Virus World

By applying machine learning to medical record data, scientists found that secondary bacterial pneumonia that does not resolve was a key driver of death in patients with COVID-19. It may even exceed death rates from the viral infection itself. The scientists also found evidence that COVID-19 does not cause a “cytokine storm,” so often believed to cause death. "Our study highlights the importance of preventing, looking for and aggressively treating secondary bacterial pneumonia in critically ill patients with severe pneumonia, including those with COVID-19," said senior author Dr. Benjamin Singer, an associate professor of medicine at Northwestern University Feinberg School of Medicine and a Northwestern Medicine pulmonary and critical care physician. 

The investigators found nearly half of patients with COVID-19 develop a secondary ventilator-associated bacterial pneumonia.  “Those who were cured of their secondary pneumonia were likely to live, while those whose pneumonia did not resolve were more likely to die,” Singer said. “Our data suggested that the mortality related to the virus itself is relatively low, but other things that happen during the ICU stay, like secondary bacterial pneumonia, offset that.” 

The study findings also negate the cytokine storm theory, said Singer, also the Lawrence Hicks Professor of Pulmonary Medicine at Feinberg.  “The term ‘cytokine storm’ means an overwhelming inflammation that drives organ failure in your lungs, your kidneys, your brain and other organs,” Singer said. “If that were true, if cytokine storm were underlying the long length of stay we see in patients with COVID-19, we would expect to see frequent transitions to states that are characterized by multi-organ failure. That’s not what we saw.” The study analyzed 585 patients in the intensive care unit (ICU) at Northwestern Memorial Hospital with severe pneumonia and respiratory failure, 190 of whom had COVID-19. The scientists developed a new machine learning approach called CarpeDiem, which groups similar ICU patient-days into clinical states based on electronic health record data. This novel approach, which is based on the concept of daily rounds by the ICU team, allowed them to ask how complications like bacterial pneumonia impacted the course of illness.  These patients or their surrogates consented to enroll in the Successful Clinical Response to Pneumonia Therapy (SCRIPT) study, an observational trial to identify new biomarkers and therapies for patients with severe pneumonia. As part of SCRIPT, an expert panel of ICU physicians used state-of-the-art analysis of lung samples collected as part of clinical care to diagnose and adjudicate the outcomes of secondary pneumonia events. 

“The application of machine learning and artificial intelligence to clinical data can be used to develop better ways to treat diseases like COVID-19 and to assist ICU physicians managing these patients,” said study co-first author Dr. Catherine Gao, an instructor in pulmonary and critical care medicine at Feinberg and a Northwestern Medicine physician.

“The importance of bacterial superinfection of the lung as a contributor to death in patients with COVID-19 has been underappreciated because most centers have not looked for it or only look at outcomes in terms of presence or absence of bacterial superinfection, not whether treatment is successful or not,” said study co-author Dr. Richard Wunderink, who leads the Successful Clinical Response in Pneumonia Therapy Systems Biology Center at Northwestern. The next step in the research will be to use molecular data from the study samples and integrate it with machine learning approaches to understand why some patients go on to be cured of pneumonia and some don’t. Investigators also want to expand the technique to larger datasets and use the model to make predictions that can be brought back to the bedside to improve the care of critically ill patients.  Other Northwestern authors on the paper include Nikolay S. Markov, Thomas Stoeger, Anna E. Pawlowski,Mengjia Kang,Prasanth Nannapaneni, Rogan A. Grant,Chiagozie Pickens, James M. Walter, Jacqueline M. Kruser, Luke V. Rasmussen, Daniel Schneider, Justin Starren, Helen K. Donnelly, Alvaro Donayre, Yuan Luo, Scott Budinger and  Alexander Misharin.  The study was supported by the Simpson Querrey Lung Institute for Translational Sciences and grant U19AI135964 from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. 

Study Published in  the J. Clin. Investig. (April 27, 2023):

https://doi.org/10.1172/JCI170682 

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

It is unclear why people’s immune response to the SARS-CoV-2 coronavirus varies so widely. Tracking patient responses over time sheds light on this issue, and has implications for efforts to predict disease severity. A dysregulated immune response, a cytokine storm and cytokine-release syndrome1,2 are some of the terms used to describe the overexuberant defence response that is thought to contribute to disease severity in certain people who become seriously ill with COVID-19. However, a precise definition of this type of immune dysfunction remains elusive. On page 463, Lucas et al. 3 fill in some gaps in our knowledge.

A holy grail of COVID-19 research is the ability to assess a person’s immune response, to pinpoint early the individuals who have mild symptoms but who are on track to develop the intense defence response that is associated with severe disease. This is important because there is a broad spectrum of clinical disease in people infected with SARS-CoV-2, the coronavirus that causes COVID-19: some infected individuals can be asymptomatic, whereas others are at risk of dying, and require hospitalization in an intensive-care unit and use of a ventilator machine to breathe4,5. Identifying those whose dysregulated immune-response signature predicts the development of severe disease would enable them to be monitored more intensively to minimize disease progression. Lucas and colleagues performed extensive analyses of immune responses over time (longitudinal studies) in 113 people hospitalized with COVID-19 who had moderate or severe disease, and assessed a similar number of SARS-CoV-2- free healthy people as controls. The authors analysed molecules in blood plasma (Fig. 1) and monitored peripheral blood mononuclear cells — white blood cells of the immune system such as CD4 T cells, CD8 T cells and B cells. The longitudinal nature of this study enables conclusions to be drawn that wouldn’t be possible from analysing cross-sectional studies that don’t follow individuals over time. 

The authors found that levels of several molecules that promote inflammation  — immunomodulatory molecules termed cytokines, including IL-1α, IL-1β, IFN-α, IL-17A and IL-12 p70 — were higher in all of the people who had COVID-19 than in the healthy controls, providing a ‘core’ COVID-19 signature. Other cytokines, such as IFN-λ, thrombopoietin (which is associated with abnormalities in blood clotting), IL-21, IL-23 and IL-33, were upregulated to a greater extent in people with severe COVID-19 than in those with moderate...

Published in Nature (August 20, 2020):

https://doi.org/10.1038/d41586-020-02379-1 

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.)..