INTRODUCTION

Covid 19 infection is caused by ‘severe acute respiratory syndrome coronavirus 2(SARS-CoV-2). As of the day of writing, there have been over 169 million infections worldwide and over 3 million deaths(1). Up to April 2021, Sri Lanka had recorded 106,484 cases and only 667 deaths(2). Resurgence of Covid 19 infected cases from Mid-April, has become a national emergency, necessitating lockdown measures. This brief communication hopes to identify the clinical features of the present wave and offer best management practices.

CATEGORIES OF PATIENTS SEEN BY FIRST CONTACT DOCTORS

Category 1 – First level Covid contacts who develop symptoms while they await PCR testing or have been tested and are awaiting the result. For some this has taken 10 days or more. During which time symptoms appear.

Category 2 – Those who develop symptoms at home without PCR testing as they did not consult any medical officer or when they consulted, it was treated as a passing infection.

Category 3 – Stayed at home in spite of contact history and developed no symptoms but recovered on their own

PATHOGENESIS

Spike protein (S protein) of SARS-CoV2 virus is known to attach to angiotensin-converting enzyme-2 (ACE2) receptors, in the upper respiratory tract, in gaining entrance to the human body (3). The virus will gain access to alveolar tissues very quickly. If the virus spreads and the immunological inflammation is not arrested with early treatment, the body’s immunological response will affect the lung, specifically air diffusion – oxygen and carbon dioxide diffusion via alveolar capillary membrane (ACM) (4)

.STAGES OF COVID INFECTION

Figure 1: Staging of COVID infection (Staging system was proposed by Siddiqi et al (5) Reproduced from https://emcrit.org/pulmcrit/steroid-covid/(6)
Figure 1: Staging of COVID infection (Staging system was proposed by Siddiqi et al (5) Reproduced from https://emcrit.org/pulmcrit/steroid-covid/(6)

CLINICAL PROGRESSION

Gets worse after 4th day with early lung involvement
Mild symptoms worsening on 8th day. Observation needed from 7th day evening.

WORSENING SYMPTOMS

Characteristic feeling of being unwell, “unable to do anything”.
Initial low-grade fever which spikes or afebrile initially and sudden onset fever
Mild throat scratch/soreness becomes deep throated cough
Difficulty in breathing – You may be able to pick up early lung involvement with breathlessness on exertion (eg: one minute sit to stand test few times as they can, stop if any discomfort) and with use of a pulse oximeter.
Sudden persistent headache
Diarrhoea, severe loss of appetite

PROPOSED MANAGEMENT OF COVID-19 PATIENTS

PREVENTION OF THROMBOTIC COMPLICATIONS AND SUPPORTIVE CARE

NON- PHARMACOLOGICAL

Steam inhalation (ensure safety), coriander water, warm fluids
Avoidance of alcohol and smoking

PHARMACOLOGICAL

1. H1 and H2 receptor blocker – Promethazine 25 mg bd – to prevent further lung damage (7)
2. Vitamin C, zinc sulphate 50 mg daily known antiviral action (8). Many of the expert protocols for the treatment and prevention of covid-19 includedvitamin D3, vitamin C and zinc.
3. Vitamin D loading dose 60000 IU and daily supplements. Immunomodulatory effect (9)
4. Inhaled budesonide 800 mcg twice daily – Early administration improves recovery time and is an effective treatment when started early (10)
5. Dexamethasone resulted in lower mortality in those needing respiratory support(11). Methyl prednisolone – has been given on 4th day after symptoms. While viraemia increased, patients improved clinically because of immune inhibition action. This will prevent thrombosis later. Better results rather than waiting until worsening hypoxia occurs. In hypoxic COVID-19 patients, methylprednisolone showed better clinical effect compared to dexamethasone(6)(11). Ministry of Health Sri Lanka recommends corticosteroids for patients with moderate to severe COVID in hospitalized patients (12).
6. Appropriate antibiotics as indicated for possible bacterial infection

REPURPOSED DRUGS UNDER REVIEW

ASPIRIN

Low dose aspirin – 75 mg daily – Aspirin may be associated with decreased severity of COVID-19 and death by preventing platelet aggregation (13)

HYDROXYCHLOROQUINE

Early therapy with hydroxychloroquine for high risk patients or patients with worsening symptoms – HCQ 400 mg twice daily loading dose on day 1, 200 mg twice daily for 7 days with Zinc has been recommended by Peter Macculough et al (14). In five randomized controlled clinical trials enrolling 5,577 patients HCQ was associated with a 24% reduction in COVID-19 infection, hospitalization or death, P=.025 (15). HCQ blocks spike protein attachment to ACE2 receptor. HCQ also increases pH in lysosomes & reduce vital replication. HCQ blocks IL 6 which is a major mediator of cytokine storm (15).

IVERMECTIN AND COMBINATION THERAPY

Ivermectin has potential to reduce viral load (16) (17). The high binding activity of ivermectin to the SARS-CoV-2 spike protein could limit binding to either the ACE-2 receptor or sialic acid receptors, respectively, either preventing cellular entry of the virus or preventing hemagglutination, a recently proposed pathologic mechanism in COVID-19 (18) (19).

Early treatment with Ivermectin at onset of disease promoted faster viral clearance which may prevent significant immune system involvement and quicker recovery. Early intervention also reduced the viral load faster and thismay hinder disease transmission in the general population (20). In a pilot, randomized, placebo-controlled, double blind trial conducted among patients with non-severe COVID-19 and no risk factors for severe disease, those receiving a single 400 mcg/kg dose of ivermectin within 72 h of onset of fever or cough, were found to have no difference in the proportion of PCR positives. However a marked reduction of self-reported symptoms such as anosmia/hyposmia and cough and a tendency to lower viral loads and lower IgG titres were also noted(20).

Conclusions drawn from the British Ivermectin Recommendation Development meeting held in February 2021 were to use ivermectin for the prevention and treatment of covid-19 in order to reduce morbidity and mortality and to prevent covid-19 infection among those at higher risk (21).

Statistically significant reductions in mortality, clinical recovery time, and virus clearance were shown in the meta-analysis of 18 treatment RCTs and 3 prophylaxis RCTs of ivermectin in COVID-19 which included more than 2500 patients. The research panel found robust evidence for ivermectin’s effects on mortality benefit and they recommended unconditional adoption for use in the prophylaxis and treatment of COVID-19. (22). It was also noted multiple, large “natural experiments” occurred in regions that initiated “ivermectin distribution” campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns (22). In another metanalysis consisting of 21 RCTs involving 2741 participants, Bryant et al reports similar findings and suggests early treatment to could reduce number of people progressing to severe disease. The apparent safety profile and cost effectiveness further supports the use in a pandemic (23).

Professor Thomas Borody who developed triple-therapy for Helicobacter pylori infection, has recommended that GPs prescribe a triple therapy protocol using ivermectin, doxycycline and zinc (24). Doxycycline is a known inhibitor of IL-6, TNF-alfa and MMP enzymes which play a pathological role in Covid-19 (25) (26). These mechanisms are independent of viral strains.

These findings propose using ivermectin as an add on therapy for treatment and prevention of COVID-19. Trials are ongoing on the treatment dose for treatment and prophylaxis and the use of combination therapy.

In another development the Ministry of health and family wwelfare, India revised its guidelines on home isolation of mild/asymptomatic COVID-19 cases on 28th April 2021 to include Ivermectin (200 mcg/kg once a day, to be taken empty stomach for 3 to 5 days) and budesonide inhalation (800 mcg twice daily for 5 to 7 days) for fever and/or cough persisting for more than 5 days. The caregiver of home isolated patients and all close contacts are recommended hydroxychloroquine as prophylaxis (27). It is observed active and daily cases in India have declined which is attributed to the introduction of these medications (28).

CONCLUSION

Early treatment with Ivermectin with other combination medications for prevention of pulmonopathy and severe disease have been used. As first contact doctors in the community there is a responsibility of averting death, reduce hospital admissions and reduce need for ventilation and ICU care. It’s time to read up and be up to date in scientific knowledge at a time science is politicized. Further randomized clinical trials are ongoing to establish conclusive evidence.

REFERENCES

1. COVID Live Update: 169,093,368 Cases and 3,512,497 Deaths from the Coronavirus – Worldometer [Internet]. [cited 2021 May 27]. Available from: https://www.worldometers.info/coronavirus/?utm_campaign=homeAdvegas1?

2. Corona Virus 2020 [Internet]. [cited 2021 May 27]. Available from: https://www.epid.gov.lk/web/index.php?option=com_content&view=article&id=225&Itemid=481&lang=en

3. Cevik M, Bamford CGG, Ho A. COVID-19 pandemic—a focused review for clinicians [Internet]. Vol. 26, Clinical Microbiology and Infection. Elsevier B.V.; 2020 [cited 2021 May 25]. p. 842–7. Available from: /pmc/articles/PMC7182753/

4. Cevik M, Kuppalli K, Kindrachuk J, Peiris M. Virology, transmission, and pathogenesis of SARS-CoV-2. BMJ [Internet]. 2020 Oct 23 [cited 2021 May 25];371. Available from: http://dx.doi.org/10.1136/bmj.m3862

5. Timed P-. PulmCrit ( EMCrit ). 2020.

6. PulmCrit- Timed & titrated use of steroid in COVID-19? [Internet]. [cited 2021 May 25]. Available from: https://emcrit.org/pulmcrit/steroid-covid/

7. Batalha PN, Forezi LSM, Lima CGS, Pauli FP, Boechat FCS, de Souza MCBV, et al. Drug repurposing for the treatment of COVID-19: Pharmacological aspects and synthetic approaches. Vol. 106, Bioorganic Chemistry. Academic Press Inc.; 2021. p. 104488.

8. What is the role of zinc in the treatment of COVID-19? [Internet]. [cited 2021 May 25]. Available from: https://www.medscape.com/answers/2500117-201201/what-is-the-role-of-zinc-in-the-treatment-of-covid-19

9. Rastogi A, Bhansali A, Khare N, Suri V, Yaddanapudi N, Sachdeva N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: A randomised, placebo-controlled, study (SHADE study). Postgrad Med J. 2020;

10. Ramakrishnan S, Nicolau D V., Langford B, Mahdi M, Jeffers H, Mwasuku C, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med [Internet]. 2021 [cited 2021 May 26];0(0). Available from: https://doi.org/10.1016/S2213-2600

11. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med [Internet]. 2020 Jul 17;384(8):693–704. Available from: https://doi.org/10.1056/NEJMoa2021436

12. Revised clinical practice guidelines on instutional management of COVID-19 patients in Sri Lanka 25.05.2021.pdf.

13. Chow JH, Khanna AK, Kethireddy S, Yamane D, Levine A, Jackson AM, et al. Aspirin Use Is Associated with Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients with Coronavirus Disease 2019. Anesth Analg [Internet]. 2021 [cited 2021 May 25];930–41. Available from: https://journals.lww.com/anesthesia-analgesia/Fulltext/2021/04000/Aspirin_Use_Is_Associated_With_Decreased.2.aspx

14. McCullough PA, Kelly RJ, Ruocco G, Lerma E, Tumlin J, Wheelan KR, et al. Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection [Internet]. Vol. 134, American Journal of Medicine. Elsevier Inc.; 2021 [cited 2021 May 27]. p. 16–22. Available from: https://doi.org/10.1016/j.amjmed.2020.07.003

15. Ladapo JA, McKinnon JE, McCullough PA, Risch HA. Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis. medRxiv [Internet]. 2020 Sep 30 [cited 2021 May 26];2020.09.30.20204693. Available from: https://doi.org/10.1101/2020.09.30.20204693

16. Alam MT, Murshed R, Bhiuyan E, Saber S, Alam RF, Robin RC. A Case Series of 100 COVID-19 Positive Patients Treated with Combination of Ivermectin and Doxycycline. J Bangladesh Coll Physicians Surg. 2020 Jun 12;10–5.

17. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun 1;178:104787.

18. Dasgupta J, Sen U, Bakshi A, Dasgupta A, Manna K, Saha C, et al. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted. 2020 May 5 [cited 2021 May 27]; Available from: www.preprints.org

19. Dayer MR. Coronavirus (2019-nCoV) Deactivation via Spike Glycoprotein Shielding by Old Drugs, Bioinformatic Study [Internet]. []. Preprints; 2020 [cited 2021 May 27]. Available from: http://dx.doi.org/10.20944/preprints202005.0020.v1

20. Chaccour C, Casellas A, Blanco-Di Matteo A, Pineda I, Fernandez-Montero A, Ruiz-Castillo P, et al. The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine [Internet]. 2021 Feb 1 [cited 2021 May 26];32. Available from: http://creativecommons.org/licenses/by/4.0/

21. British Ivermectin Recommendation Development (BIRD). The BIRD Recommendation on the Use of Ivermectin for Covid-19 [Internet]. 2021 [cited 2021 Jun 9]. Available from: https://www.francesoir.fr/sites/francesoir/files/media-icons/bird-proceedings-02-03-2021-v151.pdf

22. Kory P, Meduri GU, Varon J, Iglesias J, Marik PE. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. Am J Ther [Internet]. 2021 May [cited 2021 May 27];28(3):e299–318. Available from: /pmc/articles/PMC8088823/

23. Bryant A, Lawrie TA, Dowswell T, Fordham E, Scott MM, Hill SR, et al. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review and meta-analysis. [cited 2021 Jun 10]; Available from: https://osf.io/k37ft/

24. Trial of Combination Therapy to Treat COVID-19 Infection – Full Text View – ClinicalTrials.gov [Internet]. [cited 2021 May 26]. Available from: https://clinicaltrials.gov/ct2/show/NCT04482686?term=Ivermectin+borody&draw=2&rank=1

25. Malek AE, Granwehr BP, Kontoyiannis DP. Doxycycline as a potential partner of COVID-19 therapies. Vol. 21, IDCases. Elsevier Ltd; 2020. p. e00864.

26. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet [Internet]. 2020 Mar 28 [cited 2021 May 27];395(10229):1054–62. Available from: https://doi.org/10.1016/

27. 28 th April 2021 Government of India Ministry of Health & Family Welfare Revised guidelines for Home Isolation of mild /asymptomatic COVID-19 cases 1. Background [Internet]. [cited 2021 May 26]. Available from: https://www.mohfw.gov.in/pdf/Guidelinesforhomequarantine.pdf,

28. India: COVID Cases Plummet After Government Promotes Use of Ivermectin and Hydroxychloroquine [Internet]. [cited 2021 May 26]. Available from: https://humansarefree.com/2021/05/india-covid-cases-plummet-after-government-promotes-use-of-ivermectin-and-hydroxychloroquine.html

 

 

 

 

 

LEAVE A REPLY

Please enter your comment!
Please enter your name here