Saturday, March 14, 2020

Covid-19 (Coronavirus) Treatment Strategy & Evidence Summary

Disclaimer: This document is not intended to replace medical advice. It is merely a compilation of research performed by Oliver Zolman MD





Use LitCovid database https://www.ncbi.nlm.nih.gov/research/coronavirus/ to keep up with the latest open-access studies each day!




Safety and efficacy evidence scoring Legend
Efficacy score 5/5 = multiple low bias RCTs with broad demographic, large populations 
Efficacy score 4/5 = Low bias RCTs but not above criteria
Efficacy score 3/5 = High bias RCTs or low bias non randomised studies 
Efficacy score 2/5 = Low bias observational studies or high bias non randomised studies
Efficacy score 1/5 = High bias observational studies
(Oliver’s method)

Safety score 5/5 = No serious or moderate risks other than very rare direct allergies
Safety score 4/5 = No serous or moderate risks other than more common direct allergies
Safety score 3/5 = Moderate risks other than direct allergy
Safety score 2/5 = Low chance of serious risks other than direct allergy
Safety score 1/5 = Non-low chance of serious risks other than direct allergy
(Oliver’s method)

Covid-19 Mild/Moderate/Severe Classification Criteria
Mild: clinical symptoms are mild, and no pneumonia manifestations on imaging. 
Moderate (Ordinary type): with fever, respiratory tract symptoms, etc., imaging shows pneumonia. 
Severe (Heavy): Meet any of the following: ① Respiratory distress, breathing rate> 30 times / min; ② In resting state, means oxygen saturation <93%; ③ Arterial partial pressure of oxygen (PaO 2 ) / inhaled oxygen (FiO 2 ) <300 mmHg (1 mmHg = 0.133kPa).

Source - http://rs.yiigle.com/yufabiao/1182323.htm ; 10.3760/cma.j.issn.1001-0939.2020.0019 ; https://www.ncbi.nlm.nih.gov/pubmed/32075365/


Prescription Treatments to consider personalised risk:benefit 

Intervention name
When to do 
Dosing protocol
Mechanism of action
Efficacy score out of 5 & evidence summary
Safety score out of 5 (5/5 = safest) (evidence summary in brackets)
Chloroquine Phosphate oral (therapeutic dose)
As soon as diagnosed, for any type of covid-19 (mild/moderate/severe), assuming no contraindications and ability to do safety monitor risk biomarkers

Likely works best in viral replication stage, within first 10 days of symptoms, ideally started within first 5 or 7 days of symptoms
Typically 500 mg 2 x per day for 5 to 10 days max, with safety monitoring including ECG, and dose reduction based on risk of side effects 

See separate section for full prescribing guide

NOTE could take lower dose to reduce risk and create a positive benefit to risk ratio in high risk demographics

USE A LICENSED DRUG INTERACTION CHECKER or manually search ; likewise with unusual forms or doses of supplements

Note contraindications 
Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV.10 Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells (Fig. 1c, d). Besides its antiviral activity, chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo. Chloroquine is widely distributed in the whole body, including lung, after oral administration- Heme polymerase inhibitor (source)
2/5 (non randomised studies high bias as full text case series papers not published yet)

Link to 20 Chinese trials on chloroquine or hydroxychloroquine (requires Google Chrome with translation mode turned on)

“Thus far, results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course according to the news briefing” (source)
1 / 5 safety as higher dose than malaria treatment doses, but dependent on demographic

800 - 1200 g total life doses may cause serious long term effects (source 2018 meta analysis)

OCT imaging may be ideal for screening for eye risk (source)

BUT

“Severe adverse reactions to chloroquine phosphate were not noted in the 100+ aforementioned patients [involved in the Chinese trials in February in 10 hospitals]” (source)
^ this suggests if sticking to the inclusion/exclusion criteria of trials severe adverse events are unlikely (<1%) to occur 
Chloroquine phosphate oral (prevention)
Started 1 week before entering endemic area and continued for 4 weeks after leaving (as used for malaria)
Theoretical based on malaria prevention efficacy 

From UK BNF - For Adult (body-weight 45 kg and above)
310 mg once weekly (equivalent to 500 mg chloroquine phosphate), started 1 week before entering endemic area and continued for 4 weeks after leaving.

USE A LICENSED DRUG INTERACTION CHECKER or manually search ; likewise with unusual supplements
As above
0/5 No studies on prevention
2/5 safety, as lower dose than therapeutic dose

See above section
Chloroquine phosphate aerosolised treatment


As above


Hydroxychloroquine sulfate oral

Hydroxychloroquine sulfate 0.2g twice daily for 14 days (source

OR

400 mg twice on first day, then 200 mg twice a day for next 4 days was simulated to be the ideal dosing protocol to maximally reduce virus 3x better than chloroquine (source in vitro study)

Another trial is using 200 mg twice a day for 5 days only (source)

See next section as complex 

NOTE could take lower dose to reduce risk and create a positive benefit to risk ratio in high risk demographics

USE A LICENSED DRUG INTERACTION CHECKER or manually search ; likewise with unusual supplements
As above
No consensus statements on outcomes 

Less case reports than chloroquine 


But one in vitro study shows 3x better against corona than chloroquine (source)
1/5 no good data showing safer than chloroquine 


 A new study indicates that toxicity is not as rare as once believed, but depends critically on daily dosage and duration of use, as well as other risk factors. With attention to dosage and other factors, and with proper screening for early signs of toxicity, HCQ can be prescribed with relative safety even over long periods of time.

800 - 1200 g total life doses may cause serious long term effects (source 2018 meta analysis)

OCT imaging may be ideal for screening for eye risk (source)
Remdesivir


RNA polymerase inhibitor 

Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination.7 Our time-of-addition assay showed remdesivir functioned at a stage post virus entry (Fig. 1c, d), which is in agreement with its putative anti-viral mechanism as a nucleotide analogue. (source)


Lopinavir + Ritonavir
As soon as diagnosed, for any type of covid-19 (mild/moderate/severe), assuming no contraindications and ability to do safety monitor risk biomarkers

Likely works best in viral replication stage, within first 10 days of symptoms, ideally started within first 5 or 7 days of symptoms

A recent systematic review showed that lopinavir/ritonavir’s anti-coronavirus effect was mainly seen in its early application, for reducing patient mortality and reduced glucocorticoid consumption. However, if the early treatment window is missed, there will be no significant effect in their late application [30]. (source 6th Feb 2020 Covid guideline)


Low-level evidences included retrospective cohort, historically controlled studies, case reports, and case series revealed that lopinavir/ritonavir alone or in combination with antivirals produced certain benefits in the treatment of SARS and MERS, such as reducing the incidence or mortality of ARDS [26,27,28,29] (source 6th Feb 2020 Covid guideline)

Ribavirin





Arbidol





Alpha-interferon (e.g., by aerosol inhalation)

5 million units  twice per day



Greg Fahy Protocol 
  • Growth hormone + DHEA-Sulphate 





AR1 Blockers (losartan etc.)





BIPAP





CPAP






Non-prescription treatments

Intervention name
When to do 
Prescrip needed?
Dosing protocol
Mechanism of action
Efficacy score out of 5 & evidence summary
Safety score out of 5 (5/5 = safest) (evidence summary in brackets)
Vitamin D3
Continue before and throughout and after
No
2000 IU per day ideally with largest meal of the day if deficient and haven’t taken > 800 IU dose of this supplement in the last 12months (food as will boost blood levels higher), NO MEGADOSING even if currently vitamin D deficiency (see separate vitamin D guide on full details)
5/5


For 75% of people that are vitamin D “insufficient” (e.g. <~75 nmol/L) may benefit most
5/5 
Garlic
Continue before and throughout and after
No
Garlic 2 medium cloves (up to 10g) or one GMP grade garlic capsule, containing 180 mg allicin powder, per day with the main meal (both positive trials used garlic supplements)
Likely 5/5 - rash may occur in some (frequency not checked) and garlic breath common (chewing peppermint or drinking various teas destroys garlic breath molecules)
Zinc 

No




Selenium

No




Daily Dozen App
Continue before and throughout and after
No
Download Daily Dozen app and aim to meet the nutritional intakes each day
Enhances every aspect of immune system
5/5
5/5
Longevity Level 1 Diet
Continue before and throughout and after
No
See separate infographic for this
Enhances every aspect of immune system
5/5
5/5
Longevity Level 1 Exercise
Continue before and throughout and after
No
LOW or MODERATE only reduces upper respiratory tract infection rates, VIGOROUS or INTENSE increases
Enhances every aspect of immune system
5/5
5/5 
Cryonics









Chloroquine Phosphate for covid-19 prescribing guideline


Evidence summary
Has the most case report evidence (100+ cases) for improving multiple outcomes in Covid-19 pneumonia

“Thus far, results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course according to the news briefing” (source)

Note
The dose used in Chinese trials is 500 mg twice a day for 5-10 days total, minimum 5 days - this is ~2.5x the malaria treatment total dose, and is 7x the daily malaria prevention or rheumatoid arthritis dose, so side effects are theoretically riskier 

Severe adverse reactions to chloroquine phosphate were not noted in the 100+ aforementioned patients [involved in the Chinese trials in February in 10 hospitals]” (source). This suggests if sticking to the inclusion/exclusion criteria of trials severe adverse events are unlikely (<1%) to occur

Take into account all details in UK BNF info for chloroquine (note chloroquine VS chloroquine phosphate molecular weight differences) - can be accessed via a UK IP address, if not in UK can use a VPN and set location to UK https://bnf.nice.org.uk/drug/chloroquine.html

Link to ongoing trial protocols
20 trials of chloroquine phosphate / hydroxychloroquine are underway in China, you can view this link to see results ASAP and find optimal dosing protocol and insights - Link to 20 Chinese trials on chloroquine or hydroxychloroquine (requires Google Chrome with translation mode turned on) 

Who and how to prescribe chloroquine phosphate for Covid-19, from Chinese guideline
Translated from Mandarin

Based on the above basic research and our recent clinical practice, combined with China's "new coronavirus pneumonia diagnosis and treatment program (trial implementation of the sixth edition)", the indications for chloroquine phosphate treatment are suggested as follows.
1. Age> 18 years and <65 years.
2. According to the diagnostic criteria of the "New Coronavirus Pneumonia Diagnosis and Treatment Program (Trial Version 6)" issued by the National Health and Health Commission [ 18 ] , it has been diagnosed as mild, common and severe patients with new coronavirus infection. The specific diagnostic criteria are as follows: (1) Mild: clinical symptoms are mild, and no pneumonia manifestations on imaging. (2) Ordinary type: with fever, respiratory tract symptoms, etc., imaging shows pneumonia. (3) Heavy: Meet any of the following: ① Respiratory distress, breathing rate> 30 times / min; ② In resting state, means oxygen saturation <93%; ③ Arterial partial pressure of oxygen (PaO 2 ) / inhaled oxygen (FiO 2 ) <300 mmHg (1 mmHg = 0.133kPa).
Contraindications and relative contraindications
1. Age <18 years or age> 65 years. 
However in the China trial registry, many trials that have reported case reports without sever adverse effects are using the drug in people age 65+, e.g. up to 75, as long as meet other inclusion/exclusion criteria. This is even in severe cases of Covid-19 pneumonia and at higher doses than described in the consensus guideline. Some trials have no upper age limit. See below example. (source)

2. Female patients during pregnancy.
3.Patients who are allergic to 4-aminoquinoline are clearly identified.
4.Patients with hematological diseases.
5.Patients with chronic liver and kidney disease and reaching end-stage.
6. Patients with arrhythmia and chronic heart disease.
7. Patients known to have retinal disease, hearing loss or hearing loss (hearing loss case report example in hydroxychloroquine and chloroquine, may be reversible if prompt cessation of drug, short course, lower dose, use of steroids and plasma expanders) 
8. Patients known to have a mental illness.
9. Skin disorders (including rash, dermatitis, psoriasis).
10.Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
11. Due to the original underlying disease, digitalis, butaparin, heparin, penicillamine, amiodarone, benpridil, domperidone, droperidol, haloperidol, azithromycin, astemizole, erythromycin must be used , Clarithromycin, posaconazole, methadone, procainamide, hydrochlorothiazide, sparfloxacin, levofloxacin, moxifloxacin, cisapride, indapamide, chlorpromazine, streptomycin, heparin, Patients with penicillamine, ammonium chloride, ondansetron, apomorphine, octreotide monoamine oxidase inhibitor, fludroprednisolone.
Dosage, usage, treatment plan, monitoring and efficacy evaluation
1. Dosage, usage, and treatment plan: Chloroquine phosphate tablets, 500 mg each time, 2 times / d for 10 days. If severe gastrointestinal reactions occur, the dose can be reduced to 1 time / d, 500 mg each time, or even discontinued. During the course of treatment, if the nucleic acid of the throat swab becomes negative and is negative for 3 days, the drug withdrawal can be considered, but the minimum course of treatment needs 5 days.
2. Surveillance and evaluation of efficacy: pharyngeal swabs were used to test for viral nucleic acid daily during chloroquine treatment; blood routine, electrolytes, and myocardial enzymes were rechecked every other day; ECG was reviewed before and after chloroquine treatment and on days 5 and 10 after treatment. If the condition is stable, review the chest CT before discharge. If the condition is unstable, check the blood gas analysis, chest X-ray or chest CT in time.
Lifting quarantine and discharge standards
The discharge criteria for patients treated with chloroquine are consistent with the sixth edition of the diagnostic and treatment plan issued by the National Health and Health Commission, including that the body temperature has returned to normal for more than 3 days, the respiratory symptoms have improved significantly, pulmonary imaging has shown significant inflammation absorption, and two consecutive respiratory pathogen nucleic acid tests Negative (sampling interval of at least 1 d), can be released from hospital or transferred to the appropriate department for other diseases according to the condition.
Observation of adverse reactions
1. General adverse reactions: dizziness, headache, dizziness, loss of appetite, nausea, vomiting, abdominal pain, diarrhea, tinnitus, irritability, etc. Most of the reactions are mild and disappear by themselves after stopping the drug.
2. Eye toxicity: (1) Because chloroquine can be secreted by the lacrimal glands and absorbed by the cornea, diffuse white particles appear on the cornea, which can disappear after stopping the drug. (2) Accumulated toxicity: A considerable part of this product accumulates in tissues, and long-term service can cause mild retinal edema and pigment accumulation, dark spots appear, and affect vision. There have been reports of retinopathy (macular degeneration), macular degeneration, and retinopathy. Risk factors include age, duration of treatment, maximum daily dose, and / or cumulative dose, often irreversible.
3.Severe external vertebral diseases: such as dystonia, dyskinesia, tongue extension, torticollis, etc. The symptoms are often relieved after drug withdrawal or symptomatic treatment.
4.Cardiotoxicity: Causes the suppression of the sinoatrial node, leading to arrhythmia and shock. In severe cases, A-S syndrome may occur, leading to death.
5.Blood system: Hemolysis, aplastic anemia, reversible agranulocytosis, thrombocytopenia, etc. are rare.
6. Others: drug-induced psychosis, leukopenia, purple scar, rash, dermatitis, photosensitive dermatitis and even exfoliative dermatitis, psoriasis, whitening of hair, hair loss, neuromuscular pain, mild transient headache, etc.
Precautions for clinical application
1. Advise the adverse reactions and precautions of chloroquine phosphate before medication.
2. The medication should be used under the guidance of a specialist.
3.The blood routine should be monitored every other day during the medication. If the white blood cells are progressively reduced, and the anemia and thrombocytopenia are progressively increased, the blood volume is reduced or discontinued, and the blood routines are closely monitored.
4.Before the treatment, perform an electrocardiogram routinely. Monitor the ECG on the 5th and 10th days of treatment. Pay attention to the QT interval. If the QT interval is prolonged or the heart rate slows down, pay attention to the reduction or withdrawal.
5.Patients are routinely asked about changes in vision during treatment, and should be reduced or discontinued if vision loss occurs.
6. Observe the patient's mental and psychological status during treatment, such as mental abnormalities or depression, and pay attention to reducing or stopping the drug.
7. Prohibited drugs: (1) Cardiovascular drugs: digitalis drugs (digoxigenin, deacetylgenin, digoxigenin, venoxin K), antiarrhythmic drugs (type Ia: quinidine , Procainamide, Procainamide, Class III: Amiodarone, Sotalol, Iblit, Dronedarone), benzprodil, hydrochlorothiazide, indapamide; (2 ) Antibiotics: quinolones, macrolides (erythromycin, clarithromycin, azithromycin), triazole antifungals (fluconazole, fluconazole, itraconazole, posaconazole) Penicillamine, streptomycin; (3) Central nervous system drugs: methadone, tricyclic antidepressants (amitriptyline, imipramine, doxepin, clomipramine, melitrazine), Citalopram, antipsychotics (haloperidol, haloperidol, chlorpromazine); monoamine oxidase inhibitors: phenylethylhydrazine, isoniazid, isocarbohydrazine, selegiline, tranylcypromine, Clobemide, pagiline, etc .; (4) Gastrointestinal medications: gastrokinetic drugs (domperidone, cisapride), antiemetics (ondansetron, dorasicon) (5) Others: Baotaisong, fludrolone, heparin, astemizole, ammonium chloride, apomorphine, octreotide, terfenadine, arsenic trioxide.

The use of chloroquine in the treatment of patients with new type of coronavirus pneumonia, the use of antibiotics such as quinolones and macrolides is forbidden, so as to avoid the risk of prolonged QT interval and leading to twisted ventricular tachycardia. At the same time, ensure that the patient's electrolyte levels (potassium, sodium, chlorine) and blood glucose, liver and kidney function are normal.

Authors: Huang Mingxing (Fifth Affiliated Hospital of Sun Yat-sen University), Tang Tiantian (Sun Yat-sen Memorial Hospital of Sun Yat-sen University)
Remdesivir for Covid-19 Prescribing Guideline


Study
Inclusion criteria 
Exclusion criteria
Drug interactions & contraindications
Dosing protocol
Safety/efficacy monitoring

  1. 18+
  2. Mild, moderate or severe COVID19
  3. Age ≥18 years at time of signing Informed Consent Form
  4. Laboratory (RT-PCR) confirmed infection with 2019-nCoV.
  5. Lung involvement confirmed with chest imaging
  6. Hospitalized with a SaO2/SPO2≤94% on room air or Pa02/Fi02 ratio <300mgHg
  7. ≤12 days since illness onset
  1. Severe liver disease (e.g. Child Pugh score ≥ C, AST>5 times upper limit)
  2. Pregnant or breastfeeding, or positive pregnancy test in a predose examination
  3. Patients with known severe renal impairment (estimated glomerular filtration rate ≤30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis

RDV 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days.

  • 18+
  • Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test ≤ 4 days before randomization
  • Currently hospitalized with fever defined as temperature ≥ 36.6 °C armpit, ≥ 37.2 °C oral, or ≥ 37.8 °C rectal
  • Peripheral capillary oxygen saturation (SpO2) ≤ 94% on room air at screening
  • Radiographic evidence of pulmonary infiltrates
  • Evidence of multiorgan failure
  • Requiring mechanical ventilation at screening
  • Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X upper limit of normal (ULN)
  • Creatinine clearance < 50 mL/min

RDV 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 5 days OR 10 days

























Inclusion Criteria:

Exclusion Criteria:

Dose






Ventilatory Support Strategy


Exercise and immunity risk 




"This case highlights 2 challenges in the diagnosis of COVID-19. First, the sensitivity of tests to detect SARS-CoV-2 from upper respiratory specimens might be insufficient. Repeated rRT-PCR testing of nasopharyngeal swabs was negative for SARS-CoV-2 before the patient was admitted to the intensive care unit. To date, diagnosis of COVID-19 is made mainly on the basis of nucleic acid detection from nasopharyngeal swabs. For suspected cases, 2 negative findings from nasopharyngeal swabs performed >24 hours apart would exclude a COVID-19 diagnosis (4). In this case, without the clinicians’ persistence because of the patient’s travel history, a COVID-19 diagnosis might never have been established. SARS-CoV-2 finally was identified by using mNGS and rRT-PCR of a BALF sample. Therefore, suitable sputum or BALF specimens are necessary to maximize detection in cases of high clinical suspicion; mNGS also might be a helpful tool for identifying SARS-CoV-2 (1,5).

Second, differentiating other causes of respiratory illness from COVID-19 is difficult, especially during influenza season, because common clinical manifestations of COVID-19, including fever, cough, and dyspnea, mimic those of influenza (6–8). In patients with COVID-19, blood tests typically show leucopenia and lymphopenia and most chest computed tomography scans show ground-glass opacity and consolidation with bilateral lung involvement (7–9). Unfortunately, influenza A and other respiratory viruses share these characteristics (10). Co-detection of SARS-CoV-2 and influenza A virus in this case demonstrates that additional challenges to detection remain, especially when patients test negative for SARS-CoV-2 but positive for another virus.

In summary, our case suggests that COVID-19 might be underdiagnosed because of false-negative tests for upper respiratory specimens or co-infection with other respiratory viruses. Broader viral testing might be needed when an apparent etiology is identified, particularly if it would affect clinical management decisions."

--> Like I predicted in my Phase 1 research of the corona report, based on old SARS data - corona tests have low sensitivity based on sample site, method used and days after symptoms 

--> due to lack of comprehensive testing availability being likely, there is a need for surrogate markers of RT-PCR/meta genomic next gen sequencing / IgM ELISA to start administering targeted therapies such as these (this is not exhaustive)
[01:00, 13/03/2020] Oli: Quote from - https://wwwnc.cdc.gov/eid/article/26/6/20-0299_article