR PATIENTS WITH POST ACUTE COVID SYNDROME (PACS) OR LONG COVID.

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Apr 2021

Sub-Acute and Chronic COVID: THERAPEUTIC PLAN FOR PATIENTS WITH POST ACUTE COVID SYNDROME (PACS) ORVLONG COVID. In a similar way as in Acute COVID, treatments against Viral Load and Persistent Clots are the main Objectives of the Therapeutic Plan. THERAPEUTIC PLAN FOR COVID. In the first document on the use of an effective drug against the Viral Load in COVID that we made available on May 2, 2020 (11), based on the publications and clinical experience to that date, a Therapeutic Plan for COVID was established in which there are indicated 3 Therapeutic Lines of Action or Objetives. As for Sub-Acute and Chronic COVID, as it is a continuation of the same COVID disease, in general this Therapeutic Plan is maintained with the 3 Objectives or Lines of Action indicated for Acute COVID (see Table 1). But it must be taken into account that in Sub-Acute and Chronic COVID there is a greater problem in what corresponds to the destruction of clots. It happens that there is an inhibition or arrest of the body's Fibrinolysis System, that is, the physiological system does not work to destroy clots [14], so the clots do not break down and persist, causing hypoperfusion in tissues and cells. Routine clotting tests more frequently are normal. Specific tests are required to identify if there is an arrest of the fibrinolysis system, such as viscoelastic tests (TEG, ROTEM, Quantra, Sonoclot, iCoagLab and others). TREATMENT REGIME FOR POST-ACUTE COVID PERSISTENT SYMPTOMS OR LONG COVID OR PACS. After evaluating a patient with Post-Acute COVID Persistent Symptoms, Long COVID or PACS, as the next step it is indicated to request diagnostic aid tests to confirm that there is a Persistent Intracellular Infection by the SARS CoV-2 virus, with which the diagnosis of Chronic COVID would be established if it has more than 3 months since the onset of symptoms, or Sub-Acute COVID if it has between 1 to 3 months of symptoms. As explained, to date within the conventional tests available, there are no tests to identify the presence of viral load in intracellular locations. Taking into account that IVM is a low-cost drug, without significant side effects and which has decades of experience in its use in humans, What we have indicated since May 2020 is a Treatment Regime that includes IVM, for PACS and Sub-Acute and Chronic COVID. We present this First Treatment Regime as a "Therapeutic Test" to be used in patients with Persistent Symptoms of COVID. In the medical field, Therapeutic Tests have been used for several decades as a diagnostic aid in various diseases. In the case of the PACS the objective is to support the Diagnosis of a Persistent Infection by SARS CoV-2 We must mention that a large part of the decision to give the name of "Therapeutic Test" to this intervention is due to the fact that by mid-2020 the vast majority of the scientific community did not accept that the SARS CoV-2 virus persisted longer than 10 days. The high percentage of patients that we have observed that respond favorably to this "Therapeutic Test" supports its usefulness to assist the diagnosis and supports the existence of viral persistence in most of the patients with PACS. "THERAPEUTIC TEST" AND FIRST TREATMENT REGIME FOR PATIENTS WITH POST ACUTE COVID PERSISTENT SYMPTOMS, LONG COVID OR PACS. In September 2020, we made available the First Treatment Regime or Protocol for patients with Post Acute COVID Persistent Symptoms, Long COVID or PACS (21), and in which the 3 Lines of Action of the Therapeutic Plan for COVID are covered: 1) Reduce Viral Load: with IVERMECTIN. 2) Reduce Platelet Hyperactivity and Break down Persistent Clots and Biofilms: with ASA. 3) Treat Nutrient Depletion, Oxidative Stress and Immune Dysfunctions: included FAMOTIDINE, SODIUM BICARBONATE and a DIET low in Arginine and Histamine and high in Lysine and Vitamin D. The First Line of Action is the main one and the one that should be emphasized, since it is aimed at reducing the Viral Load, which is the main cause that triggers the problems covered by the other 2 lines of action. Regarding the doses to be given of each drug in the "Therapeutic Test", we have already published this in detail in a previous document (19). Table 2 shows the consolidated indications for this First Treatment Regime or "Therapeutic Test" for patients with Post Acute COVID Persistent Symptoms. RESULTS OF THE APPLICATION OF THE "THERAPEUTIC TEST" IN 390 PATIENTS WITH POST ACUTE COVID PERSISTENT SYMPTOMS, LONG COVID OR PACS. In our experience of 390 patients with Persistent Symptoms of COVID who received a clinical epidemiological diagnosis of PACS, and the "Therapeutic Test" was applied, at the end of the 6 to 16 days that the Test lasts, it was obtained as a result that: - 83% of the patients presented an improvement in symptoms of between 40 to 100%, which means that the “Therapeutic Test” was Positive (see Table 3); - In 11% of the cases the improvement in symptoms was between 5% and 39%; - In 6% there was either no improvement (0%) or almost no improvement (1 to 4%), interpreting in the latter group that the test was Negative. The objectives of applying the "Therapeutic Test" are, on the one hand, to serve as a diagnostic aid test, and on the other hand to serve as a treatment. Regarding its usefulness as a diagnostic aid test: The results that we have obtained and that are shown in Table 3, support that the main cause of the diagnosis of Post Acute COVID Persistent Symptoms or Long COVID is a Persistent Infection by SARS CoV-2. It is also important to bear in mind that a Negative result of this Test would indicate that it is not a persistent SARS CoV-2 infection, so in these cases other possible causes should be investigated. Regarding its usefulness as a treatment: At the end of taking the 6 days of drugs of the “Therapeutic Test”, the patients who resulted in an improvement of 40% to 99% of All the symptoms, they were instructed to continue taking all the medications, this while they observe that the medications generate an improvement in their symptoms. The patients were specified to continue every day until one of the following 2 situations occurs: - Up to 6 days after achieving a complete (100%) improvement in symptoms, or - Until you notice that you no longer show improvement with treatment, and up to the a maximum of 10 additional days of treatment (16 days in total). INCREASED DOSE OF DRUGS AGAINST VIRAL LOAD DUE TO SARS COV-2 MUTATIONS. It should be taken into account that the SARS CoV-2 virus is constantly mutating within the body of people who have a persistent infection. Since 2021, infections due to Variants of SARS CoV-2 predominate, and in medical practice we have observed that, for the treatment of Acute COVID due to Variants, higher doses, more days of treatment and a greater number of medications given at the same time are required. Similar to Acute COVID, in Sub-Acute and Chronic COVID, it has been necessary to increase the daily doses and days of treatment of drugs against Viral Load, such as IVM, Nitaxozanide and Zinc. What is understood to happen is that the Viral Load mutates rapidly and develops more and more resistance to the drugs to which it is exposed. TREATMENT REGIME TO FOLLOW AFTER APPLYING THE “THERAPEUTIC TEST” FOR POST ACUTE COVID PERSISTENT SYMPTOMS. After having finished applying the "Therapeutic Test" or First Treatment Regime, using IVM, ASA, Famotidine, Sodium Bicarbonate and the described diet, according to our experience, 25% or more of the patients will still present Post Acute COVID Persistent Symptoms. In these cases, it should be evaluated if they are symptoms associated with the presence of tissue hypoperfusion, these symptoms are mainly: 1) Fatigue that increases with exertion, 2) Brain fog, 3) Stiffness, numbness, or lack of flexibility in the fingers on waking from bed, with increased discomfort or pain when moving them, 4) Numbness, numbness, or tingling in the fingers of the hands when waking up from bed, 5) Excessive cold in the hands and feet, 6) Chilblain-type lesions or Erythema perneum or COVID Fingers, especially on the feet, 7) Bluish or purple coloration of the hands and feet, which mainly affects the fingers, 8) Dyspnea or shortness of breath. If the patient has 2 or more of the mentioned symptoms, a D-dimer analysis should be performed. If found elevated, this result gives the diagnosis of the presence Persistent Clots. In the event that his D-dimer is normal (less than 0.5 ug/ml), the recommendation is that the patient perform another Therapeutic Test, which is what we have established as an aid to the diagnosis of Persistent Clots. This Test consists of taking 1 Antiplatelet, 1 Fibrinolytic and an H2 Blocker for 6 days, and on the 7th day the patient must undergo a new D-Dimer analysis. The test is POSITIVE if there is an improvement in symptoms associated with hypoperfusion of 3 or more points out of 10 (or > 30%), and/or the D-Dimer increases more than 30% compared to the previous analysis. A Positive Test indicates that there are Persistent Clots, which in turn are formed by a persistent infection. Then the patient would be given the diagnosis of: Persistent Infection by SARS CoV-2 with the presence of Persistent Clots. In these cases, due to the fact that, with the First Regime or "Therapeutic Test" the recovery of the patient was not achieved, we indicate a Regime that contains at least 3 medications or supplements for each of the 3 Lines of action of the Therapeutic Plan (in addition of the Diet already described). That is, it is included in the Regime at least: 1) 3 drugs to Reduce Viral Load, 2) 3 drugs to Reduce Platelet Hyperactivity and Persistent Clots and Biofilms. 3) 3 drugs to Treat Nutrient Depletion, Oxidative Stress and Immune Dysfunctions. Giving 3 or more medications or suplements against Viral Load corresponds to a Treatment Regime prepared for cases in which the patient's recovery was not achieved by applying REGIMEs that included 1 or 2 medications against Viral Load. In these cases, it should be suspected that the low or partial response to treatment is due to a lower sensitivity, or greater resistance acquired by the Viral Load, and that the Viral Load may also be hidden or protected by clots and fibrin deposits or amyloid, and/or that there is Viral Load in sites with immune privilege within the body, where immunity and medications do not adequately reach. So, REGIMEs that include 3 or more drugs against Viral Load, correspond to Treatment REGIMEs for patients with: Drug-Resistant and Undercover Viral Load. Designation of the Regime to follow. To give a name to the Treatment Regime to follow, we will use 3 numbers. Each number indicates the amount of medications or supplements for each of the 3 Lines of Action of the Therapeutic Plan. The minimum Treatment Regime would be the one that includes 3 drugs from each Line of Action. In this case, the REGIME is called 3-3-3 and it is the recommended regime for cases in which persistent symptoms are mild and the patient can carry out activities of daily living almost normally. In the event that the symptoms associated with hypoperfusion are moderate or severe, in such a way that the patient is limited, and cannot carry out his activities of daily life normally, it is recommended to apply a regime with a greater number of medications or supplements. According to the number of drugs in each Action Line, the regime will be given a name. Thus we have, regime 3-6-6, 3-6-9, 6-6-9 and 6-9-9. Duration of the Regime. The duration established for the first part of this regime is 8 days, 8 days, being able extend up to a total of 36 continuous days. which can be extended to a total of 36 continuous days. The patient must take all the drugs included in the regime for 8 days. The day after finishing taking the 8 days of medications, the patients who result, with an improvement of 40% to 99% of all symptoms, are instructed to continue taking every day, the medications indicated in the 8th day, this while observing that the treatment generates an improvement in their symptoms, and they should continue with the treatment until one of the following 2 situations occurs: o Up to the same number of days that you required to achieve total (100%) improvement in symptoms. For example, if it took 15 days to recover, it will require 15 more days of treatment, with the aim of not presenting a reactivation or rebound of the symptoms. o Until you notice that you no longer show improvement with treatment, and up to a maximum of 28 additional days of treatment, which is equivalent to a cumulative 36 days. In patients who, on the ninth day after starting the regime, achieve 100% improvement in all their symptoms, the recommendation is that, from that day on, they take IVM at a dose of 0.2 mg per kilo of weight per day, and until completing 4 additional days, that is, take the same ninth day and 3 more days at a dose of 0.2 mg per kilo, which would add up to a total of 12 days from the start of the regime. In addition to IVM, the patient must continue taking the other medications in the Schedule for an additional 2 days, which would add 10 days of taking these medications. RECOMMENDED DRUGS TO INCLUDE IN THE REGIME TO FOLLOW AND ITS ALTERNATIVES. Table 4 shows the drugs that, based on scientific references and our experience, we consider to be the first options to include a 3-3-3 or 3 x 3 Treatment Regime. In the following paragraphs, the doses of each drug or supplement included in the 3-3-3 Treatment Regime described in Table 4, and the main alternatives are described. Other possible alternatives are also mentioned, but without further detail.

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THERAPEUTISCHER PLAN FÜR PATIENTEN MIT MYALGISCHE ENZEPHALOMYELITIS/ CHRONISCHES FATIGUE SYNDROM (ME/CFS), FIBROMYALGIE, RHEUMATOIDER ARTHRITIS, SJÖGREN-SYNDROM, LUPUS, MYOSITIS, AUTOIMMUNERKRANKUNGEN, KOGNITIVE BEEINTRÄCHTIGUNG UND ANDEREN MIT MÜDIGKEIT UND/ODER CHRONISCHER SCHMERZEN. Wie beim Post-Akutes COVID-Syndrom (PACS) oder Long COVID sind Behandlungen gegen mikrobielle Belastung, Biofilme und BioKlumpen die Hauptziele des Therapieplans für ME/CFS, FM, RA, SS, SLE, EM und AIK. ResearchGate. 31. Juli 2022. ABSTRAKT. Mehrere wissenschaftliche Veröffentlichungen haben die Existenz anhaltender Infektionen durch Herpesvirus, durch andere Viren oder andere intrazelluläre Mikroorganismen bei Patienten mit ME/CFS, Fibromyalgie (FM), rheumatoider Arthritis (RA), Sjögren-Syndrom (SS), Lupus erythematodes systemisch (SLE) gezeigt, Myositis oder entzündliche Myopathien (EM) und andere Autoimmunerkrankungen (AIK). Dabei ist zu berücksichtigen, dass bei persistierenden chronischen Infektionen meist Biofilme vorhanden sind, die eine Schutzbarriere darstellen, die den Eintritt und die Wirkung von Medikamenten gegen Microbial Load deutlich reduziert und somit die Resistenzbildung durch Mikroorganismen erleichtert. Bei 80 % der Patienten mit ME/CFS wurde das Vorhandensein von Mikrogerinnseln mit einem hohen Gehalt an Amyloidfibrin nachgewiesen, die, da sie ähnliche Funktionen wie Biofilme erfüllen, von uns vorgeschlagen wurden, sie BioKlumpen zu nennen. In diesem Zusammenhang betrachten wir ME/CFS, FM, RA, SS, SLE, EM und mehrere AIK als Krankheiten, die auf Biofilmen, einschließlich BioKlumpen, beruhen. Als Referenz und basierend auf der umfangreichen erfolgreichen Erfahrung unserer Behandlungsschemata und -protokolle für Patienten mit Post-Akutes COVID-Syndrom (PACS) oder Long COVID, präsentiert dieses Dokument einen Vorschlag für einen therapeutischen Plan für Patienten mit ME/CFS, FM, AR, SS, SLE, EM, andere AIK wie Vaskulitis und Sklerodermie oder systemische Sklerose, Kognitive Beeintrachtigung und andere Erkrankungen mit Müdigkeit und/oder chronischen Schmerzen. Dieser Plan besteht aus 3 Zielen oder Aktionslinien: 1) Reduzieren Sie die virale/mikrobielle Belastung. 2) Zersetzen Sie hartnäckige Biofilme und BioKlumpen und reduzieren Sie die Blutplättchen-Hyperaktivität. 3) Behandeln Sie den Mangel an Nährstoffen, Hormonen und anderen Substanzen, oxidativen Stress und Immunstörungen. Das erste Ziel oder die erste Aktionslinie ist die wichtigste, da sie darauf abzielt, die mikrobielle Belastung zu reduzieren, die die Ursache für die Probleme ist, die von den anderen 2 Aktionslinien abgedeckt werden. Wenn eine wirksame Behandlung gegen die mikrobielle Belastung durchgeführt wird, werden die meisten der negativen Auswirkungen, die diese Mikroorganismen beim Patienten verursacht haben, rückgängig gemacht, aber im Allgemeinen bleiben einige Folgen zurück, die geringfügig sein können. Als nächstes ist das Ziel des Abbaus von Biofilmen, einschließlich persistenter BioKlumpen, von Bedeutung. Unter Berücksichtigung dieser 3 Ziele oder Aktionslinien müssen Sie auswählen, welche Medikamente, Nahrungsergänzungsmittel oder Verfahren für jedes von ihnen enthalten sein sollen. Um diese Entscheidung zu treffen, ist es sinnvoll, die Erreger zu untersuchen, dazu müssen der Patient oder Angehörige nach der Infektionsgeschichte befragt und die durchgeführten Analysen und anderen Tests überprüft werden. Es ist auch wichtig, die Häufigkeit bestimmter Infektionen am Wohnort des Patienten zu sehen. Wir haben ein sehr umfassendes Dokument veröffentlicht, das viele Alternativen zu Medikamenten, Nahrungsergänzungsmitteln und Verfahren enthält, die in den zu entwickelnden Protokollen oder Behandlungsplänen auf der Grundlage der aus der Patientenbewertung gewonnenen Informationen zu berücksichtigen sind. Wir schlussfolgern, dass nach unseren Beobachtungen angesichts der günstigen Reaktion auf Behandlungen gegen mikrobielle Belastung und basierend auf veröffentlichten Studien die Hauptursache für ME/CFS, FM, RA, SS, SLE, EM und andere AIKs wie z Vaskulitis und Sklerodermie sind, sind persistierende intrazelluläre Infektionen, die am häufigsten durch Herpesviren wie das Epstein-Barr-Virus (EBV) und das Humane Herpesvirus 6 (HHV-6) verursacht werden. Von den Bakterien sticht das übermäßige Wachstum von Staphylococcus aureus als Ursache für Müdigkeit und/oder chronische Schmerzen hervor. Bei ME/CFS und FM sind auch das Humane Herpesvirus 7 (HHV-7) und andere Viren der Familie Herpesviridae wie HSV-1, Varicella-Zoster-Virus (VZV) und Cytomegalovirus (CMV) häufig. Andere wahrscheinliche Mikroorganismen sind Borrelia burgdorferi (Lyme), Candida, Bartonella, Babesia, Mycoplasmen, Rickettsien, endogene menschliche Retroviren und Mikroorganismen aus Biofilmen oder aus Darm, Mund, Nase, Atemwegen, Niere und anderen Stellen des Organismus. Im Fall von RA würden die Bakterien Proteus mirabilis, Glaesserella parasuis, Porphyromonas gingivalis, andere Mikroorganismen aus Biofilmen wie Zahnplaque, Parvovirus B19, CMV und Hepatitis B Virus, unter anderem, in der Häufigkeit folgen. Wir schätzen, dass 3 von 4 Patienten mit ME/CFS, FM, RA, SS, SLE und anderen AIK durch eine oder mehrere persistierende intrazelluläre Infektionen verursacht werden, daher sind Behandlungen gegen virale/mikrobielle Belastung, Biofilme und persistente BioKlumpen die Hauptziele von den Behandlungsplan für diese chronischen Krankheiten. Angesichts des hohen Prozentsatzes an Resistenzen gegenüber antimikrobiellen Arzneimitteln, der bei persistierenden intrazellulären Infektionen auftritt, wird empfohlen, dass Verfahren, die eine signifikante Wirkung bei der Verringerung der mikrobiellen Belastung haben, in den Therapieplan aufgenommen werden. Zusätzlich zur Ozontherapie empfehlen wir die Beseitigung von oralen Biofilmen, Gurgeln und Mundspülungen, die nasale und intestinale Dekolonisation von Staphylokokkus aureus und anderen Mikroorganismen und die Behandlung von Bakterielle Überwucherung des Dünndarms (SIBO).

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2022 CLINICAL CLASSIFICATION OF ME/CFS, LONG COVID OR PACS, PVACS, FIBROMYALGIA, MCS, CHRONIC PAIN, RA, SJÖGREN, APS, LUPUS, MYOSITIS, SCLERODERMA, ADRENAL INSUFFICIENCY, THIROID DISORDERS, DIABETES, POTS, RLS, EBV, LYME, DYSBIOSIS, IBD, OTHER, BASED ON THE PRESENCE AND SEVERITY OF HYPOPERFUSION, HYPERCOAGULABILITY AND MICROCLOTS (HHM) SYMPTOMS. A essential step towards etiological diagnosis and specific treatments. Summary Chronic Fatigue Syndrome (CFS), Fibromyalgia and other diseases or syndromes with fatigue and/or chronic pain have been maintained for several decades as non-specific diagnoses that do not provide guidance towards possible causes or etiologies, nor towards effective specific treatments. We have observed that based on clinical evaluation that most patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome), ‘Long COVID’ or Post Acute COVID Syndrome (PACS), Post-Vaccine COVID Syndrome (PVACS) and Antiphospholipid Syndrome (APS) have symptoms and signs associated with hypoperfusion, hypercoagulability and microclots, which we abbreviate HHM symptoms. And if the presence of several of these symptoms is identified, it should be noted that there is a Hypoperfusion, Hypercoagulability and Microclots Syndrome (HHMS). Something similar has been observed, but to a lesser degree, in Fibromyalgia, Multiple Chemical Sensitivity (MCS), Chronic Pain Syndromes, Rheumatoid Arthritis (RA), Sjögren's Syndrome (SS), Systemic Lupus Erythematosus (SLE), Myositis or Inflammatory Myopathies, Scleroderma, Adrenal Insufficiency, Adrenal Fatigue, Thyroid Disorders, Diabetes, POTS, Restless Legs Syndrome (RLS), Cramp-Fasciculation Syndrome, Infection by EBV, HHV-6, Lyme, Dysbiosis, Inflammatory Bowel Disease (IBD) and other diseases, syndromes or persistent symptoms with chronic fatigue and/or pain. Thus, for its application in patients with the the diseases and syndromes mentioned, we have developed a classification through which we advance from having only 1 non-specific clinical diagnosis, to 6 more specific clinical diagnoses, which provides us with an orientation significantly better, towards the causes and potential treatments, and in this way we can better direct the next steps to follow. This classification of patients into 6 diagnoses is based on a broader clinical evaluation aimed at identifying the presence and severity of symptoms associated with HHM. In this way, the 6 most specific clinical diagnoses that we have established are: 1: Chronic Disease or Syndrome, with Severe HHMS. 2: Chronic Disease or Syndrome, with Moderate HHMS. 3: Chronic Disease or Syndrome, with Mild HHMS. 4: Chronic Disease or Syndrome, with some HHM symptoms. 5: Chronic Disease or Syndrome, without HHMS (requiring other evaluations). 6: Chronic Disease or Syndrome, without HHM symptoms. We use these 6 specific clinical diagnoses in patients with CFS/ME, Long COVID or PACS, PVACS, Fibromyalgia, MCS, Chronic Pain, RA, SS, APS, Lupus, Adrenal Insufficiency or Fatigue, Diabetes, POTS, RLS, EBV, Lyme, Dysbiosis and other chronic diseases and syndromes. We have grouped the diseases, syndromes and persistent symptoms that we have identified to be associated with HHM, according to affinity and/or similarities in their clinical characteristics, establishing at least 19 groups. To facilitate the identification of HHM symptoms through clinical evaluation, based on our extensive experience we have developed a Test that can be applied in the patient's home (at home), and with which it can be identified in a few minutes if the patient has symptoms of HHM. This test, which consists of a questionnaire of questions, in abbreviated form we called the HHM Test. As with the other tests and tests that we have created, we are interested in making this HHM Test accessible and available to the entire population at no economic cost and without having to travel to a specialized center. Thus, this Test is free and has been developed so that it can be applied either by the caregiver, a family member or even by the patient himself (self-test). Based on the result obtained in the Test, the patient will be classified in one of the 6 most specific clinical diagnoses that we have established, corresponding then to continue with other clinical evaluations to move towards a more effective treatment. In the final part of the document we mention the other clinical evaluations to be carried out to further advance in obtaining more specific diagnoses. It should be taken into account that the routine analyzes that are usually requested in hospitals and medical centers are insufficient to identify states of hypercoagulability and persistent microclots.

THERAPEUTIC PLAN FOR PATIENTS WITH MYALGIC ENCEPHALOMYELITIS/ CHRONIC FATIGUE SYNDROME (ME/CFS), FYBROMYALGIA, RHEUMATOID ARTHRITIS, SJÖGREN SYNDROME, LUPUS, MYOSITIS, OTHER AUTOIMMUNE DISEASES AND OTHER DISEASES WITH CHRONIC FATIGUE AND/OR PAIN

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THERAPEUTIC PLAN FOR PATIENTS WITH MYALGIC ENCEPHALOMYELITIS/ CHRONIC FATIGUE SYNDROME (ME/CFS), FIBROMYALGIA, RHEUMATOID ARTHRITIS, SJÖGREN SYNDROME, LUPUS, MYOSITIS, OTHER AUTOIMMUNE DISEASES AND OTHER DISEASES WITH CHRONIC FATIGUE AND/OR PAIN. As with Post-Acute COVID Syndrome or Long COVID treatments against Microbial Load, Biofilms and BioClots are the main objectives of the Therapeutic Plan for ME/CFS, FM, RA, SS, SLE and AD. ABSTRACT. Several scientific publications have shown the existence of persistent infections by Herpesvirus, by other viruses or other intracellular microorganisms in patients with ME/CFS, Fibromyalgia (FM), Rheumatoid Arthritis (RA), Sjögren's Syndrome (SS), Systemic Lupus Erythematosus (SLE), Myositis or Inflammatory Myopathies (IM) and other Autoimmune Diseases (AD). It must be taken into account that in persistent chronic infections there is usually the presence of Biofilms, which constitute a protective barrier that significantly reduce the entry and effect of drugs against the Microbial Load and thus facilitate the microorganisms to generate endurance. In 80% of ME/CFS patients, the presence of microclots with a high fibrin amyloid content has been evidenced, which, because they fulfill similar functions to Biofilms, we have proposed to call them BioClots. In this context, we consider ME/CFS, FM, RA SS, SLE, IM and several AEs to be diseases based on Biofilms, including Bioclots. Having as reference and based on extensive successful experience of our Treatment Schemes and Protocols for patients with Post-Acute COVID Sydrome (PACS) or Long COVID, this document presents a proposal for a Therapeutic Plan for patients with ME/CFS, FM, RA, SS, SLE, IM other AEs such as vasculitis and scleroderma or systemic sclerosis, and other diseases with fatigue and/or chronic pain. This Plan consists of 3 Objectives or Lines of Action: 1) Reduce the Viral/Microbial Load. 2) Break Down Persistent Biofilms and BioClots and Reduce Platelet Hyperactivity. 3) Treat Depletion of Nutrients, Hormones and other substances, the Oxidative Stress and Immune Dysfunctions. The first Objective or Line of Action is the main one, since it is aimed at reducing the Microbial Load, which is the cause that triggers the problems covered by the other 2 Lines of Action. If an effective treatment against the Microbial Load is given, most of the negative effects that these microorganisms have caused in the patient will be reversed, but in general some degree of sequelae will remain, which may be minor. Next in importance is the objective of breaking down Biofilms including Persistent BioClots. Next in importance is the goal of breaking down Persistent Biofilms and BioClots. Considering these 3 Objectives or Lines of Action, it will be necessary to choose which drugs, supplements or procedures to include for each one of them. To make this decision, it is necessary to investigate which are the causative organisms, for this, the patient or relatives should be asked about the history of infections and the analyzes and other tests that have been carried out should be reviewed. It is also important to see the frequency of certain infections in the place where the patient lives. We have published a very extensive document that includes many alternatives for drugs, supplements and procedures to be considered in the Protocols or Treatment Schemes to be prepared based on the information obtained from the patient's evaluation. We conclude that, according to what we have observed, given the favorable response to treatments against Microbial Load, and based on published studies, the main cause of ME/CFS, FM, RA, SS, SLE, IM and other AEs such as Vasculitis and Scleroderma, are persistent intracellular infections, the most frequent being those due to Herpesviruses, such as the Epstein-Barr Virus (EBV) and Human Herpesvirus 6 (HHV-6). Of the bacteria, the overgrowth of Staphylococcus aureus stands out as a cause of fatigue and/or chronic pain. In the case of ME/CFS and FM, Human Herpesvirus 7 (HHV-7) and other viruses of the Herpesviridae family such as HSV-1, Varicella Zoster Virus (VZV) and Cytomegalovirus (CMV) are also frequent. Other probable microorganisms are Borrelia burgdorferi (Lyme), Candida, Bartonella, Babesia, Mycoplasmas, Rickettsiae, Human endogenous Retroviruses and microorganisms from Biofilms or from the Intestinal, Oral, Nasal Microbiota, Respiratory Tracts, kidneys, and other locations of the organism. In the case of RA, Proteus mirabilis, Glaesserella parasuis, Porphyromonas gingivalis, other microorganisms from Biofilm such as dental plaque, Parvovirus B19, CMV, Hepatitis B Virus, among others, would follow in frequency. We estimate that 3 out of 4 patients with ME/CFS, FM, RA, SS, SLE and other AEs are caused by one or more persistent intracellular infections, therefore treatments against Viral/Microbial Load, persistent Biofilms and BioClots are the main objectives of the Treatment Plan for these chronic diseases. Given the high percentage of resistance to antimicrobial drugs that occurs in persistent intracellular infections, it is recommended to include in the Therapeutic Plan Procedures that have a significant effect in reducing the microbial load. Of these, Ozone therapies have been shown to be effective in reducing the microbial load. In addition to ozone therapy, we recommend the elimination of oral biofilms, gargling and mouthwashes, nasal and intestinal decolonization of Staphylococcus aureus and other microorganisms, and treatment of small intestinal bacterial overgrowth (SIBO).

MAYOR EFECTIVIDAD CON EL USO DE CITOCEPILLOS EN LA TOMA DE MUESTRA DE PRUEBAS MOLECULARES (PCR) PARA EL DIAGNOSTICO DE INFECCIÓN PERSISTENTE POR SARS COV-2.

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MAYOR EFECTIVIDAD CON EL USO DE CITOCEPILLOS EN LA TOMA DE MUESTRA DE PRUEBAS MOLECULARES (PCR) PARA EL DIAGNOSTICO DE INFECCIÓN PERSISTENTE POR SARS COV-2. Las muestras obtenidas con Hisopos dan Falsos Negativos frecuentemente. Se ha realizado publicaciones en las que se señala la utilidad de usar muestras citológicas (de células) en los pacientes con Síntomas Persistentes de COVID (1-4). En el presente documento damos más detalles sobre el sustento del uso de Citocepillos en lugar de Hisopos para la toma de muestra de Pruebas Moleculares (PCR) y se describe el procedimiento. COVID Sub-Aguda y Crónica son infecciones intracelulares persistentes. Las infecciones virales con frecuencia tienden a hacerse persistentes. De acuerdo con las denominaciones propuestas (3), los pacientes que se enferman de COVID y presentan Síntomas Persistentes, al superar las 4 semanas de evolución, pasan a denominarse COVID Sub-Aguda o Post-Aguda, y cuando pasan de las 12 semanas o los 3 meses se les denomina COVID Crónica (ver gráfico). Gráfico 1 En publicaciones que hemos realizado (2,3,4), señalamos la baja utilidad de las pruebas moleculares disponibles que usan muestras de secreciones nasal y faríngea obtenidas con hisopos en los pacientes con Síntomas Persistentes de COVID, esto debido a que la COVID Sub-Aguda y Crónica son infecciones intracelulares persistentes, es decir, que el SARS CoV-2, al igual que otros virus, se localiza en el interior de las células del organismo, por lo que la falta de implementación del uso de muestras citológicas para las Pruebas Moleculares, sigue constituyendo una limitación importante de los sistemas de salud para poder realizar el diagnóstico etiológico en los pacientes con Síntomas Persistentes de COVID. En los primeros días de la enfermedad sí se va a encontrar al virus en las secreciones de la nariz y orofaringe, esto porque el virus ingresa por estas vías por las secreciones, y se empieza a difundir en la vía respiratoria, pero después de los primeros 10 a 15 días de enfermedad su localización es predominantemente intracelular. Pruebas Moleculares (PCR) usando Citocepillos vs Hisopos en pacientes con Síntomas Persistentes de COVID. De acuerdo con el estudio realizado por un equipo del Instituto Pasteur en París, Francia (1,2) establecemos las siguientes conclusiones: 1. En los pacientes con Síntomas Persistentes de COVID, las Pruebas Moleculares basadas en muestras nasales obtenidas mediante hisopos, en un muy elevado porcentaje dan un resultado falso negativo. En el estudio en mención (1,2), en el 100% de los 5 casos dio un falso negativo. 2. A diferencia de las Pruebas Moleculares que usan hisopos, cuando las muestras nasales son obtenidas mediante Citocepillos, en un muy elevado porcentaje, se logra la detección de Infección Persistente por SARS CoV-2. En el mencionado estudio, se detectó ARN del SARS CoV-2 en el 100% de los 5 casos de COVID Crónico (pacientes con más de 12 semanas de enfermedad). 3. En base a resultados negativos de Pruebas Moleculares por hisopos, no se puede afirmar que el paciente no presenta una infección por el SARS CoV-2. Este resultado negativo, solo nos indica que no hay carga viral a nivel de las secreciones nasales. 4. En los pacientes con Síntomas Persistentes de COVID se debe indicar pruebas moleculares que usen muestras citológicas, ya que se ha demostrado que las muestras de secreciones dan falsos positivos. En la Tabla 1 se muestra de manera resumida los resultados del estudio señalado (1,2). Por un lado, se tiene que las Pruebas Moleculares que usaron muestras citológicas obtenidas con Citocepillo, en todos los 5 casos (100%) identificó ARN del SARS CoV-2. Por otro lado, las Pruebas Moleculares convencionales, basadas en muestras obtenidas mediante hisopado, no detectaron el ARN del SARS CoV-2 en ninguno de los casos (0%). Antecedentes del uso de Cepillado Nasal. Al procedimiento de la toma de muestra usando Citocepillos se le denomina Cepillado Nasal, la cual es una técnica no invasiva que ha sido utilizada anteriormente en pacientes para estudiar enfermedades neurodegenerativas, infecciosas, alérgicas e inflamatorias crónicas (5,6,7,8,9). Técnica del procedimiento de Cepillado Nasal. El enlace a un video, donde se describe este procedimiento, está disponible en la referencia 9 (ver en la parte final de este documento). En el estudio en mención (1), se aplicó un anestésico local (xilocaína o lidocaína al 5%) en la parte superior de la cavidad nasal, que es donde se ubica el epitelio olfativo. Luego la toma de muestra se realiza utilizando un Citocepillo. Se puede usar un cepillo endocervical de 3,5 mm, de los que se utilizan para las pruebas de Papanicolaou (PAP). El Citocepillo se introduce por la fosa nasal, y se dirige hacia la parte superior para que se tome la muestra a nivel del techo de la cavidad nasal, donde se encuentra la mucosa olfativa o epitelio olfativo. A ese nivel, el Citocepillo suavemente se gira 360°, 5 veces. Se recalca que el lugar de donde se toma la muestra citológica es diferente a la del procedimiento tradicional, en el cual el hisopo se dirige a la parte posterior e inferior de la nariz, ubicación que corresponde a la nasofaringe. Este procedimiento lo debe realizar un personal de la salud con capacitación y experiencia. Un muestreo muy enérgico puede provocar sangrado y alterar la muestra.

ESTUDIO CIENTÍFICO DEMUESTRA QUE LOS SÍNTOMAS PERSISTENTES DE COVID SON CAUSADOS POR INFECCIÓN POR EL VIRUS SARS COV-2 NO DETECTABLE CON PRUEBAS MOLECULARES (PCR) USANDO HISOPOS.

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Sep 2021

ESTUDIO CIENTÍFICO DEMUESTRA QUE LOS SÍNTOMAS PERSISTENTES DE COVID SON CAUSADOS POR INFECCIÓN POR EL VIRUS SARS COV-2 NO DETECTABLE CON PRUEBAS MOLECULARES (PCR) USANDO HISOPOS. Usando Citocepillos para obtener muestras de células del epitelio olfatorio se evidenció Persistencia de la Infección por SARS CoV-2 hasta por más de 6 meses. Un equipo del Instituto Pasteur en París, Francia, luego de la correspondiente revisión por pares (la cual duró varios meses), ha publicado un estudio en una de las Revistas del portafolio de Science, en el cual mediante pruebas moleculares (PCR) utilizando citocepillos para obtener muestras de células del epitelio olfatorio, evidenciaron en la totalidad de los 5 pacientes evaluados, que los Síntomas Persistentes de COVID que presentaban hasta por más de 6 meses desde el inicio de síntomas, estaban asociados a Infección Persistente por el virus SARS CoV-2 (1). El estudio tiene como título en español “La Anosmia relacionada con COVID-19 se asocia con Persistencia Viral e inflamación en el epitelio olfatorio humano e infección cerebral en hámsteres”. El estudio consta de varias partes, en el presente documento describiremos principalmente lo referente a las pruebas moleculares realizadas en base a muestras citológicas (de células), tanto en pacientes con COVID Aguda como en pacientes con Síntomas Persistentes de COVID. PRUEBAS MOLECULARES REALIZADAS EN PACIENTES CON COVID AGUDA. En esta parte del estudio se incluyó a 11 personas para ver cómo la infección por el virus SARS COV-2 afecta el sentido del olfato. De las 11 personas, 7 eran pacientes con alteración aguda del olfato por COVID y 4 eran controles sanos. Características de los pacientes. De los 7 pacientes con COVID Aguda, 6 presentaban Anosmia, es decir, una pérdida total del olfato, y también tenían Disgeusia (alteración del gusto). Mientras que 1 paciente presentaba Hiposmia solamente, sin alteración en el gusto. Además, los 7 pacientes presentaban al menos otro síntoma más perteneciente al espectro clínico de COVID-19, como diarrea, tos, disnea, conjuntivitis, fiebre, fatiga, dolor de cabeza, dolor muscular, laringitis o dolor de garganta. El tiempo desde los primeros síntomas relacionados con COVID-19 hasta la inclusión en el estudio varió de 0 a 13 días. Ninguno de los 7 pacientes requirió hospitalización. Realización de Pruebas Moleculares (PCR) usando Citocepillos. Para investigar si la infección por el virus en la mucosa olfativa estaba asociada a la pérdida funcional olfativa, a todos los 7 pacientes se les tomo muestras de células de la mucosa olfativa, para lo cual se usó citocepillos. El resultado fue que todos los 7 pacientes (100%), pero ninguno de los 4 controles sanos, presentaron ARN detectable del SARS-CoV-2 en las muestras citológicas de la mucosa olfativa utilizando la técnica de PCR basado en SYBR Green, de esta manera se confirmó inequívocamente el diagnóstico de infección por SARS-CoV-2 a nivel de múltiples tipos de células del neuroepitelio olfativo de todos pacientes. El SYBR Green es un compuesto orgánico que se utiliza como colorante para la realización de PCR cuantitativa. Pruebas Moleculares (PCR) usando Citocepillos vs Hisopos en la COVID Aguda. Usando los hisopos nasofaríngeos convencionales, el virus no fue detectado en 3 de los 7 pacientes en los que sí se detectó el virus usando muestras obtenidas con el uso de citocepillos. Esto representa un 42.9% de Falsos Negativos con la prueba convencional. Por lo tanto, el diagnóstico de Infección Aguda por SARS-CoV-2 mediante el uso de citocepillos es bastante más sensible y específica. PRUEBAS MOLECULARES REALIZADAS EN PACIENTES CON SÍNTOMAS PERSISTENTES DE COVID. En esta parte del estudio se incluyó a 5 pacientes con Síntomas Persistentes de COVID, los cuales fueron reclutados de un Hospital dedicado a la atención de pacientes con Síntomas Persistentes de COVID (o Long COVID o COVID Crónico). Características de los pacientes. De los 5 pacientes, 4 presentaban anosmia y ageusia (pérdida del gusto) dentro de sus Síntomas Persistentes, y además al menos otro síntoma relacionado con COVID-19, como fiebre, fatiga, diarrea, tos, disnea, dolor de cabeza, dolor muscular, laringitis, dolor de garganta. El quinto paciente presentaba varios Síntomas Persistentes de COVID incluido ageusia, pero no presentaba anosmia ni el antecedente de este. Los otros síntomas persistentes que presentaba este paciente eran el vértigo, parestesia, astenia, tremor (pequeñas contracciones musculares localizadas), hormigueo en la cara, nariz, brazos y piernas. El tiempo transcurrido desde los primeros síntomas relacionados con COVID-19 hasta la inclusión en el estudio de cada uno de los 5 pacientes con Síntomas Persistentes de COVID fueron los siguientes: 1) 110 días (15 semanas y 5 días o, 3 meses y 19 días). 2) 136 días (19 semanas y 3 días o, 4 meses y 15 días). 3) 158 días (22 semanas y 4 días o, 5 meses y 6 días). 4) 196 días (28 semanas o, 6 meses y 14 días). 5) 141 días (20 semanas y 1 día o, 4 meses y 20 días). Los 4 primeros pacientes corresponden a los que presentaban dentro de sus Síntomas Persistentes a la Anosmia. Otros síntomas otorrinolaringológicos que presentaron fueron congestión nasal en 3 pacientes y rinorrea en 2 pacientes. Como se muestra, el paciente con mayor tiempo tenía 196 días, lo que equivale a 6 meses y medio de evolución hasta la fecha del estudio. Ninguno de los 5 pacientes requirió hospitalización durante el tiempo de su enfermedad. Pruebas Moleculares (PCR) usando Citocepillos vs Hisopos en pacientes con Síntomas Persistentes de COVID. Los 5 pacientes con Síntomas Persistentes de COVID presentaron ARN detectable del SARS-CoV-2 mediante las pruebas moleculares realizadas en base a muestras citológicas obtenidas de la mucosa olfativa usando citocepillos. En ellos se utilizó la técnica de PCR basado en SYBR Green, confirmando inequívocamente el diagnóstico de Infección Persistente por SARS-CoV-2. Sin embargo, en todos los 5 pacientes las pruebas de PCR realizadas por el procedimiento convencional, con muestras obtenidas mediante hisopado nasal y faríngeo, resultaron negativas. Baja o nula utilidad de las pruebas moleculares que usan Hisopos en los pacientes con Síntomas Persistentes de COVID. En la Tabla 1 se muestra de manera resumida los resultados de esta parte del estudio. Por un lado, se tiene que en todos los 5 casos (100%) las pruebas que usaron Muestras Citológicas de la mucosa olfativa obtenida con citocepillo identificó ARN del SARS CoV-2. Por otro lado, las pruebas moleculares convencionales, basadas en muestras obtenidas mediante hisopado nasal y faríngeo, no detectaron el ARN del SARS CoV-2 en ninguno de los casos (0%), entonces, esta prueba dio Falsos Negativos en la totalidad de los pacientes con Síntomas Persistentes de COVID, con lo cual se confirma que es mínima la sensibilidad de estas pruebas para estos casos, por lo que no podemos basarnos en pruebas que usan hisopado para hacer un diagnóstico en pacientes con Síntomas Persistentes de COVID. En publicaciones que hemos realizado (2,3), señalamos la baja utilidad de las pruebas moleculares disponibles que usan muestras de secreciones nasal y faríngea en los pacientes con Síntomas Persistentes de COVID. Se debe tener en cuenta, que la COVID Crónica es una infección intracelular persistente, es decir que el virus SARS CoV-2 se localiza en el interior de las células del organismo, por lo que la falta de implementación de pruebas basadas en muestras citológicas, sigue constituyendo una limitación importante de los sistemas de salud para poder realizar el diagnóstico etiológico en los pacientes con Síntomas Persistentes de COVID. Diagnóstico de Infección por SARS CoV-2 usando Citocepillo en paciente con Síntomas Persistentes de COVID pero sin Anosmia. Al quinto paciente, que presentaba Síntomas Persistentes de COVID-19 pero su sentido del olfato era normal, se le detectó ARN del SARS-CoV-2 en la muestra celular obtenida con el uso de citocepillo. Se tiene entonces que el PCR de Muestras Citológicas obtenidas con citocepillo también tendría utilidad en los pacientes con Síntomas Persistentes de COVID así no presenten Anosmia. La presencia del virus SARS CoV-2 en el epitelio olfatorio, sin que genere Anosmia u otra alteración en el olfato, nos indica que el virus puede estar presente de manera latente o silente en algunas partes el organismo sin generar síntomas.

COVID-19: PERSISTENCE OF THE SARS COV-2 VIRUS IN THE ADVANCED PHASES.

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Jun 2021

COVID-19: PERSISTENCE OF THE SARS COV-2 VIRUS IN THE ADVANCED PHASES. (Formerly titled: THE ERROR OF THE INFLAMMATORY PHASE WITHOUT THE PRESENCE OF VIRUSES). New study shows a greater viral presence as the disease progresses and indicates that viral load therapy should be considered during all phases of the disease. On June 16, 2021, an article was published in the journal Cell Research (from Nature's portfolio) whose title is: A cohort Autopsy study defines COVID-19 Systemic Pathogenesis (1). The study is based on autopsies performed on 26 patients who died from COVID-19. In them, SARS-CoV-2 was detected up to 67 days after the onset of symptoms in the lungs and in multiple extrapulmonary organs. The median duration from the onset of symptoms to the patient's death was 38.5 days. The presence of SARS-CoV-2 in all cases was confirmed by molecular tests PCR, immunohistochemical (IHC) staining of viral spike or nucleoprotein or electron microscopy. Severe organ damage is due to the presence of high Viral Load. Autopsies performed on the patients showed that, in those in whom the disease progresses generating severe organ damage, the presence of a high SARS-CoV-2 Viral Load is identified, mainly in the lungs and also in extrapulmonary organs. And it was observed that the lung areas with the highest SARS-CoV-2 Viral Load presented greater diffuse alveolar damage (DAD) and airway obstruction associated with dysfunction of pulmonary ventilation, which supports the direct cytopathic effect of SARS-CoV- 2 virus, leading to lung damage and respiratory failure. These findings indicate that direct viral invasion is the pathogenicity mechanism in COVID-19, leaving aside the previous theory that suggested that organ damage was caused by a state of hyperinflammation without the presence of viruses. In addition to infecting blood vessel cells, the virus is found in macrophages and monocytes. In this study it was identified that the SARS-CoV-2 virus is found within macrophages and monocytes, both in the circulating found intravascularly in the blood, and in the infiltrants (outside the bloodstream) identified at the level of the pulmonary alveoli, spleen, and lymph nodes and kidneys. Several previous studies had already shown the presence of the virus in the walls of blood vessels, both in endothelial cells and in pericytes (2,3,4). But this study supports that the virus is also found inside monocytes and macrophages, which are blood cells with the ability to engulf microorganisms or their remains that are circulating or at the level of the tissues. Systemic Disease? o Multi-organ and later Vascular and Intravascular Disseminated. In this study, the term systemic is used in the sense that the COVID-19 disease in an initial phase is characterized by presenting a Viral Load located mainly in the respiratory tract, and as the disease progresses, there is an affectation that is no longer localized, but would be systemic, but using this term would imply that the entire organism would be affected. We consider that it is better to be more specific, since the term systemic implies that the entire organism is infected, and what happens in reality is that there is a tropism or affinity of the virus for certain types of cells of the organism, this tropism is mainly due to: - The cells located in the pulmonary alveoli: this especially in the acute phases of the COVID-19 disease. - The cells of the vascular walls: endothelial cells and pericytes. - Blood cells: the virus is found within circulating and infiltrating macrophages and monocytes, and also in megakaryocytes, platelets, and other blood cells. In Acute COVID, in severe cases when the disease progresses, it includes several organs in addition to the lungs, and the term multi-organic is used to refer to the fact that several organs are compromised in their functioning (5). But unlike what happens in Acute COVID, in Persistent SARS CoV-2 Infection the Viral Load is no longer concentrated mainly in the lungs and other organs, but a disseminated infection occurs without a large viral load located in certain organs. Viral Load is scattered and located at the level of the walls of blood vessels and in blood cells, so, instead of systemic, on our part we prefer to consider that COVID in its Post-Acute stages (Chronic COVID or Long COVID) corresponds to a disseminated persistent infection, which generates vascular and intravascular compromise disseminated. There are viable viruses, they are not just particles. Previously, several studies have identified the presence of viable viruses in advanced phases of COVID disease (2,3,4,6-13). In one of these studies (6), 193 cell cultures were performed through which the viability and infectivity of the SARS CoV-2 virus was demonstrated for more than 4 weeks in severe cases, and the conclusion of the study indicated that in severe and critical cases of COVID viable viruses can be present for long periods of time. Implications in the Therapeutic Plan. As the study described (1) points out, viral load therapy should be considered throughout the course of the disease. If it were only inflammation, it would be enough to use anti-inflammatories and immunosuppressants. In our experience, we have observed a good response in the advanced phases of the disease with the use of drugs with effects against viral load. But it must be taken into account that in severe and critical cases due to a higher viral load, significantly higher doses are required (14 to 18), since if the regular doses used in the initial phases are given, these will be insufficient against the very high viral load present in the advanced phases of the disease. Implications for the Diagnosis of Viral Persistence. As described, the virus is located intracellularly in the advanced stages of the disease. But currently available conventional molecular tests only use swabs to take samples of secretions from the nose and throat, so these tests do not analyze cells, so they are not useful for detecting intracellular viral persistence (5,19,20). Based on the negative results of the Molecular Swab Tests, it cannot be confirmed that the patient does not have a persistent SARS CoV-2 infection. These negative results only indicate that there is no viral load in the secretions. As the samples obtained with Swabs frequently give False Negatives in patients with Chronic COVID or Long COVID, it is proposed that the performance of molecular tests using cell samples (cytological) be standardized. Unlike secretion tests that use swabs, when nasal samples are obtained by cytobrushes and from the area of the olfactory epithelium located in the upper part of the nasal cavity (not from the back: nasopharynx), in a very high percentage the detection of Persistent Infection by SARS CoV-2. In a study conducted by researchers at the Pasteur Institute in Paris, France (11), SARS CoV-2 was detected in 100% of the 5 reported cases of Chronic COVID, all of whom had more than 12 weeks of illness. Cytological samples of blood cells may also be obtained. This requires that the blood be centrifuged or subjected to filters (as occurs in HELP Apheresis and other similar procedures that use filters). In the cases described, if the initial molecular test is negative using the conventional PCR technique, special techniques that improve the sensitivity of the PCR should be used. Graph 1 shows the sequential phases of Acute COVID, through which patients whose disease progresses to the advanced phase in which multi-organ involvement occurs. The Graph also shows that the detection of viral load by PCR of nasopharyngeal and oropharyngeal secretions (which are extracellular) be carried out mainly within the first 9 days of illness, subsequently, because it has a predominantly intracellular location, it is indicated that cytological samples be taken. This Chart was featured in a previous publication (5) that we titled: Charts that do not show high viral load in severe and critical cases need to be updated. Conclusions. The technical documents, guides, schemes and therapeutic plans must be updated considering that the SARS CoV-2 virus persists in the advanced phases and throughout the COVID-19 disease, and that the damage in the organism is mainly produced by the direct effect of the virus and not by a state of hyperinflammation without the presence of virus as previously suggested. Regarding diagnostic tests, since it is an intracellular infection, it is proposed that tests be standardized in the advanced and post-acute phases using samples of cells and not secretions, recommending molecular tests of samples obtained from the epithelium olfactory with the use of cytobrushes or centrifuged or filtered blood samples, with the aim of obtaining a cytological sample.

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TABLE 2021, COVID-19: THERAPEUTIC PLAN AND POTENTIAL THERAPIES. January 2021.

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