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Abstract

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.
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
TherapeuticPlan
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 POTENTIALTHERAPIES. Aguirre-Chang, Gustavo; Trujillo F, Aurora; CórdovaM,José Aníbal. February2021b
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: 100mg 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 1mg/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 200 mg, 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 400mg 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 60mg 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, 27-30 h. after the treat begins
DOXYCYCLINE
100mg ev/12h x 7
d. >90kg ev/8h; or
AZITHROMYCIN
500mg/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
Located in the nose and pharynx. The Variants frequently affect the intestines at this phase.
DEXAMETHASONE 4 mg. TB or
AMP: 6 to 8mg. x day x 2 - 5d, or
METHYLPREDNISOL.125mg x2dor
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: 200-250mgx 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 every8 hours x 6 to 12days
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-ACETYLCYSTEINE 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 °Cgive 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.
... The details of this diet, with the foods that should be avoided and those that should be consumed in greater quantity, are shown in Table 2. The support and the corresponding scientific references that support this diet is available in the publication where we describe the "Therapeutic Trial" (22). It is recommended to follow this diet for 9 days, that is, up to 1 day after finishing taking the medications in the Treatment Scheme, this because on day 9 the response to the applied Scheme is evaluated. ...
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THERAPEUTIC PLAN FOR COVID-19. In the first document on the use of IVM 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-19 was established in which they are indicated 3 main Therapeutic Lines of Action. As for Sub-Acute and Chronic COVID (or Persistent COVID or Long COVID), as it is a continuation of the same COVID disease, in general this Therapeutic Plan is maintained with the 3 Therapeutic 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, 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 SCHEMES FOR PERSISTENT SYMPTOMS OF COVID. After evaluating a patient with Persistent Symptoms of COVID, in a majority group of patients the clinical-epidemiological diagnosis of Sub-Acute or Chronic COVID Syndrome will be established, 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, but as already 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 wich as decades of experience in its use in humans, What we have indicated since May 2020 is a Treatment Scheme that includes IVM, for Sub-Acute and Chronic COVID. We present this First Treatment Scheme 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 Sub-Acute and Chronic COVID, 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 as to assist the diagnosis and supports the existence of viral persistence in most of the patients with Persistent COVID Symptoms. "THERAPEUTIC TEST" AND FIRST TREATMENT SCHEME FOR PATIENTS WITH PERSISTENT SYMPTOMS OF COVID. In September 2020, the First Treatment Scheme to be used in patients with Persistent Symptoms of COVID (21) was made available, and in which the 3 Lines of Action of the Therapeutic Plan for Sub-Acute and Chronic COVID are covered: 1) Reduce Viral Load: with IVERMECTIN. 2) Reduce Platelet Hyperactivity and Break down Persistent Blood Clots: 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 of the Therapeutic Plan for COVID-19 is the main one, and it is aimed at reducing the Viral Load, this action should be emphasized, since it is directed to the cause that triggers the problems that encompass 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 Scheme or "Therapeutic Test" for patients with Persistent Symptoms of COVID. RESULTS OF THE APPLICATION OF THE "THERAPEUTIC TEST" IN 390 PATIENTS WITH PERSISTENT SYMPTOMS OF COVID. In our experience of 390 patients with Persistent Symptoms of COVID who received a clinical epidemiological diagnosis of Sub-Acute or Chronic COVID Syndrome, and the "Therapeutic Test" was applied, at the end of the 6 to 16 days that the Test last, 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 Persistent Symptoms of COVID or of Post Acute and Chronic COVID Syndrome 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 4 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 SCHEME TO FOLLOW AFTER APPLYING THE “THERAPEUTIC TEST” FOR PERSISTENT SYMPTOMS OF COVID. After having finished applying the "Therapeutic Test" or First Treatment Scheme, using IVM, ASA, Famotidine, Sodium Bicarbonate and the described diet, according to our experience, 25% or more of the patients will still present Persistent Symptoms of COVID. Adormecimiento, entumecimiento, In these cases, it should be evaluated if they are symptoms associated with the presence of tissue hypoperfusion, these symptoms are mainly: 1) Fatigue or weakness that increases with activity and effort, 2) Mental fog, 3) Dyspnea or shortness of breath , 4) Tachycardia, 5) Stiffness and joint pain in the fingers of one or both hands when waking up from bed, 6) Numbness, numbness, tingling or cold in the hands and feet, 7) Chilblains, erythema perneum or COVID Fingers, on all in the feet, 8) Acrocyanosis or bluish discoloration of the hands and feet, which mainly affects the fingers and 9) Symptoms associated with orthostatic intolerance (when standing up). 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), or slightly increased (up to 0.6 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 Scheme or "Therapeutic Test" the recovery of the patient was not achieved, we indicate a Scheme 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 Scheme at least: 1) 3 drugs against Viral Load, 2) 3 drugs against platelet hyperactivity and persistent clots. 3) 3 drugs against nutrient depletion, oxidative stress and immune dysfunctions. Giving 3 or more medications or suplements against Viral Load corresponds to a Treatment Scheme prepared for cases in which the patient's recovery was not achieved by applying Schemes 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, Schemes that include 3 or more drugs against Viral Load, correspond to Treatment Schemes for patients with: Drug-Resistant and Undercover Viral Load. Designation of the Scheme to follow. To give a name to the Treatment Scheme 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 Scheme would be the one that includes 3 drugs from each Line of Action. In this case, the Scheme is called 3-3-3 and it is the recommended Scheme 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 Scheme with a greater number of medications or supplements. According to the number of drugs in each Action Line, the Scheme will be given a name. Thus we have, Schemes 3-6-6, 3-6-9, 6-6-9 and 6-9-9. Duration of the Scheme. The duration established for the first part of this Scheme 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 Scheme 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 6 days after achieving total (100%) improvement in symptoms, or 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 Scheme, 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 Scheme. 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 SCHEME 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 Treatment Scheme. In the following paragraphs, the doses of each drug or supplement included in the 3-3-3 Treatment Scheme described in Table 4, and the main alternatives are described. Other possible alternatives are also mentioned, but without further detail. 1ST LINE OF ACTION OF THE THERAPEUTIC PLAN: REDUCE THE VIRAL LOAD: In Sub-Acute and Chronic COVID, the first day of the Treatment Scheme begins with the drugs of the 2nd Line of Action, the drugs against viral load are not yet taken. It is from day 2 to day 8 of the Scheme (7 days in total), that medications aimed at reducing viral load are taken.
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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.
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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.
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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 ventilation dysfunction, 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 can probably also be found in other blood cells. In Acute COVID, in severe cases when the affectation 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 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, they will be insufficient for an adequate treatment. Implications for the Diagnosis of Viral Persistence. It is suggested that in the advanced phases of the disease the virus is located intracellularly and in a disseminated way in the cells of the walls of the blood vessels (endothelial cells and pericytes) and also inside part of the blood cells (19). In the present study, the virus was identified within macrophages and monocytes, both circulating and infiltrating (1). The conventional molecular tests currently available use swabs to take samples of secretions, it is then that these tests do not analyze cells, so they are not useful for detecting intracellular viral persistence (19,20,21). It is then proposed that molecular tests be carried out using blood cells samples. As it is an intracellular infection, the blood must be centrifuged, or subjected to filters (as occurs in HELP apheresis) in order to obtain a cytological sample. And if the initial molecular test is negative using the conventional PCR technique, one must resort to special techniques that improve the sensitivity of the PCR. 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. As for the diagnostic tests, since it is an intracellular infection, in the advanced and post-acute phases it is necessary to resort to using cell samples and not secretions, proposing molecular tests of centrifuged or filtered blood simples, in order to obtain a sample cytological.
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