Ivermectin fulfills Bradford Hill

With Professor Colleen Aldous

Critical appraisal of multidrug therapy in the ambulatory management of patients with COVID-19 and hypoxemia Part II: Causal inference using the Bradford Hill criteria

We continue the critical appraisal of three published case series of 119 COVID-19 patients with hypoxemia, treated in the United States, Zimbabwe, and Nigeria with similar ivermectin-based multidrug treatments, to assess the available evidence supporting a causal relationship between treatment and reduction in hospitalizations and mortality. A narrative review was conducted to assess the Bradford Hill criteria for a causal association. We used a previously proposed refinement of the Bradford Hill criteria that reorganized them into three categories of direct, mechanistic, and

parallel evidence. The efficacy of the two most aggressive ivermectin-based multidrug protocols is supported by the Bradford Hill criteria for temporality, strength of association, biological gradient, biological plausibility, coherence, consistency, and analogy. The causal relation between the treatment of hypoxemic COVID-19 patients using these protocols and the reduction in hospitalizations and mortality is supported as an inference to the best explanation.

Critical appraisal of multidrug therapy in the ambulatory

management of patients with COVID-19 and hypoxemia

Part I. Evidence supporting the strength of association

On March 11, 2020, Coronavirus Disease 2019 (COVID-19), the disease caused by the Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization (WHO) [1]. Worldwide, 768,187,096 confirmed cases of COVID-19 and 6,945,714 deaths have been reported to the WHO as of June 21 2023, amounting to an average Case Fatality Rate (CFR) of 0.9% [2]. During 2020, while several governments and public health agencies were focused on contagion control and in-hospital patient care, several medical doctors from all around the world innovated and discovered early outpatient multidrug treatments using several repurposed medications in combination [3–15]. In the United States, several independent efforts coalesced into the formulation of a sequenced multidrug protocol [10, Fig. 3] (hereafter, McCullough protocol), which is based on the pathophysiological understanding of COVID-19 as a triphasic illness with three overlapping phases: (1) viral proliferation; (2) hyperinflammatory cytokine storm (COVID-19 pneumonia); and (3) thrombosis. McCullough’s protocol proposed a combination antiviral therapy for treating the viral proliferation phase, immunomodulators for treating the cytokine storm, and antiplatelet agents and antithrombotics for handling the thrombotic stage, based on risk stratification and how the disease presents in each individual patient. Thus, the McCullough protocol is an algorithmic treatment using sequenced multiple drugs in combination and customized to the individual patient and their response to treatment; no single drug is necessary nor sufficient to achieve treatment efficacy towards reducing hospitalizations and deaths. A recently published update of the McCullough protocol [16, Fig. 3] introduced some adjustments including virucidal nasal washes and oral gargles [17–24]. A large case series of 869 high-risk patients [25, 26], who were treated using an early version of the McCullough protocol, has been compared against population-level and historical controls [27], showing the existence of efficacy with respect to the reduction of mortality and hospitalizations, which is also resilient with respect to random selection bias, provided that patients are treated early enough within the first 3 to 5 days from the onset of illness. Indeed, an earlier study by Fazio et al.[28] showed that the ideal window of opportunity for initiating an effective early outpatient treatment of COVID-19 to prevent hospitalization is approximately within the first 3 days.