A new study published in Nature [1] draws the most detailed picture yet of SARS-CoV-2 infection in the lung, revealing mechanisms that result in lethal COVID-19, and may explain long-term complications and show how COVID-19 differs from other infectious diseases.

Led by researchers at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center, the study found that in patients who died of the infection, COVID-19 unleashed a detrimental trifecta of runaway inflammation, direct destruction and impaired regeneration of lung cells involved in gas exchange, and accelerated lung scarring.

Though the study looked at lungs from patients who had died of the disease, it provides solid leads as to why survivors of severe COVID may experience long-term respiratory complications due to lung scarring.

“It’s a devastating disease, but the picture we’re getting of the COVID-19 lung is the first step towards identifying potential targets and therapies that disrupt some of the disease’s vicious circuits. In particular, targeting cells responsible for pulmonary fibrosis early on could possibly prevent or ameliorate long-term complications in survivors of severe COVID-19,” says Benjamin Izar, MD, PhD, assistant professor of medicine, who led a group of more than 40 investigators to complete in several months a series of analyses that usually takes years.

This study and a companion paper [2] led by researchers at Harvard/MIT, to which the Columbia investigators also contributed, were published in the journal Nature on April 29.

Study creates atlas of cells in COVID lung

The new study is unique from other investigations in that it directly examines lung tissue (rather than sputum or bronchial washes) using single-cell molecular profiling that can identify each cell in a tissue sample and record each cell’s activity, resulting in an atlas of cells in COVID lung.

“A normal lung will have many of the same cells we find in COVID, but in different proportions and different activation states,” Izar says. “In order to understand how COVID-19 is different compared to both control lungs and other forms of infectious pneumonias, we needed to look at thousands of cells, one by one.”

Izar’s team examined the lungs of 19 individuals who died of COVID-19 and underwent rapid autopsy (within hours of death) – during which lung and other tissues were collected and immediately frozen – and the lungs of non-COVID-19 patients. In collaboration with investigators at Cornell University, the researchers also compared their findings to lungs of patients with other respiratory illnesses.

Drugs targeting IL-1ß may reduce inflammation

Compared to normal lungs, lungs from the COVID patients were filled with immune cells called macrophages, the study found.

Typically during an infection, these cells chew up pathogens but also regulate the intensity of inflammation, which also helps in the fight.

 

 

“In COVID-19, we see expansion and uncontrolled activation of macrophages, including alveolar macrophages and monocyte-derived macrophages,” Izar says. “They are completely out of balance and allow inflammation to ramp up unchecked. This results in a vicious cycle where more immune cells come in causing even more inflammation, which ultimately damages the lung tissue.”
One inflammatory cytokine in particular, IL-1ß, is produced at a high rate by these macrophages.
“Unlike other cytokines such as IL-6, which appears to be universally prevalent in various pneumonias, IL-1ß production in macrophages is more pronounced in COVID-19 compared to other viral or bacterial lung infections,” Izar says. “That’s important because drugs exist that tamp down the effects of IL-1ß.”
Some of these drugs are already being tested in clinical trials of COVID patients.

Severe COVID also prevents lung repair

In a typical infection, a virus damages lung cells, the immune system clears the pathogen and the debris, and the lung regenerates.

But in COVID, the new study found that not only does SARS-CoV-2 virus destroy alveolar epithelial cells important for gas exchange, the ensuing inflammation also impairs the ability of the remaining cells to regenerate the damaged lung.

Though the lung still contains cells that can do the repairs, inflammation permanently traps these cells in an intermediate cell state and leaves them unable to complete the last steps of differentiation needed for replacement of mature lung epithelium.

“Among others, IL-1ß appears to be a culprit in inducing and maintaining this intermediate cell state,” says Izar, “thereby linking inflammation and impaired lung regeneration in COVID-19. This suggests that in addition to reducing inflammation, targeting IL-1ß may help take the brakes off cells required for lung repair.”

Preventing accelerated fibrosis

The researchers also found a large number of specific fibroblast cells, called pathological fibroblasts, that create rapid scarring in COVID-19 lungs. When the fibroblast cells fill the lung with scar tissue, a process called fibrosis, the lung has less space for cells involved in gas exchange and is permanently damaged.

Given the importance of pathological fibroblasts in the disease, Izar’s team closely analysed the cells to uncover potential drug targets. An algorithm called VIPER, developed previously by Andrea Califano, Dr, chair of systems biology at Columbia University Vagelos College of Physicians and Surgeons, identified several molecules in the cells that play an important role and could be targeted by existing drugs.

“This analysis predicted that inhibition of STAT signalling could alleviate some of the deleterious effects caused by pathological fibroblasts,” Izar says.

“Our hope is that by sharing this analysis and massive data resource, other researchers and drug companies can begin to test and expand on these ideas and find treatments to not only treat critically ill patients, but also reduce complications in people who survive severe COVID-19.”

References

[1] A molecular single-cell lung atlas of lethal COVID-19. Nature (2021).
https://doi.org/10.1038/s41586-021-03569-1

[2] COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature (2021).
https://doi.org/10.1038/s41586-021-03570-8

Johnson & Johnson has announced the selection of a lead COVID-19 vaccine candidate on which it expects to initiate human clinical studies by September at the latest with the first batches of the vaccine available for emergency use authorization in early 2021.
In addition, the company announced the significant expansion of the existing partnership between the Janssen Pharmaceutical Companies of Johnson & Johnson and the Biomedical Advanced Research and Development Authority (BARDA).
Johnson & Johnson also said the company will rapidly scale up its manufacturing capacity with the goal of providing a global supply of more than one billion doses of the vaccine.
Through the new partnership, BARDA and Johnson & Johnson together have committed more than $1 billion of investment to co-fund vaccine research, development, and clinical testing. The company says will use its validated vaccine platform and is allocating resources, including personnel and infrastructure globally, as needed, to focus on these efforts.
BARDA is part of the Office of the Assistant Secretary for Preparedness and Response (ASPR) at the U.S. Department of Health and Human Services.
Commenting on the initiative, Alex Gorsky, Chairman and Chief Executive Officer, Johnson & Johnson, said: “The world is facing an urgent public health crisis and we are committed to doing our part to make a COVID-19 vaccine available and affordable globally as quickly as possible. As the world’s largest healthcare company, we feel a deep responsibility to improve the health of people around the world every day. Johnson & Johnson is well positioned through our combination of scientific expertise, operational scale and financial strength to bring our resources in collaboration with others to accelerate the fight against this pandemic.”
The company’s expansion of its manufacturing capacity will include the establishment of new U.S. vaccine manufacturing capabilities and scaling up capacity in other countries. The additional capacity will assist in the rapid production of a vaccine and will enable the supply of more than one billion doses of a safe and effective vaccine globally.
Paul Stoffels, M.D., Vice Chairman of the Executive Committee and Chief Scientific Officer, Johnson & Johnson, said: “We are very pleased to have identified a lead vaccine candidate from the constructs we have been working on since January. We are moving on an accelerated timeline toward Phase 1 human clinical trials at the latest by September 2020 and, supported by the global production capability that we are scaling up in parallel to this testing, we expect a vaccine could be ready for emergency use in early 2021.” In addition to the vaccine development efforts, BARDA and Johnson & Johnson have also expanded their partnership to accelerate Janssen’s ongoing work in screening compound libraries, including compounds from other pharmaceutical companies. The company’s aim is to identify potential treatments against the novel coronavirus. Johnson & Johnson and BARDA are both providing funding as part of this partnership. These antiviral screening efforts are being conducted in partnership with the Rega Institute for Medical Research (KU Leuven/University of Leuven), in Belgium.

Sanofi and Luminostics have signed an agreement to evaluate a collaboration on a unique self-testing solution for COVID-19, using Luminostics’ innovative technology, and further adding to Sanofi’s ongoing efforts to fight the COVID-19 pandemic on multiple fronts.
Luminostics would contribute its proprietary technology for consumer-diagnostics for COVID-19 testing while Sanofi would bring its clinical research testing experience and capabilities. The goal is to provide a smartphone-based solution that eliminates the current need for healthcare professional administration or laboratory tests.
“This partnering project could lead to another important milestone in Sanofi’s fight against COVID-19. The development of a self-testing solution with Luminostics could help provide clarity to an individual – in minutes – on whether or not they are infected” says Alan Main, Executive Vice President, Head of Sanofi Consumer Healthcare.
The goal of this collaboration is to provide a consumer-based test that can detect the COVID-19 virus with high sensitivity and specificity from respiratory samples. The total time from specimen collection to results is expected in the range of 30 minutes or less. It is based on Luminostics’ unique technology that utilizes a consumer smartphone’s optics, controlled by an iOS/Android app paired with an inexpensive adapter, in combination with “glow-in-the-dark” nanochemistry and signal processing artificial intelligence.
The diagnostic platform is composed of:

• an iOS/Android app to instruct a user on how to run the test, capture and process data to display test results, and then to connect users with a telehealth service based on the results;
• a reusable adapter compatible with most types of smartphones; and
• consumables for specimen collection, preparation, and processing.

During the current COVID-19 crisis it became obvious that rapid, reliable mass testing is one of the key strategies for successful containment of a pandemic outbreak. While point-of-care tests were made available relatively quickly – although not in a sufficient quantity – no over-the-counter self-testing solution is currently available. A rapid self-testing solution would come with multiple advantages, including:

• easy access and availability to patients at thousands of points-of-sale including e-commerce;
• no further interpersonal contact necessary to conduct the testing, thereby lowering the infection risk for patient, HCP, and laboratory staff; and
• immediate availability of results allowing fast decision making, providing consumers both public health and out-of-pocket cost benefits.

Thirona, a Dutch start-up company specialising in AI to analyse medical images, is offering one of their products for free to medical imaging specialists in an effort to combat the COVID-19 pandemic. International Hospital speaks to Dr Eva van Rikxoort, the Managing Director and founder of Thirona, about the company and its products.
International Hospital: Thirona is a Dutch company established in 2014. Can you give our readers a bit of background about the company?
Eva van Rikxoort: Thirona started in 2014 as a spin-off from the Radboud University in Nijmegen. We started with two full-time employees and we have built our company to 25 full-time employees and 20 part-time medical analysists. Together, we developed artificial intelligence software to analyse chest CT scans, chest X-ray images and retina images. Healthcare specialists around the world use our AI software for diseases like asthma, COPD, tuberculosis and diabetic retinopathy.
IH: What led you to set it up?
EVR: I was doing research on chest CT analysis at the Radboud University with my co-founder Prof. Bram van Ginneken. We saw that there was a gap between research that was being done on potential clinical solutions and putting those into clinical practice; Thirona was founded with the vision to bridge that gap.
IH: What products did you have at that time?
EVR: We started with two launching customers for one solution – our AI solution for chest CT analysis.
IH: Where does the name Thirona come from?
EVR: The name Thirona comes from the Celtic goddess named Thirona, worshipped for healing. Although more commonly spelled as ‘Sirona’ in the Latin alphabet, the spelling Thirona was chosen to reflect our roots in thoracic image analysis.
IH: Delft Imaging appears to be part of Thirona. Can you tell us a bit more about Delft Imaging and the relationship between Thirona and Delft Imaging?
EVR: Technically, Thirona and Delft Imaging are separate companies, although we collaborate extensively and practically work together as sister companies. Where Thirona specialises in artificial intelligence software for medical imaging, Delft Imaging specialises in diagnostic innovations that can be used in developing countries. For example, our AI solution for chest X-ray analysis (CAD4TB) is developed by Thirona and distributed by Delft Imaging.
IH: Can you tell us briefly about your key products and where they are being used?
EVR: We essentially offer three categories of products. AI software for chest CT analysis focusing on COPD and asthma, called LungQ; AI software for X-ray analysis – focusing on tuberculosis, called CAD4TB; and AI software for the analysis of retinal images – focusing on DR, AMD and Glaucoma, called RetCAD. LungQ allows for the quantification of chest CTs and is used for patient monitoring, treatment planning and clinical trial analysis.It is mostly used across the United States and European Union. CAD4TB is used in 40 countries around the world and has screened more than 6 million people for tuberculosis. RetCAD is being rolled out across Europe and Asia.
IH: If we look at how the company has grown over the past 5-6 years — can you explain what has been the driving force behind the growth?
EVR: As a spin-off of the Radboud University, our company (and our solutions) is rooted in science. Every software product we develop is thoroughly validated (through 150+ publications to date) and that level of validation drives our growth, I believe; our customers know the type of quality we aim to offer.
IH: What guided your research and development? In other words, why did you take the product development route you have taken?
EVR: We are a demand-driven organisation. Meaning, we develop and work on where our customers and partners have needs to be supported. That has led us on the route we have been on for the past sevearl years.
IH: What are the main challenges have you faced and how have you overcome them?
EVR: One of the main challenges was keeping the same culture in the company during the growth from a small team of a few people with similar backgrounds to a larger more diverse team. We did this by installing a management team structure. By making it a focus for each team allowed us to overcome any difficulties.
IH: Most recently, you are offering a free AI-powered COVID-19 tool – the CAD4COVID-Xray. I understand it has been developed on the back of your successful TB-screening AI tool, CAD4TB. Can you explain how the CAD4TB tool works and how you adapted it for COVID-19 screening.
EVR: Yes, we developed two AI-powered COVID-19 tools actually: one for chest X-ray analysis and one for chest CT. Both have been built on the technical foundation of our existing and proven CAD4TB and LungQ solutions. Because there were underlying algorithms already in place, we were able to rapidly pivot these for the detection of COVID-19.
IH: How will this tool help healthcare facilities and COVID-19 patients?
EVR: CAD4COVID-XRay and CAD4COVID-CT automatically detect COVID-19 related abnormalities and thereby help with triage before any follow-up testing, like RT-PCR. This helps to reduce the workload of healthcare personnel and alleviate the burden on RT-PCR tests. Furthermore, both solutions show the percentage of affected lung tissue, thereby helping to track disease progress and recovery.
IH: How has the AI tool been validated? Has it been approved for use in Europe? In which other countries / regions has it been approved?
EVR: We have done several studies for both solutions (a publication on CAD4COVID-XRay was recently published in Radiology), through which we were able to prove that the software performs on par with expert human readers. For both solutions we have applied for class IIa CE certification, which we expect to receive soon.
IH: Are the CAD4COVID tools specific to certain platforms?
EVR: Both solutions are system agnostic. They process DICOM images which can be from any type of system.
IH: Are you receiving many requests for the CAD4COVID-Xray AI tool?
EVR: The response has been tremendous, which is probably also because we made the software available free-of-charge. CAD4COVIDXRay was launched first (March 31st) and has since been made available to 30+ healthcare facilities across more than 20 countries. We are especially focusing on resource-constrained settings (mostly in developing countries) because in those settings CT often has limited availability, making X-ray all the more important. CAD4COVID-CT was launched a month later and is available at 15+ facilities across 10 countries. We are also integrating it in several platforms through collaborations with partner companies like Smart Reporting.
IH: Why are you offering it for free?
EVR: We knew that for CAD4COVID to have the biggest impact during the pandemic and provide the most support to healthcare specialists globally, we needed to roll it out rapidly. In order to do that, we wanted to avoid as many hurdles as possible that could cause a delay in facilities being able to use the software. We believe cost is a big factor in that. That’s why we, supported by several organisations, have made it available to use free-of-charge.
IH: Can it be shared easily with healthcare facilities that want to use it?
EVR: Yes, people can fill in a form on www.delft.care/cad4covid (for CAD4COVID-XRay) and www.thirona.eu/cad4covid (for CAD4COVID-CT) and our team will reach out to them to help them set it up for their facility.
IH: Is any training required to use the CAD4COVID tools?
EVR: The tool is designed to be very intuitive, but we have developed an onboarding tool to guide new users on how to use the software effectively.
IH: Lastly, what’s in the pipeline for Thirona and how do you envisage development of the field of AI in medical imaging?
EVR: We are quickly expanding into other areas like cystic fibrosis on chest CT analysis, silicosis on chest X-ray analysis and cataract on retinal images. I believe that AI still has to prove itself in many settings, for many different use cases, but that it will become more and more accepted over time, and we already see this happening at incredible speed. In time, AI will leverage the efforts of our healthcare specialists, helping them to diagnose and determine treatment planning quicker, more effectively and reduce their workload in the meantime.