COVID-19 Patient with Multifocal Pneumonia and Respiratory Difficulty Resolved Quickly: Possible Antiviral and Anti-Inflammatory Benefits of Quercinex (Nebulized Quercetin-NAC) as Adjuvant

Background: SARS-CoV-2 (COVID-19) is a viral pandemic with no current vaccine or effective treatment. Hydroxychloroquine and azithromycin are not without cardiovascular risk or complications, and these treatments can fail to aid in full recovery from COVID-19. As new treatments become approved for the pandemic, an inexpensive, non-toxic, and safe adjunctive therapy is needed. Case Presentation: A 59-year-old male presented with respiratory symptoms. Chest X-ray revealed classic indications of COVID-19 pneumonia. A PCR nasopharyngeal swab test confirmed a COVID-19 infection and hospital doctors prescribed Rocephin, azithromycin, and hydroxychloroquine. The patient was then prescribed Quercinex, a nebulized formula of quercetin-(cyclo-dextrin) (20 mg/mL) and N-acetylcysteine (100 mg/mL) three times daily for 14 days by physicians at Envita Medical Center for continued COVID-19 respiratory symptoms. Following 30 minutes after each nebulization treatment, the patient experienced immediate deep breathing relief that lasted for mul-tiple hours. Within the following 48 hours after the first treatment, respiratory symptoms continued to diminish and resolve quickly. Finally, post-treat-ment follow-up be considered for further clinical study as an adjuvant or on its own for COVID-19 and possibly other viral pulmonary conditions.


Background
COVID-19 is a viral pandemic that desperately needs effective clinical treatment to confront this global crisis. Currently, no vaccine exists to effectively combat this virus and treatments are widely ineffective with potentially hazardous side effects. The FDA has recommended that hydroxychloroquine only be used in a hospital setting because of potential heart rhythm problems [1]. Also, studies have suggested that azithromycin can increase the risk of cardiovascular death [2]. Furthermore, drugs like Remdesivir may show promise for the treatment of COVID-19, but they are expensive and unavailable to many. Finally, the hopes of a successful vaccination look slim with issues like vaccine immunity, patient reinfection, and the many failed attempts to create vaccines for similar viruses.
The unique conditions of this pandemic make finding a cheap, effective, and non-toxic treatment for COVID-19 of high importance.
Quercinex is a nebulizer treatment consisting of a formula with quercetin and NAC as its active ingredients. Quercetin and N-acetylcysteine (NAC) are considered generally safe for human consumption, either as a food ingredient in the case of quercetin or as a medicine [3] [4] [5]. Quercetin also has a dietary monograph and is in category 1 of FDA guidance to 503A compounders [3]. Quercetin is the primary antiviral component of the patented Quercinex formula.
Along with antiviral action [6] [7], peer-reviewed research has identified potential anti-inflammatory [8] [9] and antioxidant actions [10] as well. Research studies have observed quercetin to demonstrate activity against herpes simplex virus, polio, respiratory syncytial virus, parainfluenza, MERS, and certain other retroviruses [11]. In cell cultures, quercetin has been shown by research to impede viral replication and reduce the infectivity of viruses, possibly through the mechanism of binding to viral capsid proteins, induction of interferon, or inhibition of DNA gyrase and DNA proteases [11]. Also, quercetin has anti-inflammatory properties that could be relevant in preventing the type of lung scarring seen in severe COVID-19 infections [9]. Potential adverse reactions from quercetin include tingling of extremities and headache for oral use; and flushing, sweating, nausea, vomiting, and injection site pain after infusion for IV [12].
With IV infusions > 945 mg/m 2 Nephrotoxicity can occur [12]. Caution is advised for patients with renal impairment and liver dysfunction [12]. Due to a lack of data, quercetin should not be used during lactation or pregnancy [12].
NAC is an FDA approved agent used for the treatment of acetaminophen overdose and to loosen thick mucus in individuals with cystic fibrosis or chronic obstructive pulmonary disease [4] [5] [13]. It can be taken intravenously, by mouth, or inhaled as a mist [13]. NAC has been correlated with many different anti-inflammatory [14], antioxidant [8] [9] [15], and antiviral properties [16] [17]. Reported side effects from NAC include diarrhea, nausea, vomiting and rash with or without fever [18].
Cyclodextrin is a non-active ingredient in Quercinex. Cyclodextrin is currently used in intravenous drug preparations approved by the FDA, such as Cardio Tec used for Myocardial imaging or Pazeo for ophthalmic applications [19].
Cyclodextrins have been well studied and shown to increase the solubility of poorly soluble drugs as well as to increase their stability and bioavailability [19].
Envita Medical Center has many years of experience using both Quercetin and NAC separately. Quercetin has been compounded for IV use and nebulized for the adjunctive treatment of cancer patients at Envita Medical Center. Envita's doctors have performed thousands of treatments using quercetin with no serious adverse effects. To date, Envita Medical Center has also conducted over 600 nebulized Quercinex treatments safely. Quercinex was prescribed by Envita's doctors (via 503A compounded pharmacy prescriptions) as an adjuvant to the current standard of care recommendations for COVID-19. Quercinex has been observed by Envita's Doctors to be clinically safe and non-toxic with a proposed mechanism that could enhance other drug regimens or to act on its own to improve clinical outcomes significantly.

Case History
A 59-year-old male called into Envita Medical Center (Scottsdale, AZ) on 3/23/ 2020 utilizing our telemedicine system for the reduction of exposure of symptomatic patients. He reported that after returning from New York while on business, he was experiencing symptoms of high fever, chills, cough, general malaise, and fatigue, beginning from six days prior on Tuesday, March 17th. He reported that his symptoms progressively worsened over time, and on 03/23/2020 began to experience shortness of breath and increased fatigue. It is important to note that the patient did not commonly have a medical history of asthma, pneumonia, Chronic obstructive pulmonary disease (COPD), or any other pulmonary conditions. Sociodemographic and clinical characteristics of the patient can be viewed in (Table 1).
He was referred immediately to the emergency department for imaging, evaluation, and COVID-19 screening. Upon arrival at the nearest hospital, Honor Health Shea (Scottsdale, AZ), a full workup was performed, which included chest X-rays ( Figure 1), COVID-19 screening, CBC with diff and platelets, and CMP. The patient was admitted to a full contact and droplet isolation room. The chest X-ray ( Figure 1) reveled patchy opacities in the periphery of both lungs The patient was discharged from the hospital 3/26/20 and given home quarantine instructions as per CDC guidelines. He was asked to continue azithromycin 500 mg and Hydroxychloroquine 200 mg twice a day. The patient began to stabilize (the patient reported that he experienced an improvement in the hospital but maintained a sensation of drowning when breathing and continued shortness of breath

Case Management and Protocols
The patient was prescribed Quercenix: 1 mL of quercetin (20 mg/mL) and 1 mL NAC (100 mg/mL), 3 times daily via nebulization by Envita Medical Center. The prescription was prepared by a 503A custom compounding pharmacy that has extensive experience with this formula. The patient completed a hospital prescribed protocol of Azithromycin and Hydroxychloroquine while undergoing

Results & Responses to Treatment
Patient Response: COVID-19 positive Multifocal Pneumonia It was not until the patient began the nebulizer protocol of Quercinex that he reports he was able to breathe far deeper and overall better. The shortness of breath and drowning sensation greatly improved within 30 min of each treatment, and the recovery would last for three or more hours; we consider this to be a notable and beneficial response. After each therapeutic nebulizer treatment, within 30 min of finishing the treatment, the patient reported that his breathing was much deeper and improved directly related to treatment. After starting the protocol, the patient felt that his recovery was much faster and directly attributed his recovery to breathing nebulized Quercinex. The protocol was associated with a self-reported significant improvement in breathing, and this improvement was noticeable after each subsequent nebulization treatment. After two days of Quercinex treatment, the patient reported that his lung function continued to significantly improve.
As an additional detail, within the first two days of the nebulizer treatment, the patient had improved so greatly that he reported being able and inclined to build a gym in his garage. At this time, the patient started moving about with more energy and improved breathing. After finishing the protocol, the patient has not reported any sensation of shortness of breath since. All symptoms appear to be entirely resolved, and the patient has resumed his cardiovascular exercise with no complaints. No adverse event was reported, but the patient stated that he had increased expectorant of mucus and sneezing after the first two treatments. The patient follow-up included a chest X-rays completed on 4/24/20 ( Figure 3) revealed the following evidence of recovery from the infection: Clear lung fields bilaterally, no effusions, normal heart size, and no skeletal abnormalities. No active cardiopulmonary abnormalities. It is important to note that no pulmonary fibrosis was seen in the patient's lungs post COVID-19 bilateral pneumonia treatment with Quercinex when compared with pre-Quercinex treatment (Figure 4).

Discussion
This case history is representative of the current clinical environment and the  Noteworthy to reiterate is that symptom improvement was reported 30 minutes directly after each nebulizer treatment, further signifying Quercinex's potential adjuvant benefits. The treatment is directly administered to the lungs where the ACE2 receptors on Type II pneumocytes are located and the Coronavirus spike proteins favor infiltration, invasion and, replication within the respiratory system [21]. The nebulized mist of the Quercinex potentially blocks the invasion of the virus with a non-toxic and safe adjuvant antiviral therapy directly to the respiratory tissue under attack, and for this reason we feel it to be clinically relevant for care during this crisis, and more importantly, for future research.
It is promising that the formula appears to be effective and that the reported fast symptomatic relief is linked directly to nebulization of Quercinex.
Potential complications from this Quercinex protocol include copper deficiency via zinc supplementation [22] [23], and safety precautions involving patients with liver dysfunction and renal impairment from quercetin [12]. All other possible side effects are considered mild. Despite these precautions, peer-reviewed literature considers quercetin to be generally well-tolerated [12]. In human studies, no adverse effects on blood parameters of liver and kidney function, hema-tology, or serum electrolytes were found in doses up to 1000 mg/day for several months [20]. Also, the levels of zinc used in this protocol are not high enough to suspect copper deficiency [23]. All the agents in this protocol are substances that are considered generally safe at these doses. He leads us to believe that for doses used in this protocol, the potential for complications is extremely low, and no further complications are anticipated.
Both Quercetin and NAC have been nebulized separately and administered to patients at Envita Medical Center over several years. We are publishing this case study now to illuminate the effect the combined formula has had on a confirmed case of COVID-19. After the notable reversal of symptoms soon after administration and the fact that the patient fully recovered from respiratory symptoms quickly and without any lung scarring, we believe that this Quercinex formula warrants further investigation for its potential benefits in symptom management for the current health crisis and potentially other viral lung infections as well. The inexpensiveness and ease of production of both quercetin and NAC lends itself to potential widescale distribution if the formula is found to be effective in other large-scale studies. Currently the formula can be ordered by prescription via compounding pharmacies. The non-toxic, inexpensive and safe nature of the agent warrants its consideration as adjuvant treatment for COVID-19 respiratory symptoms.

Availability of Data and Material
All available information is contained within the manuscript.