The “McCullough Protocol” (©pending), otherwise known as sequenced multidrug therapy for SARS-CoV-2 infection, COVID-19 syndrome, was initially published in the August issue of the American Journal of Medicine, 2020 and later updated in December 2020.^1,2 The concept was that there are three overlapping phases of SARS-CoV-2 infection: 

1) viral replication,
2) inflammation or cytokine storm, and
3) micro thrombosis or small blood clots obstructing the capillaries in the lungs.³

Because these are three distinct problems within the body, it was known early that a single medication would be insufficient to treat high-risk patients. The evidence that was utilized from the medical literature was broadly considered searching for drugs that had signals of benefit and acceptable, well-characterized safety profiles.

In the setting of a novel coronavirus outbreak, doctors did not have the luxury of having years of prior randomized, double-blind, placebo-controlled trials or medical society-based guidelines which rely on those trials available for outpatient therapy. Such trials usually take 3-5 years. In a complicated illness such as COVID-19, a definitive outpatient randomized trial would take ~20,000 patients in order to discern an impact of a therapy on the outcomes of hospitalization or death.

More importantly, the same sized trial or larger would be needed in order to rule out a treatment effect of a drug that doctors had already found useful in treatment. Neither of these scenarios has played out in the first several years of the pandemic. Thus, the ”McCullough Protocol” and its principles are commonly found in the bedrock of community standard of care for ambulatory treatment of COVID-19.

With the contemporary Omicron strain, the symptoms are milder, and the risks of hospitalization and death are markedly diminished compared to earlier strains. Thus, for individuals under age 50 who are healthy, often just viricidal nasal washes with dilute povidone iodine or hydrogen peroxide plus the “OTC Bundle” are all that is needed to get through the illness in the shortest period of time with the least risk of transmitting the illness to others. Those over age 50 and or with multiple medical problems and younger persons presenting with severe symptoms are at higher risk and warrant additional prescription treatment.

At the time of this writing, monoclonal antibodies are either unavailable or being phased out of most markets. Thus, the oral antiviral box is next in the treatment protocol, and there are a variety of choices for the doctor and patient to settle upon. Hydroxychloroquine is long-acting and safe for most patients, but its effect is modest on the COVID-19 syndrome. Ivermectin at 0.6 mg/kg of body weight per day is the most dynamic for prompt symptom relief and is a favorite choice for many doctors.

Paxlovid is available under emergency use in many countries but has over three dozen drug interactions and is difficult to use in older patients on multiple medications. Paxlovid should be utilized only in the unvaccinated, and the US CDC warns the public about “Paxlovid Rebound” in the vaccinated, making the syndrome worse and lasting longer with a prolonged period of infectivity to others.⁴ Mulnipiravir is seldom used since its impact on the syndrome is modest and given its known mutagenic risks theoretically, including cancer and promotion of mutations in SARS-CoV-2.

Azithromycin and doxycycline are commonly added to treat the bacteria in nasotracheal secretions and concurrent atypical bacterial infections. Inhaled budesonide is proven to reduce the risk of hospitalization and makes breathing easier. Oral steroids later in the course help breathing and provide great relief from fatigue and body aches with the illness. Colchicine is used for chest soreness and has also been shown to reduce hospitalization and death. Aspirin is now the main blood thinner used in the Omicron variant.

Rarely do doctors need to prescribe heparin or other blood thinners unless a large blood clot is identified. Home oxygen can be added, and very rarely would a well-treated patient need to go to the hospital.

The first three days of illness are the “golden window” for effective care.⁵ For high-risk patients, it takes about 4-6 drugs for 5, 10, or even 30 courses, depending on age, medical problems, and severity of illness. Doctors have always had a duty to treat or a duty to refer to a treating doctor, and the community standard of care is established by local doctors who have taken on the challenge to treat COVID-19 in order to avoid hospitalization and death.⁶

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McCullough Protocol

References:

¹ https://www.amjmed.com/article/S0002-9343(20)30673-2/fulltext
² https://www.imrpress.com/journal/RCM/21/4/10.31083/j.rcm.2020.04.264
³ McCullough PA, Vijay K. SARS-CoV-2 infection and the COVID-19 pandemic: a call to action for therapy and interventions to resolve the crisis of hospitalization, death, and handle the aftermath. Rev Cardiovasc Med. 2021 Mar 30;22(1):9-10. doi: 10.31083/j.rcm.2021.01.301. PMID: 33792243
⁴ https://emergency.cdc.gov/han/2022/pdf/CDC_HAN_467.pdf
⁵ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725339/
⁶ https://www.ijirms.in/index.php/ijirms/article/view/1100#downloadTab