242020Mar
COVID-19 in Three Parts: Virus Biology, Our Immune Response, & Recommendations

COVID-19 in Three Parts: Virus Biology, Our Immune Response, & Recommendations

In the ongoing COVID-19 pandemic crisis, social media and mainstream medical media are mainly focusing on the virus epidemiology (incidence and control) and not so much on the virus biology and clinical issues relevant to the severity of the COVID-19 driven illness.

Therefore, I have pulled together published data and break down the information regarding the virus into three parts.
1. Biology of the coronavirus
2. Immune mechanisms involved in response to coronavirus
3. Common sense approach to COVID-19 prevention and therapy

The information in parts one and two are very technical—a summary of each section will appear at the beginning of each part that provides the main points of interest.

PART 1. Making Sense Out of Chaos

Summary of Part 1
COVID-19 belongs to the group of highly pathogenic coronaviruses. The highly pathogenic coronaviruses infect the lower respiratory tract and cause severe pneumonia, which sometimes leads to fatal acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), resulting in high morbidity and mortality.

The main mechanism associated with the development of ALI and ARDS is a cytokine storm, which includes overproduction of proinflammatory cytokines.

People with chronic conditions, such as diabetes, congestive heart failure, liver cirrhosis and renal insufficiency among others are at risk of having more severe COVID-19 associated disease.

Despite the obvious high virulence of COVID-19 to humans, the ultimate outcome of the COVID-19 infection is defined by your immune system’s plasticity and its ability or inability to control the cytokine production induced by the virus.

Biology of the Coronavirus

COVID-19 is a coronavirus belonging to the virus family Coronaviridae of enveloped, positive-sense RNA viruses. The coronavirus genome is approximately 31 Kb, making these viruses the largest known RNA viruses. Coronaviruses infect a variety of host species, including humans and several other vertebrates. These viruses predominantly cause respiratory and intestinal tract infections.
Coronaviruses infecting the respiratory tract have long been recognized as significant pathogens in domestic and companion animals and as the cause of mild and severe respiratory illness in humans.

In general, coronaviruses infecting humans can be classified into low pathogenic hCoVs, which include HCoV-229E, HCoVOC43, HCoV-NL63, and HCoV-HKU and highly pathogenic CoVs such as severe acute respiratory syndrome CoV (SARSCoV) and Middle East respiratory syndrome CoV (MERSCoV). By definition, COVID-19 belongs to the group of highly pathogenic coronaviruses.
Coronavirus particle. The virion has a nucleocapsid composed of genomic RNA and phosphorylated nucleocapsid (N) protein, which is buried inside phospholipid bilayers and covered by the spike glycoprotein trimmer (S). The membrane (M) protein (a type III transmembrane glycoprotein) and the envelope (E) protein are located among the S proteins in the virus envelope.

coronavirus particle

Image source: Journal of Medical Virology

Low pathogenic hCoV infect upper airways and cause seasonal mild to moderate cold-like respiratory illnesses in healthy individuals. In contrast, the highly pathogenic hCoVs (pathogenic hCoV or hCoV hereafter) infect the lower respiratory tract and cause severe pneumonia, which sometimes leads to fatal acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), resulting in high morbidity and mortality.

Recent identification of SARS-like coronaviruses in bats and MERS-CoV in domesticated camels makes it likely that these viruses will continue to cross species barriers and cause additional outbreaks in human populations. These highly pathogenic hCoVs cause a wide spectrum of clinical manifestations in humans, with a large fraction of patients developing short period of moderate clinical illness and a small but a substantial number of patients experiencing severe disease characterized by ALI and ARDS.

The disease severity in pathogenic hCoV infections is influenced by several factors such as initial viral titers in the airways as well as the age and comorbid conditions of the infected individual. While younger individuals below 18 years experience mild-to-moderate clinical illness, elderly individuals exhibit worse outcomes after infection with SARS-CoV or MERS-CoV. Also, individuals with comorbid conditions such as diabetes, morbid obesity, congestive heart failure, and renal failure among others experience severe disease.
Clinicopathological studies from humans who died of SARS and studies in animal models suggested that coronavirus-dysregulated immune response results in an exuberant inflammation and lethal disease.

The clinical course of SARS presents in three distinct phases. The initial phase was characterized by robust virus replication accompanied by fever, cough, and other symptoms, all of which subsided in a few days. The second clinical phase was associated with high fever, hypoxemia, and progression to pneumonia-like symptoms, despite a progressive decline in virus titers towards the end of this phase. During the third phase, ∼20% of patients progressed to ARDS, which often resulted in death. Because of a progressive decline in virus titers, the third phase is thought to have resulted from exuberant host inflammatory responses.

The most common clinical manifestations of MERS include flu-like symptoms such as fever, sore throat, nonproductive cough, myalgia, shortness of breath, and dyspnea, which rapidly progress to pneumonia. Other atypical presentations include mild respiratory illness without fever chills, wheezing, and palpitations. MERS-CoV in humans also causes gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea. The majority of MERS patients with dyspnea progress to develop severe pneumonia and require admission to an intensive care unit. Although most healthy individuals present with mild-moderate respiratory illness, immunocompromised and individuals with comorbid conditions experience severe respiratory illness, which often progressed to ARDS. Overall, MERS-CoV caused severe disease in primary index cases, immunocompromised individuals and in patients with comorbid conditions, but secondary cases of household contacts or healthcare workers were mostly asymptomatic or showed mild respiratory illness.

Cytokines and chemokines have long been thought to play an important role in immunity and immunopathology during virus infections.
High serum levels of pro-inflammatory cytokines (IFN-γ, IL-1, IL-6, IL-12, and TGFβ) and chemokines (CCL2, CXCL10, CXCL9, and IL-8) were found in SARS patients with severe disease compared to individuals with uncomplicated SARS. Conversely, SARS patients with severe disease had very low levels of the anti-inflammatory cytokine, IL-10. In addition to pro-inflammatory cytokines and chemokines, individuals with lethal SARS showed elevated levels of IFN (IFN-α and IFN-γ) and IFN-stimulated genes (ISGs) (CXCL10 and CCL-2) compared to healthy controls or individuals with mild-moderate disease.

Similar to SARS, MERS-CoV infection of human airway epithelial cells induces significant but delayed IFN and pro-inflammatory cytokine (IL-1β, IL-6, and IL-8) responses. While MERS-CoV replicates both in naïve and activated human monocyte-macrophages and DCs, only activated T cells support MERS-CoV replication. Recent studies showed elevated levels of serum pro-inflammatory cytokines (IL-6 and IFN-α) and chemokines (IL-8, CXCL-10, and CCL5) in individuals with severe MERS compared to those with mild to moderate disease. High serum cytokine and chemokine levels in MERS patients correlated with increased neutrophil and monocyte numbers in lungs and in the peripheral blood, suggesting a possible role for these cells in lung pathology.

Causes of disproportionally intense virus-mediated immune responses

  • Rapid virus replication
  • hCoV infection of airway and/or alveolar epithelial cells
  • Delayed IFN responses
  • Monocyte-macrophages and neutrophil accumulation

Consequences of cytokine storm

  • Epithelial and endothelial cell apoptosis and vascular leakage
  • Suboptimal T cell response
  • Accumulation of alternatively activated macrophages and altered tissue homeostasis
  • ARDS

Schematic representation of protective versus pathogenic inflammatory responses to pathogenic hCoV infections.

inflammatory response schematic
Image source: Seminars in Immunopathology

Coronavirus Case Studies from China

Recent clinical data on COVID-19 based on recent Chinese publications indicate its strong similarities with SARS-CoV and MERS-CoV infections.

CASE STUDY: OXYGEN SATURATION
Clinical analysis of 69 patients who were hospitalized in Union hospital in Wuhan between January 16 and January 29, 2020 with confirmed COVID-19 infection revealed that the median age of the patients was 42.0 years, and 32 patients (46%) were men. The most common symptoms were fever (87%), cough (55%), and fatigue (42%). Most patients received antiviral therapy (98.5%) and antibiotic therapy (98.5%). As of February 4, 2020, 18 (26.9%) of 67 patients had been discharged, and five patients had died, with a mortality rate of 7.5%.

According to the lowest SpO2 during admission, cases were divided into the SpO2≥90% group (n=55) and the SpO2<90% group (n=14). All 5 deaths occurred in the SpO2<90% group. Compared with SpO2≥90% group, patients of the SpO2<90% group were older, and showed more comorbidities and higher plasma levels of IL-6, IL-10, lactate dehydrogenase, and C reactive protein. The article concluded that COVID-19 appears to show frequent fever, dry cough, and increase of inflammatory cytokines, and induced a mortality rate of 7.5%. Older patients or those with underlying comorbidities are at higher risk of death.

CASE STUDY: COVID-19 PNEUMONIA
Another recent publication described 29 patients with COVID-19 admitted to the isolation ward of Tongji hospital affiliated to Tongji medical college of Huazhong University of Science and Technology. According to the relevant diagnostic criteria, the patients were divided into three groups: mild (15 cases), severe (9 cases) and critical (5 cases). The expression levels of inflammatory cytokines and other markers in the serum of each group were detected, and the changes of these indicators of the three groups were compared and analyzed, as well as their relationship with the clinical classification of the disease.

The main symptoms of COVID-19 pneumonia was fever (28/29) with or without respiratory and other systemic symptoms. Two patients died with underlying disease and co-bacterial infection, respectively. The blood test of the patients showed normal or decreased white blood cell count (23/29), decreased lymphocyte count (20/29), increased hypersensitive C reactive protein (hs-CRP) (27/29), and normal procalcitonin. In most patients, serum lactate dehydrogenase (LDH) was significantly increased (20/29), while albumin was decreased (15/29).

Alanine aminotransferase, aspartate aminotransferase, total bilirubin, serum creatinine and other items showed no significant changes.
CT findings of typical cases were single or multiple patchy ground glass shadows accompanied by septal thickening. When the disease progresses, the lesion increases and the scope expands, and the ground glass shadow coexists with the solid shadow or the stripe shadow. There were statistically significant differences in the expression levels of interleukin-2 receptor (IL-2R) and IL-6 in the serum of the three groups (P<0.05), among which the critical group was higher than the severe group and the severe group was higher than the mild group. However, there were no statistically significant differences in serum levels of tumor necrosis factor-alpha (TNF-α), IL-1, IL-8, IL-10, hs-CRP, lymphocyte count and LDH among the three groups (P>0.05). It was concluded that the increased expression of IL-2R and IL-6 in serum is expected to predict the severity of the COVID-19 pneumonia and the poor prognosis in correspondent patients.

CASE STUDY: CORONAVIRUS CHARACTERISTICS & INCUBATION
And finally, recent data from Beijing. 262 confirmed cases of COVID-19 were analyzed. Among them, 46 (17.6%) were severe cases, 216 (82.4%) were common cases, which included 192 (73.3%) mild cases, 11(4.2%) non-pneumonia cases and 13 (5.0%) asymptomatic cases respectively.

The median age of patients was 47.5 years old and 48.5% were male. 192 (73.3%) patients were residents of Beijing, 50 (26.0%) of which had been to Wuhan, 116 (60.4%) had close contact with confirmed cases, 21 (10.9%) had no contact history.
The most common symptoms at the onset of illness were fever (82.1%), cough (45.8%), fatigue (26.3%), dyspnea (6.9%) and headache (6.5%). The median incubation period was 6.7 days, the interval time from between illness onset and seeing a doctor was 4.5 days. As of Feb 10, 17.2% patients have discharged and 81.7% patients remain in hospital. In our study, the fatality of COVID-19 infection in Beijing was 0.9%.

Coronavirus: Those at Severe Risk

The people who are at greater risk of having severe COVID-19 infection are those with:

  • Congestive heart failure
  • Insufficiently controlled diabetes
  • Recent chemotherapy and ongoing immunosuppression
  • Bone marrow transplantation
  • Adrenal insufficiency
  • End-stage renal disease
  • Emphysema/COPD
  • Poorly controlled asthma
  • Mast cell disorders
  • Interstitial lung disease
  • Scleroderma
  • Sarcoidosis
  • Lupus
  • Poorly controlled Sjogren’s syndrome
  • Chronic therapy with biologic agents
  • Chronic mycoplasmosis and chlamydioidosis
  • Chronic histoplasmosis and Valley fever
  • Cystic fibrosis
  • Chronic bronchopulmonary aspergillosis
  • Active CMV infection
  • Insufficiently controlled vasculitis
  • Advanced fatty liver and liver cirrhosis

In summary, despite the obvious high virulence of COVID-19 to humans, the ultimate outcome of the COVID-19 infection is defined by immune system plasticity and its ability or inability to control the cytokine production induced by the virus.

Therefore, in Part Two we will discuss the main pathways leading to aberrant cytokine production and in Part Three we will summarize the practical steps to control the COVID-19-induced cytokine storm.

REFERENCES:

Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017 Jul;39(5):529-539. doi: 10.1007/s00281-017-0629-x.

Chen L, Liu HG, Liu W, Liu J, Liu K, Shang J, Deng Y, Wei S.[Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):203-208. doi: 10.3760/cma.j.issn.1001-0939.2020.03.013.

Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, Pan P, Wang W, Hu D, Liu X, Zhang Q, Wu J. Coronavirus infections and immune responses. J Med Virol. 2020 Apr;92(4):424-432. doi: 10.1002/jmv.25685.

Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, Tian DS. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020 Mar 12. pii: ciaa248. doi: 10.1093/cid/ciaa248.

Tian S, Hu N, Lou J, Chen K, Kang X, Xiang Z, Chen H, Wang D, Liu N, Liu D, Chen G, Zhang Y, Li D, Li J, Lian H, Niu S, Zhang L, Zhang J. Characteristics of COVID-19 infection in Beijing. J Infect. 2020 Feb 27. pii: S0163-4453(20)30101-8. doi: 10.1016/j.jinf.2020.02.018.

Wang Z1, Yang B2, Li Q1, Wen L1, Zhang R1. Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. 2020 Mar 16. pii: ciaa272. doi: 10.1093/cid/ciaa272.

Part 2. Immune Mechanisms Involved in Response to Coronavirus

Summary of Part 2
Over the last several weeks I have analyzed available research publications on the pathogenesis of severe coronavirus infections and the molecular nature of the virus-induced cytokine storm. My analysis revealed that hyper activation of transforming growth factor beta 1 (TGF-beta 1, TGF-β1) is one of the key events in the pathogenesis of severe coronavirus infection.

Analysis of the previous severe coronavirus infection, SARS-CoV, demonstrated that this infection was associated with remarkable elevation of the TGF-beta1 in plasma and lung tissues in patients with early phases of SARS and contributed to the cytokine storm later during the development of pulmonary complications of this illness. Furthermore, a significant portion of patients who recovered from SARS were later diagnosed with pulmonary fibrosis, a condition with definitive TGF-β1 dependent drive.

The blood level of TGF-β1 can be easily measured via several commercial laboratories, for example LabCorp. If your TGF-β1 level is within a high normal or above normal range, you may consider bringing it down to optimal range before the virus hits you. Outside of the coronavirus-related problems, strong overproduction of TGF-β1 is known to be a marker of mycotoxin (mold)-related human illnesses. Therefore, it is logical to predict that humans exposed to mold are more susceptible to coronavirus-induced complications.

Pathogenesis of COVID-19 and  TGF-beta-1

Over the last several weeks I have analyzed available research publications on the pathogenesis of severe coronavirus infections and the molecular nature of the virus-induced cytokine storm. My analysis revealed that hyper activation of transforming growth factor beta 1 (TGF beta 1) is one of the key events in the pathogenesis of severe coronavirus infection. However, to my surprise I could not find much data regarding the use of this molecule as a therapeutic target in COVID-19. Let’s explore this topic.

Based on the published literature and clinical observations of COVID-19 patients as well as patients with other coronavirus infections, it is obvious that initially the virus attaches to the epithelial cells on the mucous membranes, especially nasal and larynx mucosa, and then enters the lungs. This is why the early, most common symptoms of the infection are fever and cough.

Subsequently, the virus penetrates into the bloodstream causing a virus in the blood (viremia) and attacks internal organs that express ACE2 (Angiotensin Converting Enzyme type 2) receptor, such as lungs, heart, kidneys, and gastrointestinal tract. COVID-19 can be detected in fecal samples, indicating that it affects the liver and is secreted into the gastrointestinal tract via biliary tree.

The described COVID-19 symptoms in complicated cases manifest in two phases. The first, uncomplicated phase typically lasts up to a week. In the second phase, complications, including ARDS, described in Part 1, typically occur after 7-8 days from the onset of the infection. Most of the patients with complicated COVID-19 have enormously elevated levels of IL-6. The lethal outcomes were characterized by significantly elevated levels of neutrophils (type of white blood cell), D-Dimer (presence of blood clots), blood urea nitrogen, and creatinine.

Analysis of the previous severe coronavirus infection, SARS-CoV, demonstrated that this infection was associated with remarkable elevation of the TGF beta-1 in plasma and lung tissues in patients with early phases of SARS and contributed to the cytokine storm later during the development of pulmonary complications of this illness. Furthermore, a significant portion of patients who recovered from SARS were later diagnosed with pulmonary fibrosis, a condition with definitive TGF-β1 dependent drive.

TGF-β1 in Controlling COVID-19

TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and (cell death) apoptosis.

TGF-β1 plays fundamental roles in regulating the differentiation of T cells into effector and regulatory subsets. The effects of TGF-β1 on T cell differentiation are highly concentration-dependent. At low concentrations it drives anti-inflammatory responses (good), and at high concentrations it becomes strongly pro-inflammatory (bad).

Regulation of multiple CD4+ T cell phenotypes by TGF-β
tgf beta regulation

Image source: Annual Review of Immunology

Recently, it was demonstrated that similarly to SARS-CoV, COVID-19 spikes glycoprotein and interacts with CD26, one of the key regulators of TGF-β1 production. Furthermore, TGF-β1 induces strong IL-6 production in human lung fibroblasts creating a strong foundation for the cytokine storm.

Outside of the coronavirus-related problems, strong overproduction of TGF-β1 is known to be a marker of mycotoxin (mold)-related human illnesses. Therefore, it is logical to predict that humans exposed to mold are more susceptible to coronavirus-induced complications.

How to Reduce TGF-β1

It is obvious to predict that pharmaceutical or nutraceutical agents capable of inhibiting TGF-β1 overproduction can benefit COVID-19 infected patients.

Among pharmaceuticals, hydroxychloroquine, an antimalarial drug is known to inhibit TGF-β1 production. An in fact, recent data confirms that this drug benefits patients with COVID-19. Another drug capable of reducing TGF-β1 overproduction in lung fibroblasts is cyclosporine A.

The nutraceutical world offers broader and very efficient options for controlling TGF-β1 overproduction.

These include:

  • Bioflavonoids – my favorite one for this purpose is hesperidine
  • Silymarin (milk thistle extract)
  • Various Chinese Medicinal mushrooms. Last year we introduced a new product, TGF Beta-Norm, to treat TGF-β1 overproduction mainly in patients with toxic mold syndrome. Data from our clinic, based on blood results, demonstrates an excellent activity of this product in lowering of the serum levels of elevated TGF-β1.

The following images are blood test results from our clinic demonstrating the efficacy of our TGF-Beta Norm product at lowering TGF-β1.

tgf beta blood test results
Click here for larger image.

tgf beta blood results

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tgf beta blood results

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What Does This Mean for You?

Here is our practical recommendation:

The blood level of TGF-β1 can be easily measured via several commercial laboratories, for example LabCorp. If your TGF-β1 level is within a high normal or above normal range, you may consider bringing it down to optimal range before the virus hits you.

REFERENCES:

Eickelberg O, Pansky A, Mussmann R, Bihl M, Tamm M, Hildebrand P, Perruchoud AP, Roth M. Transforming growth factor-beta1 induces interleukin-6 expression via activating protein-1 consisting of JunD homodimers in primary human lung fibroblasts. J Biol Chem. 1999 Apr 30;274(18):12933-8.

Li SW, Wang CY, Jou YJ, Yang TC, Huang SH, Wan L, Lin YJ, Lin CW. SARS coronavirus papain-like protease induces Egr-1-dependent up-regulation of TGF-β1 via ROS/p38 MAPK/STAT3 pathway. Sci Rep. 2016 May 13;6:25754. doi: 10.1038/srep25754.

Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection–a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020 Mar 20:1-14. doi: 10.1080/22221751.2020.1746199.

Reinhold D, Bank U, Bühling F, Täger M, Born I, Faust J, Neubert K, Ansorge S. Inhibitors of dipeptidyl peptidase IV (DP IV, CD26) induces secretion of transforming growth factor-beta 1 (TGF-beta 1) in stimulated mouse splenocytes and thymocytes. Immunol Lett. 1997 Jun;58(1):29-35.

Travis MA1, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol. 2014;32:51-82. doi: 10.1146/annurev-immunol-032713-120257. 

Vankadari N, Wilce JA. Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect. 2020 Mar 17;9(1):601-604. doi: 10.1080/22221751.2020.1739565.

Zhou Z, Kandhare AD, Kandhare AA, Bodhankar SL. Hesperidin ameliorates bleomycin-induced experimental pulmonary fibrosis via inhibition of TGF-beta1/Smad3/AMPK and IkappaBalpha/NF-kappaB pathways. EXCLI J. 2019 Aug 29;18:723-745. doi: 10.17179/excli2019-1094.

Zhu Y, Li J, Bai Y, Wang X, Duan N, Jiang H, Wang T, Wang W. Hydroxychloroquine decreases the upregulated frequencies of Tregs in patients with oral lichen planus. Clin Oral Investig. 2014 Nov;18(8):1903-11. doi: 10.1007/s00784-013-1176-z.

Part 3. Practical Recommendations for Prevention of Coronavirus

These are recommendations based on my research, it is up to you to take the information and make decisions that are best for your situation.

Protective Devices
Start wearing physically protective devices: face mask if you anticipate close contact with other humans and eye glasses (remember…the virus can enter your nose via your eyes – and your eyes are connected to your nasal cavity through the nasolacrimal duct).

Negative Ion Generators
It is a good idea to wear personal negative ion generators which reduce up to 90% of your chances of contracting various respiratory infections. The best brands have a very low ozone emission rate. From my standpoint, the best available brand is Air Tamer.

Xylitol nasal spray
Xylitol has a broad-spectrum antiviral and anti-inflammatory activities with minimal side effects. Several brands of xylitol-based nasal spray are available on Amazon. Use it every 4-6 hours and especially when you anticipate new human-to-human contact.

Dietary Supplements

Mucosal Immune Response
You may consider using supplements that stimulate protective mucosal immune response, especially IgA production.

In our practice, we recommend:
Epicor
Mannan Oligosaccharides (MOS

Anti-viral Activity
Also, you may consider using herbal preparations with broad-scope anti-viral activity including:
Andrographis
Lomatium
Berberine
Artemisia annua (Artemisinin).
Note: You need to be completely off alcohol if taking Artemisinin.

High TGF-β1
As discussed in Part Two, if your TGF-β1 blood levels are high, we recommend daily use of:
Citrus-derived Bioflavonoids
Milk Thistle Extract
TGF Beta-Norm

Thoughts on hydroxychloroquine (Plaquenil)
Recently, more and more data indicate that aminoquinolines, such as chloroquine phosphate and hydroxychloroquine can be used for prevention and therapy of COVID-19 infection. A few clinical trials in China have shown chloroquine phosphate, an aminoquinoline used in malaria treatment, to be effective against COVID-19 at a dose of 500 mg/d.

Chloroquine acts by increasing the pH of intracellular vacuoles and altering protein degradation pathways through acidic hydrolases in the lysosomes, macromolecule synthesis in the endosomes, and post-translational protein modification in the Golgi apparatus.
In macrophages and other antigen-presenting cells, chloroquine interferes with the antigen processing, thereby achieving an anti-rheumatic response.

Studies have demonstrated that chloroquine also confers its considerable broad-spectrum antiviral effects via interfering with the fusion process of these viruses by increasing the pH.

Additionally, it alters the glycosylation of the cellular receptors of coronaviruses. Hydroxychloroquine, a less toxic aminoquinoline, has an N-hydroxy-ethyl side chain in place of the N-diethyl group of chloroquine.

Remember, this is a drug, not a supplement. Administration should be done under strict physician supervision by physicians who have sufficient experience in dealing with these drugs (mainly rheumatologists).

If you start experiencing symptoms suspicious for COVID-19 infection, go to the hospital without delay. There are quite a few drugs which can make a difference in the recovery from complicated COVID-19, including steroids, low molecular weight heparin, DMARDs (Disease Modifying Anti-Rheumatic Drugs), biologics targeting IL-6, intravenous immunoglobulins, antiviral products etc.

In the right hands, the mortality of complicated COVID-19 infection can be significantly minimized.

REFERENCES:

Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z, Zhong W, Wang M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020 Mar 18;6:16. doi: 10.1038/s41421-020-0156-0.

Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines Against Coronavirus Disease 2019 (COVID-19): Chloroquine or Hydroxychloroquine. Int J Antimicrob Agents. 2020 Mar 16:105945. doi: 10.1016/j.ijantimicag.2020.

Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother. 2020 Mar 20. pii: dkaa114. doi: 10.1093/jac/dkaa114.



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