Godofreda R Vergeire-Dalmacion^1*, Pedrosa Glenda²

¹Department of Clinical Epidemiology, College of Medicine, University of the Philippines Manila; Manila, Philippines
²Division of Educational Leadership and Professional Services, College of Education, University of the Philippines, Diliman; Quezon City, Philippines

*Corresponding Author: Godofreda R Vergeire-Dalmacion, Department of Clinical Epidemiology, University of the Philippines, Manila, Paz Mendoza Bldg, Ermita Manila, Philippines;
Email: [email protected]

Published Date: 07-07-2022

Copyright^© 2022 by Vergeire-Dalmacion GR, et al. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: Several meta-analyses have shown low to moderate certainty for Ivermectin (IVM) to reduce all-cause mortality from COVID -19 infection by 68% and to prevent infection by about 86%.

Objectives: The aim of our study is to determine the effects of oral IVM for treating mild to moderate COVID infections and the effects of demography, symptomatology, co-morbidities, IVM dose and combination or single immunomodulating supplements on clinical recovery

Method: An ex post facto research design involving covid 19 patients treated with ivermectin covering the period of April 2021 to June 2021 was used. The participants were clinicians in Metro Manila who prescribed IVM for home care treatment of their COVID-19 patients.

Result: Out of 338 evaluable patients, 95.6% (323/338) showed full recovery at the end of the study, 0.59% (2/338) was still recovering, 2.36% (8/338) are long haulers and 1.47% (5/338) succumbed to the infection. Mild cases received IVM at 0.2 to 0.8 mg/kg body weight (kgbw) and 1.0 to 1.8 mg /kgbw for moderate cases for 5-7 days. The p-values of 0.022 for gender and 0.000 for co-morbidity showed that these factors can significantly affect the recovery of COVID-19 patients. Shortness of breath (p-value of 0.000), muscle pain (p-value =.002) and headache (p-value=0.011) have significant effects on recovery. Among the co-morbidities, hypertension (p-value=0.000), diabetes (p-value=.006), cardiovascular diseases (p-value=0.001) and obesity (p-value=0.014) have statistical significant effects on clinical outcomes. Using Kruskal Wallis H statistics, the intake of combination immunomodulators has significant effect on the recovery of COVID-19 patients (p-value of 0.027). Using Mann-Whitney statistics, Zinc alone showed statistically significant effect (p-value of 0.002) for recovering from COVID.

Conclusion: IVM is effective for COVID infections provided it is given early and the dose is adjusted for severity and co-morbidities. The graduated dose regimen of IVM and the predilection of the virus to mutate will become a challenge for designing future randomized clinical trials.

Keywords

Home Care; COVID-19; Ivermectin; Patient-Centered Therapeutic; Viral Mutation

Abbreviations

AES: Acute Encephalitis Syndrome; COVID: Corona Virus Disease of 2019; SARS-CoV-2: Severe Acute Respiratory Syndrome Corona Virus 2; CDC: Center for Disease Control; FLCCC: Frontline Line Critical Care COVID Alliance; EUA: Emergency Use Authorization; NIH: National Institutes of Health; CDC PH: Concerned Doctors and Citizens of the Philippines; SOB: Shortness of Breath

Introduction

The sheer magnitude of the disruptions to human existence brought about by the COVID-19 pandemic pales beyond comparison to any natural or man-made calamities that have besieged our world in the last 50 years or perhaps more. The cause of the Coronavirus-2019 (COVID-19) pandemic was traced back to Wuhan, China in early January 2020 from a novel positive sense single stranded genomic RNA virus, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It belongs to the family of Coronaviridae which is the largest group of viruses causing respiratory and gastrointestinal infections including the ubiquitous common cold [1]. SARS-CoV-2 contains the largest known RNA genome with a size of around 30,000 bases long. The genome-based features of SARS-CoV-2 are unique compared to other known β-CoVs. These features may explain the reason behind heightened infectivity and transmission ability of the virus in humans [2,3].

Much earlier in the pandemic, the role of drug therapies was noticeably dismissed in favor of a priori belief that only vaccines can and should control the pandemic [4]. This belief was accepted as immutable truth by many members of the medical community and government despite having only a primitive knowledge of the pathophysiology of the disease and what the virus is capable of doing to the human body, especially to its immune system, as we battle it while awaiting the development of the vaccine. The vital role of vaccines against future biological warfares has always been held by the US government as early as the 9/11 infamous attack [5]. It is not surprising that US government agencies notably the FDA, Center for Disease Control (CDC), together with the World Health Organization and the Big Pharmas will implement mass vaccination for the current pandemic. In order to fully disseminate this narrative, Facebook became the self-appointed fact checker about COVID-19 and its management [6]. The clinical course of COVID-19 infection although clearer and slightly reassuring now is still shrouded with many uncertainties and unknown long term outcomes.

As early as 2011, researchers already discovered the anti-viral and anticancer properties of Ivermectin (IVM), an anti-parasitic drug which effectively eradicated River Blindness in Africa. IVM was one of the 480 preselected compounds they studied as probable importin inhibitors. Importin alpha and beta are nuclear cargo protein that carry viral proteins into the nucleus where they are assembled to become new virions [7]. Only IVM showed positive results which was later replicated in their studies of HIV and Dengue, both RNA viruses like SARS CoV2. Additionally, IVM was demonstrated to dock to the SARS CoV2 receptor binding domain attached to the ACE2 receptors [7]. This action of IVM interferes with the attachment of the spike protein of the putative virus into the ACE2 receptors and the subsequent entry of the virus into the human cell membrane. Once inside the cell, the virus’ primary objective is to hijack the cellular host’s machineries for its replication. These purported mechanism of actions of IVM can lower viral load, decrease viral shedding and prevent the further spread of the virus. More recent studies demonstrated the ability of IVM to inhibit the release of interleukin 6 and TNF which are responsible for the cytokine storm and mortalities of most of COVID-19 cases [8].

In March 2021, as the pandemic raged across continents, Caly published the results of an in-vitro study using the anti-parasitic agent against SARS-CoV-2 in Vero cells [9]. This seminal study reported the ability of IVM to significantly reduce the replication of SARS-CoV-2 and established its potential use for treating the early phase of the infection. As the pandemic neared the last quarter of the year, more scientific papers on IVM for treating COVID-19 infections were published showing trend for its efficacy and safety [10]. But the WHO and US National Institutes of Health (NIH) issued warnings against the use of the drug unless in clinical trials [11]. Subsequently, the US CDC would soften its recommendation for either for or against the use of IVM for COVID-19 and left the decision between the physician and patient to make. By assuming a neutral stand, IVM could not be given an Emergency Use Authorization (EUA) by the US FDA [12].

Many studies involving small sample sizes and published by mostly independent researchers from low-income and middle-income countries have shown a trend towards the reduction of all – cause mortality, early viral clearance and prevention of COVID-19 cases with the use of IVM [13-15].

Objectives

The aim of our study is to describe the recovery of patients with mild to moderate of COVID-19 infections treated with oral human grade IVM combined with supplements and vitamins, which were prescribed for their mechanism of action as immunomodulators. It also aims to statistically test the significant difference between the level of recovery from IVM based on patient’s demography symptomatology, co-morbidities, side effects of IVM, dosage of IVM and combined or single immunomodulators. Ivermectin either in capsule or tablet form was prescribed at the recommended dose by the Frontline Line Critical Care COVID Alliance (FLCCC) as modified by Concerned Doctors and Citizens of the Philippines (CDC PH) [6].

Methods

We conducted an ex post facto research design involving   COVID-19 patients in Metro Manila treated at home  with oral ivermectin from April 2021 to June 2021 by doctors who are known prescribers of IVM. The case report forms in an Excel Database were sent to consenting doctors to be filled out.  A method similar to crowd sourcing, in this instance physician sourcing was used to purposively target doctors known to be prescribers of IVM. The form did not require information about the names or addresses of their patients or any data that can violate the latter’s privacy. Instructions on how to fill up the form was included in the file but access to the primary investigator was open to all participating doctors for any questions or clarifications. Henceforth, this study took advantage of the secondary data via non-probability sampling, particularly, purposive sampling. The descriptive statistics applied in this research is the Mode in order to ascertain the most number of patients per profile, symptomatology, co-morbidities, side effects of IVM, dosage of IVM, combined and single immunomodulators. Moreover, Mean of age was also computed. In testing the significant difference in the level of recovery, Mann-Whitney U test and Kruskal-Wallis were applied. Mann-Whitney was analyzed for profile of patients with two (2) categories only such as gender, clustering effect, symptoms and comorbidities. Kruskal-Wallis was applied for profile of patients with more than 2 categories such as age, side-effects and combined immunomodulator.

The data were analyzed via SPSS version 26. All the raw data were reassessed to validate the encoded data by identifying inaccuracies and discrepancies during the encoding process.

Prior to start of the study, the Ethics approval was obtained on January 12, 2022 from the Research Ethics Committee of the Asian Hospital and Medical Center.

Ethical Consideration

The study did not pose any risk, damage or harm whether emotional, mental or physical to any persons because only secondary data were collected. The study which involved the review of existing medical records containing anonymized list of COVID-19 patients, was done in coordination with consenting physicians who voluntarily participated. The data gathered and participant information were kept confidential following the provisions of the Philippine Data Privacy Act of 2012.

Results

A total of 338 patients treated with IVM at varying doses were eligible for analysis. Their Mean age is 43 years old and common gender is male (count = 172). Their profile consists of their demography, symptomatologies, comorbidities and clusters are seen in Table 1. Unlike the early phase of the pandemic in 2020 when patients consulted alone, at the time of our study, many patients came with other family members, with other neighbors or with co -workers. It was for this reason that the patients were categorized as either a part of a cluster or otherwise when consulting individually.

Table 1: Profile of the patients.

Patients who were 25 years old and below have a recovery rate of 100% which was the highest among the age categories. The test of significant difference on the level of recovery of the patients yielded a level of significance of p-value of 0.302 for age category, 0.628 for clustering effect and 0.177 for symptoms. Thus, age category, clustering effect and symptoms have no significant effects on the recovery of COVID-19 patients. However, the computed p-value of 0.022 for gender and 0.000 for comorbidity significantly showed that gender and co-morbidity can adversely affect the recovery of COVID-19 patients. In the same token, among the different variables under the patients’ profile, comorbidity has the most significant effect.

Out of 338 evaluable patients, 268 (79%) presented with symptoms as seen in Table 2.

Table 2: Symptoms of patients with COVID-19 infections.

Patients mostly presented with cough (146) while the least presenting symptom was dizziness [7]. Patients presenting with diarrhea and dizziness (100%) have the greatest percentage of recovery while the least chance of recovery (84.1%) were those with Shortness of Breath (SOB). Aside from SOB (p-value = 0.000), the symptoms with significant effect on recovery are muscle pain (p-value = 0.002) and headache (p-value = 0.011).

Table 3 illustrates the type of medical conditions or comorbidities that the patient had at the time of their COVID infections.

Table 3: Comorbidities or associated medical conditions of patients who consulted for COVID-19 infection.

The number of cases per comorbidity is not comparable. Ascertaining which comorbidity has the highest or lowest number of recovered patients is not applicable. The test of significant difference has computed level of significance with p-value of 0.234 for asthma, 0.959 for autoimmune disease and 0.051 for overweight. Thus, asthma, autoimmune disease and overweight have no significant effect on the recovery of COVID-19 patients. On the other hand, the p-values of 0.000 for hypertension, 0.006 for diabetes, 0.001 for cardiovascular diseases e.g., ischemia, arrhythmia and 0.014 for obesity imply that these illnesses have significant effects on the recovery from COVID-19.

All patients received IVM in either capsule or tablet form with dose ranging from 0.2 mg/kg body weight (kbw) to the highest dose of 1.8 mg/kgbw. Only one patient, male and 35 years old who presented with shortness of breath and the whole range of respiratory symptoms received the 1.8 mg/kgbw dose. There were only a few patients given more than 1 mg/kg body weight. The usual recommended dose of 0.2-0.4 mg/kgbw were given to those with mild symptoms while those with moderate symptoms were given doses greater than 0.4 mg/kgbw up to 1.2 mg/kgbw. There were only two sources of IVM for this batch of patients because all of the prescribing physicians are members of an advocate group for early treatment of COVID-19 infections. Both sources were compounded while towards the end of the study, IVM came also from the only drug company that was approved to market it locally. Table 4 shows the test of significant differences according to the dosages of IVM. The test statistics used was Kruskal -Wallis H or also known one way ANOVA on ranks which is a rank based non parametric test.

Table 4: Test of significant difference on the dosage of IVM.

The computed value for the Kruskal -Wallis H test was 2.014 with a p-value = 0.57, which shows that the dosage of IVM has no significant effect on the recovery of COVID-19 patients. Table 5 shows the side effects of IVM according to the different clinical outcomes. Mostly, patients did not experienced side-effects from IVM (count = 303) and if they did, the side effects were often dizziness and headache.

Table 5: Descriptive statistics of the side effects of IVM.

Table 6 displays the result of the Kruskal-Wallis H computed value of 0.983 and a p-value of 0.805, which is showing that the side effects of IVM have no significant effect on the recovery of COVID-19 patients.

Most patients were either already taking or placed on various types of vitamins and supplements which are believed to be capable of modulating the immune responses against the SARS-Cov2 virus. Table 7 shows the descriptive statistics of the combined immunomodulators according to clinical outcomes while Table 8 shows the statistical test for significant effect of combined immunomodulators on the recovery from COVID-19.

Based on Table 8, the greatest number of patients were prescribed Vitamin C, D and Zinc while a few were given Vitamin C and D alone [2]. The analysis of which combination of immunomodulators has the highest percentage of recovered patients cannot be ascertained as there is no comparable number of cases.

Table 6: Kruskal-Wallis Statistics of the side effects of IVM.

Table 7: Descriptive statistics of the combined immunomodulators.

Table 8: Kruskal-Wallis Statistics of the combined immunomodulators.

Table 8 reveals the Kruskal-Wallis Statistics of the combined immunomodulators, which shows a computed value of 15.753 and p-value of 0.027. Thus, combined immunomodulators have significant effect on the recovery of COVID-19 patients. This results are compared with the effect from a single immunomodulator shown in Table 9.

Table 9: Effect of a single immunomodulator on the recovery from COVID-19.

Most of the patients were prescribed Vitamin C (Count = 297) and less number of patients were given Vitamin D (Count = 102).

The Mann-Whitney test of significant difference resulted to a level of significance with p-value of 0.254 for patients with Vitamin C, 0.694 combined with Vitamin D and 0.356 with Melatonin. Consequently, Vitamin C, Vitamin D, Melatonin as immunomodulators have no significant effect on the recovery of COVID-19 patients. But there is a level of significance with p-value of 0.002 for zinc indicates that the intake of zinc with IVM by patients with COVID-19 infection has significant effect on their clinical outcomes.

Discussion

The constraint imposed by the Department of Health and the early misinformation from the Director General of the Philippine Drug Regulatory Agency (FDA) effectively discouraged local physicians from using IVM for the early treatment of COVID-19 [16,17]. On the other hand, conducting randomized clinical trials with a placebo as comparator was considered unethical, adversarial to government’s COVID control program and a logistical nightmare. Despite our study ex post factor, important hypothesis can still be generated and a positive trend confirmed existing experiences of other researchers of IVM. Nonetheless, we recommend caution in generalizing the results of the study because of the study’s high risk for selection bias and no comparative group.

Up to this date, the standard of care for COVID-19 remains to be isolating patients and prescribing supportive treatment until the resolution of their symptoms. Hospitalization is advised only when the patient’s conditions turn to worse. The Greek philosopher Celsus in the proem to De Medicina wrote that “the art of medicine should be rational and all doctors aspire for rational prescribing. But doctors forget that rationality is not the same as appropriate” [18]. Rational prescribing should result to appropriate prescribing but rational prescribing need not be appropriate. This is best exemplified by the fate that befell IVM which was disapproved for the early treatment and prevention of COVID-19 infection, allegedly due to the low certainty evidence of its efficacy. This pronouncement was based on the contentious paradigm that randomized clinical trial is the best evidence if not the only evidence to prove efficacy of any intervention regardless of the potential harm or delay it will cause while being investigated. Our health officials, encouraged by the WHO, prescribed the isolation and supportive treatment for COVID-19 cases believing this is a rational approach to managing the COVID-19 infection. During the Delta variant surge, more COVID-19 cases progressed to the severe state requiring hospitalization. Many patients were reported to succumb to the infection while at the parking lot of our local hospitals waiting for vacancies, an intervention that was neither appropriate or public health in nature [19].

The purported antiviral property of IVM against the influenza virus, Venezuelan equine encephalitis, dengue fever virus and West Nile Virus has been consistently shown in many earlier studies [20-23]. IVM was regarded as a possible candidate for the treatment of COVID-19 infection based on these studies. Despite the abundance of evidence for IVM, the country’s health officials and alleged experts persisted in pushing for mere isolation and mass vaccination once the vaccines became available. However, it should be more reasonable to just allow low and middle-income countries to explore other countermeasures for the COVID-19 infections that are cheap, equally effective, safe and available due to the high probability that vaccines will be expensive and likely inaccessible for poorer countries with constrained budget and health delivery system like the Philippines [24]. The safety profile of IVM is firmly established by its regular inclusion for many years in the WHO Essential Medicine List under “Drugs for Several Parasitic Diseases”. This includes the current 21^st edition of the WHO electronic Essential Medicine List updated in June 2019 [23]. We also believe in the saying that what will not kill you, will make you stronger.

The varied doses that doctors used for IVM have always been a subject of criticisms but doses always hovered between 0.2 to 0.4 mg/kgbw until the emergence of the Delta variant in the country [25]. By 2021, local prescribers gained more confidence from their unexpected clinical successes with IVM even for severe COVID-19 cases. IVM was also shown to improve oxygen saturation as low as 90%. For the most part, physicians in the last months of 2020 prescribed IVM using the conservative dose of 0.150 mg/kg as recommended in the package insert for parasitism and the recommended protocol of the US based FLCCC [6]. During the Delta surge, local prescribers of IVM started giving doses ranging from 0.5 to 0.8 mg/kgbw for severe cases which resulted to apparently faster onset of action and resolution of symptoms. In our study, blurring vision occurred in two patients who received high doses of IVM. The elevated liver function tests manifested by two different patients had no baseline values for comparison. Thus, it is unclear whether the deranged liver function tests was due to the IVM, to the COVID infection itself or to a pre -existing liver problem. In addition, due to the many medical literature confirming the adverse effects on the clinical course of COVID-19 in patients with comorbidities such as diabetes or obesity, the presence of these illnesses eventually become primary considerations for prescribing higher dosages of IVM [27].

Ironically, the use of face shields was imposed in the country with nary any strong evidence of their efficacy for preventing transmission of COVID infections except for increasing waste and polluting the environment. Yet, in contrast to IVM, the wearing of face shields was indiscriminately enforced up to the second quarter of 2022. Up to the September 2021, in spite the draconian measures of lockdowns, compulsory face shields, wide scale COVID-19 immunization and restricting mobility of unvaccinated people, the country continued to have an average daily new cases of COVID of about 18,000 in September of 2021 with a mortality rate of 319.67. In contrast, Vietnam our nearest neighbor which did not impose donning of face shields, had at the same time, an average daily new COVID cases of around 14,000 and mortality rate of 127.93 [28]. Currently, the Department of Health of the Philippines reported 1,295 new cases of COVID-19 infections from May 30 to June 5, 2022, of which 16 cases were severe/critical and 1 confirmed death [29].

Our study involved 338 COVID cases treated with oral IVM by 8 clinicians. The clinical outcomes measured were full recovery, recovering, long hauler and death after treatment. At the end of the study. The test of significance showed that gender (p-value =0.022) and co- morbidity (p-value=0.000) have effects on the recovery of COVID -19 patients. Hypertension, CVS diseases, DM and Obesity carry statistically significant effects on the clinical outcomes. The age category, clustering effect and symptoms have no statistical significant effect on recovery of COVID-19 patients. Nevertheless, SOB (p-value =0.000), muscle pain (p-value= 0.002) and headache (p-value = 0.01) have significant effects on the recovery of COVID-19 patients. The intake of combination immunomodulators has significant effect on the recovery of COVD-19 patients at a p-value of 0.027 using Kruskal Wallis H statistics. Using Mann-Whitney test for single immunomodulator, zinc showed a p-value of 0.002 which indicates a statistically significant effect of zinc on the recovery from COVID-19 [30-32].

Conclusion

The results of our study revealed the effectiveness of IVM for treating COVID-19 infection provided it is given early and the dose is adjusted based on severity and co-morbidities of cases. Patients’ Bill of Rights to information and informed consent must be upheld notwithstanding a pandemic. Our results also suggest that government would fare better in controlling the pandemic by implementing focused protection based on age, gender and co- morbidities. The government should adopt a less myopic and terrified approach to managing the pandemic which includes long term lockdowns in various permutations with artificial effects. Opportunities for use and access to IVM and other drugs with preclinical or clinical evidence of antiviral properties should be allowed for the treatment of COVID infections by competent and licensed physicians. Finally, until a sterilizing vaccine is available, the most promising and cost effective treatment to control the pandemic may be a combination drug therapy with or without vaccines provided there is transparency of information on their benefit to risk ratio.

The graduated dosing of IVM to treat COVID-19 based on severity of symptoms and the predilection of the virus to mutate will prove challenging in designing a randomized clinical trial both ethically, morally and scientifically. A more ethical but scientifically sound paradigm to test the effectiveness of treatments for emerging novel infections is imperative because infections are an imminent threat to the security of the world.

Acknowledgement

I would like to express our gratitude for the moral and technical support of the Concerned Doctors and Citizens of the Philippines (CDC PH) especially to Drs. Sham Quinto, Homer Lim, Miles dela Rosa, Rafaal Castillo, Jade del Mundo, Romeo Quijano and Marivic Villa and the Speaking the Truth in Love; Engrs. Ric Casabuena, Manolo Gonzalez and Drs. Jean Tay, Rhodora Reyes and Ma. Luisa Manlapaz.

Author’s contribution

GRVD: Sole author and proponent, conceptualized, designed and created the database for the survey, analyzed the data and wrote majority of the paper.

Glenda Pedrosa: Co-author who helped tremendously in cleaning the data, performing the statistical tests and critically appraising the final paper.

Funding statement

The study did not receive any research grant and was done using personal funds of the proponent.

Competing Interest

I declare no conflict of interest. I and my co-author are not connected with any manufacturer or distributor of Ivermectin.

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Article Type

Research Article

Publication History

Received Date: 11-06-2022
Accepted Date: 27-06-2022
Published Date: 07-07-2022

Copyright© 2022 by Vergeire-Dalmacion GR, et al. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation: Vergeire-Dalmacion GR, et al. The Use of Oral Human Grade Ivermectin with Supplements Known As Immunomodulators for Treating Patients with COVID-19 Infections At Home. J Clin Immunol Microbiol. 2022;3(2):1-16.

Table 1: Profile of the patients.

Table 2: Symptoms of patients with COVID-19 infections.

Table 3: Comorbidities or associated medical conditions of patients who consulted for COVID-19 infection.

Table 4: Test of significant difference on the dosage of IVM.

Table 5: Descriptive statistics of the side effects of IVM.

Table 6: Kruskal-Wallis Statistics of the side effects of IVM.

Table 7: Descriptive statistics of the combined immunomodulators.

Table 8: Kruskal-Wallis Statistics of the combined immunomodulators.

Table 9: Effect of a single immunomodulator on the recovery from COVID-19.