- 24–72 h after TCZ administration
- 10 days after TCZ administration
- Patient characteristics
- Laboratory findings
- Methods
- Discussion

Outcomes among 100 severe COVID-19 patients in Brescia, Italy during 10-day follow-up after Tocilizumab (TCZ) infusion

Figure illustrating how Tocilizumab calms the inflammatory storm by blocking IL-6 receptors

- Patients with severe cases of COVID-19 were given tocilizumab
- Tocilizumab lowered the patients’ body temperature, this returning the fever to normal (after 1 day)
- 15/20 patients required less oxygen therapy (after 5 days)
- The lymphocyte count (in peripheral blood) in about half the patients returned to the normal range
- Lowered C-reactive protein to a safe level in 16/19 patients
- All the patients were discharged after approximately 15 days


Severe COVID-19 cases and the impact of tocilizumab

- Common toxicities of TCZ include nasopharyngitis, headaches, hypertension, increased levels of aspartate aminotransferase, infusion related reactions and an increase in upper respiratory tract infections 
- Major toxicities of TCZ include hematologic effects, hepatotoxicity, gastrointestinal perforations, and hypersensitivity reactions 

Toxicities of TCZ

A retrospective observational study at 13 hospitals in New Jersey was conducted to compare the clinical outcomes in individuals infected with COVID-19 who received tocilizumab (TCZ) to infected individuals who did not receive TCZ.  Hospital-related mortality was the primary endpoint established for the study.  All 630 patients included in the study required support from the intensive care unit (ICU).  420 patients did not receive TCZ and 210 patients did receive TCZ.  

49% of the patients who received TCZ died and 61% of patients who did not receive TCZ died.  A multivariable Cox regression analysis was conducted which revealed an association between getting TCZ and lower hospital-related mortality.  Patients who needed support from a ventilator and patients who were under the age of 65 showed an especially favorable decrease in hospital-related mortality upon receiving TCZ.  Additionally, patients with concentrations of 15 mg/dL or above of C-reactive protein who received TCZ also especially exhibited a favorable decrease in hospital-related mortality.  

Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study

This case report was conducted on a 65 year old man with stage IV lung adenocarcinoma being treated with chemo-immunotherapy who developed COVID-19 pneumonia.  The patient was hospitalized and received therapy and additional oxygen support, but his clinical conditions did not get better.  However, upon administering two doses of tocilizumab to the patient, an immediate improvement in clinical conditions was observed.  The patient's level of C reactive protein decreased significantly from 212 mg/dl to 37 mg/dl, his ratio of arterial oxygen partial pressure to fractional inspired oxygen improved, and additional required oxygen supplementation decreased gradually.  There were no acute side effects that occurred.  The patient was eventually discharged.
 

Case Report of Tocilizumab for COVID-19 Pneumonia in a Non Small Cell Lung Cancer Patient Treated with Chemo-Immunotherapy

A cohort study of 778 patients with COVID-19 in a hyperinflammatory state was conducted to investigate the effect of treatment with tocilizumab and corticosteroids on intubation and death.  The patients were categorized into the following exposure groups: tocilizumab treatment, treatment with pulse dose of corticosteroids (PDC), treatment with intermediate-high dose of corticosteroids (IHDC), combination therapy of both corticosteroids and tocilizumab, and no treatment.
- 11.4% of 88 patients treated with tocilizumab were either intubated or died.  

- 23.1% of 117 patients who received IHDC were either intubated or died.  

- 15.4% of 78 patients who received PDC were either intubated or died.  
- 25.6% of 151 patients who received combination therapy were either intubated or died.  

- 21.1% of 344 patients who did not receive treatment were either intubated or died.

- Treatment with tocilizumab alone was associated with a reduced hazard of death and intubation.  

- Treatment with PDC appeared to be associated with a reduced risk of death, but the results were not consistent.  

- No significant association was detected between IHDC treatment or combination therapy and death/intubation.  

Treatment with Tocilizumab or Corticosteroids for COVID-19 Patients with Hyperinflammatory State

Tocilizumab (TCZ) inhibits Interleukin-6 (IL-6), a mechanism that may mitigate the extreme inflammatory response among COVID-19 patients. Its application has been investigated across severe cases and hyperinflammatory states to assess its impact on fever reduction, oxygen requirements, and mortality, as well as to monitor potential toxicities.

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- Amlodipine
- Apilimod
- Arbidol + lopinavir/ritonavir 
- Azithromycin
- Azithromycin+Hydroxychloroquine
- Camostat mesylate
- Chloroquine
- Chloroquine + macrolide (Azithromycin or clarithromycin)
- Clofazimine
- Colchicine
- Corticosteroids 
- Diltiazem
- Dexamethasone
- Famotidine
- Favipiravir
- Felodipine 
- Heparin
- Hydroxychloroquine
- Interferon-α2b 
- Lopinavir-Ritonavir
- Nifedipine
- Nitazoxanide
- Oseltamivir
- Propolis
- Rapamycin
- Remdesivir
- Ribavirin
- Tocilizumab
- Verapamil
- Statin
-Tofacitinib

Use of existing drugs to mitigate COVID-19

Immunomodulatory agents which directly targets cytokines involved in COVID-19 also have the potential to lower hyperinflammation in severe cases, which is important when elevated levels of IL6 in the blood has proved to be a predictor for fatal outcomes in COVID-19 patients. Tocilizumab, an antibody which blocks IL6 has been recommended for patients with severe or critical illness, extensive lesions in bilateral lungs, and confirmed elevated levels of IL6. A study on 20 patients with severe COVID-19 illustrated reduction in fever and lung lesion opacity and recovery of percentage of peripheral blood lymphocytes after treatment with tocilizumab. 

Tocilizumab and COVID-19

The IL-6 receptor is a proposed target for treatment because IL-6 is responsible for inducing the cytokine storm. Tocilizumab is an anti-IL-6 receptor antibody used to treat certain forms of arthritis. In China, it has been demonstrated to reduce fever and improve respiratory function in patients with severe COVID-19. Sarilumab is another anti-IL-6 receptor antibody treatment option that binds and blocks IL-6 recptors.

Blocking IL-6 Signaling 

Remdesivir, an antiviral drug developed by Gilead Sciences, is undergoing various clinical trials to assess its effectiveness in treating COVID-19. Preliminary studies suggest high expectations for drug efficacy and it has been authorized to treat severe infections in the U.S. and Japan.

- Early randomized trials are unable to provide evidence for reducing time to clinical improvement, clearance of virus, or mortality
- Adverse health effects
- Results concerning Remdesivir benefits 
- Availability of Remdesivir 
- Global production of Remdesivir 
- Global clinical trials map
- Intracellular processing of Remdesivir 
- Toxicities of Remdesivir 

Findings about use of Remdesivir as COVID-19 intervention

This combination of drugs does not appear to improve COVID-19 outcomes and may increase risk of negative outcomes.

- findings in support
- findings opposed
- findings indicate no significant difference in comparison to standard care 

Azithromycin (AZM) + Hydroxychloroquine (HCQ) as treatment for COVID-19

There is insufficient evidence that this therapy improves COVID-19 outcomes and may increase risk of other negative outcomes

-Studies in favor
- Studies opposed

Chloroquine + macrolide (Azithromycin or clarithromycin) as a treatment for COVID-19

Anticoagulants like heparin may improve outcomes in COVID-19 patients. Many patients exhibit unusual clotting patterns that may be alleviated by use of anticoagulants.  Heparin has been shown to directly bind to the S1 subunit of SARS-CoV-2 S protein which may interfere with its ability to infect cells.

Heparin as a treatment for COVID-19

Interferon-α2b is a broad spectrum anti-virals responsible for having direct inhibitory effects on viral replication. In addition, IFN-α2b promotes an immune response in order to clear a viral infection.

- Findings in support 
- Finding opposed 

Interferon-α2b Treatment for COVID-19

Dexamethasone is a steroid evaluated for use in improving outcomes for COVID-19 patients through mitigating the inflammatory response during infection.

- 28-day mortality and other clinical outcomes in a randomized controlled trial of patients in the UK through the RECOVERY project
- Financial benefits 

Dexamethasone as a treatment for COVID -19

Arbidol is an antiviral drug that binds to the antigenic protein hemagglutinin and prevents host cell adhesion and membrane fusion and is used to treat influenza. Lopinavir and ritonavir are HIV protease inhibitors that target 3CL protease. 

- Combined therapy of arbidol and lopinavir/ritonavir, rather than lopinavir/ritonavir only, have shown to improve COVID-19 outcomes significantly.
- Arbidol monotherapy may be superior to lopinavir/ritonavir in treating COVID-19 
- Toxicities of Arbidol 
- Toxicities of Lopinavir/Ritonavir 
- Scaffold morphing of arbidol to create analogues for treatment of COVID-19


Arbidol + lopinavir/ritonavir as treatment for COVID-19

Ivermectin+Azithromycin+Hydroxychloroquine treatment was shown to result in a better cure rate and shorter hospital stay compared to control.
- groups used
- results demonstrating better cure rate
- results demonstrating shorter hospital stay
- important considerations

Ivermectin+Azithromycin+Hydroxychloroquine Treatment for COVID-19

The purpose of this drug is to hinder the viral RNA polymerase that is dependent on RNA. There is a lack of data for the activity of ribavirin with COVID-19; therefore, its effect must be studied further. There are also safety concerns for this drug. The combination of this inconclusive data and the safety concerns for Ribavirin give it limited merit for treating COVID-19. 

Ribavirin as a treatment for COVID-19

This drug is an antiviral used to treat the flu. It has yet to show any in-vitro activity against COVID-19. Therefore, it is not a likely treatment for the novel coronavirus. 

Oseltamivir as a treatment for COVID-19


This drug has had in vitro activity against MERS and SARS-CoV-2. Due to its antiviral activity, immunomodulatory effects, and safeness, it is a potential treatment option for COVID-19. More research still needs to be done though with this drug. 

Nitazoxanide as a treatment for COVID-19

This drug works by hindering the host serine proteins, TMPRSS2, thus prohibiting the nCoV cell entry in vitro. Future research needs to be done though with this drug to indicate if it can be a COVID-19 treatment. 


Camostat mesylate as a treatment for COVID-19


This drug works by hindering the viral RNA polymerase, thus stopping viral replication. It requires doses at the higher end of the dosing range to tread COVID-19. Overall, it is well tolerated, but it may have some mild effects. With limited clinical experience for treating COVID-19, Favipiravir is not accessible in the US for clinical use. 

- Toxicities of Favipiravir 
- Favipiravir mechanism of action 

Favipiravir as a treatment for COVID-19

Corticosteroids are used to minimize host inflammatory responses in the lungs that can have damaging effects on the lungs and respiratory system. The corticosteroids, however, can cause delayed viral clearance and a larger risk of secondary infection. The evidence for the use of corticosteroids with COVID-19 is also limited. Due to their potential harm and the lack of proven helpfulness, it is overall not recommended to use corticosteroids on COVID-19 patients. 
Studies have shown that using corticosteroids has reduced deaths by 35% in ventilated patients and by 20% among those receiving oxygen only compared with those in the standard care group. In addition, 93% improvement in the intervention group in days when organ support was not needed.


Corticosteroids as a treatment for COVID-19

Many researchers believe that antibodies from recovered COVID-19 patients could be useful with free virus and infected cell immune clearance. Because more safety and efficacy trials need to take place before immunoglobulin therapy is used as a COVID-19 treatment, on March 24th, 2020 the FDA requested emergency investigational new drug application and screener donors for COVID-19 containing plasma. 

Immunoglobulin Therapy as a treatment for COVID-19

Due to a lack of clinical trials with interferon and conflicting in-vitro and animal data with the drug, interferon cannot be recommended as a treatment for COVID-19 currently. 


Interferon

In a study from France, 12 patients in stage 2b or 3 COVID-19 associated pneumonia were treated with i.v. anakinra and compared to 10 patients receiving standard-of-care treatment. Those within the experimental group significantly improved clinically, experienced no deaths, and experienced decreased usage of mechanical ventilation. The main drawback of the study is the small sample size.

Application of Anakinra to Treat Inflammation-Associated Respiratory Failure in COVID-19

Remdesivir is a nucleotide analog that inhibits viral RNA-dependent RNA polymerase (RDRP) and has strong potential to be a therapeutic for COVID-19. 
Replication of the single-stranded RNA genome of SARS-CoV-2 depends on an RDRP. Remdesivir is a prodrug that, after metabolized to remdesivir triphosphate, acts as an analog of ATP, competing for incorporation by RDRP and interfering with viral RNA replication.

There have been successful case reports for the drug’s use against COVID-19, and clinical trials are continuing to evaluate its safety and efficacy. In fact, the National Institution of Health (NIH) is currently conducting an adaptive, randomized, double-blind placebo-controlled trial with remdesivir. The drug at this time is not currently FDA approved. Therefore, it can only be obtained by compassionate use, expanded access, or enrollment in a clinical trial.  


Remedesivir may reduce time for clinical improvement and decrease mortality. It has no effect on need for ventilation or length of hospital stay.

Remdesivir as a treatment for COVID-19


- Findings in support of using HCQ for COVID-19 treatment
- Findings opposed to use of HCQ for COVID-19 treatment 
- HCQ Mechanism of action
- Toxicities of HCQ

Findings Related to the Use of Hydroxychloroquine (HCQ) as treatment for COVID-19

Hydroxychloroquine (HCQ) is a drug that is thought to prevent the SARS-CoV-2 virus from entering host cells through inhibiting the glycosylation of host receptors, proteolytic process, and endosomal acidification.  Safer and more potent in antiviral properties than aminoquinolines chloroquine, HCQ has been widely used for the treatment of malaria and rheumatic diseases. Due to its anti-inflammatory and antiviral effects, some sources also claim it can serve as effective treatment for COVID-19. On March 30, 2020, the US FDA issued an Emergency Use Authorization, which suggested using these drugs for patients with pneumonia, and after this event, HCQ has been widely used to treat COVID-19 patients around the world. However, no robust clinical studies have supported the effectiveness of this treatment.

Hydroxychloroquine as Treatment for COVID-19

Previously used drugs approved by the FDA have been repurposed in order to be tested against COVID-19. However, clinical trials are underway for several anti-malarial drugs in order to test their effects against the disease.

In silico approaches that are currently used for drug repurposing, including molecular docking, molecular dynamics, and computational chemistry, constitute valuable tools to aid preclinical and clinical studies of nanomaterials directed for disease treatment. 


Drug re-purposing against COVID-19

Famotidine, a histamine-2 receptor antagonist, is a widely available, cheap over the counter drug. It is currently being investigated as a treatment for COVID-19. Computer simulations have identified a 3-chymotrypsin-like protease as a potential target for famotidine in the fight against COVID-19.  

- A retrospective cohort study of non-hospitalized COVID-19 patients taking Famotidine

Famotidine as a treatment for COVID-19 

Statin inhibits HMG-CoA reductase and is used to lower cholesterol. It has anti-inflammatory and immunomodulatory properties and also increases the cellular expression of ACE2. Further studies should be conducted to learn about the full effects of this drug.

Statin as a treatment for COVID-19

Chloroquine is a drug that is thought to prevent the SARS-CoV-2 virus from entering host cells through inhibiting the glycosylation of host receptors, proteolytic process, and endosomal acidification.  There is current no strong evidence to support this hypothesis, and unfavorable effects have been observed in COVID-19 patients taking the drug.   

Chloroquine as Treatment for COVID-19

Amlodipine is a dihydropyridine calcium channel blocker that is commonly used to treat hypertension. Also, amlodipine has shown to be a safe and effective pulmonary vasodiltor in patients with chronic obstructive pulmonary disease and has shown to lead to an improvement in the right heart function. This drug is currently undergoing clinical trials to test its effectiveness against coronavirus. 

- A retrospective review of elderly COVID-19 patients receiving either amlodipine or nifedipine to investigate effects on mortality, hospitalization, and overall progression of the disease

Amlodipine as a treatment for COVID-19 treatment 

Nifedipine, a dihydropyridine calcium channel blocker, is widely used to treat hypertension. Studies have shown that nifedipine can increase pulmonary vasodilation without lowering arterial oxygenation levels or causing systemic hypotension in patients that experience pulmonary hypertension from chronic airflow limitation. Nifedipine is currently being investigated as a treatement for COVID-19 

- A retrospective review of elderly COVID-19 patients receiving either amlodipine or nifedipine to investigate effects on mortality, hospitalization, and overall progression of the disease


Nifedipine as a treatment for COVID-19

In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. 

Lopinavir-Ritonavir as a treatment for COVID-19

Rapamycin, also commonly known as sirolimus, is an FDA-approved antibiotic that has proven to be effective in preventing immunosuppressive and antiproliferative properties for diseases such as tuberous sclerosis, psoriasis, and malignancy.

In fact, Dr. Nir Barzilai, a professor at the Albert Einstein College of Medicine, claims that “rapamycin could decrease severity of coronavirus in the elderly by 50%.”


Rapamycin as a Treatment for COVID-19

Apilimod, also known as LAM-002A is an anti-cancer drug that is viewed to have high potential in effectively treating COVID-19.

In fact, Dr. Sumit Chanda, a lead investigator at the Sanford Burnham Prebys Medical Discovery Institute claims that apilimod is one of the top candidates to represent a treatment option for COVID-19. 


Apilimod as a Treatment for COVID-19

- Propolis is a compound produced by honey bees that has been widely used as an immune booster and antiviral compound. Multiple aspects of propolis demonstrate its potential as an effective treatment for Covid-19. 

Findings about use of Propolis as a therapeutic treatment for Covid-19

Tocilizumab (TCZ) as a Treatment for COVID-19

Azithromycin (AZM) appears to have no significant effect on COVID-19 outcomes, but its use does not increase the risk of other negative health outcomes in patients.

Azithromycin (AZM) as treatment for COVID-19

There is insufficient evidence demonstrating that chloroquine is an effective treatment for COVID-19. Furthermore, its use as a therapeutic intervention may increase the risk of negative clinical outcomes in patients.

Chloroquine as a COVID-19 Therapy

Clofazimine, an FDA-approved drug traditionally used to treat leprosy, is undergoing clinical evaluation as a potential repurposed treatment for COVID-19.

Clofazimine as a Treatment for COVID-19

Siltuximab is an inhibitor of soluble IL-6 receptors via its action as a chimeric human-mouse monoclonal antibody. It has been approved for the treatment of multicentric Castleman disease.

- Outcomes among 30 patients at Azienda Socio Sanitario Territoriale Papa Giovanni XXIII Hospital in Bergamo, Italy

Siltuximab as a Treatment for COVID-19

Sarilumab is a competitive inhibitor of Interleukin-6 (IL-6) through its action as a anti-IL-6 receptor monoclonal antibody. Like tocilizumab, it can inhibit both the cis and trans transduction pathways of IL-6 signaling since it can inhibit both membrane-bound and soluble IL-6 receptors. However, sarilumab has a higher affinity than tocilizumab.

- Outcomes among 8 patients at Hospital San Giovanni di Dio in Florence, Italy

Sarilumab as a Treatment for COVID-19

Aged garlic extract increased IL-10 In peripheral blood monocytes by inhibiting TNF-a and IL-6, which are inflammatory cytokines that play a key role in the pathogenesis of SARS-CoV-2. 

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