Virus World

The Food and Drug Administration has approved Tocilizumab for use against moderate to severe Covid-19 symptoms. The FDA has approved an early gift for those suffering from Covid-19 this holiday season. Tocilizumab, branded Actemra by pharmaceutical company Genentech, is a monoclonal antibody now approved for treating Covid-19 in hospitalized adult patients in moderate to severe conditions. All treatments to this point of the pandemic were only temporarily approved via emergency use authorization, speaking to the value of Tocilizumab. Here we discuss how the antibody was discovered and how it works. Unlike many monoclonal antibody treatments we discuss, Tocilizumab has a long history dating back 25 years. Clinical development of the antibody began in 1997 by Chugai Pharmaceuticals in Japan to treat rheumatoid arthritis. Chugai Pharmaceuticals and Genentech are now under the Roche Group umbrella, a Swiss multinational healthcare company. The researchers at Chugai Pharmaceuticals found that specific mouse antibodies contained anti-human IL-6 receptors. Interleukin-6, or IL-6, is a secreted cytokine protein expressed by white blood cells. In terms of disease, IL-6 stimulates inflammatory processes when the body is exposed to various pathogens and clinical conditions such as diabetes, multiple sclerosis, and rheumatoid arthritis.

Upon identifying the anti-human IL-6 receptors in mice, the researchers grafted the receptor onto a human IgG constant Fc region using recombinant DNA technology, effectively humanizing the receptor. Later research by Kishimoto et al. confirmed that the engineered mouse antibody receptor grafted to the human IgG constant Fc exclusively blocked IL-6 trans-signaling without affecting other significant pathways. IL-6 inhibition sufficiently blocks inflammation without inhibiting other immune defenses against infection. Contrary to popular belief, many of the classic symptoms we experience when we are sick are not directly caused by an invading pathogen but rather consequences of our immune system fighting off the pathogen. Inflammation is one of the most prominent causes of body pain, fatigue, fever, rash, and other significant symptoms most endure during sickness. In severe cases, inflammation may cause severe pain, lack of appetite, and severe headaches and chills. To produce the drug en masse, Chugai Pharmaceutical used genetic manipulation of host cells. They encoded the genes that code for tocilizumab production onto a human host T-cell. The encoded T-cell is then transfected into Chinese hamster ovary cells. These cells are then manipulated to express countless tocilizumab genes, creating a master that can be copied several times.

Lancet’s translational research journal EBioMedicine.Test could inform doctors on best treatment options. Scientists have developed, for the first time, a score that can accurately predict which patients will develop a severe form of Covid-19. The study, led by researchers at RCSI University of Medicine and Health Sciences, is published in The Lancet’s translational research journal EBioMedicine. The measurement, called the Dublin-Boston score, is designed to enable clinicians to make more informed decisions when identifying patients who may benefit from therapies, such as steroids, and admission to intensive care units. Until this study, no Covid-19-specific prognostic scores were available to guide clinical decision-making. The Dublin-Boston score can now accurately predict how severe the infection will be on day seven after measuring the patient’s blood for the first four days.

The blood test works by measuring the levels of two molecules that send messages to the body’s immune system and control inflammation. One of these molecules, interleukin (IL)-6, is pro-inflammatory, and a different one, called IL-10, is anti-inflammatory. The levels of both are altered in severe Covid-19 patients. Based on the changes in the ratio of these two molecules over time, the researchers developed a point system where each 1-point increase was associated with a 5.6 times increased odds for a more severe outcome. “The Dublin-Boston score is easily calculated and can be applied to all hospitalised Covid-19 patients,” said RCSI Professor of Medicine Gerry McElvaney, the study’s senior author and a consultant in Beaumont Hospital. “More informed prognosis could help determine when to escalate or de-escalate care, a key component of the efficient allocation of resources during the current pandemic. The score may also have a role in evaluating whether new therapies designed to decrease inflammation in Covid-19 actually provide benefit.”

The Dublin-Boston score uses the ratio of IL-6 to IL-10 because it significantly outperformed measuring the change in IL-6 alone.  Despite high levels in blood, using only IL-6 measurements as a Covid-19 prognostic tool is hindered by several factors. IL-6 levels within the same patient vary over the course of any given day, and the magnitude of the IL-6 response to infection varies between different patients.

Published in EbioMedicine (Oct. 8, 2020):

https://doi.org/10.1016/j.ebiom.2020.103026

Many Covid-19 patients may be dying from their immune response to the virus, not from the virus itself. Can science figure out how to save them? Back in April, as the pandemic was cresting over New York, Iris Navarro-Millán, a physician at Weill Cornell Medicine in Manhattan, treated a Covid-19 patient, a Hispanic woman in her 60s, who would prove to be a turning point in how she approached the disease. The woman was just a little short of breath when Navarro-Millán first saw her; a day later, she deteriorated so rapidly that she was rushed to intensive care, put on a ventilator and hooked up to a dialysis machine for her failing kidneys. Navarro-Millán feared that she would die. (She survived after spending two months sedated on the breathing machine.) When Navarro-Millán saw another Covid-19 patient soon after — a white man in his 60s already struggling to breathe — her first thought was, Not again. Believing that the prevailing standard of care — which, lacking drugs to directly fight the virus, consisted primarily of supportive measures like supplemental oxygen — was insufficient, she resolved to try something different, a treatment that was heretical in some circles but that she thought could save his life.

Navarro-Millán had unusual expertise for a hospitalist. Weill Cornell had asked her to move into that role when the pandemic hit, but she was a rheumatologist by training, a doctor whose specialty is autoimmune ailments in which the immune system, tasked with defending the self from invading pathogens, inexplicably turns on the body’s own tissues. Now she drew on her experience to try to help this Covid-19 patient. She suspected that the greatest danger here wasn’t the coronavirus itself but an immune overreaction so severe that it could cause lungs to fill up with fluid and prompt organs to shut down, possibly killing the patient. Rheumatologists often describe this type of immune reaction as a “cytokine storm” or “cytokine release syndrome.” Cytokines are proteins released by cells in order to send messages to other cells — signaling, for instance, that a viral invasion is underway. The number of different cytokines is large, perhaps exceeding 100, and each one calls for a specific response. To save her patient, Navarro-Millán decided that she would have to calm his immune system and prevent that storm from getting started. Early in her career, Navarro-Millán worked at the University of Alabama at Birmingham, where most of her patients had lupus, an autoimmune disease that can affect various parts of the body, including the kidneys, blood and even the brain. Its sufferers are especially prone to cytokine storms, which are often triggered by viral infections. What Navarro-Millán saw now in her Covid-19 patients wasn’t, she thought, all that different from what she encountered in Alabama.

A major lesson learned from her years there was that saving patients from cytokine storms often required doctors to intervene early, preferably long before the patients landed in the I.C.U., when it was frequently too late to bring the immune system to heel. So, the sooner she treated her Covid patient by tamping down his inflammatory response, she figured, the better. At the same time, she was leery of subduing his immune system for too long or too profoundly, because that might hobble his body’s ability to fight the virus that was making him sick in the first place. An array of drugs was available to her, ranging from antibodies that target specific pathways in the immune system to molecules that have a more widespread effect on the body. One, called tocilizumab, blocked the cytokine interleukin-6, but it remained in the body for up to a month — too long, in her view. Steroids, which dampen the entire immune system, might open the door to other infections. (Hydroxychloroquine, an antimalarial drug that has been promoted by President Trump for its supposed coronavirus-fighting potential, also happens to suppress the immune system. But because this effect, which is mild, comes only after months of daily use, it is unlikely to be suitable as a way to quell an immune firestorm started by an infection. The evidence so far suggests that it doesn’t work as an antiviral remedy, either, and that it can cause severe side effects.)..

A study of a drug that mutes the body’s immune response found that it did not prevent the deaths of people with moderate COVID-19, dealing a blow to a once-popular hypothesis about treatments for the disease. In some people with severe COVID-19, the immune system launches an excessive inflammatory response, suggesting a link between grave illness and an overly vigorous immune defence against SARS-CoV-2. The link is bolstered by the association between high levels of a protein called IL-6, which stimulates the immune system, and both death and the need for ventilation in people with COVID-19.

John Stone at the Massachusetts General Hospital in Boston and his colleagues tried to dampen inflammation in people with COVID-19 by treating them with the drug tocilizumab, which interferes with IL-6 activity (J. H. Stone et al. N. Engl. J. Med. https://doi.org/ffjp; 2020). But in a randomized, controlled trial of 243 people with moderate disease, the team found no statistically significant reduction in deaths or the need for ventilation among those who received tocilizumab compared with those who didn’t. The study does not rule out the possibility that a larger trial with more statistical power could uncover a benefit.

Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been proposed to mitigate the cytokine storm syndrome associated with severe COVID-19. We aimed to investigate the association between tocilizumab exposure and hospital-related mortality among patients requiring intensive care unit (ICU) support for COVID-19. We did a retrospective observational cohort study at 13 hospitals within the Hackensack Meridian Health network (NJ, USA). We included patients (aged ≥18 years) with laboratory-confirmed COVID-19 who needed support in the ICU. We obtained data from a prospective observational database and compared outcomes in patients who received tocilizumab with those who did not. We applied a multivariable Cox model with propensity score matching to reduce confounding effects. The primary endpoint was hospital-related mortality. The prospective observational database is registered on ClinicalTrials.gov, NCT04347993.

Between March 1 and April 22, 2020, 764 patients with COVID-19 required support in the ICU, of whom 210 (27%) received tocilizumab. Factors associated with receiving tocilizumab were patients’ age, gender, renal function, and treatment location. 630 patients were included in the propensity score-matched population, of whom 210 received tocilizumab and 420 did not receive tocilizumab. 358 (57%) of 630 patients died, 102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. Overall median survival from time of admission was not reached (95% CI 23 days–not reached) among patients receiving tocilizumab and was 19 days (16–26) for those who did not receive tocilizumab (hazard ratio [HR] 0·71, 95% CI 0·56–0·89; p=0·0027). In the primary multivariable Cox regression analysis with propensity matching, an association was noted between receiving tocilizumab and decreased hospital-related mortality (HR 0·64, 95% CI 0·47–0·87; p=0·0040). Similar associations with tocilizumab were noted among subgroups requiring mechanical ventilatory support and with baseline C-reactive protein of 15 mg/dL or higher. In this observational study, patients with COVID-19 requiring ICU support who received tocilizumab had reduced mortality. Results of ongoing randomised controlled trials are awaited.

Study published in The Lancet (August 14, 2020):

https://doi.org/10.1016/S2665-9913(20)30277-0

The COVID-19 pandemic caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to more than 100,000 deaths in the United States. Several studies have revealed that the hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum IL-6, IL-8, TNF-a, and IL-1b in hospitalized COVID-19 patients upon admission to the Mount Sinai Health System in New York.

Patients (n=1484) were followed up to 41 days (median 8 days) and clinical information, laboratory test results and patient outcomes were collected. In 244 patients, cytokine measurements were repeated over time, and effect of drugs could be assessed. Kaplan-Meier methods were used to compare survival by cytokine strata, followed by Cox regression models to evaluate the independent predictive value of baseline cytokines. We found that high serum IL-6, IL-8, and TNFa levels at the time of hospitalization were strong and independent predictors of patient survival.

Importantly, when adjusting for disease severity score, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-a serum levels remained independent and significant predictors of disease severity and death. We propose that serum IL-6 and TNF-a levels should be considered in the management and treatment of COVID-19 patients to stratify prospective clinical trials, guide resource allocation and inform therapeutic options. We also propose that patients with high IL-6 and TNF-a levels should be assessed for combinatorial blockade of pathogenic inflammation in this disease.

Preprint available at medRxiv (May 30, 2020):

https://doi.org/10.1101/2020.05.28.20115758