This study shows that ivermectin use is associated with reduced duration of the febrile illness in an outpatient setting, thus promoting early recovery from COVID-19 infection, especially when started early in the course of the illness.

There are several advantages of this study. This study included COVID-19 patients suffering from febrile illness who had presented most frequently on 3^rd day of febrile illness (unimodal distribution). The severity of illness and treatment was uniform and suggested an effective, feasible and very affordable method of treatment at community level.

There are some limitations of this study such as a case-control design, and exclusion of severely ill or hospitalized patients. Many patients were diagnosed on the basis of the clinical syndrome rather than the molecular testing, as it was neither widely available nor within reach of the majority of population within the country. Moreover, there are serious concerns over the COVID-19 testing in Pakistan at the community level [16,17] rendering its feasibility in our setting. At places where the molecular testing is considered more standardized, the presence of false positive and false negative results remains a limiting factor within the country creating speculations about the testing itself. RT-PCR is commonly used for a diagnostic test; however, its accuracy is questionable as the absence of the virus cannot be ruled out depending on the basis of PCR alone. The probability of false-negative results is high early in the disease, however, despite a relative reduction of false-negative results by the end of first week of exposure the clinical picture remains the main consideration among those presenting with the COVID-19 infection [18].

Earlier the antimalarial drugs chloroquine and hydroxychloroquine were claimed to possess antiviral activity [19,20], however, such studies were mainly in vitro and needed clinical trials to validate their efficacy and safety in humans. This was even more concerning when chloroquine or hydroxychloroquine in combination with another potentially cardiotoxic drug azithromycin was considered to treat COVID-19 [21,22]. However, recent studies do not support chloroquine or hydroxychloroquine for the treatment of COVID-19 as follows. A comparative observational study involving COVID-19 patients reported that hydroxychloroquine was not superior to control group in terms of worsening of symptoms, respiratory distress, or overall survival, all by the end of 3 weeks of treatment [23]. A clinical trial found no difference in seroconversion rate at 28^th day of COVID-19 illness among those receiving hydroxychloroquine compared to control group [10]. Thus, AZI+HCQ does not impart any beneficial effect in COVID-19 and is as good as placebo, albeit with an increased risk of cardiotoxicity.

The adequate safety profile of any drug is pivotal to consider it as a potential drug to treat different diseases and ivermectin certainly possesses this quality. Its safety profile is established in adults on fixed daily doses of up to 36 mg without producing any significant adverse effects [24]. Apart from the antiparasitic effect, ivermectin is known for its antimicrobial, antiviral, and anticancer potential. In this study ivermectin was used in a fixed dose of 12 mg once a day for six days without any reported side effect, thus confirming other similar studies where ivermectin has been used safely in a variety of conditions. With its good safety profile, ability to produce beneficial effects against many RNA and DNA viruses, and effects on various biological mechanisms, they can be considered as a potential treatment of COVID-19 infection.¹² In this study, a dose of 12 mg once daily was used for six days leading to a highly feasible cost of under three dollars for the entire course of ivermectin over six days.

Thus, it could be implied that use of ivermectin in COVID-19 could potentially save many patients from adversely progressing to a severer illness thus saving precious lives, reducing direct load on healthcare facilities and preventing high cost of management.

Ivermectin has various effects on different organisms such as regulation of glucose and cholesterol, suppression of cell proliferation, inhibition of viral replication, and reduction in survival in insect vectors [25]. Despite its multiple therapeutic applications, its mechanism of action is still not accurately known. Another beneficial effect of ivermectin is the modulation of the immune system as it decreases immune cell proliferation and cytokine production.²⁵ Both of these effects can be the reason for showing a positive effect in COVID-19 patients as discussed here. Ivermectin inhibits cytokine production as estimated in bronchoalveolar lavage fluids as well as the reduction in serum IgE and IgG1 levels, thus reducing airway inflammation [26]. A recent proteomic investigation, utilizing cell-based assay, suggests a role of ivermectin as an immunomodulator in COVID-19 [27].

There is an evidence that ivermectin also works directly against some viruses, such as HIV1, dengue and yellow fever viruses. Ivermectin is believed to disrupt important cellular processes of HIV1 by inhibiting HIV integrase and non-structural protein 5 polymerase in dengue virus [26]. It is suggested that it also reduces the replication of flaviviruses which cause yellow fever and dengue by inhibiting viral RNA helicase [25]. In an in vitro study, ivermectin showed anti-viral activity in SARS-CoV2 infected Vero/hSLAM cells [9]. RNA viruses rely on importin α/β1 heterodimers for protein translocation during replication, which is blocked by ivermectin [9]. It is postulated that by a similar mechanism it might inhibit replication of SARS-CoV2 [28].

A recent study suggested that ivermectin used in hospitalized patients suffering from severe pulmonary complications would reduce mortality among COVID-19 patients [29]. However, it was a retrospective study, conducted among hospitalized patients many of whom required a combination of various drugs, had multiple confounders requiring statistical adjustments, the administration of ivermectin did not follow a consistent dosing regimen and many of the patients were given ivermectin later in the course of the disease. The primary and secondary end-points were also different as compared to our study. Another study conducted among healthcare personnel suggested a beneficial role of ivermectin in COVID-19 patients [30]. However, it was a cross-sectional study conducted on COVID-19 patients presenting with a wide range of severity including asymptomatic patients as well as severely ill. Further, the study included mixed treatment regimens. In this study, the group taking ivermectin showed a much quicker recovery from the febrile illness at all time-points consistently with an odds ratio being highly significant as discussed below. The most drastic difference was seen within first 5 days, suggesting the potential of ivermectin to bring about a sharp improvement among COVID-19 patients. To complement our observation, logistic regression analysis shows ivermectin being the only significant factor underlying the shorter duration of febrile illness among patients. Similarly, the survival analysis further supports this inference as the Kaplan-Meier curve showed a clear and highly significant advantage of using ivermectin among COVID-19 patients presenting with febrile illness. Interestingly, like other drugs being tried and used for COVID-19, this study suggests that the sooner the treatment is started, the better the magnitude of benefit in terms of a shorter duration of febrile illness. Recently, it has been postulated [31] that hydroxychloroquine may act synergistically with ivermectin to improve recovery in patients infected with SARS-CoV-2, however, we were not able to explore this in our study. An adequately designed randomized trial should provide the evidence for this hypothesis.