Seasonal COVID-19 Outbreaks

Today, Dr. Anthony Fauci warned that the SARS-CoV-2 virus can have a seasonal infection cycle.

There have been numerous reports and some correlative studies that suggest that coronavirus will die down in the summer in the United States as the weather gets warmer.

However, Dr. Fauci mentioned that we are starting to notice outbreaks of COVID-19 in countries in the southern hemisphere. As these countries go into their winter season, Dr. Fauci mentions that it will be inevitable that we will face another coronavirus infection outbreak in the fall. More details are available here.

The current COVID-19 pandemic has outbreaks along the same latitude line, suggesting that there is an optimal temperature and humidity range for spreading coronavirus (Sajadi et al. SSRN 2020).

Sajadi et al. SSRN 2020.

Sajadi et al. showed that virus transmission was significant in cities with an average temperature between 5 and 10 degrees Celsius and a specific humidity between 2 and 7 g/kg.

Sajadi et al. SSRN 2020.

Based on this, they predicted that the cities most likely to be affected by COVID-19 in March to April, notably London, Berlin, and New York. This is exactly what we have noticed, where these cities have been hit the hardest by the disease.

Sajadi et al. SSRN 2020.

These areas are exactly where the cases have been rising the fastest.

Source: NYTimes. March 26, 2020
Source: https://nextstrain.org/ncov

However, the concerning part of this graph is that we are starting to see outbreaks in Australia, Brazil, and Democratic Republic of the Congo, southern hemisphere countries about to enter into their winter season.

Sajadi et al. speculated that perhaps like the 2003 SARS-CoV virus, the current pandemic may not sustain itself in the summer and may disappear. However, the increasing outbreaks in the Southern Hemisphere may lead to the creation of seasonal peaks just like influenza.

The influenza virus is extremely at adept at evading the immune system and creating new mutant strains. Consequently, the antibodies we make against the influenza virus in one year may not be effective for the mutant influenza virus the next year. We are more likely to get sick from influenza n the winter months, when we are often indoors, in crowded areas with ambient temperature and indoor heating, and more likely to air travel. This is why we are recommended to get yearly flu vaccine shots.

We already know that COVID-19 is rapidly evolving and mutating, with some strains more virulent than others. Just like influenza, the coronavirus may persist at lower levels in tropical regions and then rise again next fall. We may face a grim reality in which we face yearly coronavirus outbreaks.

Splitting Ventilators for Multiple Patients

The world needs ventilators to treat COVID-19. Governor Andrew Cuomo this week mentioned in every media outlet that New York needs 30,000 ventilators but the state only has 11,000 at present. Yesterday, Governor Cuomo mentioned that New York will be trialing splitting ventilators for use in multiple patients.

On Twitter, you can find several images of split ventilators in the hospital as below.

You can also find many tutorials about how to create a split ventilator apparatus on YouTube.

Apparatus for Split Mechanical Ventilator

The initial setup for splitting a mechanical ventilator was first described by Neyman and Babcock. Source: https://onlinelibrary.wiley.com/doi/epdf/10.1197/j.aem.2006.05.009.

The inspiratory limb coming out of a ventilator needs to be split into distinct limbs using a T-tube (image below). Similarly, the expiratory limb coming back into the ventilator needs a similar T-tube attachment. You can split the T-tube one more time to subsequently ventilate four distinct lungs at a time. Theoretically, you can keep splitting these adaptors to provide ventilation to more people.

Source: Neyman and Babcock. Academic Emergency Medicine 2006.

In their initial experiments, Neyman and Babcock ventilated lung simulators using both volume control and pressure control settings. They were able to observe roughly equivalent excursion in all lung models without respiratory stacking or airway pressures exceeding 35 mm H2O.

Animal Experiments with Split Ventilators

Paladino et al. used this split apparatus to provide simultaneous ventilation to four sheep. Source: https://www.resuscitationjournal.com/article/S0300-9572(07)00582-5/fulltext.

In their experiments, they employed volume controlled ventilation with a respiratory rate of 16 breaths/min, tidal volume of 6 ml/kg, PEEP of 5 cm H2O, and FiO2 of 100% oxygen. They noted that simultaneous ventilation is feasible in a 12 hour setting, but required frequent repositioning and monitoring to maintain appropriate oxygen and carbon dioxide levels (figures below).

Source: Paladino et al. Resuscitation 2008.
Source: Paladino et al. Resuscitation 2008.

Challenges for Simultaneous Ventilation

Branson et al. studied the efficacy of simultaneous split ventilation in scenarios where patients have different lung compliance and resistance values. Source: http://rc.rcjournal.com/content/57/3/399. To study this, they had 4 test lungs in which the resistance and compliance values were constant (case 1), constant resistance but variable compliance (case 2), variable resistance but constant compliance (case 3), and variable resistance and compliance (case 4).

They attempted both volume control and pressure control ventilation, and measured the degree to which simulated patient lungs received consistent tidal volume. In their experiments, consistent tidal volume between patients was only achieved when the compliance between every patient was constant.

Source: Branson et al. Respiratory Care 2012.
Source: Branson et al. Respiratory Care 2012.

Suggestions for Patient Use

Smith and Brown showed that simultaneous ventilation is feasible in humans. Source: https://www.resuscitationjournal.com/article/S0300-9572(09)00263-9/fulltext.

Dr. Josh Farkas provided some guidelines for how to employ simultaneous split ventilation for the current COVID-19 crisis. https://emcrit.org/pulmcrit/split-ventilators/.

In brief, he recommended:

  • Pressure-cycled ventilation with high PEEP and low driving pressure
  • Locked out ventilator trigger
  • Deep sedation
  • End tidal CO2 monitor in line with endotracheal tube
  • Viral filters to prevent cross contamination

To overcome the challenge of compliance variability, he recommended different ventilator stations depending on severity of lung injury. For example, he suggested to have a station for mild injury (FiO2 50%, PEEP 10 cm, Peak pressure 20 cm), moderate injury (FiO2 60%, PEEP 14 cm, Peak pressure 26 cm) and severe hypoxemic injury (FiO2 100%, PEEP 22 cm, peak pressure 35 cm).

Dr. Matthias Mergeay provided a recommendation for how to titrate ventilation for each patient individually, described more in detail here:

In brief, we add a rotary valve like below to our tubes, which we can modify to increase or decrease our desired pressure.

SISTO-16RGA diaphragm valve
Source: https://www.ksb.com/ksb-en/Products_and_Services/building-services/water_supply/SISTO-Membranventile/

Conclusions

Split mechanical ventilation is feasible. Providing consistently equal tidal volume to patients with different lung compliance values is challenging. Pressure control ventilation is recommended as the ventilation mode to have control over the maximal airway pressure and driving pressure. Individual patient pressures can be titrated using a rotary valve you can buy from Home Depot.

Convalescent Serum to Treat COVID-19

History

Before the advent of antibiotics, physicians treated infectious diseases with serum from other patients who previous recovered from the same illness.

The basic idea is that when people are infected from a pathogen like bacteria, virus, fungi, or parasites, they develop antibodies against that specific pathogen. These antibodies are contained in the plasma or serum of blood, and can be theoretically transferred to someone else to fight the same pathogen. This is called passive antibody transfer, and had been used in the 1890s-1930s to treat a variety of illnesses including pneumonia, meningitis, diphtheria, measles, poliomyelitis, and mumps. At the time, this treatment option was relatively costly since it took a lot of resources to collect serum and inactivate the pathogen, but also came with side effects of serum sickness, characterized by weeks of rash, body aches, and joint pains. After the first sulfanamide drugs and penicillins were discovered in the 1930s-1940s, serum therapy quickly fell out of favor.

In more recent times, people used convalescent serum to fight against emerging pandemics. For example, convalescent serum was used in the Ebola crisis and decreased the fatality rate from 44% to 27.9% (Sahr et al. Journal of Infection 2017).

In light of our current COVID-19 pandemic, doctors and scientists have speculated about whether convalescent serum could be a viable treatment strategy.

Convalescent Serum to Treat Past Coronaviruses

Mair-Jenkins et al. provided a systematic review to assess the evidence of convalescent serum to treat the 2003 SARS pandemic.

In their analysis, this therapy significantly reduced the viral load of SARS, decreased hospital length of stay, and decreased mortality. They suggested that early initiation of treatment is critically important for effective therapy.

Source: Mair-Jenkins et al. Journal of Infectious Diseases 2015.

In Vitro Virus Neutralization of SARS-CoV-2

Zhou et al. examined whether serum from patients who recovered from COVID-19 can be used to neutralize the coronavirus grown in a petri dish. They showed that IgG antibodies collected from patients who recovered from COVID-19 can neutralize the virus at a dilution of 1:40-1:80.

Source: Zhou et al. Nature 2020

Clinical Studies

China has begun convalescent serum therapy on their patients infected with COVID-19 and even sent some serum to Italy.

A recent pilot study from Duan et al. assessed the clinical response to convalescent serum in 19 patients. Although this was not a clinical trial and had many confounding therapies, they showed that patients who received convalescent serum had decreased C-reactive protein, increasing oxygen saturation levels, decreasing RNA viral loads, and decreasing ground glass opacities on CT imaging, all shown below. Importantly, none of the patients who received this therapy had any significant adverse effects.

Source: Duan et al. 2020
Source: https://www.medrxiv.org/content/10.1101/2020.03.16.20036145v1.full.pdf
Source: Duan et al. 2020
Source: https://www.medrxiv.org/content/10.1101/2020.03.16.20036145v1.full.pdf
Source: Duan et al. 2020
Source: https://www.medrxiv.org/content/10.1101/2020.03.16.20036145v1.full.pdf

Shen et al. published a case series of 5 critically ill patients with COVID-19 and ARDS who received convalescent serum therapy. Following transfusion, the patients had improved oxygen saturation, decreased viral loads, normalized body temperature, and improvement of vital signs. These patients were critically ill, and lots of experimental antiviral therapies and steroids were also coadministered. It is really remarkable to see this level of therapeutic improvement so quickly.

Clinical improvement with convalescent plasma in critically ill patients
Shen et al. JAMA 2020.

Logistics of Convalescent Serum Therapy

Casadevall and Pirofski outlined the logistics, benefits, and risks of convalescent serum to treat COVID-19. Source: https://www.jci.org/articles/view/138003#B3

In brief, they recommend this therapy to patients who are at high risk for decompensation. For this therapy to be effective there needs to be

  • A population of donors who recovered from COVID-19
  • Blood banking facilities to process serum
  • Availability of assays to detect SARS-CoV-2 in serum and measure viral neutralization
  • Randomized clinical trials showing efficacy
  • Regulatory compliance

One pharmaceutical, Takeda, is already gearing up infrastructure for this treatment strategy.

Future of Convalescent Therapy

I am personally intrigued by this treatment option as we have a ton of patients who have the illness but will recover without adverse symptoms. This means we will have a ton of serum in the population that can be redirected to help people who are suffering from COVID-19. I do not know if this will be more effective than standard of care supportive therapy, but I am all in favor of anything that can lighten the load of limited ventilators.

New York will be the first state to try this out in the United States.

Source: https://www.nbcnews.com/health/health-care/new-york-will-be-first-state-test-treatment-coronavirus-blood-n1167136

The FDA just approved convalescent serum on March 24, 2020. This is a major breakthrough.

Source: https://www.npr.org/sections/coronavirus-live-updates/2020/03/24/820939536/fda-expedites-treatment-of-seriously-ill-covid-19-patients-with-experimental-pla

More details from the FDA are here:

https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds

The FDA writes: Therefore, given the public health emergency that the expanding COVID-19 outbreak presents, while clinical trials are being conducted, FDA is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of single patient emergency Investigational New Drug Applications (eINDs) for Individual patients under 21 CFR 312.310. 

Airborne Transmission of COVID-19 in the Hospital

There has been a lot of talk about how COVID-19 is spread in the community and how it is spread within a hospital. The current understanding is that in the community, this disease is mostly spread through droplets (i.e. sneezing, coughing, or talking to infected people). One reason this virus may have spread so rapidly and broadly is through droplet transmission between asymptomatic individuals.

In the hospital, healthcare workers are wondering to what extent COVID-19 is an airborne illness, meaning how much of the virus is spread from small virus particles that linger in the air.

This is especially relevant nowadays when there is a massive shortage of personal protective equipment in the hospital as well as confusion about what type of equipment is needed in different settings. Currently, the CDC recommends using an N95 respiratory which filters 95% of airborne particles for protection in scenarios where disease transmission is airborne and a surgical mask when disease transmission is large droplet. Notably, this is different from the Chinese recommendations, which recommended N95 respirators for all inpatient hospital care during the Wuhan epidemic (Source: https://www.alibabacloud.com/universal-service/pdf_reader?spm=a3c0i.14138300.8102420620.dreadnow.6df3647fwVQwvF&pdf=Handbook_of_COVID_19_Prevention_en_Mobile.pdf).

CDC Infographic for N95 vs Surgical Mask
Source: https://www.cdc.gov/niosh/npptl/pdfs/UnderstandDifferenceInfographic-508.pdf

SARS-CoV-2 is Viable in Air for >3 Hours

van Doremalen et al. simulated aerosolization of SARS-CoV-2 virus with a nebulizer and a Goldberg drum apparatus and found that high viral loads remained in the air for more than three hours and that the stability of the virus was similar to the 2003 SARS virus. See: https://www.nejm.org/doi/full/10.1056/NEJMc2004973 for more details. This is significant because we can turn to the medical literature for what lessons we learned from the original SARS outbreak.

Source: van Doremalen et al. NEJM 2020

Lessons Learned from 2003 SARS Outbreak

The 2003 SARS virus was a respiratory disease that also emerged from China. Similar to our COVID-19 pandemic, the 2003 SARS disease also had an incubation time for about a week, was characterized by symptoms of fever, body aches, and cough, and had imaging findings of atypical pneumonia which could progress to ARDS.

The outbreaks of SARS were predominant in healthcare settings with large transmission to nurses, doctors, and hospital visitors. Many frontline healthcare professionals involved with aerosolized procedures contracted SARS and developed serious illness. For example, critical care nurses involved with intubation, suctioning, and nebulizer treatment had a four times increased risk of infection (Loeb et al. Emerging Infectious Diseases 2004. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322898/). SARS transmission was also associated with other procedures like noninvasive pressure ventilation and cardio-pulmonary resuscitation (Siegel et al. CDC 2007 Source: https://www.cdc.gov/infectioncontrol/pdf/guidelines/isolation-guidelines-H.pdf). The healthcare workers who contracted SARS the most were those who did not consistently use personal protective equipment (Gamage et al. Journal of Infection Control 2005. Source: https://www.ajicjournal.org/article/S0196-6553(04)00639-X/fulltext).

Tran et al. summarized all the aerosol generating procedures associated with increased SARS transmission (Tran et al. PLoS One 2012. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338532/). They found that tracheal intubation was the most consistent procedure associated with increased SARS. Statistically significant analysis of the other procedures was limited due to small sample size, but other procedures that had point estimates of increased transmission risk included suction before intubation, manipulation of oxygen masks, bronchoscopy, noninvasive ventilation, chest compressions, and collections of sputum samples.

Tran et al. Plos One 2012.

Summary

The big takeaways that I learned when reading about the 2003 SARS outbreak were that healthcare workers were the most at risk for infection, personal protective equipment and training are needed to decrease transmission of disease, and that extra precaution is needed during aerosol-generating procedures.

What we need now is more personal protective equipment. I agree with Andrew Cuomo’s call for the Federal Government to nationalize the medical supply chain. Without enough supplies, we are sending healthcare workers into a dangerous environment where they can get sick and die from illness.

Indirect Transmission of COVID-19

There has been a lot of talk in the news about how to avoid COVID-19. Recommendations include social distancing, minimizing time in groups, and maintaining at least six feet of distance between people.

While it seems obvious that coronavirus can spread if someone sneezes on you or if someone coughs on their hands and then shakes your hand, one nonobvious way coronavirus can transfer is through indirect contact.

Source: Atkinson et al. WHO 2009.

For example, someone with COVID-19 can sneeze on to their hands and then wipe their hands on a door knob. If you touch that door knob and wipe your face, you have the potential to also get infected with the virus.

Persistence of COVID-19 on Surfaces

Human coronaviruses can remain infectious on inanimate surfaces at room temperature for days. Recently, van Doremalen et al. showed that the SARS-CoV-2 virus remained in aerosols for more than 3 hours, can remain on on plastic and stainless steel for more than 3 days, similar to the 2003 SARS virus. See https://www.nejm.org/doi/full/10.1056/NEJMc2004973 for more details.

Source: van Doremalen et al. NEJM 2020.

Coronaviruses have the capacity to survive on a wide variety of materials including metals, plastics, fabric, paper, wood, glass, stethoscopes, and tissue paper. Ye et al. examined how many objects were contaminated with COVID-19 during the outbreak in Wuhan, China and found that printers, keyboards, door knobs, and medical equipment were frequently contaminated with SARS-CoV-2 RNA. Source: https://www.medrxiv.org/content/10.1101/2020.03.11.20034546v1.full.pdf

Ye et al. 2020
https://www.medrxiv.org/content/10.1101/2020.03.11.20034546v1.full.pdf

They also found that personal protective equipment like gloves and hand sanitizer dispensers frequently contained positive samples of SARS-CoV-2 RNA.

Ye et al. 2020
https://www.medrxiv.org/content/10.1101/2020.03.11.20034546v1.full.pdf

Indirect Transmission

This is particularly problematic because humans inadvertently touch their faces 23 times per hour and contact mucous membranes 44% of the time (Kwok et al, Journal of Infection Control 2014). Source: https://www.ajicjournal.org/article/S0196-6553(14)01281-4/fulltext

We do not have the full estimate of how many people contracted COVID-19 from indirect contact with surfaces, but we do know that in the previous previous 2003 SARS outbreak, some individuals who contracted the virus were hospital cleaners who had no direct contact with patients (Ho et al, Annals of Internal Medicine 2003). Source: https://annals.org/aim/fullarticle/716820.

Solutions

Vigilant hygiene is the solution to prevent unneeded spread of COVID-19.

Kampf et al. showed that surface disinfection with 0.1% sodium hypochloride can reduce coronavirus infectivity more than 1000 fold in less than 1 minute (Kampf et al. Journal of Hospital Infection. 2020). Source: https://www.journalofhospitalinfection.com/article/S0195-6701(20)30046-3/fulltext.

For the general public, the WHO recommends to wash your hands frequently, maintain social distancing, avoid touching eyes, nose, and mouth, and practicing good respiratory hygiene. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public

In the hospital, my personal opinion is that we should avoid unnecessary physical exams, tools, and procedures. Dr. Jeremy Faust got a lot of flak for this recent tweet:

My opinion is that the evidence supports that he is right.

No Robust Evidence for Favipiravir to Treat COVID-19

There has been a lot of hype in media news outlets and twitter about any possible medication that can be repurposed to treat COVID-19. However, in times like these we need to fully evaluate the evidence to discern what is fact and fiction.

One medication that received a lot of excitement in the past couple days is favipiravir, a Japanese antiviral drug that was originally designed to treat influenza. For example, here are the headlines you find if you search twitter for this drug:

Source: Twitter

In this post, I’ll describe the latest research literature I found for favipiravir in COVID-19.

Background

Favipiravir was developed in a joint industry collaboration with Toyama Chemical with the hopes of developing a medication better than Tamiflu (oseltamivir) to treat influenza.

In mice, Takahashi et al. showed that favipiravir is more effective than oseltamivir for lethal influenza and does not easily produce drug-resistant virus strains.

Source Takahashi et al. Antiviral Chemistry and Chemotherapy, 2003

However, favipiravir was found to have significant teratogenic and embryotoxic side effects, so this medication was not recommended for general use, but the Japanese government stockpiled this drug in case they needed it for future influenza pandemics.

Mechanism of Action

Favipiravir is a selective and potent inhibitor RNA-dependent RNA polymerase (RdRp), which halts replication of the viral genome. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC549233/

Favipiravir reduces production of RNA polymerase
Source: Furuta et al. 2005

This is why clinicians and scientists thought that this medication can be repurposed to treat other RNA viruses.

Anti-Viral Activity Against RNA Viruses

Favipiravir has been tried against a variety of RNA viruses including arena-, bunya-, falvi-, and filo- viruses, all of which are without a vaccine or existing effective antiviral therapy. In all of these cases, favipiravir did show mortality improvement in mice infected with virus. Notably, there has been no substantial evidence that showed efficacy for favipiravir in animal models of coronavirus like SARS or MERS. Source: https://www.ncbi.nlm.nih.gov/pubmed/28769016

A summary of the prior uses of favipiravir against other RNA viruses is tabled below. More detail is here: https://www.ncbi.nlm.nih.gov/pubmed/32097670

Source: Shiraki and Daikoku. Pharmacological Therapy 2020.

No Robust Support of Favipiravir in COVID-19

The evidence for favipiravir in COVID-19 has been limited to date.

Wang et al. showed that the selective antiviral activity against COVID-19 in vitro was relatively weak (EC = 62 mM) and came at the cost of significant cytotoxicity. In their experience, Wang et al. showed that remdesivir and chloroquine were far more effective antiviral medications. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054408/

Source: Wang et al. Cell Research 2020

The clinical experience with favipiravir has not been definitive. Most of the reported experiences have been from anecdote and media reports quoting individual doctor experiences, such as the following:

One clinical study I found online showed that favipiravir was not more effective than arbidol, another broad spectrum antiviral drug. Full details are here: https://www.medrxiv.org/content/10.1101/2020.03.17.20037432v1.full.pdf

Source: Chen et al. 2020
https://www.medrxiv.org/content/10.1101/2020.03.17.20037432v1.full.pdf

Another clinical study I found online showed that favipiravir was more effective than lopinavir/rotonavir in treating COVID-19. The authors claimed that patients who received favipiravir had a shorter viral clearance time and greater improvement in chest imaging findings. They excluded all pregnant women and reported minimal adverse side effects with this therapy. More details here: https://www.sciencedirect.com/science/article/pii/S2095809920300631. I personally struggle in interpreting this trial because we recently saw from NEJM that the lopinavir/rotonavir is not better than placebo, so I am not sure how to interpret this research. I would need to see another study to make a claim one way or the other.

Source: Cai et al. 2020
https://www.sciencedirect.com/science/article/pii/S2095809920300631#f0015

Summary

Favipiravir is an antiviral drug that was optimized to treat against influenza. However, there has been no significant evidence showing that this drug is effective against coronavirus, especially considering this drug comes with significant cytotoxic and teratogenic side effects.

We still are awaiting more evidence for favipiravir, but I do not anticipate positive results for this drug given that the in vitro experiments and current clinical experience are not robustly supportive.

Tocilizumab for Treatment of COVID-19 Cytokine Storm

Background

There is growing evidence that the rapid progression from mild to severe symptoms in COVID-19 is due to cytokine storm. During this process, the virus rapidly replicates and activates inflammatory cytokines, which leads to vascular leak, acute lung injury, and acute respiratory distress syndrome.

In August 30, 2017, the FDA approved tocilizumab for cytokine storm syndrome. Tocilizumab is a monoclonal antibody against the interleukin-6 (IL-6) receptor, and IL-6 cytokine has been shown to be a key cytokine responsible for fever and acute phase reactions in inflammation.

Treatment of Severe COVID-19 with Tocilizumab

Recently, Xu et al showed that tocilizumab is effective for treating patients with severe COVID-19 infection. Source: http://www.chinaxiv.org/abs/202003.00026

In their study, 21 patients were treated with tocilizumab. These patients had severe infection, which the authors defined as a respiratory rate > 30 breaths per minute, an oxygen saturation < 93%, and a PaO2/FiO2 ratio < 300 mm Hg. Every patient had elevated IL-6 levels (mean of 132 pg/ml, normal is < 7 pg/ml), CT findings of ground glass opacities with focal consolidation in the peripheral lungs, and elevated C-reactive protein levels (mean of 75 mg/L).

However, patients had dramatic improvement with this medication. After a few days with tocilizumab, patients had a significant reduction in inflammatory marker levels, reduction of fever, reduction of their inspired oxygen requirement, and improvement of their oxygen saturation.

Source: Xu et al. 2020
http://www.chinaxiv.org/abs/202003.00026

Patients also had significant reduction of their abnormal imaging findings on CT. In the figure below, we can clearly see that the amount of ground glass opacification in three patient lungs significantly declined.

Source: Xu et al. 2020
http://www.chinaxiv.org/abs/202003.00026

19/21 of the patients eventually were discharged home. 2 are still hospitalized, but now are in stable condition with improvement of symptoms and without fever.

China Approves Tocilizumab

In light of these results, China’s National Health Commission approved tocilizumab for patients with high IL-6 levels and serious lung damage. These treatment guidelines are available here: http://www.nhc.gov.cn/yzygj/s7652m/202003/a31191442e29474b98bfed5579d5af95.shtml

China National Health Commission Report for Treatment of COVID-19

Italian Experience with Tocilizumab

There have also been positive reports (albeit very limited) in Italy with this medication. In Napoli, three patients were reported to improve with this Toliciumab according to the Dr. Paolo Ascierto, the head of clinical immunology. Source: http://www.ansa.it/english/news/general_news/2020/03/13/3-patients-get-better-on-arthritis-drug_90d4764d-d93f-463e-ab07-168b34b084d0.html

Clinical Trials

Genentech is launching several clinical trials with tocilizumab in the United States, taly, and China. Source: https://www.genengnews.com/virology/coronavirus/genentech-launches-phase-iii-trial-of-actemra-as-coronavirus-treatment/. I’m optimistic that this is another medication that can be used in our global fight against COVID-19.

Cytokine Storm in COVID-19

Background

A cytokine storm is a severe, overreactive inflammatory response, which can lead to multi-organ failure and eventual death. This process occurs when a large number of white blood cells are activated, release inflammatory cytokines, and then create a vicious loop in which more white blood cells are activated. Cytokine storms are associated with a wide number of conditions such as infections, autoimmune diseases, CAR-T therapy, and graft-versus-host disease.

There is accumulating evidence that the progression of COVID-19 to acute respiratory distress syndrome or fulminant myocarditis is through a cytokine storm mechanism.

Coronavirus Infections Lead to Early Cytokine Storm

Human coronaviruses replicate to high viral loads very early after infection. This leads to rapid activation of inflammatory cytokines and recruitment of macrophages and neutrophils into damaged tissue. The result is increased cell death, breakdown of vasculature, and impaired virus clearance.

This leads to acute lung injury which can rapidly progress to acute respiratory distress syndrome. This mechanism is why we see reports of young patients quickly progressing to respiratory failure a couple days after they have their first symptom of coronavirus. More detail about the pathophysiology of cytokine storm in coronaviruses is available here: https://link.springer.com/article/10.1007%2Fs00281-017-0629-x

Early cytokine storm leads to acute lung injury, respiratory failure, and death after coronavirus infection.
Source: Channappanavar and Perlman. Seminars in Immunopathology 2017

Cytokine Storm in Severe COVID-19

There are several reports that suggest now that patients with severe COVID-19 have an inflammatory cytokine storm. Ruan et al. showed that patients who died from COVID-19 have elevated C-reactive Protein and Interleukin-6 levels compared to those who recovered. https://link.springer.com/article/10.1007/s00134-020-05991-x

Source: Ruan et al. Intensive Care Medicine 2020

This was confirmed by Zhou et al, who showed that patients requiring ICU admission had increased levels of IL-6 and CM-CSF, which in turn create more pathogenic Th1 cells, a type of inflammatory white blood cell. Source: https://academic.oup.com/nsr/advance-article/doi/10.1093/nsr/nwaa041/5804736?searchresult=1

Patients with severe COVID-19 infection had greater inflammatory marker levels (IL-6 and GM-CSF)
Source: Zhou et al. National Science Review 2020

Repeated overactive, inflammatory cytokine activation eventually leads to T cell exhaustion, which decreases our ability to fight infection and may be the reason why some infected individuals take so long to recover.

T cell exhaustion after cytokine storm in patients with COVID-19
Source: Zhou et al. National Science Review 2020.

In Zhou et al’s experience, the patients in the ICU with features suggestive of worsening cytokine storm had greater C-reactive protein, lower albumin, greater ALT/AST, and greater lactate dehydrogenase levels. These are relatively easy values we can track daily in patients.

Increased CRP, ALT/AST, LDH and decreased albumin in COVID-19 patients in the ICU
Source: Zhou et al. National Science Review 2020.

Summary

Patients with COVID-19 infection are prone to early cytokine storm, leading to ARDS. We should be on the look out for patients that have elevated inflammatory markers or liver function enzymes.

Remdesivir as Treatment for COVID-19

Gilead’s drug Remdesivir has attracted a lot of attention for its potential therapeutic benefit in combatting COVID-19. In this post, I’ll summarize what we currently know about this drug (as of March 18, 2020).

Background

Remdesivir first hit the news during the Ebola epidemic from 2013-2016. At that time, the United States Army Medical Research Institute of Infectious Diseases showed promising evidence that it blocked the Ebola virus in Rhesus monkeys.

That research is more fully described here: https://www.nature.com/articles/nature17180. Once daily dosing of this drug for 12 days suppressed the Ebola virus, improved clinical disease and pathophysiological markers, and led to 100% survival of monkeys.

Rhesus monkeys with Remdesivir survived from Ebola virus
Source: Warren et al. Nature 2016

In light of these findings, remdesivir was fast tracked through clinical trials, where its safety profile was established, and even used in one human patient with Ebola. Because of its mechanism against RNA viruses, clinicians and researchers supported research for this drug against other infectious diseases.

Mechanism of Action

Remdesivir is a type of nucleotide analog, which contain a sugar molecule, three phosphate groups, and a dummy nucleic acid analog. The basic idea is that during viral replication, a virus needs nucleotides to make viral RNA or DNA and thus more virus. However, if the virus incorporates this dummy nucleotide analog, it cannot form a complete viral genome, so the virus eventually becomes defective and dies.

Below is the molecular profile of remdesivir. This drug mimics an alanine metabolite, and once it gets incorporated into a nucleotide triphosphate, it interferes with RNA-dependent RNA-polymerases leading to premature termination and thus decreases virus RNA production.

Molecular profile of remdesivir.
Source: Warren et al. 2016.
Source: https://www.nature.com/articles/nature17180

Application for Coronaviruses

Back in 2017, scientists were thinking about using remdesivir for human and zoonotic coronaviruses. At that time, scientists were trying to develop therapies against the endemic MERS-CoV virus which was prominent from 2013-2016, but they astutely noted that this therapy is most important for pandemic coronaviruses that may emerge in the future (Sheahan et al. Science Translational Medicine 2017). Source: https://stm.sciencemag.org/content/9/396/eaal3653

In their studies, Sheahan et al. showed that remdesivir successfully inhibited the MERS and SARS coronaviruses at safe doses, was effective in suppressing various animal coronaviruses (bat, pig, camel), and improved pulmonary function in mice infected with SARS virus. Notable figures from their study are below.

Lung tissue restored to normal after treatment with remdesivir in mice with SARS coronavirus.
Source: Sheahan et al. Science Translational Medicine 2017.
Therapeutic and prophylactic treatment with remdesivir improved pulmonary function in mice with SARS coronavirus.
Source: Sheahan et al. Science Translational Medicine 2017.

Application for COVID-19

The big question on everyone’s mind is whether this new drug can be used to combat the COVID-19 pandemic. Wang et al. evaluated the efficacy of this drug in vitro with cells affected with COVID. They remarked that this drug blocked virus infection at low micromolar concentrations and showed high selectivity. My understanding of these experiments is that remdesivir is effective in decreasing viral loads, but may be even more effective if given before the virus is administered in the first place. Source: https://www.nature.com/articles/s41422-020-0282-0/

Remdesivir significantly inhibits virus replication if given pre and post infection.
Source: Wang et al. Nature 2020.

Clinical Experience with Remdesivir

Given these past studies, there have been many clinical arguments favoring the use of remdesivir for COVID-19. In fact, the first case of COVID-19 in the USA was treated with remdesivir for compassionate use after day 7 of pneumonia. This patient’s condition improved the following day without any significant adverse effects. Gilead is now involved with several clinical trials to examine the efficacy of this drug to fight our current pandemic.

A preprint of the first 12 patients with COVID-19 in the USA is now online. https://www.medrxiv.org/content/10.1101/2020.03.09.20032896v1.full.pdf

Three of these patients received remdesivir shown below (patients 6, 8, 9 with the purple shading). My interpretation of this data is that all of these patients benefited from this drug, with increasing oxygen saturation/decreasing oxygen requirement, decreasing fever, and decreasing viral loads.

Patients had transient gastrointestinal symptoms including nausea, vomiting, gastroparesis, or rectal bleeding following administration of remdesivir. 2/3 patients had a significant increase in their liver function enzymes.

Source: https://www.medrxiv.org/content/10.1101/2020.03.09.20032896v1.full.pdf
Black dot: PCR Positive; White dot: PCR Negatve; Gray dot: PCR inconclusive
Red square: Virus isolation succesful; Gray square: virus isolation not successful
Source: https://www.medrxiv.org/content/10.1101/2020.03.09.20032896v1.full.pdf

Obtaining Remdesivir in the United States

Here are the steps it takes to get remdesivir for compassionate use from Gilead:

Source: Twitter

Gilead is now transitioning from compassionate use requests to expanded access programs for this medication as of March 22.

Conclusions

In summary, there are a lot of reasons to be optimistic about remdesivir. I am quite hopeful that these clinical trials will show good results to suppress COVID-19. I do wonder however about antiviral resistance, safety profile, and access to the millions of people across the world who may need this drug.

Chloroquine as Treatment for COVID-19

There has been a lot of speculation in twitter and in news media outlets about whether chloroquine can be used as treatment for COVID.

In this post, I summarize what we know about chloroquine from previous experiments, research reports and tweets.

History

In ancient Peru, indigenous people extracted the bark of the Cinchona tree to fight fevers and chills. This was then introduced in Europe and used to fight malaria. The extracts of this bark were then purified in science laboratories to make quinine and chloroquine. Chloroquine was discovered by Hans Andersag in Bayer labs and then popularized in World War II for its antimalarial purposes.

At present, its most common use is for treatment and prevention of malaria, which is from parasitic infection of red blood cells. Chloroquine also enters red blood cells, binds to heme and becomes highly toxic to the red blood cell, leading to cell lysis. In red blood cells infected by the malarial parasite, this effectively destroys the parasite.

Antiviral Properties

In addition to antimalarial effects, chloroquine has several antiviral effects, more thoroughly described here by Deveaux et al. International Journal of Antimicrobial Agents 2020.

In brief, chloroquine has antiviral activity against RNA viruses such as rabies virus, hepatitis A, Dengue virus, Zika virus, and notably even the 2003 SARS virus, which bears great resemblance to the current COVID pandemic. In vitro, chloroquine inhibits the replication of HCoV-229E in epithelial lung cultures.

Mechanism of Action

Chloroquine’s antiviral properties are through a number of mechanisms.

Fig 1
Red arrows are all the areas in which chloroquine may prevent COVID progression
Source: Deveaux et al. 2020

Chloroquine interferes with viral protein binding to cell receptors, by inhibiting quinone reductase 2, preventing sialic acid production, which is needed for ligand recognition by cells. We know that the current COVID coronavirus infection is mediated through spike protein receptor recognition by angiotensin converting enzyme-2 receptors on lung.

Chloroquine also alters the pH environment which interferes with glycosylation and thus endosomal viral entry.

Finally, chloroquine interferes with post-translational modification of viral proteins which then interfere with proteases and glycosyltransferases. This may be especially relevant to the current COVID virus, which requires serine proteases to enter cells.

Chloroquine in COVID-19

A systematic review for the efficacy of chloroquine in COVID-19 is described here.

In summary, there are six relevant articles regarding its use and there are 23 current clinical trials in process regarding the efficacy of chloroquine.

One research letter from a group of Chinese researchers examined the efficacy of chloroquine to prevent infection multiplicity in vitro with cells infected by COVID, and showed the drug was highly effective in reducing viral replication.

Chloroquine and remdesivir effective in preventing viral replication of COVID-19
Source: Wang et al. Cell Research 2020
Source: https://www.nature.com/articles/s41422-020-0282-0

A few editorials strongly recommended chloroquine. A group of Chinese authors mentioned that Chloroquine had demonstrated marked efficacy and safety in treating COVID-19 from their experience with more than 100 patients. This panel recommended chloroquinine phosphate tablets at a dose of 500 mg twice per day for 10 days for all mild, moderate, and severe COVID pneumonia.

In France, their clinicians recommended chloroquine given its high safety and low expenditure. The Dutch Center of Disease control also recommended chloroquine, but recommended stopping the treatment after 5 days to reduce the risk of side effects. The Italians followed the Chinese recommendations, but extended treatment to even longer depending on the clinical course.

Clinical Trials

A recent open labeled French clinical trial showed that chloroquine was effective in reducing COVID19. The details are in this report here.

Transcribed from the press conference is the following:

On this graph, the Y axis is the percentage of patients with a positive viral load. You can see 90% of those having received no plaquenil still have a positive viral load at day 6. On the other hand, only 25% of people on plaquenil had a positive viral load.

A result that half-surprised us was that the effect of azithromycin. For a long time, we and other people often recommend covering viral respiratory infectious with antibiotics to avoid bacterial complication. So anyone with signs pointing towards developing bacterial complication would get azithromycin – remember that in JAMA there’s an article that azithromycin reduces the risk of people with viral infectious in general. Another reason is azithromycin in the laboratory setting has been shown to be efficacious against a number of virus, even though it’s an antibiotic. So, when it comes to choosing an antibiotic, we choose one with presumed antiviral activity.

Everyone that dies (except those who die of secondary complications) from coronavirus, dies with the virus. So, if you remove the virus, the prognosis by definition changes. This is infectious disease. You remove the pathogen, you save the patient.

The authors strongly support the combination of chloroquine with azithromycin.

Conclusion

The conclusion from most texts is that there is enough theoretical, experimental, and clinical evidence for using chloroquine in treatment of COVID-19. The FDA granted emergency use authorization for chloroquine, assessing that the potential benefits outweigh the risks.

Please see this post for updates about chloroquine.