key: cord-1041462-e543lgys
authors: Theoharides, Theoharis C.; Guerra, Lucy; Patel, Kapilkumar
title: Successful Treatment of a Severe COVID-19 Patient Using an Integrated Approach Addressing Mast Cells and Their Mediators
date: 2022-02-26
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2022.02.049
sha: 280c656451474f5514de6ad30bec386a6db297ef
doc_id: 1041462
cord_uid: e543lgys

SARS-CoV-2 infects cells leading to a complex immune response that involves the release of mediators, most of which are released from mast cells, leading to lung edema, fibrosis, inflammation, and micro thromboses, hallmarks of COVID-19. Here we report on a patient who was initially hospitalized with severe COVID-19 pneumonia, as well as physical and mental fatigue. In spite of her having been treated with albuterol, azithromycin, ceftriaxone, convalescent plasma and dexamethasone, she continued to worsen to the extent that she was considered for double lung transplant. Four months after a novel integrative treatment approach primarily aiming at inhibiting mast cells and their mediators, using rupatadine, famotidine, misoprostol, vitamin D3 luteolin, quercetin, and erythropoietin, the patient recovered fully.

SARS-CoV-2 infects cells leading to a complex immune response that involves the release of mediators, most of which are released from mast cells, leading to lung edema, fibrosis, inflammation, and micro thromboses, hallmarks of COVID-19. Here we report on a patient who was initially hospitalized with severe COVID-19 pneumonia, as well as physical and mental fatigue. In spite of her having been treated with albuterol, azithromycin, ceftriaxone, convalescent plasma and dexamethasone, she continued to worsen to the extent that she was considered for double lung transplant. Four months after a novel integrative treatment approach primarily aiming at inhibiting mast cells and their mediators, using rupatadine, famotidine, misoprostol, vitamin D3 luteolin, quercetin, and erythropoietin, the patient recovered fully. This is a 49-year-old Caucasian female subject whose only significant medical history was in situ breast cancer. She tested positive for COVID-19 on 11/30/2020 and complained of dyspnea and fatigue.

The patient was admitted to the hospital on 12/20/2020 severely hypoxic with a diagnosis of acute respiratory failure. Initial bloodwork showed significantly reduced oxygen saturation (O 2 saturation=42%, PO 2 =29, PCO 2 =56, HCO 3 =34). C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were elevated. Lung computed tomography (CT) showed peripheral nodular and ground glass opacities in the lung bases indicative of diffuse inflammation, and she was given the diagnosis of acute hypoxic respiratory failure due to COVID-19. She was treated with azithromycin, ceftriaxone, albuterol, dexamethasone, and convalescent plasma, but was not intubated. She was discharged on 12/15/2020 with the diagnosis of acute hypoxic respiratory failure, secondary to COVID-19 pneumonia, and she was prescribed dexamethasone, and tizanidine for muscle spasms.

She was prescribed home oxygen, 2 liters (Lit) by nasal cannula (nc). However, on 12/31/2020 the patient's oxygen levels dropped and stayed at around 70% saturation prompting her to visit the walk-in COVID clinic and from there she was transported by ambulance to the emergency room (ER), from where she was discharged on 10 Lit oxygen by nc. On 1/6/2021, the patient went back to the ER where she coughed up a blood clot. Chest radiogram, CT of the lungs and CT angiogram of the pulmonary arteries were normal with no evidence of acute pulmonary embolism. An echocardiogram was also normal. The patient was discharged with no further treatment recommendations.

On 1/20/21, the patient again visited the COVID clinic, she was noted to have decreased distal pulses and was referred for high resolution CT and pulmonary function test with diffusing capacity for carbon monoxide (DLCO). On 2/5/2021, the high-resolution CT showed some scarring/atelectasis in the right middle lobe. The pulmonary function test performed on 2/9/2021 was normal, but DLCO was abnormal. She was prescribed albuterol.

In the ensuing weeks, in addition to the difficulty breathing, the patient felt extremely fatigued with severe brain fog that necessitated leaving her demanding professional job. Oxygen saturation was in the low 90s% at rest and in mid-70s% to mid-80s% when ambulating even at 10 Lit nc oxygen administration.

A cardiac magnetic resonance imaging (MRI) performed on 2/16/2021 was normal, but the cardiologist prescribed rivaroxaban. A ventilation-perfusion (V/Q) scan done on 3/1/2021 revealed coarse heterogenous perfusion of the lungs bilaterally, suggestive of the presence of diffuse inflammation and micro thromboembolic disease (Fig. 1A) ; these findings correlated to those of chest radiograms. The patient was referred to the Center for Advanced Lung Disease and Lung Transplant Program where it was noted that the clots were apparently fossilized and deep within the lungs rendering a thromboendartectomy not a viable option. The patient remained on 10 Lit pc oxygen supplementation while ambulating.

A close friend of the patient was a fellow graduate from the Harvard Kennedy School with one of the authors (TCT), who happened to deliver a lecture on the role of mast cells in COVID-19 (Theoharides, 2020a) while on sabbatical leave at Nova Southeastern University at the Tampa campus, and she approached him for advice. On review of the medical history, it became apparent that the patient was very sensitive to histamine-rich foods, consumption of which promptly resulted in mouth pruritus and swelling suggestive of mast cell activation.

Interestingly, such hypersensitivity symptoms along with cognitive dysfunction, are similar to those experienced by patients with Mast Cell Activation Syndrome (MCAS) (Theoharides and Conti, 2020; Afrin, et al., 2020) . Moreover, mast cell activation symptoms are increased in Long-COVID patients (Weinstock, et al., 2021) .

On 3/10/2021, the patient was started on an integrative treatment regimen aimed at inhibiting release of pro-inflammatory, prothrombotic and fibrotic mediators mostly from mast cells, while increasing oxygen transport capacity and reducing brain fog.

 Acetyl salicylic acid (ASA, 81 mg/day) was added to rivaroxaban to prevent the development of micro thromboses.

 The dual histamine-1 and platelet activating factor (PAF) antagonist rupatadine (Rupall, available in Canada, 10 mg, twice per day) was used because it also inhibits the action of PAF, which may contribute to microthrombi (Demopoulos, et al., 2020) and the release of pro-inflammatory cytokines from mast cells (Alevizos M, et al., 2013) .

 The histamine-2 receptor antagonist famotidine was added because it was reported to improve clinical outcomes in hospitalized COVID-19 patients (Freedberg, et al., 2020) , but also because it suppresses mast cell activation (Shah, et al., 1994) .

 The Prostaglandin E1 analogue misoprostol (Cytotec, 100 mcg/day) was added because it is antifibrotic and decreases mast cell activation (Shah, et al., 1994) .

 Vitamin D3 (5,000 IU/day) was added because low levels have been associated with severe course of COVID-19 (Karonova, et al., 2021) , and because Vitamin D3 can regulate atopic reactions (Theoharides, 2017) , especially mast cell activation (Yip, et al., 2014; Liu, et al., 2017) .

 Erythropoietin (100 units/kg subcutaneous injection, three times/week for 12 weeks) was added, even though there was no anemia, to improve oxygenation to the brain and lungs (Ehrenreich, et al., 2020) .

 Methyl prednisolone (4 mg/day) was used to reduce inflammation and protect vascular integrity.

 Two dietary supplements (formulated in olive pomace oil to increase oral absorption), one containing the natural flavonol quercetin and the structurally related flavone luteolin (FibroProtek ® ) and the other containing luteolin, calcium folinate, hydroxytyrosol and berberine (BrainGain ® ) were also used as 2 softgels of each, twice/day. These flavonoids have anti-inflammatory properties and inhibit mast cells (Theoharides, 2020a) . They have also been proposed as prophylaxis or treatment against COVID-19 (Theoharides, 2020a; . In particular, a number of studies using in-silico approaches identified quercetin and luteolin as potential strong blockers of SARS-CoV-2 spike protein's receptor binding domain (RBD) attaching to the Angiotensin Converting Enzyme 2 (ACE2) receptor (Shadrack, et al., 2021) . Berberine, also contained in BrainGain ® , suppressed expression of SARS-CoV-2-related receptors and cytokines (Wang, et al., 2021) .

The patient gradually improved to the point that no oxygen was required except on occasion. A brain single positron emission (SPECT) scan done on 8/4/2021 was normal and a repeat V/Q perfusion scan performed on 8/6/2021 showed minimal, if any, heterogeneity of uptake (Fig. 1B) . The patient's clinical examination was normal and oxygen saturation was maintained at over 95%. As a result, the patient was taken off the lung transplant list.

The SARS-CoV-2 infects cells by first binding to ACE2 leading to a complex immune response (Zhou, et al., 2020) that in most cases involves the release of pro-inflammatory chemokines and cytokines, leading to the development of the clinical presentation of COVID-19. (Brodin, 2021) . These inflammatory mediators include CCL5, CCL-11, chymase, IL-1, IL-6, TGF, and PAF mostly released from mast cells in response to environmental triggers including SARS-CoV-2 (Theoharides, 2020b; Motta Junior, et al., 2020) . Moreover, mast cell activation in COVID-19 patients was confirmed through serum elevation of the mast cell-specific protease chymase (Tan, et al., 2021) . A recent paper reported that the SARS-CoV-2 spike protein could directly stimulate mast cells in ACE2 humanized mice and result in lung injury (Wu, et al., 2021) , and it was proposed that the spike protein may be the key pathogenetic factor in Long-COVID syndrome (Theoharides, 2022) .

The present case illustrates that mast cell activation may be associated with and an integrated treatment approach addressing mast cells and their pro-inflammatory mediators could be quite effective. Similar approaches may also be useful in managing patients at risk of anaphylaxis after COVID-19 vaccination (Gangemi, et al., 2021) , as well as Long-COVID (Theoharides, 2022) .

TCT is the Scientific Director of Algonot, LLC (Sarasota, FL) that develops flavonoid-containing dietary supplements.

Ethical Approval: The patient has provided written permission to review her medical records and write this report.

LG, the COVID Clinic physician and CP, the Advanced Lung Disease and Transplant Clinic physician, were directly responsible for the care of this patient, reviewed and approved the manuscript. TCT was consulted, discussed the case, provided the integrative approach, searched the literature and wrote the manuscript. 

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